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Background: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902)., Methods: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy., Results: Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings., Conclusions: The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients., (© 2023. Springer Nature Limited.)

Aims: Patients with advanced urothelial carcinoma (UC) who progress after platinum-based chemotherapy have a poor prognosis, and there is a medical need to improve current treatment options. Ramucirumab plus docetaxel significantly improved progression-free survival but not overall survival (OS) in platinum-refractory advanced UC (RANGE trial; NCT02426125). Here, we report the exposure-response (ER) of ramucirumab plus docetaxel using data from the RANGE trial., Methods: Pharmacokinetic (PK) samples were collected (cycle 1-3, 5, 9 [day 1] and 30 days from treatment discontinuation), and PK data were analysed using population PK (popPK) analysis. The minimum ramucirumab concentration after first dose administration (C min,1 , or trough concentration immediately prior to the second dose) was derived by popPK analysis and used as the exposure parameter for ER analysis. Cox proportional hazards regression models and matched case-control analyses were used to evaluate the relationship between C min,1 and OS. The C min,1 relationship with safety was assessed descriptively., Results: Several poor prognostic factors (ECOG 1, haemoglobin concentration <100 g/L, presence of liver metastases) appeared more frequently in the lower exposure quartiles, suggesting a possible disease-PK interaction. A significant association was identified between C min,1 and OS (P = .0108). Higher exposure quartiles were associated with longer survival and smaller hazard ratios compared to placebo. No new exposure-safety trends were observed within the exposure range (ramucirumab 10 mg/kg once every 3 weeks)., Conclusions: This prespecified ER analyses suggests a positive relationship between efficacy and ramucirumab exposure, with an imbalance associated with disease prognostic factors. Further investigation may elucidate a possible disease-PK relationship., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggests patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab., (© 2022. The Author(s).)

