Multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine in patients with post-resection melanoma at high risk of recurrence.

BACKGROUND: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. METHODS: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. RESULTS: For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). CONCLUSIONS: Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. TRIAL REGISTRATION NUMBER: NCT01546571.

A phase 2 safety study of accelerated elotuzumab infusion, over less than 1 h, in combination with lenalidomide and dexamethasone, in patients with multiple myeloma.

Elotuzumab, an immunostimulatory SLAMF7-targeting monoclonal antibody, induces myeloma cell death with minimal effects on normal tissue. In a previous phase 3 study in patients with relapsed/refractory multiple myeloma (RRMM), elotuzumab (10 mg/kg, ∼3-h infusion), combined with lenalidomide and dexamethasone, demonstrated durable efficacy and acceptable safety; 10% (33/321) of patients had infusion reactions (IRs; Grade 1/2: 29; Grade 3: 4). This phase 2 study (NCT02159365) investigated an accelerated infusion schedule in 70 patients with newly diagnosed multiple myeloma or RRMM. The primary endpoint was cumulative incidence of Grade 3/4 IRs by completion of treatment Cycle 2. Dosing comprised elotuzumab 10 mg/kg intravenously (weekly, Cycles 1-2; biweekly, Cycles 3+), lenalidomide 25 mg (daily, Days 1-21), and dexamethasone (28 mg orally and 8 mg intravenously, weekly, Cycles 1-2; 40 mg orally, weekly, Cycles 3+), in 28-day cycles. Premedication with diphenhydramine, acetaminophen, and ranitidine (or their equivalents) was given as in previous studies. If no IRs occurred, infusion rate was increased in Cycle 1 from 0.5 to 2 mL/min during dose 1 (∼2 h 50 min duration) to 5 mL/min for the entire infusion by dose 3 and also during all subsequent infusions (∼1-h duration). Median number of treatment cycles was six. No Grade 3/4 IRs occurred; only one Grade 1 and one Grade 2 IR occurred, both during the first infusion. These data support the safety of a faster infusion of elotuzumab administered over ∼1 h by the third dose, providing a more convenient alternative dosing option for patients.

Phase II multicenter study of docetaxel and bevacizumab with or without trastuzumab as first-line treatment for patients with metastatic breast cancer.

BACKGROUND: Adding bevacizumab to docetaxel or paclitaxel in the first-line improves the progression-free survival (PFS) of metastatic breast cancer (MBC) patients. Docetaxel has been studied with bevacizumab at the maximally tolerated dose of 100 mg/m(2). We investigated the effects of combining bevacizumab with docetaxel (75 mg/m(2)) with or without trastuzumab for human epidermal growth factor receptor 2-positive (HER2(+)) and HER2-negative (HER2(-)) patients, respectively. PATIENTS AND METHODS: We conducted a phase II study, stratified by HER2 status, of patients with locally advanced breast cancer or MBC who had received no prior chemotherapy for metastatic disease and showed no evidence or history of central nervous system metastases. Stratum 1 (HER2(-)) treatment consisted of bevacizumab (15 mg/kg) followed by docetaxel (75 mg/m(2)) administered every 3 weeks; stratum 2 (HER2(+)) treatment was the same as that of stratum 1 with the addition of trastuzumab (8 mg/kg loading dose on day 2 of cycle 1, and 6 mg/kg on day 1 of all subsequent cycles). RESULTS: The trial accrued 73 patients (stratum 1, 52 patients; stratum 2, 21 patients). The most common grade 3 or 4 adverse event (all strata) was fatigue (stratum 1, 11.5%; stratum 2, 10%). The incidence of grade 3 hypertension was 6% for stratum 1 and 5% for stratum 2. The median PFS was 8.4 months (95% CI, 5.2-10.4 months) in stratum 1; the median PFS in stratum 2 was 13.3 months (95% CI, 11.9-35.4 months). The overall response rate for stratum 1was 58% and for stratum 2 was 81%, and the clinical benefit rates were 67% and 81%, respectively. CONCLUSION: In first-line treatment of MBC, adding docetaxel (75 mg/m(2)) to bevacizumab administered every 3 weeks in HER2(-) patients, and docetaxel plus trastuzumab plus bevacizumab treatment in HER2(+) patients are feasible and safe, with high response rates and promising PFS compared with those of bevacizumab-naive historic controls.

