Randomized Phase Ii Research Articles

A Randomized Phase Ii Trial of Cisplatin Plus Gemcitabine Versus Carboplatin Plus Gemcitabine in Patients with Completely Resected Non-Small Cell Lung Cancer: Hokkaido Lung Cancer Clinical Study Group Trial (Hot0703)

ABSTRACT Aim: The combination of platinum and gemcitabine (GEM) (P/G) is one of the most beneficial regimens in advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of P/G in adjuvant chemotherapy of postoperative NSCLC and select the P/G arm for a phase III trial. Methods: Patients with postoperative stage IB-IIIA NSCLC were randomly assigned to either cisplatin (CDDP) 40 mg/m2 on days 1 and 8 plus GEM 1000 mg/m2 on days 1 and 8 (GP arm) or carboplatin (CBDCA) AUC 5 on day 8 plus GEM 1000 mg/m2 on days 1 and 8 (GC arm) every 3 weeks for 4 cycles. The primary endpoint was 2-year disease-free survival (DFS); secondary endpoints were safety, feasibility, overall survival (OS), and biomarker analyses. Results: 102 patients were randomized (stages: 22% IB, 36% II, 42% IIIA; histology: 74% adenocarcinoma, 26% non-adenocarcinoma). Thirty-seven (73%) of 51 patients in each arm completed 4 cycles. Compliance was greater with GP than GC (dose intensity 87.6% vs. 77.9%, respectively; P Conclusions: Both P/G combination regimens were feasible and well-tolerated and, thus, may be potential options for adjuvant treatment in postoperative NSCLC. Although there were no significant differences in DFS between the two regimens, the data presented favor adopting GC for further evaluation. Disclosure: All authors have declared no conflicts of interest.

414O - Randomized Phase Ii Trial Avareg (Ml25739) with Bevacizumab (Bev) or Fotemustine (Ftm) in Recurrent Gbm: Final Results from the Randomized Phase Ii Trial

ABSTRACT Aim: The treatment of recurrent glioblastoma (GBM) remains an open issue and the role of BEV has been largely debated since only few data compared this agent with the standard agents. Methods: A multicenter, open label, randomized (2:1), non-comparative phase II study (EudraCT 2011-001363-46; AVAREG - ML25739) with BEV 10 mg/m2 iv every 2 weeks or FTM 75 mg/m2 iv day 1-8-15 followed, after a 35 days interval, by FTM 100 mg/m2 every 3 weeks was conducted. Primary endpoint was overall survival at 6 months (OS6). Stratification factors were age ( 55 yrs) and resection for recurrent disease (yes vs no). Results: 91 patients (pts) with recurrent GBM were enrolled among 10 Italian centers between 11/2011 and 9/2012. Median age was 57 yrs (range: 28-78), ECOG PS was 0/1/2 in 42/35/14 pts. All pts received RT/TMZ accordingly with EORTC 26981-22981/NCIC CE3. Time from diagnosis to 1st recurrence was 331 days in the BEV arm and 460 days in the FTM arm. At the time of recurrence, 21 pts (23.1%) underwent re-resection before the inclusion into the study (13/8 pts in BEV/FTM arms, respectively). Fifty-nine pts were enrolled in the BEV arm and 32 pts in the FTM arm. OS6 was 62.1% (95%CI: 48.4 - 74.5) and 73.3% (95%CI: 54.1 - 87.7), OS9 was 37.9% (95%CI: 25.5–51.6) and 46.7% (95%CI 28.3–65.7) in the BEV and FTM arms, respectively. Median OS was 7.3 months (95%CI: 5.8 - 9.2) in the BEV arm and 8.7 months (95%CI: 6.3-15.4) in the FTM arm. In the BEV arm, OS6 and OS9 were 77.8% (95%CI: 57.7–91.4) and 59.3% (95%CI: 38.8 - 77.6) in pts ≤55 yrs, and were 48.4% (95%CI: 30.1 - 66.9) and 19.3% (95%CI: 7.4 - 37.5) in pts >55 yrs. HR for OS in BEV group for pts >55 yrs compared with pts ≤55 yrs was 2.0 (95%CI: 1.0-4.1, p = 0.05). G 3-4- toxicity BEV FTM Neutropenia 1 (1.7%) 4 (12.5%) Thrombocytopenia 0 7 (21.9%) Intestinal perforation 2 (3.4%) 0 Cerebral ischaemia/haemorrage 2 (3.4%) 0 Pulmonary embolism 1 (1.7%) 0 Acute myocardial infarction 1 (1.7%) 0 Conclusions: BEV in recurrent GBM showed survival rates superimposable with FTM. Disclosure: V. Zagonel: Roche – Speaker; M. Reni: Genentech - Advisory board; G. Rosti: Roche - Speaker A. Galli: Roche – employee; S. Doria: Roche – employee; All other authors have declared no conflicts of interest.

