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Background: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. Methods: Adult patients with advanced solid tumours received peposertib 100–200 mg once daily or 150–400 mg twice daily (BID) in 21-day cycles. Results: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1–2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3–6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. Conclusions: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. Clinical trial registration: NCT02316197, SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). Patients and Methods: Multicenter, open-label, phase Ib drug–drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. Results: Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess–related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor–naïve patients and 14% (6/42) of AR signaling inhibitor–treated patients. Conclusions: Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.

Background In the first part of this extensive phase I study (NCT00516724), continuous olaparib twice daily (bid) with carboplatin and/or paclitaxel resulted in myelosuppression and dose modifications. Here, we report the safety, tolerability, and efficacy of intermittent olaparib dosing combined with carboplatin and paclitaxel. Methods Patients with advanced solid tumors (part D) and enriched for ovarian and breast cancer (part E) received olaparib (capsule and tablet formulations) using intermittent schedules (2 to 10 days of a 21-day cycle) combined with carboplatin/paclitaxel. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs), and physical examinations. Pharmacokinetic assessments of olaparib capsule and tablet combined with carboplatin/paclitaxel were performed. Tumor responses (RECIST) were assessed every 2 cycles. Results In total, 132 heavily pre-treated patients were included. One DLT of grade 3 elevated alanine aminotransferase lasting for 8 days was reported (olaparib tablet 100 mg bid days 3–12, carboplatin area under the curve 4 and paclitaxel 175 mg/m2). The most common hematological AEs were neutropenia (47%) and thrombocytopenia (39%), which frequently led to dose modifications. Non-hematological AEs were predominantly grade 1–2, including alopecia (89%) and fatigue (84%). Overall objective response rate was 46%. Conclusions Discontinuous dosing of olaparib resulted in significant myelosuppression leading to dose interruptions and/or delays. Anti-tumor activity was encouraging in patients enriched with BRCA-mutated breast and ovarian cancer. The most appropriate olaparib tablet dose for use in further studies evaluating olaparib in combination with carboplatin and paclitaxel is 50 mg bid (days 1–5).

Contains fulltext : 235017.pdf (Publisher’s version ) (Open Access) BACKGROUND: For many patients with advanced cancer, the decision whether to participate in early phase clinical trials or not is complex. The decision-making process requires an in-depth discussion of patient values. We therefore aimed to synthesize and describe patient values that may affect early phase clinical trial participation. METHODS: We conducted a systematic search in seven electronic databases on patient values in relation to patients' decisions to participate in early phase clinical cancer trials. RESULTS: From 3072 retrieved articles, eleven quantitative and five qualitative studies fulfilled our inclusion criteria. We extracted ten patient values that can contribute to patients' decisions. Overall, patients who seek trial participation usually report hope, trust, quantity of life, altruism, perseverance, faith and/or risk tolerance as important values. Quality of life and humanity are main values of patients who refuse trial participation. Autonomy and social adherence can be reported by both trial seekers or refusers, dependent upon how they are manifested in a patient. CONCLUSIONS: We identified patient values that frequently play a role in the decision-making process. In the setting of discussing early phase clinical trial participation with patients, healthcare professionals need to be aware of these values. This analysis supports the importance of individual exploration of values. Patients that become aware of their values, e.g. by means of interventions focused on clarifying their values, could feel more empowered to choose. Subsequently, healthcare professionals could improve their support in a patients' decision-making process and reduce the chance of decisional conflict.

Purpose In tumours with wild-type TP53, the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours ( NCT01636479 ). Methods In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible. In the MTD expansion cohort, only patients with de-differentiated liposarcoma were included. Primary end-points were MTD and efficacy in the MTD expansion cohort. Secondary end-points included safety, pharmacokinetics and pharmacodynamics biomarkers. Results Seventy-four patients were treated with SAR405838 (50–800 mg once daily [QD], 800–1800 mg weekly and 1800 mg twice weekly). Two patients treated with SAR405838 400 mg QD had thrombocytopaenia as a dose-limiting toxicity (DLT). The MTD for the QD schedule of SAR405838 was 300 mg QD. No DLTs were observed with the weekly schedule; one patient had a DLT of nausea with the 1800 mg twice-weekly dose. Treatment with SAR405838 was associated with increased plasma MIC-1, reflecting p53 pathway activation. In the de-differentiated liposarcoma MTD cohort, 89% of the patients had HDM2 amplification at baseline and no TP53 mutations were observed; best response was stable disease in 56% and progression-free rate at 3 months was 32%. Conclusion SAR405838 had an acceptable safety profile with limited activity in patients with advanced solid tumours. The MTD of SAR405838 was 300 mg QD; MTD was not reached with the weekly schedule.

Background The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high-quality tumor samples. As cancer evolves over time, tissue is ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next-generation DNA/RNA sequencing (NGS) but also for making other emerging systematic techniques such as proteomics and metabolomics possible. Here, we describe the first 469 image-guided biopsies collected in a large collaboration in The Netherlands (Center for Personalized Cancer Treatment) and show the utility of these specimens for NGS analysis. Patients and Methods Image-guided tumor biopsies were performed in advanced cancer patients. Samples were fresh frozen, vital tumor cellularity was estimated, and DNA was isolated after macrodissection of tumor-rich areas. Safety of the image-guided biopsy procedures was assessed by reporting of serious adverse events within 14 days after the biopsy procedure. Results Biopsy procedures were generally well tolerated. Major complications occurred in 2.1%, most frequently consisting of pain. In 7.3% of the percutaneous lung biopsies, pneumothorax requiring drainage occurred. The majority of samples (81%) contained a vital tumor percentage of at least 30%, from which at least 500 ng DNA could be isolated in 91%. Given our preset criteria, 74% of samples were of sufficient quality for biomarker discovery. The NGS results in this cohort were in line with those in other groups. Conclusion Image-guided biopsy procedures for biomarker discovery to enable personalized cancer treatment are safe and feasible and yield a highly valuable biobank.

BACKGROUND Capmatinib is a highly potent, selective MET-inhibitor known to cross the BBB, and intracranial activity with capmatinib has been previously reported. Updated results for overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and brain metastases (BM) activity from the GEOMETRY mono-1 study are presented here. METHODS GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in METΔex14-mutated or MET-amplified NSCLC patients. Patients (≥18 years) with ECOG PS 0–1, ALK-/EGFR-wt, and stage IIIB/IV NSCLC were eligible. Patients with asymptomatic BM were allowed. METΔex14-mutated patients were assigned to Cohorts 4 (1–2 prior lines of treatment) and 5b (treatment-naive) and received capmatinib 400mg BID. Endpoints by BIRC: ORR (primary, RECIST v1.1), DOR, and PFS. Ad hoc BIRC neuro-radiologic assessments of all Cohort 4 and 5b patients with baseline BM were performed. RESULTS As of April 15, 2019, 97 patients (Cohort 4: 69 patients; Cohort 5b: 28 patients) were evaluable for efficacy. BIRC assessments: ORR (95%CI): 40.6% (28.9–53.1) in Cohort 4; 67.9% (47.6–84.1) in Cohort 5b. Median DOR (95%CI): 9.7 (5.55–12.98) and 11.1 (5.55-NE) months and median PFS (95%CI): 5.4 (4.17–6.97) and 9.7 (5.52–13.86) months for Cohorts 4 and 5b, respectively. Of 13 evaluable patients with BM at baseline, 7 (54%) had intracranial response by BIRC, including 4 patients with complete resolution of brain lesions, and 12/13 had intracranial disease control. Responses in the brain were as fast as systemic responses. Most common treatment-related AEs (≥15%, all grades) across all cohorts (N=334): peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%); most AEs were grade 1/2. CONCLUSION These data confirm capmatinib to be a promising new treatment option for patients with METΔex14-mutated advanced NSCLC regardless of line of therapy, with deep and durable responses including in patients with brain metastases, and a manageable toxicity profile.

Background Overexpression/activation of focal adhesion kinase (FAK) in human malignancies has led to its evaluation as a therapeutic target. We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor. Objective Our objectives were to identify the maximum tolerated dose (MTD), and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker expression, and preliminary activity. Patients and Methods The study comprised a standard 3 + 3 dose-escalation phase followed by an expansion phase in patients with selected advanced, nonhematologic malignancies. Results Thirty-three patients received BI 853520 in the dose-escalation phase; the MTD was 200 mg once daily (QD). Dose-limiting toxicities included proteinuria and fatigue, both of which were grade 3. Preliminary PK data supported QD dosing. In the expansion cohort, 63 patients received BI 853520 200 mg QD. Drug-related adverse events (AEs) in > 10% of patients included proteinuria (57%), nausea (57%), fatigue (51%), diarrhea (48%), vomiting (40%), decreased appetite (19%), and peripheral edema (16%). Most AEs were grade 1–2; grade 3 proteinuria, reported in 13 patients (21%), was generally reversible upon treatment interruption. Nineteen patients underwent dose reduction due to AEs, and three drug-related serious AEs were reported, none of which were fatal. Preliminary PD analysis indicated target engagement. Of 63 patients, 49 were evaluable; 17 (27%) achieved a best response of stable disease (4 with 150 + days), and 32 (51%) patients had progressive disease. Conclusions BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies. ClinicalTrials.gov identifier NCT01335269. Electronic supplementary material The online version of this article (10.1007/s11523-018-00617-1) contains supplementary material, which is available to authorized users.

