Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas. METHODS: We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517. FINDINGS: Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group. INTERPRETATION: The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas. FUNDING: Sanofi.

Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. FINDINGS: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. INTERPRETATION: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. FUNDING: Bristol-Myers Squibb.

A phase 2 randomized clinical trial of abiraterone plus ADT, apalutamide, or abiraterone and apalutamide in patients with advanced prostate cancer with non-castrate testosterone levels (LACOG 0415).

BACKGROUND: Androgen deprivation therapy (ADT) combined with apalutamide, abiraterone acetate plus prednisone, enzalutamide, or docetaxel are the standard treatments for advanced castration-sensitive prostate cancer (CSPC). We investigated ADT-free alternatives for advanced CSPC. PATIENTS AND METHODS: LACOG 0415 is a phase 2, open-label, non-comparative, randomized trial. Patients with advanced CSPC were randomized (1:1:1) to receive goserelin plus abiraterone acetate and prednisone (ADT plus AAP arm), apalutamide (APA arm), or apalutamide plus abiraterone acetate and prednisone (APA plus AAP arm). The primary endpoint was the proportion of patients with PSA of ≤0.2 ng/mL at week 25 in the modified intention-to-treat population. Safety analyses were performed in all patients with at least one dose of the study drug. RESULTS: Of 128 randomized patients, 120 patients were evaluable for PSA response at week 25; 17.2% had a high-risk biochemical recurrence, 8.6% had locally advanced disease, and 74.2% had distant metastases. At week 25, PSA of ≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%-87.6%), 60.0% (95%CI 43.3%-75.1%), and 79.5% (95%CI 63.5%-90.7%) of patients in ADT plus AAP, APA, and APA plus AAP arms, respectively. PSA decline of ≥80% was observed in 100%, 90.0%, and 97.4%, respectively. Grade 3-4 AEs were observed in 31.0%, 21.4% and 36.4%, respectively. Testosterone levels increased significantly in the APA arm and decreased significantly in ADT plus AAP and APA plus AAP arms. CONCLUSIONS: ADT-free alternatives provide a high PSA response in advanced CSPC, although the APA arm did not reach the expected rate of PSA of ≤0.2 ng/mL at week 25. These results warrant further investigation of ADT-free treatments as alternatives in advanced CSPC. SOURCE STUDY REGISTRATION: ClinicalTrials.govNCT02867020.

Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors.

BACKGROUND: The phase 3 trial CA184-043 evaluated radiotherapy to bone metastases followed by Ipilimumab or placebo in men with metastatic castrate-resistant prostate cancer (mCRPC) who had received docetaxel previously. In a prior analysis, the trial's primary endpoint (overall survival [OS]) was not improved significantly. OBJECTIVE: To report the final analysis of OS. DESIGN, SETTING, AND PARTICIPANTS: A total of 799 patients were randomized to receive a single dose of radiotherapy to one or more bone metastases followed by either Ipilimumab (n = 399) or placebo (n = 400). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was analyzed in the intention-to-treat population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed. RESULTS AND LIMITATIONS: During an additional follow-up of approximately 2.4 yr since the primary analysis, 721/799 patients have died. Survival analysis showed crossing of the curves at 7-8 mo, followed by persistent separation of the curves beyond that point, favoring the ipilimumab arm. Given the lack of proportional hazards, a piecewise hazard model showed that the hazard ratio (HR) changed over time: the HR was 1.49 (95% confidence interval 1.12, 1.99) for 0-5 mo, 0.66 (0.51, 0.86) for 5-12 mo, and 0.66 (0.52, 0.84) beyond 12 mo. OS rates were higher in the ipilimumab versus placebo arms at 2 yr (25.2% vs 16.6%), 3 yr (15.3% vs 7.9%), 4 yr (10.1% vs 3.3%), and 5 yr (7.9% vs. 2.7%). Disease progression was the most frequent cause of death in both arms. In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long-term safety signals were identified. CONCLUSIONS: In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher in the ipilimumab arm. PATIENT SUMMARY: After longer follow-up, survival favored the group of men who received ipilimumab, with overall survival rates being two to three times higher at 3 yr and beyond.

Evaluation of quality of life in patients with metastatic colorectal cancer treated with capecitabine.

PURPOSE: This study evaluated the effects of oral capecitabine on the quality of life (QOL) of Brazilian patients with metastatic colorectal cancer who received capecitabine (1000 or 1250 mg/m2 twice a day on days 1-14, every 3 weeks) in a prospective, multicenter, open-label, noncomparative study. PATIENTS AND METHODS: Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires before cycle 1, at weeks 7 and 13, and at the end of treatment. In total, 1437 patients (mean age, 59.6 years [+/- 13.5 years]) were enrolled. RESULTS: In women, statistically significant improvements were observed in 6 QLQ-C30 and 6 QLQ-CR38 domains (QLQ-C30: emotional function, nausea/ vomiting, pain, constipation, financial problems, and body image; QLQ-CR38: future perspective, micturition problems, defecation problems, stoma-related problems, weight loss and global health status). In men, statistically significant improvements were observed in 8 QLQ-C30 and 5 QLQ-CR38 domains (QLQ-C30: emotional function, social function, pain, insomnia, appetite loss, constipation, financial problems, and future perspective; QLQ-CR38: micturition problems, defecation problems, stoma-related problems, weight loss, and global health status). Statistically significant worsening of sexual function/enjoyment occurred in both sexes. CONCLUSION: Overall, 59%-86% of patients maintained or improved QOL during capecitabine therapy.

Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer.

Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.

Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2.

PURPOSE: To compare single-agent pemetrexed (P) versus the combination of carboplatin and pemetrexed (CP) in first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. PATIENTS AND METHODS: In a multicenter phase III randomized trial, patients with advanced NSCLC, ECOG PS of 2, any histology at first and later amended to nonsquamous only, no prior chemotherapy, and adequate organ function were randomly assigned to P alone (500 mg/m(2)) or CP (area under the curve of 5 and 500 mg/m(2), respectively) administered every 3 weeks for a total of four cycles. The primary end point was overall survival (OS). RESULTS: A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. The response rates were 10.3% for P and 23.8% for CP (P = .032). In the intent-to-treat population, the median PFS was 2.8 months for P and 5.8 months for CP (hazard ratio [HR], 0.46; 95% CI, 0.35 to 0.63; P < .001), and the median OS was 5.3 months for P and 9.3 months for CP (HR, 0.62; 95% CI, 0.46 to 0.83; P = .001). One-year survival rates were 21.9% and 40.1%, respectively. Similar results were seen when patients with squamous disease were excluded from the analysis. Anemia (grade 3, 3.9%; grade 4, 11.7%) and neutropenia (grade 3, 1%; grade 4, 6.8%) were more frequent with CP. There were four treatment-related deaths in the CP arm. CONCLUSION: Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2.