Background We report a Phase 1 study of LY3076226, an antibody-drug conjugate composed of human IgG1 monoclonal antibody against the human FGFR3 attached with a cleavable linker to the maytansine derivative DM4 in patients with advanced or metastatic cancer. Methods This study was comprised of two parts: (A) dose escalation in patients with advanced or metastatic cancer and (B) dose expansion in patients with urothelial carcinoma with locally determined FGFR3 alterations. The dose range of LY3076226 tested was 0.2-5.0 mg/kg as an intravenous infusion on Day 1 of each 21-day cycle. The primary objective was to determine a recommended phase 2 dose (RP2D). Results Twenty-five patients were enrolled (Part A: 22, Part B: 3) and received ≥ 1 dose of LY3076226. No dose-limiting toxicities were reported. LY3076226 was generally well tolerated; most of the toxicities were Grade 1 or 2. Two patients experienced treatment-related Grade 3 toxicity (embolism and decreased platelet count). Four patients experienced serious adverse events (not treatment-related), all in Part A. Dose-proportional exposure was observed, with an estimated half-life of 2-7 days. No responses were seen with LY3076226 treatment. Stable disease persisting for > 6 months was observed in 1 patient receiving 3.2 mg/kg of LY3076226. Conclusion The study demonstrates acceptable safety and tolerability of LY3076226 up to the 5.0 mg/kg dose. Recruitment was stopped due to pipeline prioritization. Dose escalation of LY3076226 beyond 5.0 mg/kg in patients with advanced tumors may be possible. The trial was registered on August 19, 2015 under identifier NCT02529553 with ClinicalTrials.gov., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Addition of veliparib to carboplatin-paclitaxel, with continuation of veliparib monotherapy if carboplatin-paclitaxel was discontinued, improved progression-free survival (PFS) in patients with germline BRCA-associated locally advanced/metastatic HER2- breast cancer and ≤2 lines of previous cytotoxic therapy for metastatic disease in BROCADE3. A pre-planned subgroup analysis evaluated efficacy and safety in patients without previous cytotoxic therapy for metastatic disease., Methods: Patients were randomised 2:1 to receive veliparib (120 mg orally BID) or placebo on days -2 to 5. Carboplatin (AUC 6) was administered on day 1, and paclitaxel (80 mg/m 2 ) on days 1, 8 and 15 (21-day cycles). Patients discontinuing carboplatin-paclitaxel for reasons besides progression could continue veliparib/placebo monotherapy (300 mg BID, increasing to 400 mg BID if tolerated) until progression. The primary end-point was PFS assessed by investigator., Results: Of 509 patients in the intention-to-treat population (98.6% female; mean age 47, standard deviation 11), 413 (81%) had no previous cytotoxic therapy for metastatic disease (274, veliparib; 139, placebo). In the first-line subgroup, median PFS was 16.6 months (95% confidence interval [CI] 13.4-18.7) versus 13.1 months (95% CI 11.4-14.5) for the veliparib versus control groups (hazard ratio 0.70, 95% CI 0.54-0.89, P = .004). More patients were alive and progression-free at 2 years (36% versus 23.2%) and 3 years (27.9% versus 13.3%) in the veliparib versus control group. Adverse events unrelated to progression leading to study drug discontinuation occurred in 25 (9.1%) and 8 (5.8%) patients., Conclusions: Veliparib with carboplatin-paclitaxel led to durable disease control among first-line patients, suggesting a benefit of this treatment approach in early lines., Clinical Trial Registration: NCT02163694., Competing Interests: Conflict of interest statement BK Arun has received research support to her institution from AbbVie, PharmaMar, Astra Zeneca and Invitae, and is a Steering Committee (non-paid) member for AbbVie. HS Han has received research funding to her institution from AbbVie, Arvinas, Prescient, Horizon, Karyopharm, BMS, Novartis, Pfizer, GSK, Marker Therapeutics, Seattle Genetics and Zymeworks. She has received a grant from the Department of Defense and is on the speakers’ bureau for Lilly. B Kaufman is an Advisory Board member for AbbVie, Astra Zeneca, Roche, Novartis and Pfizer. H Wildiers’ institution received consulting fees and honoraria from Roche, Astra Zeneca, Amgen, Lilly, Novartis, AbbVie, Vifor Pharma, Pfizer, Celldex Therapeutics, Janssen-CILAG, TRM Oncology, PUMA Biotechnology, ORION Corporation and an unrestricted research grant from Roche. He received travel support from Roche and Pfizer. M Friedlander reports a consulting/advisory role for AstraZeneca, MSD, AbbVie, Lilly, Takeda and Novartis. He is on the speakers’ bureau for AstraZeneca. He has received honoraria from AstraZeneca, MSD, Lilly, Takeda, Novartis and GSK, and has received research funding from BeiGene, AstraZeneca and Novartis. JP Ayoub has received research funding to his instituion from AbbVie and Boston Biomedical. He is a consultant for Astra Zeneca, Eisai, Eli Lilly, Novartis, Pfizer, Puma and Roche. SL Puhalla is a consultant for AbbVie, MedImmune, Celldex, Puma, Pfizer, AstraZeneca, Eisai and Nanostring. She has received research funding to her institution from AbbVie, Pfizer, Lilly, Novartis, Incyte, Covance-Bayer, Astra Zeneca, Genentech and Medivation. VC Diéras reports a consulting/advisory role to Roche/Genentech, Novartis, Lilly, Pfizer, Astellas, AbbVie, MSD, Tesaro, Daiichi Sankyo, Odonate, Seattle Genetics and Astra Zeneca. KM Bell-McGuinn, BA Bach, CK Ratajczak and D Maag are AbbVie employees and own stock. M Kundu is a former AbbVie employee and may own stock., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate how women with epithelial ovarian cancer (EOC), dichotomized by BRCA status, tolerate intravenous (IV) or intraperitoneal (IP) chemotherapy given with veliparib and bevacizumab (bev) on a GOG phase I study (GOG 9923, NCT00989651)., Methods: This is an unplanned, post hoc analysis of an IRB approved, multi-institutional, prospective study (GOG 9923). Clinical characteristics and toxicity data based on BRCA status were evaluated and descriptive statistics were used to summarize baseline patient characteristics and toxicities. The Kaplan Meier method was used to generate survival estimates., Results: Four hundred twenty-four patients were evaluable. Patients were treated with IV carboplatin, paclitaxel, and bev every 21 days (regimen 1), weekly IV paclitaxel with carboplatin and bev (regimen 2) or IV paclitaxel and bev with IP cisplatin (regimen 3). Bev was continued as maintenance in all arms. Within each of these regimens, veliparib was given either twice daily for the entirety of each cycle (continuous) or on days -2 to 5 (intermittent). Ten percent of patients treated on regimen 1, 12% on regimen 2, and 19.8% on regimen 3 had BRCA-associated tumors. Patients with BRCA-associated tumors, when compared to wild type, experienced similar rates of anemia, febrile neutropenia (, abdominal pain, colonic perforation, nausea, vomiting, and peripheral sensory neuropathy. Median progression free survival (PFS) was not significantly different between BRCA-associated and wild type cancers (HR 0.96, CI 0.65-1.42), though this study's primary aim was not to evaluate outcomes., Conclusions: Germline BRCA mutations positively affect chemosensitivity in EOC, but whether differences in toxicities among BRCA-associated and BRCA wild type tumors existed was previously not reported. In this population with newly diagnosed ovarian cancer no differences in reported toxicity between the two groups was observed., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial., Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues., Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5-13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3-4·8] vs 2·8 months [2·6-2·9]; HR 0·696 [95% CI 0·573-0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9-11·4) in the ramucirumab group versus 7·9 months (7·0-9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724-1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group., Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population., Funding: Eli Lilly and Company., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC., Methods: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles., Findings: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID., Interpretation: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651)., Funding: National Cancer Institute., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257.