Contains fulltext : 202591.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity in ovarian cancer models. This has not previously been assessed in the clinical setting. METHODS: Clonogenic and plasmid-based HR repair assays were performed to compare BRCA1-mutant COV362 ovarian cancer cells with or without 53BP1 gene deletion. Archival biopsies from ovarian cancer patients in the phase I, open-label clinical trial of PARPi ABT-767 were stained for PARP1, RAD51, 53BP1 and multiple components of the nonhomologous end-joining (NHEJ) DNA repair pathway. Modified histochemistry- (H-) scores were determined for each repair protein in each sample. HRD score was determined from tumor DNA. RESULTS: 53BP1 deletion increased HR in BRCA1-mutant COV362 cells and decreased PARPi sensitivity in vitro. In 36 women with relapsed ovarian cancer, responses to the PARPi ABT-767 were observed exclusively in cancers with HR deficiency. In this subset, 7 of 18 patients (39%) had objective responses. The actual HRD score did not further correlate with change from baseline tumor volume (r=0.050; p=0.87). However, in the HR-deficient subset, decreased 53BP1 H-score was associated with decreased antitumor efficacy of ABT-767 (r=-0.69, p=0.004). CONCLUSION: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.

$\textbf{PURPOSE}$ Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. $\textbf{METHODS}$ Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m$^{2}$), B (moderate renal impairment: CrCL 30 to

Background: WNT974, a Porcupine inhibitor, has shown evidence of Wnt pathway inhibition in clinical trials. Dysregulated Wnt signaling has been linked to immunotherapy resistance, suggesting WNT974 may act synergistically with checkpoint inhibitors. Spartalizumab is an αPD-1 mAb with demonstrated clinical activity in solid tumors. Methods: In this Phase I, open-label trial (NCT01351103) adult pts received WNT974 ± spartalizumab; here we report on the dose escalation of the combination. Eligible pts had melanoma (including uveal), lung SCC, HNSCC, esophageal SCC, cervical SCC, or TNBC. Pts with melanoma, lung SCC, or HNSCC must have had a best response of progressive disease (primary refractory) to prior αPD-1 therapy; other pts were naïve or primary refractory to prior αPD-1. WNT974 was dosed orally QD in 28-day cycles (2.5-10 mg, Days 1-8 or 1-15 of Cycles 1 or 1-4); spartalizumab was dosed IV at 400 mg Q4W. Objectives were to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE), safety, pharmacokinetics (PK), pharmacodynamics, and activity of WNT974 + spartalizumab. Pre- and on-treatment pt samples were collected: skin samples for RT-PCR analysis of AXIN2, a marker of Wnt pathway activity; tumor samples for RNAseq of AXIN2 and immune cell markers. Results: As of Sept 2, 2019, 27 pts were enrolled: 24 discontinued (18 due to disease progression; 67%), 3 were ongoing. Most common tumor types were non-uveal melanoma (n=8), TNBC (n=7), and uveal melanoma (n=5); 63% had received prior αPD-1. PK parameters for WNT974 + spartalizumab were consistent with prior single agent data. Dose-limiting toxicities were reported in 2 pts: Grade (G) 2 spinal compression fracture that occurred in the setting of trauma and G3 arthralgia. 78% of pts experienced a treatment-related AE, the most common being hypothyroidism (19%); 4 pts (15%) had 7 suspected-related G3/4 AEs (arthralgia, atrial fibrillation, diabetes mellitus, diabetic ketoacidosis, hyperglycemia, hyponatremia, and maculopapular rash). One pt (4%) with TNBC had a partial response, 11 pts (41%) had stable disease (SD), 13 pts (48%) had progressive disease; response was unknown in 2 pts. SD was reported in 9/17 pts (53%) who were primary refractory to prior αPD-1; 4 remained on study >24 wks. All pts with uveal melanoma (n=5) had SD. Evidence of Porcupine inhibition, assessed by skin AXIN2 suppression, was detected at all dose levels studied. Pts with the largest reductions in tumor size had on-treatment increases in immune marker mRNA in tumor samples, including a pt with αPD-1 primary refractory melanoma with high baseline AXIN2 expression and 42% reduction in the sum of target lesion diameters; this pt remained on study at 48 wks at the cutoff date. Conclusions: WNT974 + spartalizumab was well tolerated; MTD/RDE have not been determined. Preliminary data suggest blocking Wnt signaling may enable response to checkpoint inhibition in some pts. Citation Format: Filip Janku, Filip de Vos, Maria de Miguel, Patrick Forde, Antoni Ribas, Misako Nagasaka, Guillem Argiles, Ana Maria Arance, Aitano Calvo, Marios Giannakis, Maritza Melendez, Jiachang Gong, Sebastian Szpakowski, Rebecca Kan, Susan E. Moody, Maja De Jonge. Phase I study of WNT974 + spartalizumab in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT034.

e15668 Background: Eftozanermin alfa (eftoza; formerly known as ABBV-621), a 2nd-generation tumor necrosis factor-related apoptosis-inducing ligand receptor agonist, is being evaluated in previously treated solid and hematologic malignancies (NCT03082209). In a dose-expansion cohort, patients (pts) with KRAS-mutant colorectal cancer (n = 24) and pancreatic cancer (n = 24) were evaluated at 3 dose levels with 12 mandatory paired biopsies per tumor type (pretreatment [Tx] and on-Tx collection). Following eftoza dosing, RNA and protein expression including posttranslational modifications were assessed in tumor biopsies to understand the target engagement and downstream pathway activation. Plasma was evaluated for changes in somatic mutant allele frequency and M30, M65 (circulating apoptotic markers). Methods: Biopsies were collected anytime during the screening period (pre-Tx) and 24±4 h following 2nd or 3rd infusion (on-Tx). Of the requested 4–6 fresh biopsy cores, 1–2 cores were collected as formalin fixed paraffin embedded (FFPE) and the rest were frozen tissue. FFPE tissue was analyzed by multiplex immunohistochemistry (IHC) and RNAseq; reverse phase protein array was used for frozen cores. Plasma was collected at cycle 1 predose and 2, 8, 24, 48, and 168 h postdose and analyzed for M30, M65 (by ELISA) and circulating tumor DNA (64-gene PlasmaSELECT assay). Results: Twenty-five pts consented to biopsies; paired biopsies were obtained from 16 pts at a 64% success rate: FFPE (n = 15) and frozen cores (n = 12). Tumor cells were detected in 11/15 (73%) FFPE and 4/12 (33%) frozen cores. Increase in M30, activated caspases, and cleaved PARP levels was observed in on-Tx biopsy samples compared with pre-Tx, thus serving as evidence for apoptosis induction in tumors following eftoza dosing. Changes in the tumor microenvironment were observed post-Tx by RNAseq and multiplex IHC (eg, CD68 level). Downregulation of prosurvival signaling pathways (eg, AKT/MEK) was also observed following eftoza dosing. Thirteen out of 16 pts showed transient increase in mutant allele fractions post eftoza Tx that correlated with increased plasma circulating tumor markers M30 and M65 at similar time points, suggesting activation of apoptosis pathway. Increase in M30, M65 levels also preceded increase in liver enzymes (ALT/AST) at 2, 48 hr post-Tx. Conclusions: Pharmacodynamic effect of eftoza was successfully demonstrated in blood and tumor tissue, including induction of apoptosis and modulation of PI3K and MEK signaling pathways. Clinical trial information: NCT03082209.

