Clinical Significance of Transient Asymptomatic Elevations in Aminotransferase (TAEAT) in Oncology.

Monitoring for liver injury remains an important aspect of drug safety assessment, including for oncotherapeutics. When present, drug-induced liver injury may limit the use or result in the discontinuation of these agents. Drug-induced liver injury can exhibit with a wide spectrum of clinical and biochemical manifestations, ranging from transient asymptomatic elevations in aminotransferases (TAEAT) to acute liver failure. Numerous oncotherapeutics have been associated with TAEAT, with published reports indicating a phenomenon in which patients may be asymptomatic without overt liver injury despite the presence of grade ≥3 aminotransferase elevations. In this review, we discuss the occurrence of TAEAT in the context of oncology clinical trials and clinical practice, as well as the clinical relevance of this phenomenon as an adverse event in response to oncotherapeutics and the related cellular and molecular mechanisms that may underlie its occurrence. We also identify several gaps in knowledge relevant to the diagnosis and the management of TAEAT in patients receiving oncotherapeutics, and identify areas warranting further study to enable the future development of consensus guidelines to support clinical decision-making.

Need for aligning the definition and reporting of cytokine release syndrome (CRS) in immuno-oncology clinical trials.

As cancer immunotherapies continue to expand across all areas of oncology, it is imperative to establish a standardized approach for defining and capturing clinically important toxicities, such as cytokine release syndrome (CRS). In this paper, we provide considerations for categorizing the variety of adverse events that may accompany CRS and for recognizing that presentations of CRS may differ among various immunotherapies (e.g., monoclonal antibodies, CAR T cell therapies and T cell engagers, which can include bispecific antibodies and other constructs). The goals of this paper are to ensure accurate and consistent identification of CRS in patients receiving immunotherapies in clinical studies to aid in reporting; enable more precise evaluation of the therapeutic risk-benefit profile and cross-study analyses; support evidence-based monitoring and management of important toxicities related to cancer immunotherapies; and improve patient care and outcomes. These efforts will become more important as the number and variety of molecular targets for immunotherapies broaden and as therapies with novel mechanisms continue to be developed.

A phase 1 study of LY3076226, a fibroblast growth factor receptor 3 (FGFR3) antibody-drug conjugate, in patients with advanced or metastatic cancer.

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.

The effect of sonidegib (LDE225) on the pharmacokinetics of bupropion and warfarin in patients with advanced solid tumours.

AIMS: We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6). METHODS: This was a multicentre, open-label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. Cohort 1 patients received a single warfarin 15-mg dose on Day 1 of the run-in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration. Cohort 2 patients received a single bupropion 75-mg dose on Day 1 of run-in period and on C2D22 of sonidegib administration. Sonidegib 800 mg QD oral dosing began on Cycle 1 Day 1 of a 28-day cycle after the run-in period in both cohorts. RESULTS: The geometric means ratios [90% confidence interval] for (S)-warfarin with and without sonidegib were: area under the concentration-time curve from time 0 to infinity (AUCinf ) 1.15 [1.07, 1.24] and maximum plasma concentration (Cmax ) 0.88 [0.81, 0.97]; and for (R)-warfarin were: AUCinf 1.10 [0.98, 1.24] and Cmax 0.93 [0.87, 1.0]. The geometric means ratios [90% confidence interval] of bupropion with and without sonidegib were: AUCinf 1.10 [0.99, 1.23] and Cmax 1.16 [0.95, 1.42]. Sonidegib 800 mg had a safety profile that was similar to that of lower dose sonidegib 200 mg and was unaffected by single doses of the probe drugs. CONCLUSIONS: Sonidegib dosed orally at 800 mg QD (higher than the Food and Drug Administration-approved dose) did not impact the PK or pharmacodynamics of warfarin (CYP2C9 probe substrate) or the PK of bupropion (CYP2B6 probe substrate).

Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma.

Background In pancreatic ductal adenocarcinoma (PDAC), the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) axis plays a key role in immunosuppressive properties of the tumor microenvironment, patient prognosis, and chemoresistance. This phase Ib study assessed the effects of the orally administered CCR2 inhibitor PF-04136309 in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic PDAC. Methods Patients received PF-04136309 twice daily (BID) continuously plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) administered on days 1, 8, and 15 of each 28-day cycle. The primary objectives were to evaluate safety and tolerability, characterize dose-limiting toxicities (DLTs), and determine the recommended phase II dose (RP2D) of PF-04136309. Results In all, 21 patients received PF-04136309 at a starting dose of 500 mg or 750 mg BID. The RP2D was identified to be 500 mg BID. Of 17 patients treated at the 500 mg BID starting dose, three (17.6%) experienced a total of four DLTs, including grade 3 dysesthesia, diarrhea, and hypokalemia and one event of grade 4 hypoxia. Relative to the small number of patients (n = 21), a high incidence (24%) of pulmonary toxicity was observed in this study. The objective response rate for 21 patients was 23.8% (95% confidence interval: 8.2-47.2%). Levels of CD14 + CCR2+ inflammatory monocytes (IM) decreased in the peripheral blood, but did not accumulate in the bone marrow. Conclusions PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine. ClinicalTrials.gov identifier: NCT02732938.

