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Purpose: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors. Patients and Methods: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days. Results: Seventy-one patients were enrolled: 41 in arm A (0.16–4.4 mg/kg) and 30 in arm B (0.32–2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. Conclusions: ALRN-6924 was well tolerated and demonstrated antitumor activity.

Purpose: Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma. Patients and Methods: During the dose-escalation study (ClinicalTrials.gov number: NCT01087554) with the HDAC inhibitor vorinostat and the mTOR inhibitor sirolimus (V+S), a patient with Hodgkin lymphoma refractory to nine prior therapies demonstrated a partial response (PR) lasting for 18.5 months, which promoted additional enrollment of patients with Hodgkin lymphoma as well as exploration of an alternative combination of vorinostat and mTOR inhibitor everolimus (V+E). Results: A total of 40 patients with refractory Hodgkin lymphoma received V+S (n = 22) or V+E (n = 18). Patients received a median of five prior therapies, including brentuximab (n = 39), autologous stem cell transplantation (n = 26), and allogeneic stem cell transplantation (n = 12). The most frequent grade ≥3 treatment-related adverse event was thrombocytopenia in 55% and 67% of patients treated with V+S and V+E, respectively. Complete response was reported in 6 (27%) patients treated with V+S and 2 (11%) patients treated with V+E, and PR was reported in 6 patients (27%) treated with V+S and 4 (22%) patients treated with V+E (objective response rate of 55% and 33%, respectively). In summary, combined HDAC and mTOR inhibition had encouraging activity in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation. Conclusions: Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.

Background BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through the activation of alternative signaling pathways such as RAF/RAS or MET. The authors hypothesized that combining the BRAF inhibitor vemurafenib with either the multikinase inhibitor sorafenib or the MET inhibitor crizotinib could overcome therapeutic resistance. Methods Patients with advanced cancers and BRAF mutations were enrolled in a dose-escalation study (3 + 3 design) to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of vemurafenib with sorafenib (VS) or vemurafenib with crizotinib (VC). Results In total, 38 patients (VS, n = 24; VC, n = 14) were enrolled, and melanoma was the most represented tumor type (VS, 38%; VC, 64%). In the VS arm, vemurafenib 720 mg twice daily and sorafenib 400 mg am/200 mg pm were identified as the MTDs, DLTs included grade 3 rash (n = 2) and grade 3 hypertension, and partial responses were reported in 5 patients (21%), including 2 with ovarian cancer who had received previous treatment with BRAF, MEK, or ERK inhibitors. In the VC arm, vemurafenib 720 mg twice daily and crizotinib 250 mg daily were identified as the MTDs, DLTs included grade 3 rash (n = 2), and partial responses were reported in 4 patients (29%; melanoma, n = 3; lung adenocarcinoma, n = 1) who had received previous treatment with BRAF, MEK, and/or ERK inhibitors. Optional longitudinal collection of plasma to assess dynamic changes in circulating tumor DNA demonstrated the elimination of BRAF-mutant DNA from plasma during therapy (P = .005). Conclusions Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors.

Background In 2007, we initiated IMPACT, a precision medicine program for patients referred for participation in early-phase clinical trials. We assessed the correlation of factors, including genomically matched therapy, with overall survival (OS). Patients and methods We performed molecular profiling (Clinical Laboratory Improvement Amendments) (genes ≤ 182) for patients with lethal/refractory advanced cancers referred to the Phase 1 Clinical Trials Program. Matched therapy, if available, was selected on the basis of genomics. Clinical trials varied over time and included investigational drugs against various targets (single agents or combinations). Patients were followed up for up to 10 years. Results Of 3487 patients who underwent tumor molecular profiling, 1307 (37.5%) had ≥ 1 alteration and received therapy (matched, 711; unmatched, 596; median age, 57 years; 39% men). Most common tumors were gastrointestinal, gynecologic, breast, melanoma, and lung. Objective response rates were: matched 16.4%, unmatched 5.4% (p < .0001); objective response plus stable disease ≥ 6 months rates were: matched 35.3% and unmatched 20.3%, (p < .001). Respective median progression-free survival: 4.0 and 2.8 months (p < .0001); OS, 9.3 and 7.3 months; 3-year, 15% versus 7%; 10-year, 6% vs. 1% (p < .0001). Independent factors associated with shorter OS (multivariate analysis) were performance status > 1 (p < .001), liver metastases (p < .001), lactate dehydrogenase levels > upper limit of normal (p < .001), PI3K/AKT/mTOR pathway alterations (p < .001), and non-matched therapy (p < .001). The five independent factors predicting shorter OS were used to design a prognostic score. Conclusions Matched targeted therapy was an independent factor predicting longer OS. A score to predict an individual patient’s risk of death is proposed. Trial registration ClinicalTrials.gov, NCT00851032, date of registration February 25, 2009.

Preclinical data suggest that combining a checkpoint inhibition with immunomodulatory derivative can increase anticancer response. We designed a dose-escalation study using a 3 + 3 design to determine the safety, maximum tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting toxicities (DLT) of the anti–CTLA-4 antibody ipilimumab (1.5–3 mg/kg intravenously every 28 days × 4) and lenalidomide (10–25 mg orally daily for 21 of 28 days until disease progression or unacceptable toxicity) in advanced cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma, 4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per immune-related response criteria (−79% to −2%) including a PR (−79% for 7.2+ months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling, a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of the patients achieving a PR demonstrated intermediate mutation burden. In conclusion, combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671–6. ©2017 AACR.

Background In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. Methods Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. Results Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11–55). Conclusion MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. Clinical trial registration NCT01829971.

Background: Patients with advanced cancer who progress on standard therapy are potential candidates for phase I clinical trials. Due to their aggressive disease and complex comorbid conditions, these patients often need inpatient admission. This study assessed the outcomes of such patients after they were discharged to hospice care. Patients and Methods: We performed a retrospective analysis of patients with solid tumor malignancies who were discharged to hospice care from the inpatient service. Results: One hundred thirty-three patients were included in the study cohort. All patients had metastatic disease and an Eastern Cooperative Oncology Group performance status ≥3. The median survival after discharge to hospice from an inpatient setting was 16 days, with a survival rate of 5% at 3 months after discharge. The median survival after the last cancer treatment was 46 days, with survival of 17% at 3 months, and 5% at 6 months. Patients with lactate dehydrogenase (LDH) >618 IU/L had a median post-discharge survival of 11 days versus 20 days for patients with LDH ≤618 IU/L. Conclusions: Patients with metastatic cancer participating in phase I trials who have poor performance status and require inpatient admission have a very short survival after discharge to hospice. A high LDH level predicts an even shorter survival.

Purpose: Long wait times are a primary source of dissatisfaction among patients enrolled in early-phase clinical trials. We hypothesized that an automated patient check-in system with readily available display for increasing awareness of waiting intervals would improve patient flow and use of our rooms, with decreased turnover time and increased throughput. Methods: We recorded in-room wait times for patients seen in our clinic and observed the logistics involved in the blood collection process to delineate causes for delays. We then implemented a three-step strategy to alleviate the causes of these delays: (1) changing the collection of materials and the review of faxed orders, (2) improving our LabTracker automated database system that included wait time calculators and real-time information regarding patient status, and (3) streamlining lower complexity appointments. Results: After our intervention, we observed a 19% decrease in mean wait times and a 30% decrease in wait times among patients waiting the longest (95th percentile). We also observed an increase in staff productivity during this process. Modifications in LabTracker provided the biggest reduction in mean wait times (17%). Conclusion: We observed a significant decrease in mean wait times after implementing our intervention. This decrease led to increased staff productivity and cost savings. Once wait times became a measurable metric, we were able to identify causes for delays and improve our operations, which can be performed in any patient care facility.

