Randomized phase II study of weekly paclitaxel with and without carboplatin followed by cyclophosphamide/epirubicin/5-fluorouracil as neoadjuvant chemotherapy for stage II/IIIA breast cancer without HER2 overexpression.

Addition of carboplatin to neoadjuvant chemotherapy in HER2-negative breast cancer may improve pathological complete response (pCR) rates. We evaluated the efficacy and safety of carboplatin and weekly paclitaxel (wPTX) followed by cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) as neoadjuvant chemotherapy for HER2-negative breast cancer. Patients with stage II/IIIA HER2-negative breast cancer were randomly assigned to preoperatively receive CP-CEF (four 3-week cycles of carboplatin [area under the curve 5 mg/mL/min, day 1] and wPTX [80 mg/m(2), day 1, 8, 15] followed by four 3-week cycles of CEF [500/100/500 mg/m(2)] or P-CEF (four cycles of wPTX followed by four cycles of CEF). The primary objective was pCR rate. Of 181 eligible patients, 89 were randomly assigned to the CP-CEF and 92 to the P-CEF. Two patients in each arm refused to receive neoadjuvant chemotherapy. Overall 88 patients in the CP-CEF and 91 patients in the P-CEF were assessable for efficacy and safety. The pCR rate in the CP-CEF was significantly higher than that in the P-CEF (31.8 vs. 17.6 %, one-sided P = 0.01). Among patients with triple-negative breast cancer, the pCR rate in the CP-CEF was significantly higher than that in the P-CEF [61.2 (23/37) vs. 26.3 % (10/38), P = 0.003]. Grade 3-4 neutropenia was observed in the CP-CEF more frequently than in the P-CEF (65.9 vs. 38.5 %). Adding carboplatin to neoadjuvant wPTX followed by CEF for HER2-negative breast cancer improved the pCR rate and exacerbated hematotoxicity.

MASTER KEY Project: Powering Clinical Development for Rare Cancers Through a Platform Trial.

For rare cancers, challenges in establishing standard therapies are greater than those for major cancers, and effective methods are needed. MASTER KEY Project is a multicenter study based in Japan, with two main parts: prospective registry study and multiple clinical trials. Advanced rare cancers, cancers of unknown primary origin, and those with rare tissue subtypes of common cancers are targeted. The registry study accumulates highly reliable consecutive data that can be used for future drug development. The multiple trials are conducted simultaneously, targeting either a specific biomarker or a rare tumor type of interest. The first interim data set from the registry part presented here shows the prevalence of genetic abnormalities, response rates, survival rates, and clinical trial enrollment rates. From May 2017 to April 2019, 560 patients (mean age = 53) were enrolled in the project. Frequent cancer types included soft tissue sarcomas, neuroendocrine tumors, and central nervous system tumors. Among the 528 patients with assessable data, 69% (364/528) had next-generation sequencing tests, with 48% (176/364) harboring an "actionable" alteration. Seventy-one (13%) patients have been enrolled in one of the clinical trials, with an accrual rate of 3.94 patients/month. A descriptive analysis of biomarker-directed or non-biomarker-directed treatment survival was performed. This project is expected to accelerate development of treatments for rare cancers and show that comprehensive platform trials are an advantageous strategy.

Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study.

INTRODUCTION: Thymic carcinoma (TC) is a rare cancer with a poor prognosis and limited treatment options, especially after relapse. METHODS: In this open-label, two-stage, multicentre, single-arm and phase II trial, the main eligibility criteria were unresectable or recurrent TC, an Eastern Cooperative Oncology Group-performance status of 0 or 1, progression after at least one chemo(radio)therapy and no history of autoimmune disease. Nivolumab was administered at a dose of 3 mg/kg every 2 weeks. The primary end-point was response rate (RR) as evaluated by central review using Response Evaluation Criteria In Solid Tumours (RECIST), version 1.1. The planned sample size was 15 for each stage, with a threshold RR of 5%, an expected RR of 20%, one-sided alpha of 5% and power of 80%. RESULTS: Between July 1 and August 16 2016, 15 patients were accrued in the first stage. Response was assessable in all patients, and 13 had squamous histology. Median follow-up time was 14.1 months (range: 2.4-17.5). The median number of nivolumab received was eight (range: 3-33). RR was 0% (95% confidential interval [CI]: 0-21.8). Eleven patients had stable disease (SD) including five patients with SD for 24 or more weeks. Median progression-free survival was 3.8 months (95% CI: 1.9-7.0). Two patients experienced immune-related serious adverse events (grade III aspartate aminotransferase (AST) increase and grade II adrenal insufficiency). Because the early termination criteria (less than one responder) were fulfilled during the first stage, the patient accrual was terminated. CONCLUSIONS: Despite the small number of patients, nivolumab was unable to produce tumour shrinkage by RECIST in previously treated unresectable or recurrent TC.

A phase I/II trial of olaparib tablet in combination with eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer previously treated with anthracyclines and taxanes.

BACKGROUND: We conducted a multicenter phase I/II trial of olaparib plus eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer (TNBC) to determine the recommended phase II dose (RP2D) (phase I) and to examine the efficacy and safety (phase II) (UMIN00009498) of the combined therapy. PATIENTS AND METHODS: In phase I, olaparib tablet was orally administered twice daily from level 1:25 mg BID to level 7:300 mg BID, with 1.4 mg/m2 of eribulin on days 1 and 8. In phase II, patients were treated with RP2D to assess the response rate (independent review). The planned sample size was 24 with a threshold of 10%. RESULTS: One of the 24 patients enrolled in phase I experienced dose-limiting toxicity. The RP2D was established as 300 mg twice daily for olaparib and 1.4 mg/m2 for eribulin. Among the 24 patients in phase II, the median number of administered courses was 5.5 (range: 1-28). Grade ≥III adverse events included neutropenia (83.3%), leucopenia (83.3%), anaemia (41.7%), febrile neutropenia (33.3%) and thrombosis (8.3%). The response rate was 29.2% (independent; N = 7/24; 90% confidence interval [CI]; 14.6-47.9). Median progression-free survival and overall survival were 4.2 (95% CI, 3.0-7.4) and 14.5 (95% CI, 4.8-22.0) months, respectively. Germline BRCA1/2 mutation status was observed in three patients in phase I and 2 patients in phase II, respectively. The Cmax and area under the curve for olaparib increased in a dose-dependent manner, and these parameters for eribulin and olaparib were not influenced by each other. CONCLUSIONS: Combination therapy of olaparib with eribulin shows antitumour activity against advanced or metastatic TNBC, but caution must be exercised in the presence of febrile neutropenia.