Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer

Abstract

Background I-SPY 2 is a phase 2 standing multicenter platform trial designed to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to matching experimental regimens with responding patient subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin (VC). Methods Eligible women had ≥2.5 cm stage II/III breast cancer, categorized into 8 biomarker subtypes based on HER2, hormone-receptor status (HR) and MammaPrint. Patients are adaptively randomized within subtype to better performing regimens compared to standard therapy (control). Regimens are evaluated within 10 signatures, prospectively defined combinations of subtypes. VC plus standard therapy was considered for HER2-negative tumors and therefore evaluated in 3 signatures. The primary endpoint of I-SPY 2 is pathologic complete response (pCR). MR volume changes during treatment inform the likelihood that a patient will achieve pCR. Regimens graduate if and when they have a high (Bayesian) predictive probability of success in a subsequent phase 3 neoadjuvant trial within the graduating signature. Results VC graduated in triple-negative breast cancer with 88% predicted probability of phase 3 success. A total of 72 patients were randomized to VC and 44 to concurrent controls. Respective pCR estimates (95% probability intervals) were 51% (35%–69%) vs 26% (11%–40%). Greater toxicity of VC was manageable. Conclusion The design of I-SPY 2 has the potential to efficiently identify responding tumor subtypes for the various therapies being evaluated. VC added to standard therapy improves pCR rates specifically in triple-negative breast cancer.

Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE

“…These trials may incorporate common control arms for meaningful endpoints, a fluid infrastructure for adding or dropping experimental arms, and an ability to use data as it is available during the trial to alter decision-making in a prespecified manner. The most notable example is I-SPY 2 in breast cancer (3,16,17). Using such a design to evaluate new therapies for GBM requires some changes but the overall concepts and goals may still be applied (18).…”

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“…The overall benefits of treatments targeting cancer driver molecules over traditional cytotoxic chemotherapy are clear; targeted treatments result in greater efficacy and less debilitating or dose-limiting side effects [13][14][15][16][17]. Some of the earliest examples of success in molecularly targeted cancer drug development include tamoxifen and trastuzumab that specifically inhibit the protein products of the estrogen receptor 1 (ESR1) gene (estrogen receptor-alpha) and human epidermal growth factor receptor 2 (ERBB2) gene (HER2), respectively, for the treatment of breast cancer.…”