Background Combining aromatase inhibitors with PI3K/AKT/mTOR inhibitors in patients with hormone receptor (HR)-positive metastatic breast cancer has demonstrated clinical efficacy. There is limited data on associations between molecular signatures and activity. Patients and Methods We evaluated the combination of anastrozole and everolimus in 56 patients with HR-positive, metastatic breast cancer. The primary objective was to establish safety and maximum tolerated dose (MTD). Dose limiting toxicities (DLTs) were defined as serious grade 3 or 4 toxicities related to treatment that occurred during cycle 1. Dose level 1 was anastrozole 1mg PO QD and everolimus 5 mg PO QD and dose level 2 was anastrozole 1 mg PO QD and everolimus 10 mg PO QD (a dose level -1 included everolimus 2.5 mg PO QD). Secondary endpoints included evaluation of antitumor activity and molecular associations with response. When tissue was available, Next Generation Sequencing (NGS) was performed using genomic libraries selected for all exons of 236 (or 182) cancer-related genes sequenced to average depth of >500× in a CLIA laboratory (Foundation Medicine, Cambridge, MA, USA). An analysis was then performed for all classes of genomic alterations. Results The median age was 59 (range, 37-82) and the median number of prior therapies in the metastatic setting was 3 (range, 0-13). The initial oral daily dose of anastrozole 1 mg oral and everolimus 10 mg PO daily was well tolerated. Five dose-limiting toxicities (DLTs) were seen at full doses, including grade 3 thrombocytopenia (1 patient), grade 3 neutropenia (1 patient), grade 3 increased liver enzymes (1 patient), grade 3 hyperglycemia (1 patient) and, grade 3 mucositis (1 patient). The most common grade 3 or 4 treatment-related toxicities were neutropenia (5%), increased liver enzymes (5%), and hyperbilirubinemia (3%). Of the 56 patients on study, 36 were tested for at least one molecular alteration in the PI3K/AKT/mTOR pathway. Twelve of these 36 patients had NGS analysis of their tumor tissue. Eighteen of 36 patients (50%) tested had at least one alteration in the pathway, including mutations in PIK3CA (n=16), PIK3R1 (n=1), and AKT1 (n=2); PTEN protein loss (n=1); and, AKT3 amplification (n=1). Sixteen of 56 evaluable patients (29%) achieved stable disease (SD) /partial response (PR)/complete response (CR) ≥ 6 months (n = 3 (5%) with PR/CR). Thirteen of the 16 patients who achieved SD/PR/CR ≥ 6 months were tested for a genetic alteration in PI3K/AKT/mTOR pathway and 7 of these patients (54%) had at least one alteration in the pathway, including mutations in PIK3CA (n=6), PIK3R1 (n=1), and AKT1 (n=1); PTEN loss (n=1); and AKT3 amplification (n=1). Conclusions Combination anastrozole 1 mg and everolimus 10 mg is well tolerated and is active in heavily-pretreated patients with HR-positive breast cancer. The presence of a molecular alteration in the PI3K/AKT/mTOR pathway did not predict for clinical activity of this combination. Citation Format: Jennifer J Wheler, Filip Janku, Stacy L Moulder, Aung Naing, Sarina A Piha-Paul, Gerald S Falchook, Ralph G Zinner, Apostolia M Tsimberidou, Siqing Fu, David S Hong, Johnique T Atkins, Roman Yelensky, Vince Miller, Philip J Stephens, Vincente Valero, Funda Meric-Bernstam, Razelle Kurzrock. Anastrozole and everolimus in hormone receptor-positive metastatic breast cancer: Safety profile, activity and associations of molecular alterations in the PI3K/AKT/mTOR pathway [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-05-03.

Background Advanced non-small cell lung cancer (NSCLC) patients were treated as part of a Phase I dose escalation and expansion study evaluating a true human monoclonal antibody targeting IL-1α (Xilonix), which is intended to modulate the malignant phenotype—inhibiting tumor growth, spread and offering relief of symptoms. Methods Sixteen NSCLC patients were included. Patients failed a median of 4 chemotherapy regimens, including 10/16 failing anti-EGFR therapy. Disease progression was evaluated using a multi-modal approach: tumor response, patient reported outcomes (EORTC-QLQC30), and lean body mass (LBM). Patients received infusions every 2 or 3 weeks until progression, and were followed 24 months to assess survival. Results There were no infusion reactions, dose-limiting toxicities, or deaths due to therapy. Albeit not statistically significant, there was a trend in IL-6 (−2.6 ± 18.5 (0.1 [−2.8–2.4]), platelet counts (−11 ± 54 (−4[−36.0–1.0]), CRP (−3.3 ± 30.2 (0.4 [−10.7–1.8]) and LBM (1.0 ± 2.5 (0.4 [−0.5–2.6]). Self-reported outcomes revealed reductions in pain, fatigue and improvement in appetite. Median survival was 7.6 (IQR 4.4–11.5) months, stratification based on prior anti-EGFR therapy revealed a median survival of 9.4 months (IQR 7.6–12.5) for those pretreated (N = 10) versus a survival of 4.8 months (IQR 4.3–5.7) for those without (N = 6, logrank p = 0.187). Conclusion Xilonix was well tolerated, with gains in LBM and improvement in symptoms suggesting a clinically important response. Although not statistically significant, the survival outcomes observed for patients with and without prior anti-EGFR therapy raises intriguing questions about the potential synergy of IL-1α blockade and anti-EGFR therapy. Further study for this agent in NSCLC is warranted.

Olanzapine is used for treatment of psychiatric conditions but causes substantial weight gain. This study assessed safety, efficacy, and changes in metabolic cytokines associated with olanzapine administration in patients with cachexia due to advanced cancer. Patients with cancer-related cachexia were treated with olanzapine (doses ranging from 2.5 to 20 mg daily by mouth). Patients also received anti-neoplastic treatments. Serum samples were collected at baseline and after weeks 1, 2, 4, and 8 for analysis of levels of leptin, growth hormone, ghrelin, and interleukin-6 (IL-6). Of the 39 participants, 31 were evaluable for weight change (N = 6 excluded for new ascites; N = 2, incomplete body weight of data). Toxicities related to olanzapine were somnolence (n = 1), pancreatitis (n = 1), extrapyramidal symptoms (n = 1), and nausea/vomiting (n = 1) (all grade 2). The recommended dose of Olanzapine is 20 mg PO daily for cancer patients (same as FDA approved dose for psychiatric conditions). Samples from 29 patients were eligible for analysis of serum cytokine levels. Mean values of leptin, ghrelin, and growth hormone did not change on treatment, though IL-6 levels increased, perhaps due to tumor progression. There was no association between changes in cytokines and weight. The mean change in slope of weight loss before versus after therapy was 0.24 (95 % CI, −0.08, 0.56; p = 0.13) indicating a trend, albeit not reaching statistical significance, toward attenuation of weight loss. Changes in metabolic cytokines and body weight did not correlate. Treatment with olanzapine had only a modest effect in altering the trajectory of weight loss.

Background The purpose of this study was to determine the prevalence of MET amplification and mutation among GU malignancies and its association with clinical factors and responses to c-MET inhibitors. Patients and Methods Patients with GU malignancies referred to our Phase I Clinical Trials Program were evaluated for MET mutation and amplification and outcomes using protocols with c-MET inhibitors. Results MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial, and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 renal cell carcinoma [RCC] [1 clear cell and 1 papillary] and 1/16 prostate cancer). No demographic characteristics were associated with specific MET abnormalities, but patients who tested positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild type MET ). Median overall survival after phase I consultation was 6.1 and 11.5 months for patients with and without a MET alteration, respectively (hazard ratio, 2.8; 95% confidence interval, 1.1 to 6.9; P = .034). Twenty-nine (25%) patients were treated according to a c-MET inhibitor protocol. Six (21%) had a partial response (prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (range, 0.4-19.7) for all treated patients with no responses in patients with a MET abnormality or single-agent c-MET inhibitor treatment. Conclusion MET genetic abnormalities occur in diverse GU malignancies and are associated with a worse prognosis in a phase I setting. Efficacy of c-MET inhibitors was more pronounced in patients without MET abnormalities and when combined with other targets/drugs.

Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications. Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status. Results: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P = 0.007), high-grade tumors (P = 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR = 1.12; 95% confidence intervals, 0.83–1.85; P = 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response. Conclusion: MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. Clin Cancer Res; 20(24); 6336–45. ©2014 AACR.