3097 Background: The scavenger receptor CLEVER-1 mediates the clearance of “unwanted” self-components and is highly expressed on tumor associated macrophages (TAMs). CLEVER-1 expression is associated with immunotherapy resistance and poor survival in several cancers. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflammatory cytokine secretion and antigen presentation reactivating CD8 T cell responses with robust anti-tumor activity. Targeting CLEVER-1 could therefore overcome the immunosuppressive tumor microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody. Methods: The MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients (pts) with advanced cancers including immunotherapy-refractory melanoma, cholangiocarcinoma, hepatocellular carcinoma, ovarian cancer, colorectal (CRC), and pancreatic ductal adenocarcinoma. Part 1 consisted of a dose escalation phase; 30 pts (median age 65, range 30-81) were enrolled to examine 5 dose levels (0.1, 0.3, 1.0, 3.0, 10 mg/kg), to determine the optimal dose of FP-1305 for Parts 2 and 3. Two-stage time-to-event continual reassessment method (TITE-CRM) was utilized for the dose escalation in Part 1. Pts received 1-8 cycles (median 3) of FP-1305 Q3w. FP-1305 was well tolerated without dose-limiting toxicities. A consistent increase in blood NK cells, CD8/CD4 T cell ratio, B cells and a decrease in regulatory T cells was demonstrated. FP-1305 dosing led to the activation (CD25+) and Th1 skewing (CXCR3+) of T cell populations including increase in effector CD8 T-cells with downregulation of several inhibitory immune checkpoint molecules (PD-1, PD-L1, CTLA-4, and LAG3). Increased circulating IFNɣ levels were detected, with the highest levels in a heavily pretreated metastatic, microsatellite stable (MSS) colorectal cancer patient leading to a partial tumor response (-52%). FP-1305 is the first macrophage checkpoint inhibitor candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. FP-1305 represents a novel treatment option to provoke immune response especially in non-inflamed tumors. Full safety, pharmacokinetic and efficacy results of MATINS trial (Part 1) will be presented for the first time in a final late breaking abstract. Clinical trial information: 2018-002732-24 .

For advanced cancer patients deliberating early clinical trial participation, adequate information about expected effect on quality of life (HRQoL) and hope, may support decision making. The aim was to assess the potential relation of HRQoL to eligibility for phase-I trial participation, and to observe the variations in patient-reported outcomes. Patients completed questionnaires at preconsent (n = 124), baseline (n = 96), and after first evaluation of a phase-I trial (n = 76). The Mann–Whitney U test was used to test differences between eligible and ineligible patients. Univariate logistic regression was performed for eligibility. Factorial repeated-measures ANOVA compared the outcomes of patients continuing vs. stopping participation after first evaluation over time. Eligibility is associated with significant better global health OR = 0.946, 95% CI [0.918, 0.975], p = 0.001, physical functioning OR = 0.959, 95% CI [0.933, 0.985], p = 0.002, role functioning OR = 0.974, 95% CI [0.957, 0.991] and better appetite OR = 1.114 95% CI [1.035, 1.192]. HRQoL outcomes like global health, social functioning and appetite decline in all patients and differ between patients continuing or having to end participation. Over time, hope and tenacity decline in all patients and coping strategies alter in patients stopping participation. Trial participation influences patient-reported outcomes. Global health may predict for eligibility and trial continuation. Informing patients could affect patients’ decision making.

Summary Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined. Results Ninety-three patients were treated with ABT-767; 80 had a primary diagnosis of ovarian cancer. ABT-767 demonstrated dose-proportional PK up to 500 mg BID and half-life of ~2 h. Food had no effect on ABT-767 bioavailability. Most common grade 3/4 treatment-related adverse events were nausea, fatigue, decreased appetite, and anemia. Anemia showed dose-dependent increase. RP2D was 400 mg BID. Objective response rate by RECIST 1.1 was 21% (17/80) in all evaluable patients and 20% (14/71) in evaluable patients with ovarian cancer. Response rate by RECIST 1.1 and/or CA-125 was 30% (24/80) in patients with ovarian cancer. Mutations in BRCA1 or BRCA2, homologous recombination deficiency (HRD), and platinum sensitivity were associated with tumor response. Median progression-free survival was longer for HRD positive (6.7 months) versus HRD negative patients (1.8 months) with ovarian cancer. Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400 mg BID and dose-proportional PK. Patients with BRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767.

Purpose: This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas.Experimental Design: The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of squamous non–small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib.Results: Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with a numerically higher disease control rate but not ORR.Conclusions: The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels. Clin Cancer Res; 23(18); 5406–15. ©2017 AACR.

Background: Apoptotic cell death can be triggered by activation of extrinsic and intrinsic signaling pathways. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, binds to its death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) to selectively activate the extrinsic apoptotic pathway in cancer cells. ABBV-621 is a second-generation TRAIL receptor agonist with antitumor activity as monotherapy (621-mono) in preclinical models of AML and DLBCL. The intrinsic apoptotic pathway is regulated by the BCL2 protein family, commonly overexpressed in hematologic malignancies. Venetoclax (VEN), a highly selective small-molecule BCL2 inhibitor, has shown antitumor activity in combination therapy in AML and DLBCL. In preclinical and xenograft models of AML and DLBCL, the ABBV-621 and VEN combination (621-VEN) had antitumor activity superior to either agent alone. This first-in-human study evaluated ABBV-621 as single agent and in combination in pts with advanced solid tumors and hematologic malignancies (NCT03082209). Safety and tolerability of ABBV-621 in advanced solid tumors have previously been presented (Ratain et al. J Clin Oncol 2019;37[suppl]: abstr 3013). Here, we report preliminary data for 621-mono in pts with RR AML and for 621-VEN in pts with RR AML and DLBCL. Methods: Adult pts with RR AML or DLBCL (ECOG 0-2) were enrolled. Pts with AML received ABBV-621 at 1.25-, 3.75-, 7.5-mg/kg doses in the 621-mono and at 3.75-mg/kg dose in the 621-VEN arms. Pts in the DLBCL 621-VEN arm received ABBV-621 at 3.75- and 7.5-mg/kg doses. ABBV-621 was administered intravenously on D1, 8, and 15 of a 21-D cycle; in 621-VEN cohorts pts received 400 mg oral VEN daily, and could be escalated to 800 mg. The primary endpoint was safety. In addition, preliminary antitumor efficacy and ABBV-621 binding to decoy receptors on neutrophils from peripheral blood were assessed. Results: As of Jun 2019, 17 pts were enrolled. Pts in AML 621-mono arm (1.25 [1], 3.75 [1], 7.5 [2] mg/kg): 1 male; median (med) age, 75 yr (range 71-82); med prior treatments, 2.5 (range 1-4); med time on treatment, 15 D (range 1-70). Pts in AML 621-VEN arm (3.75 mg/kg [7]): 5 male; med age, 71 yr (60-79); med prior treatments, 2 (1-2); med time on treatment, 26 D (1-77). Pts in DLBCL 621-VEN arm (3.75 [3], 7.5 [3] mg/kg): 4 male; med age, 57 yr (40-75); stage 4 (3); med prior treatments, 2.5 (1 to ≥5); med time on treatment, 26 D (8-36). One pt in the AML 621-VEN 3.75-mg/kg dose cohort had increases in alanine aminotransferase, aspartate aminotransferase and bilirubin as dose-limiting toxicities. Sixteen pts experienced adverse events (AEs) irrespective of causality. A summary of AEs is shown in Table. One pt in the AML 621-mono 7.5-mg/kg dose cohort died due to AML progression, unrelated to ABBV-621. Antitumor activity was observed in 1 pt in the AML 621-VEN arm (with complex cytogenetics and TP53 mutation) who reached complete remission (CR). One pt in the DLBCL 621-VEN 3.75-mg/kg cohort had stable disease, 2 with AML had resistant disease (1 in 621-mono [7.5 mg/kg] and 1 in 621-VEN), and 7 had progressive disease (PD; 1 in AML 621-mono [1.25 mg/kg], 2 in AML 621-VEN, and 4 in DLBCL 621-VEN [2 each in 3.75- and 7.5-mg/kg] cohorts). Using flow cytometry, saturation of ABBV-621 binding to decoy receptors on neutrophils was observed at 2 h postdosing, followed by dose-dependent desaturation of receptors in pts with DLBCL at 48-168 h. In AML 621-VEN pts, ABBV-621 remained bound to decoy receptors for up to 168 h; in DLBCL 621-VEN pts, the duration of binding was higher at ABBV-621 7.5 mg/kg compared with 3.75 mg/kg. In AML, the baseline frequency of myeloblasts was higher in pts with PD than CR, while that of myelomonocytes was higher in the pt with CR. The frequency of myeloblasts and myelomonocytes expressing DR4 and DR5 at baseline was highest in the pt with CR (Figure). Conclusions: ABBV-621 was tolerated and showed antitumor activity in combination with VEN in pts with RR AML. Disclosures de Jonge: Faron Pharmaceuticals Ltd.: Consultancy. Carneiro:Actuate Therapeutics: Research Funding; Bayer: Research Funding; Pfizer: Research Funding; AstraZeneca: Research Funding; Medimmune: Research Funding; Astellas: Research Funding; AbbVie: Research Funding. Devriese:MSD: Consultancy. Penugonda:AbbVie: Employment, Other: Stock/stock options. Petrich:Abbvie: Employment, Equity Ownership. Nuthalapati:AbbVie: Employment, Other: Stock/stock options. Motwani:AbbVie: Employment, Other: Stock/stock options. Modi:AbbVie: Employment, Other: Stock/stock options. Chang:AbbVie: Employment, Other: Stock/stock options. Calvo:Celgene: Consultancy; Roche/Genentech: Consultancy, Other: travel/accommodations/expenses; Seattle Genetics: Consultancy; AstraZeneca: Consultancy, Research Funding; PsiOxus: Consultancy; Amcure: Consultancy; START: Other: stock/ownership interests, Research Funding; Janssen-Cilag: Consultancy; EUSA Pharma: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Oncoart Associated: Other: stock/ownership interests; Guidepoint Global: Consultancy; Nanobiotix: Consultancy; HM Hospitales Group: Honoraria; AbbVie: Consultancy; BeiGene: Research Funding; Servier: Consultancy; International Cancer Consultants: Other: stock/ownership interests; Foundation INTHEOS: Other: president and founder; Gerson Lehrman Group: Consultancy; Pfizer: Consultancy. Moreno:Puma Biotechnology: Consultancy; Sanofi/Regeneron: Other: travel/accommodations/expenses.

