Wael A. Harb

PRECEDENT: A Randomized Phase II Trial Comparing Vintafolide (EC145) and Pegylated Liposomal Doxorubicin (PLD) in Combination Versus PLD Alone in Patients With Platinum-Resistant Ovarian Cancer

PURPOSE Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined. PATIENTS AND METHODS Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups. RESULTS The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806). CONCLUSION Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.

CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma

Carfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m(2) [cycle 1, days 1-2]; 27 mg/m(2) thereafter). This multicenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IV infusion) on days 1, 8, and 15 of 28-day cycles. The phase 1 portion used a 3 + 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at the MTD. Patients received dexamethasone (40 mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 9+. A total of 116 patients were enrolled. The MTD was 70 mg/m(2), and 104 patients (phase 1/2) received carfilzomib 70 mg/m(2) At 70 mg/m(2), the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m(2), the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m(2) was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials.gov as #NCT01677858.

Multicenter Trial of EC145 in Advanced, Folate-Receptor Positive Adenocarcinoma of the Lung

Background: EC145 is a novel folate-receptor targeted agent consisting of a folate molecule linked to a vinca alkaloid. EC20 is a technetium-labeled folate that assesses the presence of folate receptors (FR) in vivo. The objective of this study was to determine the activity of EC145 in patients with chemotherapy refractory lung adenocarcinoma, whose tumors expressed the FR as determined by EC20 imaging. Methods: Patients with advanced adenocarcinoma of the lung, Eastern Cooperative Oncology Group performance status 0 to 2, normal organ function, those who had progressed after at least two prior cytotoxic regimens, and with EC 20 uptake in at least one index lesion were eligible. The primary objective of the study was the ability to receive four or more cycles of therapy. Results: Sixty patients were screened and 43 patients were enrolled. Eleven patients (26%) received more than four cycles (95% confidence interval [CI] 14%, 41%), and one patient had partial response (response rate (RR) = 2.3%, 95% CI 0%, 12%). Patients in whom all target tumor lesions expressed FR by EC 20 scans had a trend toward superior results in terms of clinical benefit response (50% versus 14.3 %; p = 0.10) and survival (47.2 weeks versus 14.9 weeks [HR = 0.539, p = 0.101]) compared with those in whom at least one but not all target lesions were positive for FR (FR+). Conclusion: EC145 demonstrated clinical activity with a good toxicity profile in this population. Uniform uptake of EC20 may predict activity of EC145 and be useful for prospective selection of patients in future trials.

Randomized, double-blinded, multicenter, phase II study of pemetrexed, carboplatin, and Bevacizumab with enzastaurin or placebo in chemonaïve patients with stage IIIB/IV non-small cell lung cancer: Hoosier oncology group LUN06-116

Introduction: Bevacizumab is approved in combination with chemotherapy as first-line treatment for non-small cell lung cancer (NSCLC). Preclinical data suggest that enzastaurin and bevacizumab may have complementary effects in inhibiting angiogenesis. Methods: Eligibility criteria: ≥18 years of age, chemonaïve, stage IIIB/IV nonsquamous NSCLC, and Eastern Cooperative Oncology Group performance status 0 to 1. Patients were randomized to placebo or enzastaurin 500 mg orally daily (after a loading dose), plus pemetrexed 500 mg/m2, carboplatin area under the curve 6, and bevacizumab 15 mg/kg, intravenously, every 21 days for four cycles. Patients without progression received maintenance therapy with bevacizumab and placebo or enzastaurin. The primary objective was progression-free survival (PFS). Planned sample size was 90 patients, one-sided alpha of 0.20, with two interim analyses: one for safety and the second for futility, with a PFS hazard ratio of 0.8857. Results: Forty patients were randomized. No unique safety concerns were noted at the first interim analysis. The early stopping rule for futility was met at the second interim analysis. Median PFS was 3.5 months and 4.3 months (hazard ratio: 1.04, 95% confidence interval: 0.49–2.21), and response rates were 20% and 30% (p = 0.462) for enzastaurin and placebo, respectively. Grade 3 or 4 toxicity was similar between the two arms. Two patients died on study because of respiratory arrest and pulmonary embolism. An additional patient died of sepsis secondary to a gastrointestinal perforation >30 days after study treatment discontinuation. Conclusions: Enzastaurin does not improve efficacy when combined with pemetrexed, carboplatin, and bevacizumab. This combination does not warrant further study in NSCLC.

Characterization of patients who received prior chemotherapy for advanced breast cancer (ABC) in BOLERO-2.