Purpose Genomic profiling is increasingly used in the management of cancer. We have previously reported preliminary results of our precision medicine program. Here, we present response and survival outcomes for 637 additional patients who were referred for phase I trials and were treated with matched targeted therapy (MTT) when available. Patients and Methods Patients with advanced cancer who underwent tumor genomic analyses were treated with MTT when available. Results Overall, 1,179 (82.1%) of 1,436 patients had one or more alterations (median age, 59.7 years; men, 41.2%); 637 had one or more actionable aberrations and were treated with MTT (n = 390) or non-MTT (n = 247). Patients who were treated with MTT had higher rates of complete and partial response (11% v 5%; P = .0099), longer failure-free survival (FFS; 3.4 v 2.9 months; P = .0015), and longer overall survival (OS; 8.4 v 7.3 months; P = .041) than did unmatched patients. Two-month landmark analyses showed that, for MTT patients, FFS for responders versus nonresponders was 7.6 versus 4.3 months ( P < .001) and OS was 23.4 versus 8.5 months ( P < .001), whereas for non-MTT patients (responders v nonresponders), FFS was 6.6 versus 4.1 months ( P = .001) and OS was 15.2 versus 7.5 months ( P = .43). Patients with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase pathway alterations matched to PI3K/Akt/mammalian target of rapamycin axis inhibitors alone demonstrated outcomes comparable to unmatched patients. Conclusion Our results support the use of genomic matching. Subset analyses indicate that matching patients who harbor a PI3K and mitogen-activated protein kinase pathway alteration to only a PI3K pathway inhibitor does not improve outcome. We have initiated IMPACT2, a randomized trial to compare treatment with and without genomic selection.

Purpose: We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies. Experimental Design: Patients treated on phase I protocols between December 2004 and July 2013 (n = 1,498) were included in this analysis. The primary outcome was clinical benefit, defined as stable disease ≥6 months, complete response, or partial response. Two odds ratios (OR) for achieving clinical benefit were calculated: one for patients treated with VEGF/R inhibitors (OR with VEGF/R) and another for patients treated without (OR without VEGF/R). To compare these two ORs, an interaction term was included in the multivariate model: (chemotherapy/factor of interest)×(VEGF/R). We took significant interaction terms (Pinteraction < 0.05) to suggest effect modification (either synergy or antagonism) with VEGF/R inhibitors. Results: All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [OR = 1.9; 95% confidence interval (CI), 1.5–2.4; P < 0.0001]. Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [OR with VEGF/R = 1.6 (95% CI, 1.1–2.5) vs. OR without VEGF/R = 0.4 (95% CI, 0.3–0.6), Pinteraction = 0.02]. Specifically, the antimetabolite class was associated with the greatest increase in OR for clinical benefit [OR with VEGF/R = 2.7 (95% CI, 1.5–4.7) vs. OR without VEGF/R = 0.2 (95% CI 0.1–0.3), Pinteraction = 0.004]. Conclusions: VEGF/R inhibitor was found to synergize with chemotherapeutics. This effect was most pronounced with the antimetabolite class. Clin Cancer Res; 20(23); 5956–63. ©2014 AACR.

Purpose Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAFV600-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. Patients and Methods In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). Results In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). Conclusion Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor–resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

Purpose Angiogenesis plays a pivotal role in tumor growth and metastasis. Sorafenib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), combined with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF-A), would vertically inhibit VEGF/VEGFR signaling. A phase I trial was performed to assess safety, maximum tolerated dose (MTD), and clinical correlates. Experimental design Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received sorafenib daily for 28 days and bevacizumab every two weeks. Clinical correlates included VEGF polymorphisms. Expansion cohorts of responding tumor types were enrolled. Results One hundred fifteen patients were treated, and the MTD was identified as 200 mg twice daily sorafenib and 5 mg/kg bevacizumab every two weeks. Median number of prior therapies was four. Twenty-nine patients (25 %) achieved stable disease ≥6 months; six patients (5 %) achieved a partial response (total SD ≥ 6 months/PR=35 (30 %)). 76 patients (66 %) experienced adverse events of grade 2 or higher, most commonly hand and foot syndrome (n = 27, 24 %) and hypertension (n = 24, 21 %). Dose-limiting toxicity occurred in eight patients (7 %), and 45 patients (39 %) required dose reduction for toxicity. Grade 3 and 4 hypertension was associated with longer time to treatment failure, overall survival, and higher response rate. Conclusions Combination sorafenib and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced solid tumors.

Background Children (patients ≤ 18 years of age) are not usually included on pharmaceutical industry sponsored Phase I trials. Methods We reviewed the medical records of 40 patients ≤ 18 years treated in ≥ 1 phase I trial at MD Anderson. Results The median OS was 8.5 months (95% CI, 5.5-13.2 months). In the multivariate analysis, age ≥15 only predicted increased OS (P = 0.0065), and >3 prior therapies (P = 0.053) predicted decreased OS. The median PFS was 2.8 months (95% CI, 2.3-4.1 months). In the multivariate analysis, independent factors that predicted increased PFS were age ≥15 years (P < 0.001) and prior radiation therapy (P = 0.049); performance status >1 (P < 0.001) and >3 prior therapies (P = 0.002) predicted decreased PFS. RMH score ≥ 2 and MDACC score ≥ 3 were associated with decreased median OS (P = 0.029 and P = 0.031 respectively). Conclusions It is feasible to conduct phase I studies in pediatric patients based on adult protocols. In the era of targeted therapy more trials should allow pediatric patients earlier in the drug development especially if deemed safe in adults in early phase trials. Translational Relevance Most pharmaceutical industry sponsored trials exclude patients less than 18 years in phase I clinical trials. Even in the era of targeted therapy pediatric patients usually have to wait for most phases of trials to be completed in adults before being allowed to enroll in clinical trials of new therapies, even in the advanced metastatic and relapsed setting. Some investigator initiated phase 1 trials of combinations of US FDA approved agents allow patients less than 18 years. We report the preliminary analyses of the outcomes of pediatric patients enrolled in phase I studies initially designed for adults, but allowing for enrollment of patients under 18.

Summary Background Inflammation is an important feature of the malignant phenotype and promotes angiogenesis, tumour invasiveness, metastases, and cachexia. We used a first-in-class, monoclonal antibody (MABp1) cloned from a human being to target interleukin-1α, a mediator of chronic inflammation. We aimed to assess the safety and tolerability of MABp1 for interleukin-1α blockade in a refractory cancer population. Methods We did an open-label, dose-escalation, and phase 1 study of MABp1 in adults with metastatic cancer at the MD Anderson Clinical Center for Targeted Therapy (Houston, TX, USA). We used a standard 3+3 design to identify the maximum tolerated dose. Patients received MABp1 intravenously once every 3 weeks through four dose levels: 0·25 mg/kg, 0·75 mg/kg, 1·25 mg/kg, and 3·75 mg/kg. After the dose-escalation phase, a second dosing arm was started with dosing every 2 weeks at the maximum tolerated dose. The primary objectives were safety, tolerability, characterisation of the pharmacokinetic profile, and identification of the recommended phase 2 dose. Secondary endpoints included pharmacodynamic effects and antitumour activity. All patients who received at least one dose of MABp1 were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT01021072. Findings Between March 15, 2010, and July 30, 2012, 52 patients with metastatic cancer (18 tumour types) received anti-interleukin-1α monotherapy in dose-escalation and expansion groups. MABp1 was well tolerated, with no dose-limiting toxicities or immunogenicity. Thus, the recommended phase 2 dose was concluded to be 3·75 mg/kg every 2 weeks. Pharmacokinetic data were consistent at all dose levels and showed no evidence of accumulation or increased clearance of MABp1 at increasing doses. For 42 assessable patients, median plasma interleukin-6 concentrations had decreased from baseline to week 8 by a median of 2·7 pg/mL (IQR −12·6 to 3·0; p=0·08). Of the 34 patients restaged, one patient had a partial response and ten had stable disease. 30 patients were assessable for change in lean body mass, which increased by a mean of 1·02 kg (SD 2·24; p=0·02) between baseline and week 8. The most common adverse events possibly related to the study drug were proteinuria (n=11; 21%), nausea (7; 13%), and fatigue (7; 13%). The most frequent grade 3–4 adverse events (regardless of relation to treatment) were fatigue (3; 6%), dyspnoea (2; 4%), and headache (2; 4%). Two patients (4%) had grade 5 events (death due to disease progression), which were unrelated to treatment. Interpretation MABp1 was well tolerated, no dose-limiting toxicities were experienced in this study, and disease control was observed. Further study of MABp1 anti-interleukin-1α antibody therapy for advanced stage cancer is warranted. Funding XBiotech.