3013 Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered ABBV-621 (2.5–15 mg/kg IV) on day (D) 1 (dose level [DL] 1) or D1D8 (DL2 and beyond) of each 21-day cycle. Dose escalation (DE) was guided by a Bayesian continual reassessment method. In addition to PK studies, blood-based PD markers of apoptosis (M30, M65) and drug binding were assessed. Results: As of 14 December 2018, 57 pts were enrolled in the DE portion, of which 30% had pancreatic, 23% colorectal cancer, and 47% other tumor types; 13 were KRAS mutant. Median age was 61 yrs. 60% were male; pts had a median of 4 prior regimens (range 1–10). Pts per DL: 2.5 (5 on D1, 16 on D1D8), 3.75 (12), 5 (6), 6.5 (6), 8.5 (4), 11 (4), and 15 mg/kg (4). Median duration of ABBV-621 exposure was 2 cycles (range 1–11). Seven pts had dose-limiting toxicities: respiratory failure (5 mg/kg; Grade 5, the only treatment-related death), blood bilirubin increased (3.75, 6.5 mg/kg), nausea (3.75 mg/kg), fatigue (3.75 mg/kg), increased ALT (2.5, 3.75, 6.5, 15 mg/kg), and increased AST (6.5 mg/kg). Summary of AEs is shown in Table. Clinical trial information: NCT03082209. A partial response (duration 20 weeks) was observed in a pt with pancreatic cancer (2.5 mg/kg D1D8). 27 pts had stable disease (6 pts for > 12 weeks). ABBV-621 PK was linear (mean ± SD clearance was 1.79 mL/h/kg ± 0.44) with a terminal half-life of 36.7 ± 5.55 h (n = 49). ABBV-621 bound to decoy receptors on neutrophils for up to 168 h; the duration of binding was dose-dependent. M30 and M65 increased at 8, 24, and 48 h following ABBV-621, but effect was independent of dose. Conclusions: ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209.[Table: see text]

9004 Background: Capmatinib is a highly potent and selective MET inhibitor. Previous data of GEOMETRY mono-1 study showed a clinically meaningful overall response rate (ORR) and manageable toxicity profile in patients (pts) with METΔex14–mutated NSCLC who received 1–2 prior lines of treatment (tx) (Cohort 4) and in particular a high ORR in tx-naïve pts (Cohort 5b). Here we report the results in METΔex14–mutated NSCLC for duration of response (DOR) and progression-free survival (PFS) as well as the updated results for ORR. Methods: GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in pts with METΔex14-mutated or MET-amplified advanced NSCLC across 6 cohorts. Pts (≥18 yrs) with ECOG PS 0–1, ALK and EGFR wt, and stage IIIB/IV NSCLC were eligible. Pts with METΔex14 mutation (centrally confirmed) were assigned (regardless of MET amplification status/gene copy number) to Cohorts 4 and 5b and received capmatinib tablets 400 mg BID. Primary endpoint was ORR by Blinded Independent Review Committee (BIRC) per RECIST v1.1. Key secondary endpoint was DOR by BIRC. Results: As of Nov 08, 2018, 97 pts with METΔex14-mutated NSCLC (Cohort 4: 69 pts; Cohort 5b: 28 pts) were evaluable for efficacy. ORR (95% CI) by BIRC was 39.1% (27.6-51.6) in Cohort 4 and 71.4% (51.3-86.8) in Cohort 5b. While still immature at the time of this analysis, data on durability are promising: median DOR (95% CI) by BIRC was 9.72 (4.27-11.14) and 8.41 (5.55-NE) mo for Cohorts 4 and 5b, respectively; median PFS (95% CI) by BIRC was 5.42 (4.17-6.97) and 9.13 (5.52-13.86) mo for Cohorts 4 and 5b, respectively. Safety profile remains favourable and unchanged. Most common AEs (≥25% all grades) across all cohorts (n = 315), were peripheral edema (49.2%), nausea (43.2%), and vomiting (28.3%); majority of the AEs were grade 1/2. Final efficacy analysis (12-mo f-u on DOR) including biomarker data will be presented during meeting. Conclusions: These data confirm capmatinib to be a promising new treatment option for pts with METΔex14-mutated advanced NSCLC regardless of the line of therapy with deep and durable responses and manageable toxicity profile. Clinical trial information: NCT02414139.

Background BI 853520 is a potent inhibitor of focal adhesion kinase and is currently under clinical development for the treatment of non-hematological malignancies. Objective The objective of this study was to evaluate the effect of food and liquid dispersion on the pharmacokinetics of BI 853520 in two open-label, crossover substudies. Patients and Methods Sixteen patients with advanced solid tumors were enrolled in each substudy. The order of administration was randomized, and pharmacokinetic samples were collected for 48 h after administration of a 200 mg dose of BI 853520. Lack of effect would be demonstrated if the 90% confidence interval (CI) of the ratio of the adjusted geometric mean (GMR) of the area under the plasma curve (area under the plasma concentration–time curve from time zero to the last quantifiable concentration at tz [\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{AUC}}_{{0{-}t_{\text{z}} }}$$\end{document}AUC0-tz] and observed area under the plasma concentration–time curve extrapolated from time zero to infinity [AUC0–∞,obs]) and maximum plasma concentration (Cmax) did not cross the 80–125% (bioequivalence) boundaries. Results Adjusted GMRs (90% CIs) for the fed versus fasted state were 92.46% (74.24–115.16), 98.17% (78.53–122.74), and 87.34% (71.04–107.38) for \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{AUC}}_{{0{-}t_{\text{z}} }}$$\end{document}AUC0-tz, AUC0–∞,obs, and Cmax, respectively. Although the 90% CIs were not within bioequivalence limits for the food-effect study, the limited reductions in these pharmacokinetic parameters after administration with a high-fat meal are unlikely to be clinically relevant. Compared with a tablet, administration of BI 853520 as a liquid dispersion did not strongly affect \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{AUC}}_{{0{-}t_{\text{z}} }}$$\end{document}AUC0-tz, AUC0–∞,obs, or Cmax, resulting in adjusted GMRs (90% CIs) of 1.00 (0.92–1.09), 0.98 (0.90–1.07), and 0.93 (0.86–1.01), respectively. Conclusions These studies demonstrate that BI 853520 can be given with no food restrictions, and as a liquid dispersion, without strongly impacting pharmacokinetics. These pharmacokinetic properties may help make BI 853520 dosing more convenient and flexible, improving treatment compliance. Clinical trials registration ClinicalTrials.gov identifier: NCT01335269. Electronic supplementary material The online version of this article (10.1007/s11523-018-00618-0) contains supplementary material, which is available to authorized users.

Our increasing knowledge on the pathogenetic mechanisms involved in the growth of cancer cells and on the molecular basis of cancer has influenced the development of anticancer agents. The realization that new targets should be evaluated for anti-cancer drug treatment has a.o. led to the introduction of the taxoids and topoisomerase I inhibitors. Attacking the known targets in a more sophisticated way led to the development of drugs with increased target specificity like Tomudex and Gemcitabine. Finally, using old drugs more efficiently by using pharmacokinetic and pharmacodynamic ananlysis hold a promise for the near future.

Purpose: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer. Experimental Design: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w. Results: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration–time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80–225 days). Conclusions: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards. Clin Cancer Res; 22(4); 877–85. ©2015 AACR.

In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2–p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules., Pre-clinical studies have shown that TP53 mutations can account for acquired resistance to HDM2 antagonists. This study provides clinical evidence for the emergence of TP53 mutations in circulating cell-free DNA, seen in 5 out of 20 de-differentiated liposarcoma patients treated with an HDM2 antagonist.

