Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer

Jason M Redman, Seth M Steinberg, James L Gulley, Jason M Redman, Seth M Steinberg, James L Gulley

Abstract

Advances in immunotherapy utilizing immune checkpoint inhibitors (ICIs) have transformed the treatment landscapes of several malignancies in recent years. Oncologists are now tasked with extending these benefits to a greater number of patients and tumor types. Metastatic castration-resistant prostate cancer (mCRPC) infrequently responds to ICIs, while the cellular vaccine approved for mCRPC, sipuleucel-T, provides a 4-month survival benefit but does not produce clinical responses as monotherapy. However, many novel and generally well-tolerated immune oncology agents with potential for immune synergy and/or additive effects are undergoing clinical development. This availability presents opportunities to develop adaptive-design combination clinical trials aimed to generate, expand, and facilitate antitumor immune responses. Here we describe a currently accruing phase I/II trial (NCT03493945) testing a brachyury-targeted antitumor vaccine, TGF-β TRAP/anti-PD-L1 antibody, an IL-15 agonist, and an IDO1 inhibitor in mCRPC.

Trial registration: This trial ( NCT03493945 ) was registered in National Clinical Trials on April 11th 2018.

Keywords: ALT-803; Brachyury; Combination immunotherapy; IDO1; IL-15; M7824; Metastatic castration-resistant prostate cancer; PD-L1; TGF-β; Tumor vaccine.

Conflict of interest statement

Ethics approval and consent to participate

The trial was approved by the Institutional Review Board of the Center for Cancer Research, National Cancer Institute (Consent for publication

No patient data were discussed in this article.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Multimodal immunotherapy can engage, expand, and enable the antitumor immune response. BN-Brachyury vaccine generates T-cell responses by targeting brachyury, a transcription factor involved in metastasis and associated with mCRPC aggressiveness. PD-L1 blockade by M7824 at the tumor:effector cell synapse can enhance tumor lysis. TGF-β neutralization by M7824 can further enable immune effector cell activity within the TME. ALT-803 expands and activates NK cells and effector T cells. Inhibition of the IDO1 enzyme by epacadostat can decrease immunosuppressive currents within the TME generated by myeloid-derived suppressor cells (MDSCs) and regulatory T cells toward a more immune-permissive state within the TME by dampening the inhibitory effects of MDSCs
Fig. 2
Fig. 2
Trial schema. During part A, enrollment to arms 1.1 and 2.1A begins simultaneously. Arm 1.1 is a dose-finding arm for ALT-803 in combination with M7824, open to all solid tumors. After arm 2.1A completes accrual and safety of the combination has been demonstrated, and ALT-803 dosing has been determined from arm 1.1, arm 2.2A begins accrual. After arm 2.2A completes accrual and safety of the combination has been demonstrated, enrollment to arm 2.3A begins. Each of the 3 arms enrolls a total of 13 patients during part A. At completion of part A, if there is a positive safety signal and a positive efficacy signal in arm 2.1A, 2.2A, or 2.3A, part B will begin. To further assess efficacy, arms in which an activity signal was observed (arms 2.1B, 2.2B, and/or 2.3B) may expand to a total of 25 patients. During part B, patients are randomized among all open arms to avoid selection bias

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