Background: Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population., Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m 2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125., Findings: Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96-4·47] vs 2·76 months [2·60-2·96]; hazard ratio [HR] 0·757, 95% CI 0·607-0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8-30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4-18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1-2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab., Interpretation: To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma., Funding: Eli Lilly and Company., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Immunotherapy is an emerging paradigm for the treatment of cancer, but the potential efficacy of many drugs cannot be sufficiently tested in the mouse. We sought to develop a rational combination of motolimod-a novel Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses in humans but diminished responses in mice-with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. Experimental Design: We followed an integrative pharmacologic approach including healthy human volunteers, non-human primates, NSG-HIS ("humanized immune system") mice reconstituted with human CD34 + cells, and patients with cancer to test the effects of motolimod and to assess the combination of motolimod with PLD for the treatment of ovarian cancer. Results: The pharmacodynamic effects of motolimod monotherapy in NSG-HIS mice closely mimicked those in non-human primates and healthy human subjects, whereas the effects of the motolimod/PLD combination in tumor-bearing NSG-HIS mice closely mimicked those in patients with ovarian cancer treated in a phase Ib trial (NCT01294293). The NSG-HIS mouse helped elucidate the mechanism of action of the combination and revealed a positive interaction between the two drugs in vivo The combination produced no dose-limiting toxicities in patients with ovarian cancer. Two subjects (15%) had complete responses and 7 subjects (53%) had disease stabilization. A phase II study was consequently initiated. Conclusions: These results are the first to demonstrate the value of pharmacologic approaches integrating the NSG-HIS mouse, non-human primates, and patients with cancer for the development of novel immunomodulatory anticancer agents with human specificity. Clin Cancer Res; 23(8); 1955-66. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor., Patients and Methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer., Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients., Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy., Patients and Methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175 mg/m2 on day 1, cisplatin 50 mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400 mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response., Results: Thirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting ≥3 weeks, and febrile neutropenia. At 400 mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400 mg DL, the RR was 60% (n = 3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53)., Conclusions: Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible., Clinical Trial Information: NCT01281852., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor., Methods: ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing., Findings: 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8-10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0-14·7) in the BRCA mutant subgroup, 5·7 months (5·3-7·6) in the LOH high subgroup, and 5·2 months (3·6-5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high (0·62, 0·42-0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 [22%] patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 [12%]). Common serious adverse events included small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anaemia (nine [4%]). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred., Interpretation: In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours., Funding: Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: The aim of the study was to evaluate the activity and tolerability of iniparib monotherapy in women with BRCA1 or BRCA2-associated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer., Methods and Materials: Eligible patients had advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer, germline BRCA1 or BRCA2 mutation, measurable disease, and at least 1 previous treatment regimen of platinum/taxane chemotherapy. Patients received iniparib 8 mg/kg intravenously on days 1 and 4 weekly, with imaging every 8 weeks. Treatment continued until disease progression or adverse events (AEs) prohibited further therapy. Common Terminology Criteria for AEs v3.0 was used to grade AEs. The primary endpoint was tumor response. The study was conducted with a Simon 2-stage design with 12 and 23 patients planned in the first and second stage, respectively. The study was designed to distinguish between 10% and 30% responding with types 1 and 2 error of 0.10., Results: Twelve patients were treated on study, with median exposure to iniparib of 7.5 weeks. The median number of previous chemotherapeutic regimens was 7. Treatment-related AEs (≥10%) included asthenia (83.3%), constipation (25%), diarrhea (25%), nausea (25%), abdominal pain (16.7%), and decreased hemoglobin (16.7%). All treatment-related AEs were grades 1 or 2 with the following 2 exceptions: 1 grade 3 diarrhea and 1 grade 3 hypertension. One patient had stable disease lasting 2 cycles; the remaining 11 patients had progressive disease. The study did not proceed to second stage enrollment., Conclusions: Iniparib did not show significant activity in this heavily pretreated ovarian cancer population, all of whom had BRCA1 or BRCA2 mutations.

