Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with Carboplatin, Paclitaxel, and Bevacizumab for First-Line Nonsquamous Non-Small Cell Lung Cancer.

LESSONS LEARNED: The lack of efficacy associated with anti-EGFL7 combined with standard bevacizumab and chemotherapy in this phase II trial in non-small cell lung carcinoma is consistent with the lack of benefit observed in colorectal carcinoma, highlighting the challenge of enhancing the efficacy of VEGF inhibition in unselected populations.Future efforts with agents like anti-EGFL7 should be guided by advances in pharmacodynamic and predictive biomarker development for antiangiogenic agents. BACKGROUND: Epidermal growth factor-like domain 7 (EGFL7) is an extracellular matrix-associated protein that is upregulated during angiogenesis and supports endothelial cell survival. This phase II trial evaluated the efficacy of the anti-EGFL7 antibody, parsatuzumab, in combination with bevacizumab plus platinum-based therapy for advanced or recurrent nonsquamous non-small cell lung cancer (NS-NSCLC). METHODS: Patients (n = 104) were randomized to either placebo or parsatuzumab (600 mg) in combination with bevacizumab (15 mg/kg) and carboplatin/paclitaxel, administered on day 1 of each 21-day cycle. Carboplatin and paclitaxel were administered for up to six cycles. Bevacizumab and parsatuzumab/placebo were administered for a maximum of 24 months. RESULTS: The progression-free survival (PFS) hazard ratio (HR) was 1.7 (95% confidence interval [CI], 1.0-2.8; p = .047). The median PFS was 6.7 months for the parsatuzumab arm versus 8.1 months for the placebo arm. The hazard ratio for overall survival (OS) was 1.1 (95% CI, 0.5-2.2; p = .847). The objective response rate (ORR) was 29% in the parsatuzumab arm and 56% in the placebo arm. Overall safety and tolerability were consistent with the established toxicity profile of bevacizumab. CONCLUSION: There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line NS-NSCLC.

Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.

BACKGROUND: Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS: The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS: The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).

Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.

BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).

Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer.

BACKGROUND: A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy. METHODS: We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival. RESULTS: With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group. CONCLUSIONS: Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].).

Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia.

PURPOSE: A randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies. PATIENTS AND METHODS: Patients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety. RESULTS: The long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases. CONCLUSION: IDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.

Treatment rationale and study design for a randomized, double-blind, placebo-controlled phase II study evaluating onartuzumab (MetMAb) in combination with bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal cancer.

BACKGROUND: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway is associated with poor prognosis, more aggressive biological characteristics of the tumor, and shortened survival in patients with metastatic colorectal cancer (mCRC). Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody directed against MET. We present the treatment rationale and protocol for an ongoing randomized multicenter placebo-controlled phase II study designed to evaluate the efficacy and safety of MetMAb combined with bevacizumab and mFOLFOX-6 (5-fluoruracil, leucovorin, and oxaliplatin). PATIENTS AND METHODS: Eligible patients with previously untreated mCRC are randomized 1:1 to either mFOLFOX-6 combined with bevacizumab and placebo followed by 5-fluorouracil/leucovorin plus bevacizumab and placebo or mFOLFOX6, bevacizumab plus MetMAb followed by 5 FU/LV, bevacizumab, and MetMAb. The primary end point of this study is progression-free survival (PFS) in the intent-to-treat (ITT) population. Secondary end points include overall survival (OS), objective response rate, and safety. Subanalyses will be performed to evaluate the effect of MET receptor expression on study primary and secondary end points. Correlative studies will be performed on tissue- and blood-derived biomarkers related to both HGF/MET signaling and other associated pathway markers.

Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer.

PURPOSE: Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) -targeted drugs in patients with non-small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC. PATIENTS AND METHODS: Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety. RESULTS: There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients. CONCLUSION: Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.

A randomized phase II trial of pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab in the first-line treatment of elderly patients with advanced non-small cell lung cancer.

PURPOSE: To assess time to progression (TTP) in elderly patients with previously untreated nonsquamous non-small cell lung cancer treated with pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab. METHODS: Eligible patients were aged 70 years or older with newly diagnosed stage IIIB/IV nonsquamous non-small cell lung cancer; Eastern Cooperative Oncology Group performance status 0 to 1; adequate organ function; and no active central nervous system metastasis. Patients were randomized 1:1 to cohort A (pemetrexed 500 mg/m2 IV, gemcitabine 1500 mg/m2 IV, and bevacizumab 10 mg/kg IV; days 1 and 15 of 28-day cycles) or cohort B (pemetrexed 500 mg/m2 IV, carboplatin area under the concentration-time curve =5 IV, and bevacizumab 15 mg/kg IV; day 1 of 21-day cycles). After six cycles, stable/responding patients continued bevacizumab until disease progression. RESULTS: Between March 2007 and December 2009, 110 patients (median age, 76 years; 88% stage IV) were treated for medians of 2.5 cycles (cohort A) and 6 cycles (cohort B). Overall response rate was 35% in both cohorts, with stable disease rates of 33% (A) and 45% (B). TTP by cohort was 4.7 and 10.2 months with median OS 7.5 and 14.8 months, respectively. Severe toxicities included the following: neutropenia (A, 51% and B, 45%), fatigue (A, 36% and B, 18%), anemia (A, 22% and B, 7%), infection (A, 25% and B, 7%), thrombocytopenia (A, 11% and B, 31%), and thromboembolism (A, 7% and B, 7%). Three potential treatment-related deaths occurred in cohort A (sepsis, thrombocytopenia, and myocardial infarction) and two in B (sepsis and pulmonary hemorrhage). CONCLUSIONS: Treatment with pemetrexed/carboplatin/bevacizumab was associated with improved TTP and OS in this elderly population and should be further evaluated. Treatment-related toxicities were expected and usually manageable, although deaths occurred with both regimens.

Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme.

BACKGROUND: The current study was conducted to evaluate the efficacy of sorafenib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, when added to standard radiotherapy and temozolomide in the first-line treatment of patients with glioblastoma multiforme. METHODS: After initial surgical resection or biopsy, patients with newly diagnosed glioblastoma multiforme received concurrent radiotherapy (2.0 grays [Gy]/day; total dose, 60 Gy) and temozolomide (at a dose of 75 mg/m2 orally daily), followed by 6 months of maintenance therapy with temozolomide (at a dose of 150 mg/m2 orally on Days 1-5 every 28 days) and sorafenib (at a dose of 400 mg orally twice daily). Patients were re-evaluated every 2 months; the primary endpoint of the trial was progression-free survival (PFS). RESULTS: A total of 47 patients were treated; 34 had undergone previous debulking surgery. Nineteen patients withdrew from treatment before the initiation of maintenance therapy with temozolomide and sorafenib (12 because of early tumor progression). Twenty-eight patients (60% of enrolled patients) received 4 months of maintenance therapy with temozolomide and sorafenib, and 9 patients (19%) completed the planned 6 months of maintenance therapy. The median PFS for the entire group was 6 months (95% confidence interval [95% CI], 3.7-7 months), with a 1-year PFS rate of 16%. The median overall survival was 12 months (95%CI, 7.2-16 months). Maintenance therapy with temozolomide and sorafenib was found to be well tolerated by most patients, with no grade 3/4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) reported to occur in >10% of patients. CONCLUSIONS: The addition of sorafenib did not appear to improve the efficacy of treatment when compared with the results expected with standard therapy. A substantial percentage of patients (40%) did not receive any maintenance sorafenib, most often because of early disease progression. The administration of angiogenesis inhibitors concurrently with radiotherapy and temozolomide may optimize the opportunity to improve therapy.