// Sarina A. Piha-Paul 1 , Jennifer J. Wheler 1 , Siqing Fu 1 , Charles Levenback 2 , Karen Lu 2 , Gerald S. Falchook 1 , Aung Naing 1 , David S. Hong 1 , Apostolia M. Tsimberidou 1 , Razelle Kurzrock 3 1 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, TX 2 Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 3 Moores Cancer Center, The University of California San Diego, La Jolla, CA, U.S.A Correspondence: Sarina A. Piha-Paul, email: // Keywords : Gynecologic Malignancy, Bevacizumab, Temsirolimus Received : January 31, 2014 Accepted : March 19, 2014 Published : March 20, 2014 Abstract Background: Bevacizumab and temsirolimus are active agents in gynecologic tumors. Temsirolimus attenuates upregulation of HIF-1α levels, a resistance mechanism for antiangiogenics, and targets the PI3-kinase/AKT/mTOR axis, commonly aberrant in these tumors Patients and Methods: We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus. Results: Median age of the 41 women was 60 years (range, 33-80 years); median number of prior systemic therapies was 4 (1-11). Grade 3 or 4 treatment-related toxicities included: thrombocytopenia (10%), mucositis (2%), hypertension (2%), hypercholesterolemia (2%), fatigue (7%), elevated aspartate aminotransferase (2%), and neutropenia (2%). Twenty-nine patients (71%) experienced no treatment-related toxicity greater than grade 2. Full FDA-approved doses of both drugs (bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25mg IV weekly) were administered without dose-limiting toxicity. Eight patients (20%) achieved stable disease (SD) ≥ 6 months and 7 patients (17%), a partial response (PR) [total = 15/41 patients (37%)]. Eight of 13 patients (62%) with high-grade serous histology (ovarian or primary peritoneal) achieved SD ≥ 6 months/PR. Conclusion: Bevacizumab and temsirolimus was well tolerated. Thirty-seven percent of heavily-pretreated patients achieved SD ≥ 6 months/PR, suggesting that this combination warrants further study.

Author(s): Tang, Chad; Jardim, Denis L Fontes; Falchook, Gerald S; Hess, Kenneth; Fu, Siqing; Wheler, Jennifer J; Zinner, Ralph G; Naing, Aung; Tsimberidou, Apostolia M; De Melo Galgiato, Debora; Westin, Shannon N; Meric-Bernstam, Funda; Kurzrock, Razelle; Hong, David S | Abstract: PurposeMET alterations including amplifications and nucleotide variations have been associated with resistance to therapy and aggressive clinical behavior.Experimental designThe medical records of patients presenting to the University of Texas MD Anderson Cancer Center Phase I Clinic with relapsed or metastatic ovarian cancers and known MET nucleotide variation or amplification status were reviewed retrospectively (n=178). Categorical and continuous clinical and molecular characteristics were compared using Fisher's exact and Wilcoxon rank-sum tests, respectively. Univariate and multivariate survival were assessed via Kaplan-Meier and Cox regression analysis, respectively.ResultsMET amplification occurred in 4 (3.5%) of 113 patients, whereas nonsynonomous nucleotide variations were present in 9 (7.4%) of 122 patients. No patients exhibited concomitant amplification and variation. MET variations were observed only in white women with high-grade ovarian tumors, whereas amplifications were observed in both black and white women with high-grade serous ovarian primary tumors. No patients (n=4) exhibiting a MET alteration achieved an objective response when treated on a c-Met inhibitor phase I trial. In addition, ovarian cancer patients treated with a c-Met inhibitor with multikinase activity trended towards a longer time-to-failure compared with those treated with a c-Met-specific inhibitor (median: 1.5 vs. 4.5 months, p=0.07).ConclusionsMET alterations occur in a minority of patients with ovarian cancer. c-Met inhibitors with multikinase activity may exhibit less activity in ovarian cancer than c-Met specific drugs. These findings warrant further investigation.

Purpose Preclinical data showed that trientine, a copper-lowering agent, re-sensitized cancer cells to carboplatin through enhanced human copper transporter 1 (hCtr1) -mediated platinum uptake. Experimental Design We studied carboplatin and trientine in patients (n = 55; 45 who had failed platinum) with advanced malignancies (Phase I, modified 3 + 3 design). Results The most common cancers were head and neck (n = 13), non-small cell lung (n = 10) and epithelial ovarian (n = 8). The median number of prior regimens was four. No dose-limiting toxicity or treatment-related deaths were observed at doses up to carboplatin AUC 6 given with trientine. Eight patients achieved stable disease (SD) ≥ 6 months (six platinum failures) and one patient with platinum-resistant ovarian cancer, partial response (PR) (total SD ≥ 6 months/PR = 9, 16.4 %). The mean nadir serum copper level in the nine patients with SD ≥ 6 months/PR was 0.55 μg/mL (95 % CI, 0.34–0.75) versus 1.22 μg/mL (95 % CI, 1.02–1.42) (p

Melanoma has the highest mortality of all the skin cancer subtypes. Historically, chemotherapy and immunologic therapies have yielded only modest results in the treatment of metastatic melanoma. The discovery of prevalent V600 BRAF mutations driving proliferation makes this oncogenic protein an ideal target for therapy. Dabrafenib, a reversible inhibitor of mutant BRAF kinase, improved response rates and median progression-free survival in patients with V600E BRAF-mutant metastatic melanoma, including those with brain metastases. With a well-tolerated toxicity profile, dabrafenib is effective as a monotherapy; however, resistance eventually develops in almost all patients. As a result, current research is exploring the role of combination therapies with dabrafenib to overcome resistance.

Target-matched treatment with PI3K/AKT/mTOR pathway inhibitors in patients with diverse advanced cancers with PIK3CA mutations have shown promise. Tumors from patients with colorectal cancer were analyzed for PIK3CA, KRAS, and BRAF mutations. PIK3CA-mutated tumors were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Of 194 patients analyzed, 31 (16%) had PIK3CA mutations and 189 (97%) were assessed for KRAS mutations. Patients with PIK3CA mutations had a higher prevalence of simultaneous KRAS mutations than patients with wild-type PIK3CA (71%, 22/31 vs. 43%, 68/158; P = 0.006). Of 31 patients with PIK3CA mutations, 17 (55%) were treated with protocols containing PI3K/AKT/mTOR pathway inhibitors [median age, 57 years; median number of prior therapies, 4; mTORC1 inhibitors (11), phosphoinositide 3-kinase (PI3K) inhibitors (5), or an AKT inhibitor (1)]. None (0/17) had a partial or complete response (PR/CR) and only 1 [6%, 95% confidence interval (CI), 0.01–0.27] had stable disease 6 months or more, which was not significantly different from a stable disease ≥6 month/PR/CR rate of 16% (11/67; 95% CI, 0.09–0.27) in patients with colorectal cancer without PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors (P = 0.44). Median progression-free survival was 1.9 months (95% CI, 1.5–2.3). In conclusion, our data provide preliminary evidence that in heavily pretreated patients with PIK3CA-mutant advanced colorectal cancer, protocols incorporating PI3K/AKT/mTOR inhibitors have minimal activity. PIK3CA mutations are associated with simultaneous KRAS mutations, possibly accounting for therapeutic resistance. Mol Cancer Ther; 12(12); 2857–63. ©2013 AACR.

The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m(2). Twenty-six patients were enrolled in the study. At 5.7 mg/m(2), two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1-3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m(2) with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m(2). The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m(2) and 4.3 mg/m(2), respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6-13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.

Preclinical data suggest that combined EGF receptor (EGFR) targeting with an EGFR tyrosine kinase inhibitor and an anti-EGFR monoclonal antibody may be superior over single-agent targeting. Therefore, as part of a phase I study, we analyzed the outcome of 20 patients with non–small cell lung cancer treated with the combination of erlotinib and cetuximab. EGFR mutation status was ascertained in a Clinical Laboratory Improvement Amendment–approved laboratory. There were 10 men; median number of prior therapies was five. Overall, two of 20 patients (10%) achieved partial response (PR), one of whom had a TKI-resistant EGFR insertion in exon 20, time to treatment failure (TTF) = 24+ months, and the other patient had squamous cell histology (EGFR wild-type), TTF = 7.4 months. In addition, three of 20 patients (15%) achieved stable disease (SD) ≥6 six months (one of whom had wild-type EGFR and squamous cell histology, and two patients had an EGFR TKI-sensitive mutation, one of whom had failed prior erlotinib therapy). Combination therapy with ertotinib plus cetuximab was well tolerated. The most common toxicities were rash, diarrhea, and hypomagnesemia. The recommended phase II dose was erlotinib 150 mg oral daily and cetuximab 250 mg/m2 i.v. weekly. In summary, erlotinib and cetuximab treatment was associated with SD ≥ six months/PR in five of 20 patients with non–small cell lung cancer (25%), including individuals with squamous histology, TKI-resistant EGFR mutations, and wild-type EGFR, and those who had progressed on prior erlotinib after an initial response. This combination warrants further study in select populations of non–small cell lung cancer. Mol Cancer Ther; 12(10); 2167–75. ©2013 AACR.