With the event of new Molecular targets, clinical trial design requirements to perform these trials are changing. This paper discusses some of the considerations that need to be taken into account when designing a trial, including those trials that assess combinations of targets. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Purpose: To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLT), safety, pharmacokinetics, and pharmacodynamics of tivozanib, a potent and selective oral VEGF receptor (VEGFR) tyrosine kinase inhibitor. Experimental Design: Dose levels of 1.0, 1.5, and 2.0 mg/d tivozanib for 28 days followed by 14 days of medication were explored in patients with advanced solid tumors. Results: Forty-one patients were enrolled. Animal data incorrectly predicted toxicity, resulting in DLTs at the starting dose (2.0 mg) consisting of grade 3 proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed. At an intermediate dose (1.5 mg), 1 patient experienced DLT consisting of grade 3 hypertension. This dose was determined as the MTD. Of 10 additional patients treated at 1.5 mg, 1 patient each experienced grade 3 hypertension and grade 3 fatigue, and 2 patients experienced grade 3 and 4 transaminase elevation. In 12 additional patients treated at 1.0 mg, no DLT was observed. Pharmacokinetics displayed long absorption time, dose proportional exposure, and a half-life of 4.7 days. Plasma levels of VEGF-A and soluble VEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced MRI indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal cancer, and other tumors. Conclusion: Tivozanib was well tolerated with manageable side effects. The pharmacokinetics profile revealed that tivozanib was suitable for once-daily dosing. Encouraging and durable clinical activity was observed. The recommended daily dose of tivozanib in a 4-week-on and 2-week-off dosing regimen is 1.5 mg. Clin Cancer Res; 17(22); 7156–63. ©2011 AACR.

BACKGROUND: Hairy cell leukemia is a rare, indolent, B-cell lymphoproliferative disease characterized by the BRAF V600E mutation in 90% to 100% of patients. Few treatment options are available for patients who progress on first-line therapy with a purine analogue and/or rituximab. The efficacy of combined BRAF and MEK inhibition is well established in BRAF V600-mutated melanoma, non-small cell lung cancer, and anaplastic thyroid cancer. Here we report interim results of treatment with the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in patients with recurrent/refractory BRAF V600E-mutated HCL. METHODS: In this phase 2, open-label trial (ROAR; NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including HCL, received continuous dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) until unacceptable toxicity, disease progression, or death. For the HCL cohort, eligible patients had histologically confirmed HCL (according to WHO classification) that was refractory to first-line treatment with a purine analogue or relapsed after ≥ 2 prior lines of treatment. The presence of a BRAF V600E mutation was assessed locally and confirmed by a central laboratory. The primary endpoint was investigator-assessed overall response rate (ORR) based on criteria adapted from NCCN guidelines. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Minimal residual disease (MRD) status was assessed by flow cytometry in both peripheral blood and bone marrow aspirates. For complete response (CR) without MRD, both peripheral blood and bone marrow aspirate samples had to be negative. RESULTS: At the data cutoff (January 3, 2018), 43 patients with HCL had enrolled. Median age was 67 years (range, 40-81) and 38 (88%) were male. Twenty-one patients (49%) had received ≥ 4 prior treatments. At the time of data cutoff, 35 patients (81%) remained on study treatment, 5 (12%) in follow-up; 2 (5%) had withdrawn from study (loss to follow-up and consent withdrawal [n = 1 each]), and 1 (2%) had died. Eight patients had discontinued therapy due to adverse events (AEs; 5 [12%]), study withdrawal (2 [5%]), or disease progression (1 [2%]). Median time on study treatment was 17 months (range, 1-39). Among 41 patients evaluable for response, the investigator-assessed confirmed ORR was 78% (32/41; 95% CI, 62%-89%) with 20 (49%) having CR, (6 [15%] CR without MRD and 14 [34%] CR with MRD), and 12 (29%) partial response. All responses were ongoing at the data cutoff; 16 (50%) responses were lasting ≥ 18 months. PFS and OS rates at 12 months were both 97.6% (95% CI, 83.9%-99.7%). The most common AEs in patients with HCL were pyrexia (67%), chills (51%), hyperglycemia (44%), nausea (44%), peripheral edema (42%), cough (40%), and fatigue (40%). Grade 3/4 AEs were reported in 49% of patients, with the most common (> 5%) being hyperglycemia (9%), anemia (7%), and neutropenia (7%). AEs led to dose reduction and treatment interruption in 42% and 56% of patients, respectively. AEs led to permanent discontinuation in 5 patients (12%; headache and malaise [n = 1]; pyrexia, chills and palmar-plantar erythrodysesthesia syndrome [n = 1]; fat necrosis [n = 1]; hyperglycemia and pancreatic adenocarcinoma [n = 1]; Hodgkin lymphoma [n = 1]). CONCLUSIONS: Dabrafenib + trametinib was well tolerated and demonstrated a high rate of durable responses in patients with heavily pretreated recurrent/refractory BRAF V600E-mutated HCL. Disclosures Kreitman: NIH: Patents & Royalties: Co-inventor on the NIH patent for Moxetumomab Pasudotox. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blay:Roche: Honoraria, Other: Non-financial support, Research Funding; Novartis: Honoraria, Other: Non-financial support, Research Funding. Wainberg:Merck: Consultancy; EMD Serono: Consultancy; Lilly: Consultancy; Five Prime: Consultancy; Novartis: Consultancy. Stein:Novartis: Other: Patient documentation fees; GSK: Other: Patient documentation fees. Willenbacher:Merck: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Honoraria, Other: Steering board, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau. Burgess:Novartis: Employment. Mookerjee:Novartis: Employment. Subbiah:Roche/Genentech: Research Funding; LOXO: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Bayer: Research Funding.

PURPOSE: To evaluate the safety and tolerability of LiPlaCis, a liposomal formulated platinum compound, in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous (i.v.) LiPlaCis. and to assess plasma and urine pharmacokinetics and plasma biomarkers.PATIENTS AND METHODS: Patients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1 h infusion without additional hydration every 3weeks until RECIST progression or unacceptable toxicity. Cohorts of 3-6 patients were treated at each dose level until MTD was reached.RESULTS: Eighteen patients were enrolled and 64 cycles were delivered. At the first dose level 3 patients experienced an infusion reaction. Despite prophylactic pre-medication and prolongation of the infusion to 2 h in further patients, three other patients had mild acute infusion reactions. Toxicity at the fifth dose level of 120 mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients. Peak plasma concentrations and AUC were dose proportional. The interpatient variability in the clearance of total LiPlaCis-derived platinum was 41%. Platinum was excreted via the urine mainly during the first 24 h after administration. Investigated plasma biomarkers sPLA(2) and SC5b-9 were related to, but not predictive for, acute infusion reactions.CONCLUSION: The observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development.

Background: Dysregulated Wnt/β-catenin signaling has been linked to several cancers, including pancreatic cancer (PC) and colorectal cancer (CRC). WNT974 (formerly LGK974) - a first-in-class, selective, oral inhibitor of Porcupine (an O-acyltransferase required for Wnt activation and secretion) - has shown preclinical activity in tumor models with mutations upstream in the Wnt pathway. Furthermore, dysregulated Wnt signaling has been linked to T-cell exclusion in tumor tissue and resistance to immunotherapy, suggesting WNT974 may act synergistically with checkpoint inhibitors. Methods: This ongoing Phase I, open-label, dose-escalation and -expansion study (NCT01351103) is designed to determine the maximum tolerated dose and/or recommended dose for expansion, characterize the safety and tolerability, and assess preliminary antitumor activity, pharmacokinetic (PK), and pharmacodynamic properties of WNT974, alone or combined with PDR001 (spartalizumab, an anti-PD-1 antibody) in advanced/metastatic solid tumors. Here, we focus on preliminary biomarker analyses from the single-agent part of the study. The study initially enrolled pts with lobular breast cancer and melanoma and was later amended to enroll pts with triple negative breast cancer (TNBC), PC, and CRC, and those with tumors with genetic alterations upstream in the Wnt pathway. Pre and on-treatment skin and tumor tissue specimens were collected for RT-PCR analysis of AXIN2, a marker of Wnt pathway activity. NanoString gene expression was measured in a subset of pts using remnant RNA from the tumor samples, and chemokine and dendritic cell signatures were analyzed pre and on-treatment. Results: At the data cut-off date, March 2, 2017, 94 pts were enrolled. Median age was 58.5 years (range, 28-77), 43% were male, and the most common cancer types were PC (30%), melanoma (26%), and breast cancer (21%). Patients received single-agent WNT974 orally at doses of 5, 7.5, 10, 15, 20, 22.5, or 30 mg daily, 30 or 45 mg intermittently (4 days on, 3 days off), or 5 mg twice daily. Median duration of exposure was 4.9 weeks (range, 0.1-27.7). Safety, tolerability, and PK have previously been reported. AXIN2 expression in paired samples from skin and tumor showed evidence of Wnt pathway inhibition in all indications; this was not dose-dependent in the dose range studied. Immune signature analyses of a paired tumor sample subset (n=8) revealed an inverse association between change in AXIN2 expression and change in chemokine and activated dendritic cell signatures. Conclusions: Biomarker analyses show that WNT974 can potently inhibit Wnt pathway activity in skin and tumors. Immune signature data suggest that WNT974 treatment may promote T-cell recruitment into tumors, and support investigation of the combination of WNT974 with immunotherapy. The combination part of this study evaluating WNT974 combined with PDR001 (spartalizumab) is ongoing. Citation Format: Jordi Rodon, Guillem Argilés, Roisin M. Connolly, Ulka Vaishampayan, Maja de Jonge, Elena Garralda, Marios Giannakis, David C. Smith, Jason R. Dobson, Margaret McLaughlin, Abdelkader Seroutou, Yan Ji, Sinead Dolan, Jennifer Morawiak, Susan Moody, Filip Janku. Biomarker analyses from a phase I study of WNT974, a first-in-class Porcupine inhibitor, in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT175.