Phase II study of lapatinib in combination with vinorelbine, as first or second-line therapy in women with HER2 overexpressing metastatic breast cancer.

BACKGROUND: Lapatinib in combination with capecitabine is approved for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal growth factor receptor 2 (HER2) and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Based on our phase I trial, we conducted a single arm, multicenter phase II study of lapatinib in combination with vinorelbine. PATIENT AND METHODS: Women with HER2-positive advanced breast cancer, who had received up to one prior regimen for metastatic disease, were eligible. Prior trastuzumab was allowed. Patients received daily lapatinib 1500 mg orally and vinorelbine 20 mg/m(2) intravenously on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall response rate (ORR). RESULTS: Forty-four patients received the combination treatment, including 48% as second-line therapy. The ORR was 41% (95% confidence interval [CI] 26-55%), including 9% with a complete response. Median progression-free survival was 24.1 weeks (95% CI 17-37 weeks) and median duration of response was 32 weeks (95% CI 18-42 weeks). Nearly 80% of patients did not require a dose reduction in lapatinib, although most patients required one dose reduction of vinorelbine secondary to neutropenia. The most common toxicities were grade 1 and 2 diarrhea, nausea, fatigue and rash, and grade 3 and 4 neutropenia. One case of grade 3 asymptomatic decreased left ventricular ejection fraction event was reported. CONCLUSION: The combination of lapatinib and vinorelbine was active, feasible and well tolerated in patients with HER2-positive advanced breast cancer.

Addition of bevacizumab to three docetaxel regimens as adjuvant therapy for early stage breast cancer.

Docetaxel-containing chemotherapy improves disease-free survival (DFS) and overall survival in patients with early stage breast cancer. Bevacizumab improves response rate and DFS in metastatic breast cancer. However, adding antivascular endothelial growth factor therapy to anthracycline-containing chemotherapy may increase cardiotoxicity. This trial evaluates the feasibility of adding bevacizumab to three standard adjuvant docetaxel regimens with a primary endpoint of grade ≥3 congestive heart failure (CHF). Phase IIb, randomized, non-comparative study of women with previously untreated node-positive or high-risk node-negative breast cancer. Human epidermal growth factor receptor 2 (HER2)-negative patients were randomized to: (arm A) doxorubicin + cyclophosphamide followed by docetaxel or (arm B) docetaxel + doxorubicin + cyclophosphamide. HER2-positive patients (arm C) received docetaxel + carboplatin + trastuzumab for 52 weeks. All patients received bevacizumab beginning on day 1 for 52 weeks. Safety data in 212 women (mean age = 53.1 years) show that 1 patient each in arm A (1.3 %) and arm C (1.7 %), and 3 patients in arm B (4.0 %) experienced clinical CHF grade ≥3. A decreased ejection fraction was observed in 1 patient each in arms A and C, and cardiac disorder was observed in 12.8, 22.7, and 8.5 % in arms A, B, and C, respectively. A grade 3/4 treatment-emergent adverse event was reported in 82.1, 84.0, and 52.5 % of participants in arms A, B, and C, respectively. Kaplan-Meier estimates of DFS show rates at 24 months of 85.5, 90.4, and 90.4 % in arms A, B, and C, respectively. Adding bevacizumab to three standard docetaxel-based chemotherapy regimens as adjuvant treatment in patients with node-positive and high-risk node-negative breast cancer resulted in a low rate of clinical CHF grade ≥3. Maintenance bevacizumab monotherapy did not identify any new safety signals. Breast cancer recurrence/relapse, secondary malignancies, and death were uncommon, although the follow-up time in this study was relatively short.

Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs. FOLFOX-bevacizumab in colorectal cancer.

BACKGROUND: Cetuximab (C), alone or with irinotecan, demonstrates activity in irinotecan-refractory colorectal cancer (CRC). Activity of 5-fluorouracil (5-FU), leucovorin (L), and bevacizumab (B), and preliminary data of cetuximab + bevacizumab, and toxicity profiles suggests that FOLF-CB (5-FU, L, C+B) may have activity with a favorable toxicity profile as first-line therapy. METHODS: Eligible patients were randomized at registration to either arm A (mFOLFOX6-B) (modified, 5-FU. L (folinic acid), oxaliplatin (O) + bevacizumab), administered days 1 and 15 of each 28-day cycle as bevacizumab 5 mg/kg, oxaliplatin 85 mg/m(2), leucovorin 400 mg/m(2), and 5-FU 400 mg/m(2) then 1200 mg/m(2)/day for 48 hours, or arm B (FOLF-CB), which included bevacizumab, leucovorin, and 5-FU as in arm A and cetuximab 400 mg/m(2) day 1 cycle 1; all other weekly cetuximab doses were 250 mg/m(2). RESULTS: Two hundred forty-seven patients (arm A/arm B 124/123) were enrolled, and 239 were treated (118/121). Twelve-month progression-free survival (PFS) was 45%/32%, objective response rates (ORR) (complete response [CR] + partial response [PR]) were 52%/41%, disease control rates (CR+PR+stable disease [SD]) were 87%/83%, and median overall survival (OS) was 21/19.5 months, respectively. Grade 3-4 neutropenia was higher in arm A (28%/7%), as was grade 3 fatigue (12%/3%), and grade 3 neuropathy (11%/< 1%), whereas acneiform rash was confined to arm B. Retrospective analysis of KRAS mutational status did not demonstrate KRAS as a meaningful determinant of activity, except in arm B patients with KRAS-mutated tumors, which resulted in inferior PFS. Patient satisfaction favored the control (mFOLFOX6-B). CONCLUSION: FOLF-CB was not superior to mFOLFOX6-B in terms of 12-month PFS and ORR, and was not more acceptable to patients. This trial supports the conclusion of other recently reported trials that concurrent cetuximab+bevacizumab should not be routinely used in metastatic CRC.

A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer.

INTRODUCTION: This phase II trial evaluated the efficacy and safety of cetuximab combined with FOLFOX6 (leucovorin [LV] 5-fluorouracil [5-FU]/oxaliplatin) in the first-line treatment of patients with advanced or metastatic colorectal cancer. PATIENTS AND METHODS: Patients with locally advanced or metastatic CRC who had received no previous therapy for advanced disease were treated with cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly and a FOLFOX6 regimen every 2 weeks consisting of oxaliplatin 85 mg/m2, LV 400 mg/m2, and 5-FU bolus 400 mg/m2 followed by 5-FU continuous infusion 2400 mg/m2 over 46 hours. RESULTS: A total of 82 eligible patients were enrolled; epidermal growth factor receptor expression was positive in 67 patients. The overall response rate was 44.8%. In addition, 30 patients (44.8%) in the evaluable population experienced stable disease. Median time to progression or death was 9.3 months (95% CI, 7.0-11.3 months), and median survival was 21.7 months (95% CI, 17.5-27.8 months). Patients who experienced skin toxicity had a statistically significant and longer median survival time than those patients with no skin toxicity (P = .0001). The most commonly observed toxicities were neutropenia (65%), fatigue (56.3%), diarrhea (53.8%), nausea (50%), acneiform rash (41.3%), and stomatitis (35%). CONCLUSION: Our results demonstrate that cetuximab can be safely combined with FOLFOX6 for the first-line treatment of patients with metastatic CRC (mCRC). The efficacy parameters are similar to other first-line regimens in mCRC. Because of the emergence of KRAS as a predictive marker, this regimen has promise in KRAS wild-type mCRC.