// Jennifer Wheler 1 , David Hong 1 , Stephen G. Swisher 2 , Gerald Falchook 1 , Apostolia M. Tsimberidou 1 , Thorunn Helgason 1 , Aung Naing 1 , Bettzy Stephen 1 , Filip Janku 1 , Philip J. Stephens 3 , Roman Yelensky 3 , Razelle Kurzrock 4 1 Department of Investigational Cancer Therapeutics – a Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center 2 Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center 3 Foundation Medicine, University of California, San Diego 4 Moores Cancer Center, University of California, San Diego Correspondence: Jennifer Wheler, email: // Keywords : advanced thymoma, mTOR inhibitors, response, targeted therapy, thymic carcinoma. Received : May 2, 2013 Accepted : June 9, 2013 Published : June 10, 2013 Abstract BACKGROUND: Thymomas and thymic carcinoma are rare tumors with no approved therapies. Our purpose was to analyze the molecular features and outcomes of patients referred to the Clinical Center for Targeted Therapy (Phase I Clinic). METHODS: We retrospectively reviewed the medical records of consecutive referred patients with advanced/metastatic thymoma or thymic carcinoma RESULTS: Twenty-one patients were identified (median age 52 years; 10 women; median number of prior systemic therapies = 2). Six of 10 patients (60%) treated with mTOR inhibitor combination regimens achieved stable disease (SD) ≥12 months or a partial response (PR). For patients treated on mTOR inhibitor regimens (N = 10), median time to treatment failure (TTF) was 11.6 months versus 2.3 months on last conventional regimen prior to referral (p=0.024). Molecular analyses (performed by next generation sequencing in seven patients and single polymerase chain reaction (PCR)-based assays in an additional six patients) showed diverse actionable mutations: PIK3CA (1 of 12 tested; 8%); EGFR (1 of 13; 8%); RET (1 of 7; 14%); and AKT1 (1 of 7; 14%). Of two patients with PIK3CA or AKT1 mutations, one was treated with an mTOR inhibitor-based regimen and achieved 26% regression with a TTF of 17 months. CONCLUSION: Patients with advanced/metastatic thymoma or thymic carcinoma demonstrated prolonged TTF on mTOR inhibitor-based therapy as compared to prior conventional treatment. Heterogeneity in actionable molecular aberrations was observed, suggesting that multi-assay molecular profiling and individualizing treatment merits investigation.

// Jennifer Wheler 1 , Gerald Falchook 1 , Apostolia M. Tsimberidou 1 , David Hong 1 , Aung Naing 1 , Sarina Piha-Paul 1 , Su S. Chen 2 , John Heymach 3 , Siqing Fu 1 , Bettzy Stephen 1 , Jansina Y. Fok 1 , Filip Janku 1 , Razelle Kurzrock 4 1 Department of Investigational Cancer Therapeutics – a Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Texas 2 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Texas 3 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas 4 Moores Cancer Center, University of California, San Diego Correspondence: Jennifer Wheler, email: // Keywords : EGFR mutation, EGFR wild-type, non-small cell lung cancer, phase I trials, resistance, squamous cell Received : May 10, 2013 Accepted : June 2, 2013 Published : June 4, 2013 Abstract Purpose: Single-agent EGFR inhibitor therapy is effective mainly in patients with lung cancer and EGFR mutations. Treating patients who develop resistance, or who are insensitive from the outset, often because of resistant mutations, other aberrations or the lack of an EGFR mutation, probably requires rational combinations. We therefore investigated the outcome of EGFR inhibitor-based combination regimens in patients with heavily-pretreated non-small cell lung cancer (NSCLC) referred to a Phase I Clinic. Methods: We reviewed the electronic records of patients with NSCLC treated with an EGFR inhibitor-based combination regimen: erlotinib and cetuximab; erlotinib, cetuximab and bevacizumab; erlotinib and dasatinib; erlotinib and bortezomib; or cetuximab and sirolimus. Results: EGFR mutations were detected in 16% of patients (21/131). EGFR inhibitor-based combination regimens were administered to 15 patients with EGFR -mutant NSCLC and 24 with EGFR wild-type disease. Stable disease (SD) ≥6 months/partial remission (PR) was attained in 20% of EGFR -mutant patients (3/15; two with sensitive mutations and secondary resistance to prior erlotinib, and one with a resistant mutation), as well as 26% of evaluable patients (5/19) with wild-type disease. One of three evaluable patients with squamous cell histology achieved SD for 26.5 months ( EGFR wild-type, TP53 -mutant, regimen=erlotinib, cetuximab and bevacizumab). Conclusions: Eight of 34 evaluable patients (24%) with advanced, refractory NSCLC evaluable for response achieved SD ≥6 months/PR (PR=3; SD ≥6 months=5) on EGFR inhibitor-based combination regimens (erlotinib, cetuximab; erlotinib, cetuximab and bevacizumab; and, erlotinib, bortezomib), including patients with secondary resistance to single-agent EGFR inhibitors, resistant mutations, wild-type disease, and, squamous histology.

// Rabih Said 1,* , David S. Hong 1,* , Carla L. Warneke 2 , J. Jack Lee 2 , Jennifer J. Wheler 1 , Filip Janku 1 , Aung Naing 1 , Gerald S. Falchook 1 , Siqing Fu 1 , Sarina Piha-Paul 1 , Apostolia M. Tsimberidou 1 , Razelle Kurzrock 3 1 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX 2 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 3 UCSD Moores Cancer Center * Denotes equal contribution Correspondence: David Hong, email: // Keywords : P53 mutations, PTEN loss, bevacizumab, Li-Fraumeni syndrome Received : April 10, 2013 Accepted : May 1, 2013 Published : May 1, 2013 Abstract Background: Mutations in the p53 gene are amongst the most frequent aberrations seen in human cancer. Our objective was to characterize the clinical characteristics associated with p53 mutation in patients with advanced cancer. Methods: We retrospectively reviewed and analyzed the clinical features and response to standard systemic therapy of 145 patients with documented tumor p53 mutational status (mutant-type [ mtp 53 ] vs. wild-type [ wtp 53 ]) referred to the Clinical Center for Targeted Therapy. Results: Sixty-six (45.5%) patients had mtp53. Mutations in p53 occurred more frequently in older patients (p= 0.015) and in Caucasians (p=0.024). The incidence of liver metastases was 69.2% vs. 43%, p=0.002 in mtp53 and wtp53 , respectively. PTEN loss by immunohistochemistry was found more frequently in mtp53 -bearing tumors compared to wtp53 (33.3% vs. 10%, p=0.007). The best progression-free survival (PFS) on standard systemic therapy was significantly longer with bevacizumab-containing regimens as compared to non-bevacizumab containing regimen in patients with mtp53 (median 11.0 [ 95 % CI 5 . 9 - 16 . 0 ], n=22 vs. 4.0 months [ 95 % CI 3 . 6 - 5 . 7 ], n=35, p

Patients with advanced colorectal cancer have a poor prognosis once standard therapies fail. This retrospective study presents the characteristics and outcomes in 144 patients treated in phase I clinical trials.We retrospectively reviewed the clinical outcomes in 144 consecutive patients with colorectal cancer referred to the phase I clinic at MD Anderson.Median age was 60 years (range, 35-86 years). The median number of previous systemic therapies was 4 (range, 1-7). The median PFS with the last line of conventional systemic treatment was 12.3 weeks (95% confidence interval [CI], 11.0-14.4); the median PFS of the best phase I treatment was shorter at 8.1 weeks (95% CI, 7.9-8.7 weeks; log-rank test, P.0001). In the multivariate analysis that included the RMH score, sex (male vs. female, P = .02; hazard ratio [HR], 1.57), hemoglobin (10.5 vs. ≥ 10.5 g/dL; P = .03; HR 1.79), and the RMH score (2-3 vs. 0-1; P.003; HR, 1.85) were significant predictors of poor survival.The PFS of patients with colorectal cancer in phase I treatment was shorter than it was on their last line of conventional systemic treatment. Multivariate analysis confirmed the value of the RMH score for predicting overall survival in patients with colorectal cancer enrolled in phase I studies.