151 Background: In patients with hormone receptor-positive (HR+) breast cancer, endocrine therapy is the standard of care both in the adjuvant setting and as front-line therapy for ABC. Chemotherapy (CT) is commonly used for HR+ ABC patients if disease burden is high and rapid symptom control is required (Barrios CH. GAMO. 2010). In the phase III BOLERO-2 study (NCT00863655), first-line of prior CT in the ABC setting was allowed. This subset analysis examined disease characteristics and the efficacy of everolimus (EVE) + exemestane (EXE) in patients who received CT for ABC prior to BOLERO-2 study entry. METHODS In BOLERO-2, 724 patients with HR+, human epidermal growth factor receptor 2-negative (HER2-) ABC whose disease recurred or progressed during/after a nonsteroidal aromatase inhibitor were randomized 2:1 to EVE (10 mg/d) + EXE (25 mg/d) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local investigator review (confirmed by blinded independent central review). RESULTS A total of 186 patients (26%) received prior CT for ABC (125 in the EVE + EXE group and 61 in PBO + EXE). In this subset, 54% (67 of 125) of EVE+ EXE patients received prior CT in the advanced setting only while 46% (58 of 125) of EVE + EXE patients received prior CT in both the neoadjuvant/adjuvant and advanced settings. Visceral metastases (67% vs. 56%), multiple metastases (79% vs. 66%), and ≥ 4 metastatic sites (18% vs. 15%) were more frequent in ABC patients with prior CT for ABC at study entry compared with those with no prior CT for ABC. History of disease recurrence <6 months from initial diagnosis was recorded in 32% (n = 60) of prior CT patients versus 17% (n = 93) of patients with no prior CT. Median PFS (by local assessment) in patients who received prior CT for ABC was substantially longer with EVE + EXE versus PBO + EXE (6.1 vs. 2.7 mo; hazard ratio = 0.38; 95% CI, 0.27-0.53). PFS by central review showed similar results (7.1 vs. 2.8 mo, respectively; hazard ratio = 0.42; 95% CI, 0.27-0.65). CONCLUSIONS These results demonstrate that patients with HR+, HER2 ABC who received previous CT in the advanced setting had a higher tumor burden but derived significant and clinically meaningful benefit from combination therapy with EVE + EXE. CLINICAL TRIAL INFORMATION NCT00863655.

Abstract B53: Multicenter phase Ib study of the safety and efficacy of palifosfamide plus carboplatin/etoposide (PaCE) in patients with small cell lung cancer or other selected cancers.

Palifosfamide (Pa) is a novel DNA cross linker molecule that consists of the active anti-tumor metabolite of ifosfamide (I). Potential advantages over I include the abrogation of I-metabolite related toxicities, increased activity by virtue of increased dose delivery over time, and overcoming resistance mediated by aldehyde dehydrogenase (ALDH) overexpression. ALDH overexpression is associated with cancer cell stem-like potential in several tumor types. Pa has broad activity in vitro and in vivo preclinical models and has shown early activity in humans. A previous randomized study evaluating the addition of I to cisplatin and etoposide (E) in small cell lung cancer (SCLC) demonstrated improved survival, but with disabling increase in toxicity with the three-drug combination. We hypothesized that the substitution of Pa for I could increase the therapeutic advantage of a similar three-drug regimen. We initiated a multicenter phase I, open-label, dose-escalation study assessing the safety and efficacy of Pa in combination with carboplatin and E (PaCE regimen) in SCLC and in other cancers in which C+E is considered an appropriate therapeutic option. Tumor responses were assessed by RECIST 1.1 and relevant tumor markers. A total of 15 patients (8 females and 7 males) have been treated to date: 5 with SCLC, 2 with NSCLC, 2 with ovarian, 1 with testicular and 5 with other cancers. Serious adverse events have been reported in six patients, including, thrombocytopenia (4), leukopenia (2), and neutropenia (2). The maximum tolerated dose of Pa was determined to be 130 mg/m2 when administered in combination with E 90 mg/m2 and C AUC4. The dose limiting toxicity was neutropenic fever. To date, two radiological partial responses in five patients with SCLC and one complete response assessed by tumor markers in a patient with testicular cancer have been noted. Conclusion: This study is ongoing, and an additional cohort evaluating Pa 130 mg/m2 in combination with E 100 mg/m2 and C AUC 4 is being evaluated. Further clinical data will be presented. The PaCE combination appears to be tolerable and has demonstrated clinical activity. Based on these data, a confirmatory study in SCLC is planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B53.

Abstract C27: Targeting ErbB3 and EGFR in lung cancer patients: A phase I trial of MM-121 in combination with erlotinib in patients with non-small cell lung cancer (NSCLC).

Background: The benefit of EGFR tyrosine kinase inhibitors (TKIs) is largely restricted to EGFR mutation-positive cancers and resistance invariably develops. A central theme of acquired resistance is persistent ErbB3 signaling, resulting in activation of the PI3K/AKT survival pathway. MM-121 is a fully human IgG1 monoclonal antibody (mAb) to ErbB3 with pre-clinical activity as a single agent and in combination with erlotinib in NSCLC, particularly in cancers with ligand-dependent activation of EGFR. This phase 1 study evaluated the safety and tolerability of MM-121 and erlotinib in NSCLC, as well as PK, immunogenicity, efficacy endpoints and exploratory biomarker evaluation. Methods: Patients with advanced NSCLC, good performance status and adequate organ function were enrolled. Patients were EGFR TKI-naive, unless they were EGFR mutant, in which case acquired resistance was allowed. MM-121 was administered weekly and erlotinib was administered daily. Seven cohorts were enrolled, evaluating varying dose levels of the combination, as well as alternate MM-121 infusion schedules. Dose levels were determined by safety and pharmacokinetic (PK) data. Results: Between February 2010 and July 2011, 33 patients were enrolled. Median age was 64 years and there were 19 (57.5%) women. Twenty-four patients were erlotinib-naive and 1 patient was an EGFR mutant. The most frequent adverse events were rash, diarrhea, nausea and fatigue. As of 31 July 2001, 16 patients remain on study. Full results will be presented at the meeting. Conclusions: In this phase 1 dose escalation study, MM-121 plus erlotinib was well tolerated by the majority of patients. A phase 2 study is planned. Reference:NCT00994123 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C27.