Purpose: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors., Experimental Design: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation., Results: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30-37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies., Conclusions: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies., (©2015 American Association for Cancer Research.)

Objective: GOG study 172 demonstrated improved progression-free (PFS) and overall (OS) survival for patients with stage III optimally debulked ovarian and peritoneal carcinoma treated with IV/IP paclitaxel and IP cisplatin compared to standard IV therapy. The inpatient administration, toxicity profile, and limited completion rate have been blamed for the lack of acceptance and widespread use of this regimen. We sought to evaluate the PFS, OS, toxicity, and completion rate of a modified outpatient IP regimen., Methods: Using a prospectively maintained database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage III ovarian, tubal, or peritoneal carcinoma followed by IV/IP chemotherapy from 1/05-3/09. Our modified regimen was as follows: IV paclitaxel (135 mg/m(2)) over 3h on day 1, IP cisplatin (75 mg/m(2)) on day 2, and IP paclitaxel (60 mg/m(2)) on day 8, given every 21 days for 6 cycles., Results: We identified 102 patients who initiated the modified IV/IP regimen and completed chemotherapy. The median follow-up was 43 months. The median age at diagnosis was 57 years (range, 23-76). Primary disease site was: ovary, 77 (75%); fallopian tube, 13 (13%); peritoneum, 12 (12%). FIGO stage was: IIIA, 8 (8%); IIIB, 4 (4%); IIIC, 90 (88%). Residual disease after cytoreduction was: none, 58 (57%); ≤ 1 cm, 44 (43%). The most frequent grade 3/4 toxicities were: neutropenia, 12 (12%); gastrointestinal, 8 (8%); neurologic, 6 (6%). Eighty-two (80%) of 102 patients completed 4 or more cycles of IV/IP therapy; 56 (55%) completed all 6 cycles. The median PFS and OS were 29 and 67 months, respectively., Conclusions: By modifying the GOG 172 treatment regimen, convenience, toxicity, and tolerability appear improved, with survival outcomes similar to those of GOG 172. This modified IV/IP regimen warrants further study., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Olaparib (AZD2281), an orally active poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in BRCA1- or BRCA2-deficient cells, has shown promising clinical efficacy in nonrandomized phase II trials in patients with ovarian cancer with BRCA1 or BRCA2 deficiency. We assessed the comparative efficacy and safety of olaparib and pegylated liposomal doxorubicin (PLD) in this patient population., Patients and Methods: In this multicenter, open-label, randomized, phase II study, patients with ovarian cancer that recurred within 12 months of prior platinum therapy and with confirmed germline BRCA1 or BRCA2 mutations were enrolled. Patients were assigned in a 1:1:1 ratio to olaparib 200 mg twice per day or 400 mg twice per day continuously or PLD 50 mg/m(2) intravenously every 28 days. The primary efficacy end point was Response Evaluation Criteria in Solid Tumors (RECIST) -assessed progression-free survival (PFS). Secondary end points included objective response rate (ORR) and safety., Results: Ninety-seven patients were randomly assigned. Median PFS was 6.5 months (95% CI, 5.5 to 10.1 months), 8.8 months (95% CI, 5.4 to 9.2 months), and 7.1 months (95% CI, 3.7 to 10.7 months) for the olaparib 200 mg, olaparib 400 mg, and PLD groups, respectively. There was no statistically significant difference in PFS (hazard ratio, 0.88; 95% CI, 0.51 to 1.56; P = .66) for combined olaparib doses versus PLD. RECIST-assessed ORRs were 25%, 31%, and 18% for olaparib 200 mg, olaparib 400 mg, and PLD, respectively; differences were not statistically significant. Tolerability of both treatments was as expected based on previous trials., Conclusion: The efficacy of olaparib was consistent with previous studies. However, the efficacy of PLD was greater than expected. Olaparib 400 mg twice per day is a suitable dose to explore in further studies in this patient population.