Automatic trial eligibility surveillance based on unstructured clinical data.

INTRODUCTION: Insufficient patient enrollment in clinical trials remains a serious and costly problem and is often considered the most critical issue to solve for the clinical trials community. In this project, we assessed the feasibility of automatically detecting a patient's eligibility for a sample of breast cancer clinical trials by mapping coded clinical trial eligibility criteria to the corresponding clinical information automatically extracted from text in the EHR. METHODS: Three open breast cancer clinical trials were selected by oncologists. Their eligibility criteria were manually abstracted from trial descriptions using the OHDSI ATLAS web application. Patients enrolled or screened for these trials were selected as 'positive' or 'possible' cases. Other patients diagnosed with breast cancer were selected as 'negative' cases. A selection of the clinical data and all clinical notes of these 229 selected patients was extracted from the MUSC clinical data warehouse and stored in a database implementing the OMOP common data model. Eligibility criteria were extracted from clinical notes using either manually crafted pattern matching (regular expressions) or a new natural language processing (NLP) application. These extracted criteria were then compared with reference criteria from trial descriptions. This comparison was realized with three different versions of a new application: rule-based, cosine similarity-based, and machine learning-based. RESULTS: For eligibility criteria extraction from clinical notes, the machine learning-based NLP application allowed for the highest accuracy with a micro-averaged recall of 90.9% and precision of 89.7%. For trial eligibility determination, the highest accuracy was reached by the machine learning-based approach with a per-trial AUC between 75.5% and 89.8%. CONCLUSION: NLP can be used to extract eligibility criteria from EHR clinical notes and automatically discover patients possibly eligible for a clinical trial with good accuracy, which could be leveraged to reduce the workload of humans screening patients for trials.

Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2. METHODS: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed. RESULTS: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%). CONCLUSIONS: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial.

BACKGROUND: The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. METHODS: In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. FINDINGS: Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). INTERPRETATION: Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. FUNDING: Merck KGaA, and Pfizer Inc.

A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer.

BACKGROUND: This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors. OBJECTIVES: Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity. PATIENTS AND METHODS: Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D. RESULTS: The PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m2 was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations. CONCLUSIONS: Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies.

Comparison of Triple-Drug Transcatheter Arterial Chemoembolization (TACE) With Single-Drug TACE Using Doxorubicin-Eluting Beads: Long-Term Survival in 313 Patients.

OBJECTIVE: We compared survival outcomes in 313 patients with unresectable hepatocellular carcinoma (HCC) treated with two different transcatheter arterial chemoembolization (TACE) regimens: triple-drug TACE or single-drug TACE using drug-eluting beads. MATERIALS AND METHODS: In this retrospective study, patient selection criteria were uniform. The triple-drug group (n = 166) underwent TACE using ethiodized oil with doxorubicin, cisplatin, and mitomycin-C with a microsphere embolic. The single-drug group (n = 147) underwent TACE using doxorubicin-eluting beads. Group characteristics were classified and analyzed, and survival was calculated using standard statistical methods. All patients were followed until death. Those undergoing orthotopic liver transplant (OLT) were also followed. RESULTS: There were no significant differences between the two groups in terms of demographics, Child-Pugh class, or Okuda stage. With patients undergoing OLT censored (n = 73), the mean (± standard error) survival in the triple-drug group was 23.49 ± 2.38 months, and the median survival was 16.00 ± 1.51 months. Mean survival in the single-drug bead group was 28.16 ± 2.75 months, and the median survival was 15.00 ± 1.50 months (p = 0.168). With patients undergoing OLT censored, the mean and median survival for the total cohort were 26.25 ± 1.97 and 15.00 ± 1.08 months, respectively. In the entire cohort that did not undergo OLT, patients with Child-Pugh class A disease survived significantly longer than did patients with Child-Pugh class B disease. Elevated α-fetoprotein levels were associated with shorter survival, and patients undergoing TACE with drug-eluting beads had shorter hospital stays. Although a greater percentage annual survival was observed in patients undergoing drug-eluting bead TACE who had Child-Pugh class A, Okuda stage I, and Barcelona Clinic Liver Cancer classes A and B disease starting at 36 months, this suggested survival advantage did not reach statistical significance. CONCLUSION: We found no significant survival difference in patients with unresectable HCC treated with triple-drug TACE compared with single-drug TACE using doxorubicin-eluting beads.