253O - Neoadjuvant Treatment with Docetaxel Plus Lapatinib (L), Trastuzumab (T), or Both Followed By an Anthracycline Based Chemotherapy in Her2-Positive Breast Cancer: Results of the Randomised Phase Ii Eortc 10054 Study

253O - Neoadjuvant Treatment with Docetaxel Plus Lapatinib (L), Trastuzumab (T), or Both Followed By an Anthracycline Based Chemotherapy in Her2-Positive Breast Cancer: Results of the Randomised Phase Ii Eortc 10054 Study

A Randomised Phase Ii Study of Cediranib with or Without Src Inhibition (Saracatinib) in Metastatic Clear Cell Renal Cancer (Rcc) Patients Resistant to Vegf Targeted Therapy

ABSTRACT Aim: Metastatic clear cell renal cancer (RCC) patients who are resistant to VEGF targeted therapy have a poor outcome. Further VEGF targeted therapy is a standard treatment option for these patients. It is speculated that SRC may play a role in this VEGF resistance. In the study cediranib (a VEGF tyrosine kinase inhibitor), was given with saracatinib (a SRC TKI) or placebo in VEGF resistant disease to test this hypothesis. Methods: This investigator led double bind randomised (1:1) phase II study recruited patients between 2010 and 2012 (n = 138). The primary endpoint was progression free survival (PFS) by RECIST v1.1. Toxicity was assessed using CTC V4. Patients received cediranib and saracatinib (CS) (n = 69) or cediranib and placebo (C) (n= 69). All patients had metastatic measurable RCC and had progression of disease on VEGF targeted therapy. Stratification factors included MSKCC prognostic score. Results: 15%,70%, 15% had MSKCC good, intermediate or poor risk disease respectively. Overall the characteristics of the 2 groups were well balanced. Partial responses were seen in 13% for C and 14.5% for CS respectively (p = NS). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS [HR 1.18 (0.94-1.48)], or overall survival [HR 1.28 (1.00-1.63)] for the 2 groups. The median overall survival for the whole cohort was 12.0 months (8.5-15.6 months. There was no significant difference in the frequency key adverse events. Discontinuation and dose reductions due to adverse events with C and CS occurred in 13%/8% and 19%/18% respectively. Biomarker analysis will be presented at the meeting. Conclusions: The addition of saracatinib to VEGF targeted therapy did not result in clinical benefit in VEGF resistant metastatic RCC. Cediranib appears to have modest activity in VEGF resistant disease. Disclosure: T. Powles: Research Funding from: AZ GSK Novartis. Honoraria from Pfizer GSK Novartis; R.J. Jones: Research funding from AZ; S. Chowdhury: GSK and Pfizer for speaking. All other authors have declared no conflicts of interest.

Neratinib (N) with or Without Temsirolimus (Tem) in Patients (Pts) with Non-Small Cell Lung Cancer (Nsclc) Carrying Her2 Somatic Mutations: an International Randomized Phase Ii Study

ABSTRACT Aim: Somatic HER2 (ERBB2) mutations occur in approx. 2-4% of pts with NSCLC. In vivo data suggest that combined HER2/mTOR inhibition has synergistic effects in HER2-driven lung tumors [Perera PNAS 2009]. In a phase I study, 5/7 HER2-mutated NSCLC pts showed tumor regression (PR/SD) after treatment with N, an irreversible pan-HER tyrosine kinase inhibitor, and TEM [Gandhi JCO 2014]. The effects of N alone are unknown. This randomized 2-stage phase II study compares N +/- TEM in pts with stage IIIB/IV NSCLC with HER2 somatic mutations. Methods: Pts whose tumors had a documented HER2 mutation were randomized 1:1 to receive oral N 240 mg once daily continuously +/- IV TEM 8 mg/wk (escalated to 15 mg/wk after one 3-wk cycle if tolerated). Addition of TEM was permitted in pts assigned to N alone after progression. High-dose loperamide prophylaxis for diarrhea was mandatory throughout cycle 1. Primary endpoint: overall response rate. Secondary endpoints included: clinical benefit rate, progression-free survival, safety. If > = 2 of 13 pts in each arm have a response at 12 wks in stage 1, a further 26 pts per arm will be enrolled in stage 2. EudraCT ID: 2012-004743-68. Results: 27 pts were enrolled (N, n = 13; N + TEM, n = 14) in stage 1 with approx. 12 wks between randomization of last pt and data cut-off. Baseline characteristics (n = 27): male/female 52%/48%; median age 65 yr; never smokers 63%. Two pts, both in N + TEM arm, had not received prior anticancer medications. Stage 1 results are shown in table. In all pts (n = 27), most common all-grade adverse events (AEs): diarrhea (n = 24), constipation (13), nausea (13), dyspnea (11), asthenia (11), vomiting (11); most common grade 3/4 AEs: dyspnea (4), diarrhea (3; grade 3 only), vomiting (3), nausea (2). Stage 1 Neratinib (N = 13) Neratinib + Temsirolimus (N = 14) Efficacy Overall response rate,* n (%) [90% CI] 0 (0) [0-21] 3** (21) [6-47] Partial response, n 0 3 Stable disease ( > = 12 weeks), n 4 6 Median PFS, months (95% CI) 2.9 (1.4-NE) 4.0 (2.9-9.8) Treatment-emergent diarrhea, n (%) All-grade diarrhea 10 (77) 14 (100) Grade 3 diarrhea 1 (8) 2 (14) * RECIST, version 1.1. ** Two confirmed responses; both pts had not received any prior anticancer medications. Abbreviations: CI, confidence interval; NE, not estimable; PFS, progression-free survival. Conclusions: N + TEM met the efficacy criteria for stage 1 and has been expanded into stage 2. Diarrhea was not a limiting toxicity with aggressive upfront management. Disclosure: B. Besse: Research grants from Puma; B. Yao, A. Lalani, L. McCulloch and R. Bryce: Employed by Puma Biotechnology Inc (study sponsor). All other authors have declared no conflicts of interest.