Purpose: Intraperitoneal (IP) cisplatin and intravenous (IV) or IP paclitaxel constitute a standard therapy for optimally debulked ovarian cancer. Bevacizumab prolongs progression-free survival (PFS) when included in first-line IV chemotherapy. In this study, the safety and feasibility of adding bevacizumab to a first-line IP regimen were assessed., Patients and Methods: Treatment was as follows: paclitaxel 135 mg/m(2) IV over 3 hours day 1, cisplatin 75 mg/m(2) IP day 2, and paclitaxel 60 mg/m(2) IP day 8. Bevacizumab 15 mg/kg IV was given after paclitaxel on day 1 beginning in cycle 2. After six cycles of chemotherapy, bevacizumab was given every 3 weeks for 17 additional treatments. The primary end point was safety and tolerability determined by whether 60% of patients completed six cycles of IV/IP chemotherapy., Results: Of 41 treated patients, 30 (73%) received six cycles of IV/IP chemotherapy and 35 (85%) received at least four cycles. Three (27%) of those who discontinued chemotherapy did so because of complications related to bevacizumab (hypertension, n = 2; perforation, n = 1). Grades 3 to 4 toxicities included neutropenia (34%), vasovagal syncope (10%), hypertension (7%), nausea/vomiting (7%), hypomagnesemia (7%), and abdominal pain (7%). There were three grade 3 small bowel obstructions (7%) during cycles 3, 9, and 15. One patient died following rectosigmoid anastomotic dehiscence during cycle 4. Estimated median PFS is 28.6 months (95% CI, 19.1 to 38.9 months). Three patients (7%) had IP port malfunction., Conclusion: The addition of bevacizumab to this IP regimen is feasible; however, bevacizumab may increase the risk of bowel obstruction/perforation. The observed median PFS is similar to that seen with IP/IV chemotherapy alone.

The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response.

Objective: This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed., Methods: Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression., Results: Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (>150μg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated., Conclusion: Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Patients with BRCA-associated ovarian cancer (OC) have a survival advantage over those with sporadic OC. To further explore this, we examined the impact of prognostic factors on disease-free survival (DFS) and overall survival (OS) in patients with known BRCA mutation status., Patients and Methods: We reviewed stage III-IV OC patients treated at our institution between 1 December 1996 and 30 September 2006 and also tested on protocol for BRCA mutations. Impact on DFS and OS was determined by Kaplan-Meier analysis and a Cox proportional hazards model., Results: Of the 110 patients, 36 had deleterious BRCA mutations [BRCA (+)] and 74 were BRCA wild type [BRCA(-)]. Thirty-one of 36 (86%) BRCA (+) and 60 of 74 (81%) BRCA (-) patients were platinum sensitive (P = 0.60). Median OS was longer for BRCA (+) patients (not reached versus 67.8 months; P = 0.02), but DFS was similar (26.9 versus 24.0, P = 0.3). On multivariate analysis, OS correlated with primary platinum sensitivity [HR = 0.15; 95% CI (confidence interval) 0.06-0.34] and BRCA (+) mutation status (HR = 0.33; 95% CI 0.12-0.86)., Conclusions: BRCA mutation status predicted OS independent of primary platinum sensitivity, suggesting that underlying tumor biology contributes to disease outcome and may be worthy of consideration in future clinical trial design.