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer.

BACKGROUND: Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC). METHODS: We generated autologous DCs from the peripheral blood of HLA-A2+ patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 107 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 µg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells. RESULTS: Twelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I -tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease. CONCLUSION: Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC. TRIAL REGISTRATION: NCT01410968 ; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).

A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors.

Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, a first-in-class orally available inhibitor of SK2.Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid, and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles.Results: Twenty-two patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting, and fatigue. Among the 4 patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and 2 were unable to complete cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the recommended phase II dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels.Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640. Clin Cancer Res; 23(16); 4642-50. ©2017 AACR.

Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study.

Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti-programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of any grade were fatigue/asthenia (31.8%), infusion-related reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1-positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.

Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.

Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m2 was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.

Racial Differences in Stage IV Colorectal Cancer Survival in Younger and Older Patients.

INTRODUCTION: African Americans (AAs) compared with European Americans (EAs) have poorer stage-specific survival from colorectal cancer (CRC). Recent reports have indicated that the racial difference in survival has worsened over time, especially among younger patients. To better characterize this association, we used population-based Surveillance, Epidemiology, and End Results registry data to evaluate the effect of race on stage IV CRC survival in patients aged < 50 and ≥ 50 years. PATIENTS AND METHODS: The population included 16,782 patients diagnosed with stage IV colon and rectal adenocarcinoma from January 1, 2004 and December 31, 2011. Cox proportional hazards regression was used to evaluate the association between race and other prognostic factors and the risk of death in each age group. RESULTS: Younger AAs compared with EAs had a greater prevalence of proximal CRC at diagnosis, a factor associated with a significantly greater risk of death in both races. Among patients < 50 years old, AAs had a greater risk of death compared with EAs (hazard ratio, 1.35; 95% confidence interval, 1.20-1.51), which was attenuated in patients ≥ 50 years of age (hazard ratio, 1.10; 95% confidence interval, 1.04-1.16); P for interaction = .01. CONCLUSION: The results revealed poor overall survival for AAs compared with EAs, especially for those < 50 years of age. The greater prevalence of proximal CRC at diagnosis among younger AAs (vs. EAs) might contribute to the racial difference in survival. Future studies are needed to understand how the colonic location affects the efficacy of treatment regimens.

Redox Signaling and Bioenergetics Influence Lung Cancer Cell Line Sensitivity to the Isoflavone ME-344.

ME-344 [(3R,4S)-3,4-bis(4-hydroxyphenyl)-8-methyl-3,4-dihydro-2H-chromen-7-ol] is a second-generation derivative natural product isoflavone presently under clinical development. ME-344 effects were compared in lung cancer cell lines that are either intrinsically sensitive or resistant to the drug and in primary immortalized human lung embryonic fibroblasts (IHLEF). Cytotoxicity at low micromolar concentrations occurred only in sensitive cell lines, causing redox stress, decreased mitochondrial ATP production, and subsequent disruption of mitochondrial function. In a dose-dependent manner the drug caused instantaneous and pronounced inhibition of oxygen consumption rates (OCR) in drug-sensitive cells (quantitatively significantly less in drug-resistant cells). This was consistent with targeting of mitochondria by ME-344, with specific effects on the respiratory chain (resistance correlated with higher glycolytic indexes). OCR inhibition did not occur in primary IHLEF. ME-344 increased extracellular acidification rates in drug-resistant cells (significantly less in drug-sensitive cells), implying that ME-344 targets mitochondrial proton pumps. Only in drug-sensitive cells did ME-344 dose-dependently increase the intracellular generation of reactive oxygen species and cause oxidation of total (mainly glutathione) and protein thiols and the concomitant immediate increases in NADPH levels. We conclude that ME-344 causes complex, redox-specific, and mitochondria-targeted effects in lung cancer cells, which differ in extent from normal cells, correlate with drug sensitivity, and provide indications of a beneficial in vitro therapeutic index.

A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors.

PURPOSE: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. EXPERIMENTAL DESIGN: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer. RESULTS: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. CONCLUSIONS: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity.

The effect of formulation and food consumption on the bioavailability of dovitinib (TKI258) in patients with advanced solid tumors.