Abstract OT3-1-01: A randomized phase II study of maintenance hormone therapy with or without capecitabine after induction chemotherapy with bevacizumab plus paclitaxel in hormone receptor positive and HER2 negative metastatic breast cancer (KBCSG-TR1214)

Abstract Background: The combination therapy of Bevacizumab (B) and Paclitaxel (P) has demonstrated to prolong progression free survival (PFS) in E2100 study. Because its PFS is very long, developing optimal therapeutic strategy of B+P, including management of toxicity is crucial. At the 1st International Consensus Conference for Advanced Breast Cancer, most experts agreed the maintenance endocrine therapy after effective induction chemotherapy. In KBCSG-TR 1214 study, we planned to examine the following clinical questions. 1. As a maintenance therapy, which is more effective either endocrine therapy alone (E) or endocrine therapy with Capecitabine (E+C)? 2. Can maintenance therapy reduce toxicity of B+P and restore patient's QOL.? 3. How effective is B+P re-challenge after failure of maintenance therapy? Methods: KBCSG-TR 1214 study is multicenter open-labeled randomized phaseII trial for HR-positive and HER2-nagative metastatic breast cancer(MBC) patients. Patients will receive B (10mg/kg q2w) in combination with P (90mg/m2 on day 1, 8, and 15 q4w) as an induction therapy. Patients without progression after 6 cycles of B+P will be randomized to E or E+C. Endocrine therapy will be chosen by their physician (treatment of physician's choice). Patients in E+C will receive endocrine therapy with Capecitabine 1657mg/m2 on day1 to 21 q4w. Stratification factors for randomization are menopausal status, presence of target lesion, number of prior endocrine therapies for MBC, with or without 1st line chemotherapy for MBC. After progression of maintenance therapy (E or E+C), B+P will be started again as a reintroduction therapy. Primary end point is PFS of maintenance therapy. Secondary end points include time to failure of strategy from randomization, efficacy of reintroduction therapy, overall survival and safety of induction therapy. Translational research is also planned. VEGF, angiopoetin-1, and apelin in plasma will be measured at four points (before induction therapy, at the beginning of the maintenance therapy and the re-induction therapy, and at the end of the trial). This study has just begun and planned 120 patients will be enrolled. (UMIN000008662). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-01.

Randomized Phase II Trials: Inevitable or Inadvisable?

Phase II trials remain a critical step in drug development. They are conducted “to evaluate the effectiveness of a drug for a particular tumor type and to further determine the common short-term side effects.” Given the low eventual success rate of oncology drugs entering clinical trials, it is vital that these trials efficiently screen out inactive drugs. Maximizing their positive and negative predictive values allows for a more efficient drug development process as fewer inactive drugs will progress to phase III trials, the most expensive phase of development. It has been proposed that drug development could be made more efficient through greater use of randomized phase II (RP-II) trials. Although there are a number of designs for such trials, most (approximately 90%) are two-armed studies. The use of RP-II trials is already increasing, although definitive data do not yet exist to show that the increased expenditure and patient numbers required translate into greater efficiency. This article discusses the merits of single-arm phase II (SA-II) trials versus RP-II trials (specifically, comparator trials in which patients are randomly assigned between experimental and standard therapy arms) in a debate format. Initially, Grothey and Sargent will present the merits of using RP-II trials, while Siu, Moore, Pond, and Gan will present the merits of SA-II trials. Thereafter, each team will rebut the arguments of the other. Lastly, we will conclude with a consensus statement identifying points of agreement about the appropriate use of these trial designs.