2586Background: CRAF is a key mediator of oncogenic mitogen-activated protein kinase (MAPK) pathway reactivation following MEK or BRAF inhibition. LXH254 is a BRAF and CRAF inhibitor with antitumor...

5538Background: Poly(ADP-ribose)polymerase (PARP) inhibitors have shown substantial activity in homologous recombination (HR) deficient ovarian cancer and are undergoing testing in other HR-deficie...

Introduction: EGFR inhibitors (EGFRIs) have been shown to be clinically effective in various cancers. Unique skin toxicity is commonly observed with EGFRIs and a correlation between the clinical benefit of EGFRIs and this characteristic rash has been reported. Erlotinib is a potent EGFRI approved for treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer. Methods: This is the first time in which patients were given increasing doses of an EGFRI to induce a mechanistic rash and study its associated pathology in skin. Biopsies were collected during treatment from both rash-affected and unaffected skin of 23 NSCLC patients and compared with pre-treatment biopsies. Results: Altered differentiation of appendegeal epithelium (hair follicles and sebaceous glands) was remarkable in both affected and unaffected skin, although epidermal growth was not significantly reduced. A predominantly mononuclear leucocyte infiltrate was detected in the interfollicular dermis or around skin appendages. This infiltrate included TRAIL-positive cells with a dendritic cell (DC) morphology, although T-cells, antigen-presenting DCs and macrophages were also evident. This is the first report showing the involvement of a dendritic cell subtype with EGFRI skin toxicity. Conclusions: Altered differentiation of pilosebaceous epithelium is evident in both rash-affected and unaffected skin and constitutes the primary process of EGFRI in human skin. We propose that this eventually triggers inflammation and the EGFRI rash. TRAIL-positive inflammatory cells could link rash development and immune-triggered apoptosis of epithelial cells, including those of underlying carcinomas. (C) 2010 Elsevier Ltd. All rights reserved.

PurposeSeveral constituents of cigarette smoke are known to interact with drug metabolizing enzymes and potentially affect treatment outcome with substrate drugs. The purpose of this study was to determine the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan.Patients and MethodsA total of 190 patients (49 smokers, 141 nonsmokers) treated with irinotecan (90-minute intravenous administration on a 3-week schedule) were evaluated for pharmacokinetics. Complete toxicity data were available in a subset of 134 patients receiving 350 mg/m2or 600 mg flat-fixed dose irinotecan.ResultsIn smokers, the dose-normalized area under the plasma concentration-time curve of irinotecan was significantly lower (median, 28.7 v 33.9 ng · h/mL/mg; P = .001) compared with nonsmokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 v 0.87 ng · h/mL/mg; P < .001) and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 v 4.5; P = .006). Smokers experienced considerably less hematologic toxicity. In particular, the incidence of grade 3 to 4 neutropenia was 6% in smokers versus 38% in nonsmokers (odds ratio [OR], 0.10; 95% CI, 0.02 to 0.43; P < .001). There was no significant difference in incidence of delayed-onset diarrhea (6% v 15%; OR, 0.34; 95% CI, 0.07 to 1.57; P = .149).ConclusionThis study indicates that smoking significantly lowers both the exposure to irinotecan and treatment-induced neutropenia, indicating a potential risk of treatment failure. Although the underlying mechanism is not entirely clear, modulation of CYP3A and uridine diphosphate glucuronosyltransferase isoform 1A1 may be part of the explanation. The data suggest that additional investigation is warranted to determine whether smokers are at increased risk for treatment failure.

Purpose: The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor. Experimental Design: We performed a phase I dose-escalation study according to the standard 3+3 design. Results: Even at subtherapeutic doses, mild though recurrent renal toxicity was observed in virtually all patients. Renal toxicity had not been observed in preclinical studies in rats and dogs. Additional preclinical studies pointed toward the rabbit as a suitable toxicology model, as the formation of the M10 metabolite of JNJ-38877605 specifically occurred in rabbits and humans. Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605 induced species-specific renal toxicity. Histopathological evaluation in rabbits revealed renal crystal formation with degenerative and inflammatory changes. Identification of the components of these renal crystals revealed M1/3 and M5/6 metabolites. Accordingly, it was found that humans and rabbits showed significantly increased systemic exposure to these metabolites relative to other species. These main culprit insoluble metabolites were generated by aldehyde oxidase activity. Alternative dosing schedules of JNJ-3877605 and concomitant probenecid administration in rabbits failed to prevent renal toxicity at dose levels that could be pharmacologically active. Conclusions: Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605. Clin Cancer Res; 21(10); 2297–304. ©2015 AACR.

In the treatment of advanced colorectal cancer, irinotecan has become one of the most important drugs, despite its sometimes unpredictable adverse effects. To understand why some patients experience severe adverse effects (diarrhea and neutropenia), while others do not, the metabolic pathways of this drug have to be unraveled in detail. Individual variation in expression of several phase I and phase II metabolizing enzymes and ABC-transporters involved in irinotecan metabolism and excretion, at least partly explains the observed pharmacokinetic interpatient variability. Although the difference in expression-level of these proteins to a certain amount is explained by physiologic and environmental factors, the presence of specific genetic determinants also does influence their expression and function. In this review, the role of genetic polymorphisms in the main enzyme-systems (carboxylesterase, cytochrome P450 3A, and uridine diphosphate-glucuronosyltransferase) and ABC-transporters (ABCB1, ABCC2, and ABCG2) involved in irinotecan metabolism, are discussed. Since at this moment the field of pharmacogenetics and pharmacogenomics is rapidly expanding and simultaneously more rapid and cost-effective screening methods are emerging, a wealth of future data is expected to enrich our knowledge of the genetic basis of irinotecan metabolism. Eventually, this may help to truly individualize the dosing of this (and other) anti-cancer agent(s), using a personal genetic profile of the most relevant enzymes for every patient.

Chemotherapeutic agents can produce a variety of acute and chronic organ toxicities. Since many antitumor drugs and their metabolites are cleared renally, the kidneys are vulnerable to injury. The drugs involved will determine the site of injury within the kidney, resulting in clinical manifestations ranging from an asymptomatic rise in serum creatinine to acute renal failure. The most common renal toxicities of chemotherapeutic agents are described.

Contains fulltext : 148839.pdf (Publisher’s version ) (Open Access) PURPOSE: To assess the toxicity profile and dose-limiting toxicities (DLTs), to determine the maximum-tolerated dose, and to study the pharmacokinetics of ZD9331 when administered orally to patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with oral ZD9331 given once daily (od) or twice daily (bid) for 5, 7, or 10 days; cycles were repeated every 21 days at doses ranging from 2.5 to 40 mg. For pharmacokinetic analysis, plasma sampling was performed during the first course and assayed using a validated liquid chromatographic-tandem mass spectrometry assay. Plasma levels of 2'-deoxyuridine were measured as a surrogate marker for TS inhibition. RESULTS: Forty-two patients received a total of 166 courses. The DLTs were myelosuppression and skin rash. Dose escalation of oral ZD9331 from 2.5 to 40 mg, as a single daily dose, resulted in a less than proportional increase in the plasma area under the concentration-time curve of ZD9331. The plasma drug exposure per cycle for the schedules 20 mg od for 5 days, 10 mg od for 10 days, and 10 mg bid for 5 days, all resulting in a total dose per cycle of 100 mg, were comparable. One partial response was noted in a patient with gastric cancer. CONCLUSION: DLTs in this phase I study of oral ZD9331 were myelosuppression and skin toxicity. The recommended dose for phase II studies of oral ZD9331 is 20 mg od for 5 consecutive days, every 3 weeks.