PURPOSE: This 2-arm, phase 1, crossover study compared the relative bioavailability of two dovitinib (TKI258) capsule formulations [anhydrate clinical service form (CSF) and monohydrate final market image (FMI); Arm 1] and determined the effect of food on dovitinib exposure (Arm 2). METHODS: Patients with advanced solid tumors were enrolled in one of the 2 arms. Arm 1 randomized patients to a single 500-mg dose of either CSF or FMI followed by 7 days of rest and 500 mg of the other formulation. Arm 2 patients received 300 mg of FMI once daily and were randomized to follow one of six meal sequences, each with three prandial conditions: low fat (LF), high fat (HF), or no meal (NM). RESULTS: Twenty-three and 37 patients were enrolled and 19 and 21 were evaluable in Arms 1 and 2, respectively. In Arm 1, the adjusted geometric means for FMI had small reductions relative to CSF [area under the plasma concentration-time curve (AUClast) decreased by 12%, maximum concentration (C max) decreased by 3%]. In Arm 2, the HF meal versus NM showed a 2% increase in the adjusted geometric mean for AUClast and a 5% decrease for C max. The LF meal versus NM comparison showed 9 and 6% increases for AUClast and C max, respectively. Overall, common adverse events included nausea, vomiting, diarrhea, and fatigue. CONCLUSIONS: Systemic exposure to dovitinib was similar for the FMI and CSF capsule formulations. Additionally, since prandial conditions did not affect the systemic exposure, dovitinib can be taken with or without food.

Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity of the PI3K/mTOR inhibitor PF-04691502, administered orally once daily. METHODS: Escalating doses of PF-04691502 were administered to 23 patients with advanced solid tumors in sequential cohorts across the following dose levels: 2 mg, 4 mg, 8 mg, and 11 mg. 14 additional patients were enrolled in an expansion cohort at the MTD to ensure at least five matched pre- and post-treatment biopsies for biomarkers of PI3K activity. RESULTS: The MTD of PF-04691502 was 8 mg orally once daily. There were three dose-limiting toxicities: one grade 3 fatigue at 8 mg, one grade 3 rash at 11 mg, and one intolerable grade 2 fatigue at 11 mg. Among 37 patients enrolled, treatment-related adverse events included fatigue, decreased appetite, nausea, hyperglycemia, rash, and vomiting. Across all dose levels, average steady-state plasma PF-04691502 concentrations approximated or exceeded the target concentration of 16.2 ng/mL required for ≥75 % tumor growth inhibition in preclinical models. PF-04691502 resulted in increased mean fasting serum glucose, insulin, and c-peptide levels, and produced partial blockade of PI3K signalling in five paired tumor biopsies, as demonstrated by reductions in phosphorylated Akt, FKHR/FKHRL1, and STAT3. No objective anti-tumor responses were observed. CONCLUSIONS: Daily oral administration of PF-04691502 was tolerable at 8 mg orally once daily, with a safety profile similar to other PI3K/mTOR inhibitors. PF-04691502 demonstrated PI3K pathway inhibition by changing glucose homeostasis, and by decreasing phosphorylation of downstream molecules in tumor tissue.

A phase 1, open-label, dose-escalation study of BIIB022 (anti-IGF-1R monoclonal antibody) in subjects with relapsed or refractory solid tumors.

PURPOSE: The IGF-1R signaling pathway has been implicated in multiple cancers as important for cell survival, proliferation, invasion and metastasis. BIIB022 is a non-glycosylated human IgG4 monoclonal antibody (mAb) with specificity for IGF-1R. Unlike other anti-IGF1R antibodies, BIIB022 has no effector functions. Additionally, inhibition is via an allosteric rather than competitive mechanism, which further differentiates this antibody from others. We sought to determine the safety and tolerability of BIIB022 and determine the pharmacokinetic (PK) and pharmacodynamic (PD) profile of this antibody. METHODS: A multi-institutional phase I study evaluated the safety of escalating doses of BIIB022 given IV q3wk until progression or unacceptable toxicity in patients with advanced solid tumors. Five sequential BIIB022 dose cohorts were evaluated using a standard 3 + 3 dose-escalation design (1.5, 5. 10, 20, 30 mg/kg); 10 additional patients were treated at the recommended phase 2 dose. RESULTS: 34 patients were treated. Toxicities were manageable and mostly low grade; grade 3-4 hyperglycemia was not observed. No RECIST responses were observed, although three patients had metabolic responses associated with prolonged stable disease. The PK of BIIB022 was nearly linear in the dose range from 10 to 30 mg/kg, with some nonlinearity at lower doses (1.5-5.0 mg/kg), likely due to target-mediated drug disposition of BIIB022 at low serum concentrations. PD analyses showed decrease in IGF-1R levels on leucocytes, with stable serum values of IGF-1 and IGF-2. CONCLUSIONS: BIIB022 can be safely given at 30 mg/kg IV every 3 weeks with preliminary evidence of biological activity in selected patients.