Background: Metaplastic breast cancers are considered a chemorefractory subset of triple negative breast cancers. Molecular profiling has demonstrated that metaplastic tumors are enriched for epithelial-to-mesenchymal transition (EMT), frequently express myoepithelial differentiation, make up a component of the ‘claudin-low’ subtype, and harbor relatively high rates of mutations/activation of the PI3kinase pathway (Hennessy, Cancer Research, 2009; Prat, Breast Cancer Res, 2010). Methods: Data from pts with myoepithelial/metaplastic breast cancer treated within the Center for Targeted Therapy using regimens with known inhibitors of the PI3K pathway were evaluated to determine response to therapy. Mutational analyses were performed in archived tumor samples when available. Results: 23 pts have been treated using 6 different therapy regimens and one pt was treated on two separate clinical trials for a total of 24 analyzable outcomes. Patients were treated with liposomal doxorubicin, bevacizumab and the mTOR inhibitor, temsirolimus (DAT, n=17); liposomal doxorubicin and temsirolimus (DT, n=1); paclitaxel, bevacizumab and temsirolimus (TAT, n=3); paclitaxel and temsirolimus (TT, n=1), paclitaxel in combination with an experimental PI3K inhibitor (TEx, n=1), or temsirolimus alone (tem, n=1). Response was measured every two cycles using RECIST criteria. Most pts had received prior chemotherapy, median of 2 prior regimens (range 0–7). Three patients were not evaluated for response, one who died of pneumonia during cycle 2 (DAT) and two who have not yet completed 2 cycles of therapy (DAT, TEx). Response rate (CR+PR) was 35% (CR = 2, PR=4, SD≥6 months=2, SD Conclusion: Activating mutations in the PI3K pathway are common in metaplastic breast cancers, a tumor subtype that shares molecular features with claudin-low and mesenchymal/mesenchymal-stem cell like triple negative breast cancers. DAT has demonstrated activity in myoepithelial/metaplastic breast cancer including two durable CRs to therapy. This regimen should be explored in larger, randomized trials to test superiority to chemotherapy alone. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-09.

Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

Tyrosine kinase inhibitor (TKI)-induced thyroid dysfunction has been identified as an important but manageable adverse effect of targeted therapy. Several studies have suggested that patients who develop hypothyroidism respond better to TKIs, but this relationship is not well elucidated. We evaluated the relationship between new-onset hypothyroidism and clinical response in patients with advanced cancers treated with TKIs at our institution. We retrospectively reviewed records for patients from four clinical trials that included at least one TKI therapy between January 2006 and December 2011. Patients with preexisting thyroid disease, including thyroid cancer, hypothyroidism, or hyperthyroidism, were excluded. Analysis of 197 patients was performed. Response was determined using RECIST 1.0. Clinical benefit was described as complete response, partial response, or stable disease greater than 4 months. Multivariable logistic regression analysis was performed to correlate patient characteristics with clinical response. The median age for the 197 patients was 58 years (range, 13–85 years), and 56 % were female. Of the 197 patients, 52 (26 %) developed hypothyroidism after therapy. Clinical benefit rates were 50 % in patients with new-onset hypothyroidism versus 34 % in patients without hypothyroidism. In the univariate model, the odds ratio (OR) for new-onset hypothyroidism was 1.9 [95 % confidence interval (CI) (1.0, 3.6) and p = 0.05]. We grouped tumor types into six categories (breast, colorectal carcinoma, melanoma, non-small cell lung cancer, pancreas, and other). When adjusted for tumor type, age (>50 years) and sex, the OR was 2.9 [95 % CI (1.3, 6.5) and p = 0.012] for new-onset hypothyroidism. New-onset hypothyroidism was associated with favorable clinical response in patients who received TKI treatment.

Lenalidomide and bevacizumab have antitumor activity in various tumor types. We conducted a phase I study of this combination in patients with advanced cancer. A “3 + 3” study design was used. Lenalidomide 10 or 20 mg (orally, days 1–21) and bevacizumab 5, 7.5, or 10 mg/kg, (intravenously, every 2 weeks) were given at four escalating dose levels, followed by an expansion phase at the highest maximum tolerated dose (MTD) (1 cycle = 4 weeks). Dose-limiting toxicity (DLT), MTD, adverse events, and clinical outcomes were assessed. Thirty-one patients were enrolled (median age, 60 years; men, 52 %). The most common tumor types were colorectal carcinoma (n = 11) and melanoma (n = 5). Overall, 105 cycles (median, 2) were administered. No DLTs were observed. The maximum tested dose (level 4) was used in the expansion phase. The most common toxicities were fatigue (n = 7, 23 %) and skin rash (n = 4, 13 %). One patient developed a transient ischemic attack (3.2 %); prophylactic anticoagulation became mandatory in the subsequent 17 treated patients. Of 31 patients, 27 were evaluable for response. Stable disease (SD) was noted in 10 (37 %) patients, including five patients with SD for ≥6 months (tumor types: clear cell sarcoma, germ cell tumor, colorectal carcinoma, and melanoma). The median progression-free survival and overall survival were 2.8 and 5.5 months, respectively. The combination of lenalidomide with bevacizumab in patients with advanced solid tumors was safe. Prolonged stable disease was noted in selected tumor types, warranting further clinical evaluation.

Purpose Dasatinib has been shown preclinically to overcome resistance to gemcitabine. We evaluated the safety and biological activity of the combination of dasatinib and gemcitabine in patients with advanced solid tumors. Experimental Design In a phase 1 study (3 + 3 design), patients received daily dasatinib with weekly gemcitabine on days 1, 8 and 15 of a 28-day cycle (except cycle 1 which was 8 weeks). Dose escalation began with dasatinib 70 mg orally (PO) daily and gemcitabine 800 mg/m2 intravenously (IV) weekly. Results Forty-seven patients (15 men; median age = 55 years; median number of prior systemic treatments = 4) were enrolled. Dose-limiting toxicities were grade 3 fatigue and dehydration, with the maximum tolerated dose being dasatinib 100 mg PO qd and gemcitabine 600 mg/m2 IV weekly. The most common grade 3–4 toxicities were anemia (21.5 %), thrombocytopenia (26.2 %), leukopenia (26.2 %), and pleural effusion (10.7 %). Six of 47 patients attained stable disease (SD) ≥ 6 months or partial response including 2 of 8 patients with pancreatic cancer (SD ≥ 6 months; both gemcitabine-refractory), 2 of 3 patients with thymoma (SD for 9.8 and 15 months), 1 of 1 patient with anal squamous cancer (SD 15 months) and 1 of 5 patients with inflammatory breast cancer. No significant changes in circulating tumor cells or interleukin-8 levels were observed. Conclusions The combination was well tolerated at doses of dasatinib 100 mg PO daily and gemcitabine 600 mg/m2 IV weekly. SD ≥ 6 months/ PR was observed in gemcitabine-refractory pancreatic cancer, thymoma, anal cancer and inflammatory breast cancer.

BackgroundResistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.MethodsIn this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.ResultsDose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P

Purpose Patients with advanced malignancies referred for early clinical trials have a short life expectancy. We designed this survey to ascertain the status of advance care planning in this population. Patients and Methods Patients who were seen in a phase I clinic were asked to anonymously complete an investigator-designed survey. Results Of 435 individuals approached, 215 (49%) returned completed or partially completed surveys, whereas many others stated that they wanted to avoid the topic, because they had come to the phase I clinic for cancer therapy. Most patients (n = 149; 69%) were still hopeful about their future. Approximately 42% of patients (n = 90) reported having a living will, 46% had a medical power of attorney (n = 98), and 19% had a do-not-resuscitate (DNR) order (n = 40). Approximately 20% of participants (n = 43) had not discussed advance care planning. Fifty-nine percent of patients wanted to discuss advance care planning with their physician. Having a DNR order in place was significantly more common in individuals who had a living will and/or a medical power of attorney. Conclusion Although most patients referred to a phase I clinic remained optimistic, many had discussed a living will, medical power of attorney, and/or DNR order with their physician, family, and/or attorney. However, a significant minority had not addressed this issue with anyone, and many refused to take a survey on the topic. More than half of the patients wanted to discuss these matters with their physician. These observations suggest that extra effort to address advance care planning is needed for these patients.