173 Background: APA and AA target the androgenreceptor (AR) axis via different mechanisms and may have complementary activity in mCRPC. APA is an advanced AR antagonist that targets the AR ligand-binding domain with high affinity (Clegg. Cancer Res. 2012). APA prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. This phase 1b study evaluates potential PK interactions between APA and AA + P. Here we report antitumor activity and safety of APA in combination with AA + P from 57 pts versus 29 pts presented at ASCO 2015 (NCT02123758). Methods: Pts with progressive mCRPC and ECOG PS ≤ 2 received AA (1000 mg/d) + P (5 mg BID) on Cycle 1 Day 1 (C1D1) with addition of APA (240 mg/d) on C1D8 in 28-day treatment (tmt) cycles. Efficacy assessment was based on RECIST 1.1 and PCWG2 criteria. Results: 57 pts started tmt on study; median tmt duration was 17 weeks. Median age was 70 years (range, 49-89) and median baseline PSA was 111 µg/L (range, 4-2597). Bone, nodal, and visceral disease were present in 50 (88%), 31 (54%), and 17 (30%) pts, respectively. 29 (51%), 29 (51%), and 23 (40%) pts were previously treated with a taxane, AA, or enzalutamide (ENZ), respectively. 47 pts discontinued tmt: disease progression (n = 39), consent withdrawal (n = 3), physician decision (n = 1), death (n = 1), and other (n = 3). In AA- and ENZ-naïve pts (n = 18), 67% had PSA decline ≥ 50%. In AA- or ENZ-treated pts (n = 39), 15% had PSA decline ≥ 50%. Most commonly reported ( > 10% of pts) drug-related AEs: fatigue (42%), diarrhea (21%), vomiting (21%), nausea (19%), hypokalemia (19%), decreased appetite (16%), hot flush (12%), abdominal pain (12%), and dysgeusia (11%). Grade ≥ 3 drug-related AEs reported in > 1 pt: fatigue (7%), hypokalemia (3.5%), hyponatremia (3.5%), and hypertension (3.5%). 1 pt discontinued study drug for grade 3 fatigue. Conclusions: Interim data indicate that 240 mg/d of APA with 1000 mg/d of AA + P has antitumor activity and an acceptable safety profile in mCRPC. Clinical trial information: NCT02123758. [Table: see text]

PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population. PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m2 (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non–protein-bound cisplatin in plasma by atomic absorption spectrometry. RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CLfree) was 57.1 ± 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m2 (mean, 1.86 ± 0.19 m2), with an interpatient variability of 10.4%. When CLfree was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CLfree and BSA (r = 0.42). Intrapatient variability in CLfree, calculated from 90 patients was 12.1% ± 7.8% (range, 0.30% to 32.7%). CONCLUSION: In view of the high interpatient variability in CLfree relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.

Ecthyma gangrenosum, presenting as embolic lesions caused by Pseudomonas aeruginosa infection, has distinct pathognomonic features and a high mortality rate in patients with bacteremia, but when recognized early is easily treated. In this case report we describe this disseminated infection in an adult patient treated with chemotherapy for an astrocytoma.

PURPOSE: 9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors. PATIENTS AND METHODS: Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m2/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay. RESULTS: Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m2/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r2 = 0.86). One partial response was noted in a patient with metastatic colorectal cancer. CONCLUSION: DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m2/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.

Because of their potent antitumor activity, drugs targeting microtubules are among the most commonly prescribed anticancer agents. These agents fall into the following two broad categories: agents that inhibit tubulin/microtubule polymerization and agents that stabilize preformed microtubules under depolymerizing conditions (the taxanes). The broad clinical antitumor activity of taxanes has stimulated the search for mechanistically similar agents that overcome the difficulties related to formulation and administration and yet subvert the typical mechanism of cellular resistance conferred by the drug efflux by P-glycoprotein and show preserved activity in paclitaxel-resistant cells with mutations in beta-tubulin. The epothilones (a name derived from its molecular features; epoxide, thiazole, and ketone) have emerged as a new class of microtubule-targeting agents and were originally isolated from the broth of a fermenting soil bacteria, Sorangium cellulosum. The epothilones and taxanes have overlapping binding sites to the surface of beta-tubulin, and the microtubule polymerization–inducing mechanism of epothilones seems to be similar to that of taxanes. Preclinical studies indicate a relatively broad spectrum of activity for epothilones. They are generally 5 to 25 times more potent than paclitaxel in inhibiting cell growth in cultures. Epothilones and taxanes seem to differ distinctly in their drug-resistance mechanisms because the cytotoxic effects of the epothilones are preserved in multi-drug resistance– expressing cell lines and in cells harboring tubulin mutations, which demonstrate resistance to paclitaxel. Five epothilone analogs are currently undergoing clinical assessment; these are ixabepilone (aza-epothilone, BMS-247550), BMS-310705 (a water-soluble analog of epothilone B), patupilone (epothilone B, EPO906), epothilone D (KOS-862), and ZK-EPO. Patupilone was one of the earliest epothilones entering clinical development. It has been evaluated in phase I studies using a 5-minute bolus administration weekly, administered 6 of every 9 weeks or 3 of every 4 weeks, once every 3 weeks, or daily times five as a prolonged infusion. In this issue, Rubin et al describe a dose-finding study of the weekly administration of patupilone in patients with advanced solid tumors. A total of 91 patients were treated at dose levels ranging from 0.3 to 3.6 mg/m/wk in a classic, phase I, 3 3 dose-escalation design. Dose-limiting toxicity consisting of grade 3 diarrhea was observed at both of the dose levels of 3.6 and 3.0 mg/m in the 6 weeks on and 3 weeks off dosing schedule. Therefore, the recommended dose for this schedule was set at 2.5 mg/m/wk. Because the drug-related diarrhea often peaked in severity during the fourth week of treatment, an alternative schedule (3 weeks on and 1 week off) was also studied, resulting in the same recommended dose per administration (2.5 mg/m/wk). The most common non–dose-limiting toxicities included nausea, vomiting, and fatigue. Importantly and in contrast to the results with taxanes, only one patient developed alopecia, and there was no neurologic toxicity. As with weekly taxane schedules, hematologic toxicity was limited. The pharmacokinetic data revealed that drug clearance was nonrenal and not related to body-surface area (BSA). Over the dose range studied, systemic drug exposure was dose proportional. There were three partial responses, two of which occurred in patients previously treated with taxanes, and 42% of the patients experienced disease stabilization for a median duration of 16.3 weeks. Given the absence of data on tumor growth rate before study entry, the latter data are obviously difficult to interpret. As stated, the side effects observed with weekly administration of patupilone are strikingly different from those associated with weekly administration of taxanes. Yet, it is important to note there are also major differences in adverse effect profiles between the various epothilones presently in clinical development. Ixabepilone (BMS-247550) is formulated in polyoxyethylated castor oil. Not unexpectedly, during phase I studies, hypersensitivity reactions were seen necessitating prophylactic administration of oral histamine-1 and histamine-2 blockers. Both the once every 21 days schedule and the weekly schedule resulted in doselimiting neutropenia and sensory neuropathy. Early sensory neuropathic changes were already detectable after two cycles of treatment. During the early phase II studies using the schedule of every 3 weeks, grade 3 or 4 neuropathy JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 36 DECEMBER 2

Purpose The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy. Methods Patients with advanced solid tumors (N = 83) enrolled in a Phase I dose-escalation and -expansion study of single-agent buparlisib. Patients in the dose-expansion arm (n = 43) had tumor samples with PIK3CA and/or PTEN alterations. Results The most common cancers were colorectal (n = 31) and breast cancer (n = 21). Median number of prior antineoplastic regimens was four (range: 1–12). Grade 3/4 adverse events (AEs) included asthenia (12.0 %) and performance status decrease (9.6 %). Treatment-related AEs (all grades) included decreased appetite, diarrhea, nausea (each in 33 % of patients), hyperglycemia (31 %) and rash (29 %). One confirmed partial response (PR; triple-negative breast cancer) and three unconfirmed PRs (parotid gland carcinoma, epithelioid hemangiothelioma, ER + breast cancer) were reported. Tumor molecular status did not predict clinical benefit in the full study cohort, or among the colorectal or breast cancer subpopulations. Pharmacodynamic biomarkers (18F-FDG-PET, C-peptide, pS6) demonstrated dose-dependent changes; however, tumor heterogeneity precluded a clear correlation with clinical benefit. Conclusion Buparlisib was well tolerated up to the 100 mg/day dose and showed preliminary activity in patients with advanced cancers. Future studies in more homogeneous patient populations will evaluate buparlisib in combination with other agents and further investigate the use of predictive biomarkers.