Purpose: Folate receptor α expression is highly restricted in normal adult tissues but upregulated in a wide range of human cancer types, including epithelial ovarian cancer. Farletuzumab, a humanized monoclonal antibody against folate receptor α, has shown antitumor activity and favorable toxicity in preclinical evaluation. This phase I, dose-escalation study was conducted to determine the safety of weekly i.v. farletuzumab and establish the maximum tolerated dose (MTD)., Experimental Design: Patients with platinum-refractory or platinum-resistant epithelial ovarian cancer received farletuzumab (12.5-400 mg/m(2)) on days 1, 8, 15, and 22 of a 5-week cycle. Intrapatient dose escalation was not permitted. Dose-limiting toxicity (DLT) was defined by treatment-related adverse event of grade 3 or higher, and the MTD was the highest dose at which one or none of six patients experienced a DLT. Disease progression was recorded using Response Evaluation Criteria in Solid Tumors criteria and serum CA-125., Results: Twenty-five heavily pretreated patients were included in the safety, efficacy, and pharmacokinetic analyses. No DLTs or MTDs were encountered, and dose escalation was continued to farletuzumab 400 mg/m(2). C(max) and AUC(0-24) (area under the serum concentration-time curve) increased in an approximately dose-proportional manner, and a nuclear imaging substudy confirmed tumor targeting. There were no objective responses. Stable disease by Response Evaluation Criteria in Solid Tumors was observed in nine (36%) patients and CA-125 reduction in four. Three patients received continued therapy and completed a total of up to three cycles., Conclusions: In this phase I study, farletuzumab administered as an i.v. infusion at doses of 12.5 to 400 mg/m(2) was generally safe and well tolerated in the management of heavily pretreated patients with epithelial ovarian cancer., (©2010 AACR.)

Objective: To analyze whether serum CA-125 response to cytoreductive surgery before initiation of postoperative chemotherapy is associated with progression-free survival (PFS) in patients with stage IIIC ovarian carcinoma., Methods: We included consecutive patients with paired pre- and postoperative CA-125 measurements who underwent primary cytoreductive surgery followed by platinum-based chemotherapy between 1989 and 2006. The association of perioperative CA-125 changes with PFS was investigated using a time-to-event analysis. A Cox proportional hazards model was fit using clinical, surgical, and postoperative treatment characteristics., Results: The study included 307 evaluable patients. Overall, perioperative serum CA-125 changes were associated with PFS. The risk of disease progression increased incrementally as the magnitude of the serum CA-125 response to surgery decreased (trend test; P=0.003). This association was pronounced in optimally but not observed in suboptimally debulked patients. After optimal cytoreduction, a perioperative increase of serum CA-125 levels was strongly associated with an increased risk of relapse compared to patients who experienced a decline of 80% or more (adjusted HR=4.2; 95% CI: 2.04-8.66; P=0.0001)., Conclusion: Perioperative serum CA-125 changes are strongly associated with the risk of relapse in patients with optimally resected stage IIIC disease. The results of this study provide meaningful support for additional translational research correlating perioperative serum CA-125 responses of patients with molecular tumor characteristics. This may be useful for patient counseling and risk stratification during subsequent clinical trials as well as for the development of novel prognostic models.

Increases in protease expression and activity are associated with malignant progression and poor patient prognosis in a number of human cancers. Members of the papain family of cysteine cathepsins are among the protease classes that have been functionally implicated in cancer. Inhibition of the cysteine cathepsin family using a pan-cathepsin inhibitor, JPM-OEt, led to tumor regression in the RIP1-Tag2 (RT2) mouse model of pancreatic islet cell tumorigenesis. The present study was designed to determine whether this cathepsin inhibitor, when used in combination with chemotherapy, would increase antitumor efficacy. RT2 mice were treated in a late-stage regression trial with three different chemotherapy regimens, alone or in combination with the cathepsin inhibitor, JPM-OEt. Cyclophosphamide was administered in either a maximum tolerated dose (MTD) regimen, a "metronomic" continuous low-dose regimen, or a "chemo-switch" regimen consisting of MTD followed by metronomic dosing. Mice were sacrificed at a defined end point and tumor burden was assessed followed by a detailed analysis of cell proliferation, apoptosis, vascularization, and invasiveness in the treated and control lesions. An additional cohort of mice was followed for survival analysis. The cathepsin inhibitor plus the chemo-switch regimen of cyclophosphamide led to the most pronounced reduction in tumor burden and greatest increase in overall survival. Cysteine cathepsin inhibition resulted in a significant decrease in tumor invasiveness, which was further augmented in combination with each of the chemotherapy dosing regimens. These results encourage the development and continuing evaluation of cysteine cathepsin inhibitors as cancer therapeutics.