Purpose: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics, and antitumor activity of PX-866 in patients with incurable cancers. Experimental Design: This was a phase I, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (arm 1; days 1–5 and 8–12 of a 28-day cycle) or continuous (arm 2; days 1–28 of a 28-day cycle) schedule. Additional patients were treated at the arm 2 MTD in a food effects substudy. Results: Eighty-four patients were treated in the arm 1 (n = 51), arm 2 (n = 20), and food effects (n = 13) cohorts. The most frequent study drug–related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12 and 8 mg for arm 1 and 2, respectively. The dose-limiting toxicities (DLT) consisted of grade III diarrhea (n = 3) and grade III elevated aspartate aminotransferase (AST; n = 1). The pharmacokinetics profile was dose proportional, with no evidence of drug accumulation. PX-866–associated inhibition of platelet pAKTSER473 was observed at the arm 2 MTD. The best response per Response Evaluation Criteria in Solid Tumors (RECIST) was stable disease in 22% of evaluable patients in arm 1, 53% in arm 2, and 11% in the food effects cohort. Eight patients were on study for 4 or more months. Conclusions: This first-in-human study shows that PX-866, an irreversible small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule. Clin Cancer Res; 18(15); 4173–82. ©2012 AACR.

Purpose To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. Patients and Methods Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [18F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. Results Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed. Conclusion RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.

Purpose This study assessed outcomes of individuals with advanced cancer who required admission to an intensive care unit (ICU) after referral for an early clinical trial because they did not respond to conventional therapy. Patients and Methods Outcome analyses were conducted for 212 consecutive patients admitted to The University of Texas MD Anderson Cancer Center ICU after being seen in the phase I clinic starting on May 1, 2007. All data were obtained by a review of electronic medical records of patients. Results The median survival of 212 patients with advanced cancer referred to phase I care after the initial ICU admission was 3.2 weeks (95% CI, 2.5 to 4.9 weeks). Patients who underwent cardiopulmonary resuscitation (CPR) succumbed within a median survival of 1 day (75% and 25% estimated survival of 1 and 3 days, respectively). Patients admitted for a postsurgical intervention did better than patients admitted for a nonsurgical intervention (median survival, 21.5 versus 2.1 weeks; P < .0001). The multivariate analysis revealed that a nonsurgical intervention, hypoalbuminemia, and higher Acute Physiology and Chronic Health Evaluation II scores were associated with poor overall survival. Conclusion The outcome of patients in a phase I clinic after initial ICU admission was poor, particularly when admission was for a nonsurgical intervention and/or when CPR was needed.

Background. Research biopsies are crucial for exploring the impact of novel agents on putative targets. The current study assesses the safety and success rate associated with performing such biopsies. Methods. We reviewed the medical records of 155 consecutive patients who had one or more research biopsies as part of a phase I trial from September 2004 to October 2009. Results. Of 281 research biopsies performed, 118 were paired before and after treatment biopsies (total = 236 biopsies). The most common sites of biopsy were superficial lymph node (19.9%), followed by liver (16.4%), and then soft tissue (15.7%). Ultrasound-guided biopsies were the most frequent type (53.7%). Among 142 patients who consented for mandatory biopsy, 86.6% had the biopsy performed, compared with 4.4% of 911 patients offered a biopsy on an optional basis (p < .0001). Biopsy was obtained most frequently on industry-sponsored trials; lack of funding on nonindustry trials was the most common reason that biopsies were not obtained. Of 281 single biopsies, only 4 (1.4%) had complications: pneumothorax requiring chest tube placement (n = 2), infection requiring admission (n = 1), and arrhythmia with hypotension (n = 1). All but one biopsy was successful in obtaining tissue. No deaths were attributable to biopsy. Conclusions. Our experience demonstrates that research biopsies in early phase clinical trials are safe (1.4% risk of serious complications), and a higher percentage of patients underwent mandatory biopsies (86.6%) compared with that of the patients with optional biopsies (4.4%).

A key end point of early cancer clinical trials is the assessment of toxicities and their possible association with new experimental drugs. Therefore, the concurrent use of complementary and alternative medicine (CAM) in patients with advanced malignancies seen in a dedicated phase 1 clinic was evaluated.An investigator-designed survey was anonymously completed by patients seen in the phase 1 clinic. Pharmacologic CAM included any oral, topical, or intravenous agent, including vitamins, dietary supplements, and herbal products. Nonpharmacologic CAM included prayer, meditation, hypnosis, massage, and acupuncture.Of the 404 patients approached about completing the CAM survey, 394 (98%) agreed to respond, and 309 (78%) surveys were returned. Of those 309 patients, 162 (52%) used 1 or more CAM. Of the 162 CAM users, 77% utilized pharmacologic CAM, 71% used nonpharmacologic CAM, and 48% used both modalities. The most frequent CAM used were vitamins (70%), prayer (57%), and herbal products (26%). CAM utilization was not significantly associated with race, age, level of education, employment, or income level but was used more by women than men (P.01). There was no statistically significant association between the use of CAM and quality of life as perceived by patients. Of the CAM users, 43% of patients had been using CAM for5 years. Only 5% reported having side effects from using CAM, whereas 23% did not fully disclose their CAM use to their physicians.CAM usage is common in patients with advanced malignancies seen in a phase 1 clinic.

Purpose: To compare clinical outcomes of metastatic head and neck cancer patients treated in phase I clinical trials with clinical outcomes of those patients who had their last Food and Drug Administration (FDA)–approved therapy in the setting of metastatic disease. Experimental Design: We retrospectively reviewed the outcomes of 61 consecutive patients with head and neck tumors treated in 36 phase I trials at The University of Texas M.D. Anderson Cancer Center between July 2004 and September 2009. Results: The most common histology was head and neck squamous cell carcinoma (62%). Median age was 55 years (range, 26-80). Eastern Cooperative Oncology Group performance status was 0 to 1 for 95% of patients. Fifty-nine patients had received FDA-approved drugs as the backbone of their last systemic therapy before inclusion in phase I trials (median, 2 systemic therapies). Progression-free survival (PFS) on phase I trials was not inferior to PFS on their last FDA-approved therapies (12 versus 10.7 weeks, log-rank P = 0.87). Fifty-three patients were evaluable for response by Response Evaluation Criteria in Solid Tumors criteria. Four (7%) had partial responses and 16 (26%) had stable disease for ≥4 months. In univariate analysis, number of metastatic sites, lactate dehydrogenase (LDH) levels at baseline, and Royal Marsden Hospital prognosis scores were significant predictors of survival. Only LDH was significant in multivariate analysis (hazard ratio, 6.35; P ≤ 0.0001). Conclusions: For patients with heavily pretreated advanced head and neck tumors, PFS on phase I trials is not inferior to PFS with their last FDA-approved therapy. The only significant predictor of survival in the multivariate analysis was baseline LDH. Clin Cancer Res; 16(15); 4031–7. ©2010 AACR.

Background. Ovarian metastases from pancreatic adenocarcinoma are uncommon and data on the clinical features, treatment, and survival of patients with pancreatic adenocarcinoma with ovarian metastases is limited. The purpose of this study is to define the clinical characteristics and treatment strategies for this patient population. Methods. We reviewed the charts of 18 patients with pancreatic adenocarcinoma with ovarian metastasis who had presented to The University of Texas M. D. Anderson Cancer Center from 1985 to 2005. Results. Of the 18 patients diagnosed with pancreatic adenocarcinoma and ovarian metastases, 8 (44%) presented with ovarian metastases initially and a pancreatic primary tumor became apparent only on further imaging or during surgery. On pathology review, the primary pancreatic cancers (5 out of 18) and ovarian metastases (8 out of 16) showed mucinous characteristics. Patients who underwent resection of their ovarian metastases followed by chemotherapy had a trend of longer median survival compared to patients who received chemotherapy alone without resection of the ovarian metastases (16.5 vs. 8.5 months, respectively; p =0.28). Patients who responded to chemotherapy had a trend of longer survival compared to nonresponders (19 vs. 6 months, respectively; p =0.1). No responses were observed in the ovarian metastases to chemotherapy alone. Conclusions. Primary pancreatic adenocarcinoma with synchronous ovarian metastases may present initially as symptomatic ovarian masses and they commonly have mucinous histologic characteristics. Surgical resection of ovarian metastases may play an important palliative role in the treatment of symptomatic patients with good performance status and lead to longer survival.

Background This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval. Methods Eighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival. Results Retreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156). Conclusion Our data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1701-3) contains supplementary material, which is available to authorized users.