Introduction. For anticancer drug development, it is crucial that patients participate in early-phase clinical trials. The main aim of this study was to gain insight into the motivations and other variables influencing patients in their decision to participate in phase I oncology trials. Materials and Methods. Over a period of 25 months, all patients who were informed about (specific) phase I trials in our cancer center were retrospectively included in this study. Data on providing informed consent and final phase I enrollment were collected. Results. In total, 365 patients, with a median age of 59 years and a median World Health Organization performance status score of 1, were evaluated. The majority of patients (71%) were pretreated with systemic therapy, with a median of two lines. After specific study information had been given, 145 patients (40%) declined informed consent, 54% of them mainly because of low expectations regarding treatment benefits and concerns about potential side effects. Patients who had received previous systemic therapy consented more frequently than others. After initial consent, 61 patients (17%) still did not receive study treatment, mostly because of secondary withdrawal of consent or rapid clinical deterioration prior to first dosing. Discussion. After specific referral to our hospital for participation in early clinical trials, only 44% of all patients who were informed about a specific phase I trial eventually participated. Reasons for both participation and nonparticipation were diverse. Patient participation rates could be improved by forming an experienced and dedicated study team.

Purpose: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule. Experimental Design: Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6 to 4.5 mg/m2 were explored. Results: Forty patients [24M/16F, median age 61 years (45–79)] were enrolled. At 4.5 mg/m2, dose-limiting toxicity (DLT) consisted of grade 3 diarrhea, nausea, and vomiting and grade 4 diarrhea, respectively, in two patients. At 4.0 mg/m2, DLT (grade 3 nausea, vomiting, and abdominal cramps) was observed in one patient. Frequently occurring side effects were mainly gastrointestinal. After drug discontinuation at 4.0 mg/m2, one patient experienced reversible grade 4 blurred vision. The maximum tolerated dose (MTD) is 4.0 mg/m2. No complete or partial responses during treatment were observed; one patient at 4.0 mg/m2 had a confirmed partial response after drug discontinuation. Pharmacokinetic analysis revealed a large volume of distribution, high systemic clearance, and a plasma elimination half-life of 5.3 to 15.1 hours. Overall drug exposure increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes monitored in peripheral blood mononuclear cells showed a reversible 15- to 25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a reversible 10- to 25-fold increase. Conclusion: The MTD for E7107 using this schedule is 4.0 mg/m2. Pharmacokinetics is dose-dependent and reproducible within patients. Pharmacodynamic analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107. Clin Cancer Res; 19(22); 6296–304. ©2013 AACR.

Item does not contain fulltext Vascular endothelial growth factor (VEGF) signalling plays a key role in tumour angiogenesis. Cediranib (AZD2171) is a small-molecule VEGF signalling inhibitor with potent activity against all three VEGF receptors. In this phase I, open-label, parallel-group study, adults with advanced solid tumours received a single 45 mg dose of cediranib, followed by 30 mg continuous once-daily oral dosing for 21 days after a 7-day washout period (clinicaltrials.gov identifier NCT00621725). The primary objective was to compare the single-dose pharmacokinetics (PK) of cediranib in patients with different levels of hepatic impairment classified according to the bilirubin level. Safety, tolerability, multiple-dose PK and PK stratified according to the Child-Pugh criteria were also assessed. Thirty patients received cediranib: 18 with normal-mild hepatic impairment and 12 with moderate hepatic impairment. Single-dose PK parameters were similar between the group with normal-mild hepatic impairment and the group with moderate hepatic impairment [ratio of geometric least square means: area under the curve (AUC) 1.12, 90% confidence interval (CI) 0.77-1.61; Cmax 0.95, 90% CI 0.69-1.31]. Hepatic impairment did not influence PK results in multiple dosing. After continuous once-daily dosing, the geometric least square means ratio was 0.72 (90% CI 0.51-1.03) for AUCSS and 0.67 (90% CI 0.47-0.94) for CSS,max. Similar results were obtained when patients were classified for hepatic impairment according to the Child-Pugh criteria. There was no clear difference in the incidence or the severity of adverse events between hepatic impairment groups. Moderate hepatic impairment does not appear to affect the PK profile or the tolerability of cediranib. Dose adjustments are not necessary in this patient population.

Introduction: Early signs of clinical activity are an important factor in the decision to advance development of novel targeted drugs. Response Evaluation Criteria In Solid Tumors (RECIST) has limited value however, as many patients with relatively slowly growing tumors will end up in the Stable Disease (SD) group, obscuring the distinction between a slow natural course of disease or treatment effect. Furthermore, when determining therapeutic efficacy across tumor types using progression free survival, there is also no correction for the individual tumor's natural growth rate. To address this, we developed the Time To Progression (TTP) ratio, a novel clinical trial efficacy endpoint that is based on volumetrics and an intra-patient control. Methods: A prospective multicenter biomarker discovery study (CPCT-03, NCT01566279) was designed. Unselected cancer patients, without regular treatment options, were included and received treatment with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the volumetric TTP ratio. The TTP ratio was defined as TTP1/TTP2, i.e. the quotient of the time to a prospectively determined ?30% volumetric increase in target lesions or occurrence of new lesions before treatment (TTP1) and on-treatment (TTP2). Response was classified as a TTP ratio of Results: Seventy-three patients were included, of whom 59 patients started treatment with everolimus. A TTP ratio could be determined in 43 of these patients (73%). According to RECIST, 35 patients (59%) had SD and one patient demonstrated a partial response (PR), while only 21 patients (36%) met the pre-specified criteria for treatment success according to our volumetric TTP ratio. Whereas RECIST (SD+PR) and TTP ratio were both correlated with OS (p rank test), TTP ratio also differentiated which patients had a longer median OS within the SD RECIST group (n = 28). TTP ratio responders had a median OS of 11 months (95% CI 4.4-17.6), compared to 5 months (95%CI 3.2-6.8) for non-responders (p = 0.0496, log-rank test). The inter-observer agreement (Krippendorff's alpha) for volumetric measurements was 0.78 (95%CI 0.70-0.87) for a total of 199 evaluated scans. Conclusion: These results suggest that volumetric TTP ratio is a reliable method to determine response, with a high inter-observer agreement. The TTP ratio correlates to OS and distinguishes which patients within the RECIST SD group had longer survival, which could be interpreted as a sign of clinical benefit. The TTP ratio may be an important tool to guide early clinical drug development and deserves further investigation. Citation Format: Fleur Weeber, Geert A. Cirkel, Christa G.M. Gadellaa - van Hooijdonk, Sander Bins, Marlous Hoogstraat, Erik van Werkhoven, Stefan M. Willems, Marijn van Stralen, Wouter B. Veldhuis, Nicolle J.M. Besselink, Neeltje Steeghs, Maja J. de Jonge, Marlies H.G. Langenberg, Edwin Cuppen, Jan H. Schellens, Stefan Sleijfer, Martijn P.J.K. Lolkema, Emile E. Voest. The time to progression ratio: a new individualized volumetric parameter for early detection of clinical benefit of targeted therapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT113.

9067Background: cMET dysregulation occurs in 3–10% of NSCLC and is a negative prognostic factor. INC280 is a highly selective cMET inhibitor with preclinical and clinical antitumor activity. The dose-escalation part of this ongoing Ph I study (NCT01324479) included a cMET-dysregulated NSCLC expansion group. Preliminary efficacy was seen in NSCLC pts with high cMET expression, prompting the addition of a second expansion group of pts with EGFRwt, high cMET-expressing NSCLC. We report here on both NSCLC groups. Methods: The primary objective of this Ph I study was met; INC280 RP2D was established at 400 mg BID in a tablet formulation. Secondary objectives included exploring the antitumor activity of INC280 at the RP2D in the original and additional NSCLC groups. Eligible pts (aged ≥ 18 years; ECOG PS ≤ 2) in the original group had documented cMET+ (H-score ≥ 150 or cMET/centromere ratio ≥ 2.0 or gene copy number [GCN] ≥ 5 or IHC 2+ or 3+) NSCLC. In the additional NSCLC group, pts had documented EGFRwt and c...

TPS2604Background: Combination D + T is approved for the treatment of BRAF V600E/K–mutant unresectable or metastatic melanoma. BRAF V600E mutations have also been identified in some rare cancers, including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, nonseminomatous germ cell tumor, hairy cell leukemia (HCL), World Health Organization (WHO) grade I/II glioma, WHO grade III/IV glioma, multiple myeloma, and adenocarcinoma of the small intestine. US incidence rates of these rare tumors range from 0.07 to 6.3 per 100,000, with BRAF V600E mutation frequency ranging from 3% in high-grade glioma to 90% in HCL. Therefore, the ROAR study is underway in pts with these 9 rare BRAF-mutant cancers to assess the safety and efficacy of D + T combination therapy. Methods: This international, multicenter, open-label phase 2 study (NCT02034110) uses a Bayesian hierarchical statistical design that increases study power by borrowing information across histology cohorts based on the emergin...