// Ishwaria M. Subbiah 1 , Gerald S. Falchook 2 , Ahmed O. Kaseb 3 , Kenneth R. Hess 4 , Apostolia M. Tsimberidou 2 , Siqing Fu 2 , Vivek Subbiah 2 , David S. Hong 2 , Aung Naing 2 , Sarina A. Piha-Paul 2 , Owais Akmal 3 , Filip Janku 2 and Razelle Kurzrock 5 1 Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Moores Cancer Center, University of California San Diego, San Diego, CA, USA Correspondence to: Ishwaria M. Subbiah, email: // Keywords : targeted agents, novel therapeutics, management, systemic therapy, clinical trials Received : June 01, 2015 Accepted : June 11, 2015 Published : June 23, 2015 Abstract PURPOSE: Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapeutic options. Given the rapid advanced in drug development and emergence of novel agents, we analyzed the characteristics and outcomes of HCC patients treated on early phase trials with an emphasis on targeted therapies. METHODS: We reviewed the records of consecutive HCC patients evaluated in the Phase I Clinical Trials Program at MD Anderson from March 2004. RESULTS: Thirty-nine patients were not treated due to poor performance status ( n = 22, 56%) and decision to pursue alternate therapies ( n = 10, 27%). Of 61 treated patients (median age, 60 years; median prior therapies, 3), eight patients (13%) attained stable disease lasting ≥6 months; four (7%) had a partial response, mainly with anti-angiogenic or multikinase inhibitors. Median Phase I progression-free survival (PFS) was 2.6 months versus 4.4 months ( p 0.019) and 4.1 months ( p 0.27) for their first-, and second-line FDA-approved therapy. Molecular analysis showed frequent PTEN loss (10/19 patients, 53%) and P53 mutation (4/4 patients tested). On multivariate analysis, independent factors predicting shorter survival were white ethnicity/race (p 0.031), cirrhosis ( p 0.016), and serum sodium ( p 0.0013). CONCLUSIONS: In our heavily-pretreated HCC patients, the phase I PFS was comparable to that of 2 nd -line therapy, highlighting a potential role for clinical trials after progression on first-line therapy. The response rate (SD>6 months/PR) of 20% was observed with early signals of activity in regimens combining inhibitors of angiogenesis, multiple kinases and mTOR with preliminary molecular analysis revealing prevalence of PTEN loss.

Cell-free (cf) DNA from plasma offers an easily obtainable material for BRAF mutation analysis for diagnostics and response monitoring. In this study, plasma-derived cfDNA samples from patients with progressing advanced cancers or malignant histiocytosis with known BRAFV600 status from formalin-fixed paraffin-embedded (FFPE) tumors were tested using a prototype version of the Idylla BRAF Mutation Test, a fully integrated real-time PCR-based test with turnaround time about 90 minutes. Of 160 patients, BRAFV600 mutations were detected in 62 (39%) archival FFPE tumor samples and 47 (29%) plasma cfDNA samples. The two methods had overall agreement in 141 patients [88%; κ, 0.74; SE, 0.06; 95% confidence interval (CI), 0.63–0.85]. Idylla had a sensitivity of 73% (95% CI, 0.60–0.83) and specificity of 98% (95% CI, 0.93–1.00). A higher percentage, but not concentration, of BRAFV600 cfDNA in the wild-type background (>2% vs. ≤ 2%) was associated with shorter overall survival (OS; P = 0.005) and in patients with BRAF mutations in the tissue, who were receiving BRAF/MEK inhibitors, shorter time to treatment failure (TTF; P = 0.001). Longitudinal monitoring demonstrated that decreasing levels of BRAFV600 cfDNA were associated with longer TTF (P = 0.045). In conclusion, testing for BRAFV600 mutations in plasma cfDNA using the Idylla BRAF Mutation Test has acceptable concordance with standard testing of tumor tissue. A higher percentage of mutant BRAFV600 in cfDNA corresponded with shorter OS and in patients receiving BRAF/MEK inhibitors also with shorter TTF. Mol Cancer Ther; 15(6); 1397–404. ©2016 AACR.

// Filip Janku 1 , Philipp Angenendt 2 , Apostolia M. Tsimberidou 1 , Siqing Fu 1 Aung Naing 1 , Gerald S. Falchook 1 , David S. Hong 1 , Veronica R. Holley 1 , Goran Cabrilo 1 , Jennifer J. Wheler 1 , Sarina A. Piha-Paul 1 , Ralph G. Zinner 1 , Agop Y. Bedikian 3 , Michael J. Overman 4 , Bryan K. Kee 4 , Kevin B. Kim 3 , E. Scott Kopetz 4 , Rajyalakshmi Luthra 5 , Frank Diehl 2 , Funda Meric-Bernstam 1 , Razelle Kurzrock 1, 6 1 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Sysmex Inostics GmbH, Hamburg, Germany 3 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Molecular Diagnostic Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Moores Cancer Center, The University of California San Diego, La Jolla, CA, USA Correspondence to: Filip Janku, e-mail: fjanku@mdanderson.org Keywords: EGFR, BRAF, KRAS, PIK3CA, cell-free DNA Received: December 16, 2014 Accepted: February 11, 2015 Published: March 25, 2015 ABSTRACT Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable source of biologic material for mutation analysis. Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS , and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures. Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.75, 95% confidence interval [CI] 0.63 – 0.88), in 99% cases for EGFR mutations (kappa = 0.90, 95% CI 0.71– 1.00), in 83% cases for KRAS mutations (kappa = 0.67, 95% CI 0.54 – 0.80) and in 91% cases for PIK3CA mutations (kappa = 0.65, 95% CI 0.46 – 0.85). Patients ( n = 41) with > 1% of KRAS mutant cfDNA had a shorter median survival compared to 20 patients with 1% of mutant cfDNA ( BRAF, EGFR, KRAS , or PIK3CA ) had a shorter median survival compared to 33 patients with

Background Demethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (3 + 3 study design) with azacitidine (20 to 50 mg/m2/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m2/day, IV over 2 h, D2 to 5) (maximum, six cycles). Platinum content, LINE1 methylation (surrogate of global DNA methylation), and CTR1 expression changes (pre- vs. post-treatment) were assessed. Drug pharmacokinetics were analyzed. Results Thirty-seven patients were treated. No dose-limiting toxicity (DLT) was noted at the maximum dose. The most common adverse events were anemia and fatigue. Two (5.4%) patients had stable disease and completed six cycles of therapy. Oxaliplatin (D2) and azacitidine (D1 and 5) mean systemic exposure based on plasma AUCall showed dose-dependent interaction whereby increasing the dose of oxaliplatin reduced the mean azacitidine exposure and vice versa; however, no significant differences in other non-compartmental modeled parameters were observed. Blood samples showed universal reduction in global DNA methylation. In tumor samples, hypomethylation was only observed in four out of seven patients. No correlation between blood and tumor demethylation was seen. The mean cytoplasmic CTR1 score decreased. The pre-dose tumor oxaliplatin levels ranged from

Background Patients with BRAF mutation-positive advanced melanoma respond well to matched therapy with BRAF or MEK inhibitors, but often quickly develop resistance. Methods Tumor tissue from ten patients with advanced BRAF mutation-positive melanoma who achieved partial response (PR) or complete response (CR) on BRAF and/or MEK inhibitors was analyzed using next generation sequencing (NGS) assay. Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 734X with 99% of bases covered >100X. Results Three of the ten patients (median number of prior therapies = 2) attained prolonged CR (duration = 23.6+ to 28.7+ months); seven patients achieved either a PR or a short-lived CR. One patient who achieved CR ongoing at 28.7+ months and had tissue available close to the time of initiating BRAF inhibitor therapy had only a BRAF mutation. Abnormalities in addition to BRAF mutation found in other patients included: mutations in NRAS, APC and NF1; amplifications in BRAF, aurora kinase A, MYC, MITF and MET; deletions in CDKN2A/B and PAX5; and, alterations in RB1 and ATM. Heterogeneity between patients and molecular evolution within patients was noted. Conclusion NGS identified potentially actionable DNA alterations that could account for resistance in patients with BRAF mutation-positive advanced melanoma who achieved a PR or CR but whose tumors later progressed. A subset of patients with advanced melanoma may harbor only a BRAF mutation and achieve a durable CR on BRAF pathway inhibitors. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1029-z) contains supplementary material, which is available to authorized users.