Phase I/II Trial Investigating the Safety, Tolerability, Pharmacokinetics, Immune and Clinical Activity of SX-682 in Combination With BinTrafusp Alfa (M7824 or TGF-beta "Trap"/PD-L1) With CV301 TRICOM in Advanced Solid Tumors (STAT)

Summary

Participation Requirements

Description

Background: Combination immunotherapy approaches are being actively explored to further improve responses, enhance clinical benefit, and overcome resistance to PD(L)-1 agents in cancer participants. Interleukin-8 (IL-8) is a pro-inflammatory chemokine produced by various cell types. Overexpression o...

Background: Combination immunotherapy approaches are being actively explored to further improve responses, enhance clinical benefit, and overcome resistance to PD(L)-1 agents in cancer participants. Interleukin-8 (IL-8) is a pro-inflammatory chemokine produced by various cell types. Overexpression of IL-8 and/or its receptors CXCR1 and CXCR2, is commonly seen in many human cancers including breast, cervical, melanoma and prostate. SX-682 is an oral, small molecule inhibitor of the CXCR1/2 chemokine receptors that are believed involved in MDSC-recruitment to tumor and other pro-tumoral mechanisms. Bintrafusp alfa (M7824 or MSB0011359C) is a bifunctional protein composed of the extracellular domain of the TGF-BetaRII receptor (TGF-Beta 'trap') fused to a human IgG1. Preclinical data shows bintrafusp alfa treatment increases T-cell trafficking, antigenspecific CD8+ T-cell lysis and NK cell activation. CV301 is a poxviral-based vaccine comprised of recombinant Modified vaccinia Ankara (MVA-BN-CV301, prime) and recombinant fowlpox (FPV-CV301, boost). CV301 contains transgenes encoding two (2) tumor-associated antigens (TAA), mucin 1 (MUC1) and carcinoembryonic antigen (CEA), as well as three costimulatory molecules (B7.1, ICAM-1 and LFA-3, designated TRICOM). A recent phase 1 clinical trial demonstrated that antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, brachyury, were generated in most participants. Preclinical studies performed in LTIB with SX-682, M7824 and a CEA-based vaccine showed a significant reduction in tumor growth as well as a significant increase in tumor infiltration with CD4+ and CD8+ T cells. Objectives: Arm 1 (Sequential Dose Escalation): To evaluate the safety and tolerability of single agent SX-682. To determine the MTD of SX-682 followed by M7824 and CV301 vaccines in participants with advanced or metastatic solid tumors. If the MTD is not reached the study will be focused to describe the safety and tolerability of SX-682 followed by M7824 and CV301 vaccines. Arm 2 (Combination Dose Escalation): --To determine the recommended phase 2 dose (RP2D) of SX-682 with M7824 and CV301 vaccines in participants with advanced or metastatic solid tumors. If the MTD is not reached the study will be focused to describe the safety and tolerability of the drug combination. Arm 3 (Expansion): To evaluate preliminary efficacy based on Objective Response Rate (ORR), in each disease cohort separately. Eligibility: Age > 18 years old Arms 1 and 2 (Dose-Escalation Cohort): Subjects with cytologically or histologically confirmed locally advanced or metastatic solid tumors. Arm 3 (Expansion Cohorts): TNBC: Subjects with cytologically or histologically confirmed locally advanced or metastatic Triple Negative Breast Cancer that has progressed on at least one prior treatment in the advanced or in the metastatic setting. HPV negative HNSCC: Subjects with cytologically or histologically confirmed locally advanced or metastatic, HPV negative head and neck squamous cell cancer (p16 negative for oropharyngeal) that has progressed on at least one prior treatment involving a platinum drug or cetuximab in advanced or in the metastatic setting. Prior first line systemic therapy is required unless there is no standard treatment available, the participant cannot tolerate standard first line treatment, or the participant declines standard treatment after appropriate counseling has been provided. ECOG performance status of 0 to 1 Adequate renal, hepatic, and hematologic function Subjects in Arms 1 and 2 may have disease that is measurable or non-measurable but evaluable disease (e.g. present on bone scan, rising tumor markers, non-measurable by RECIST but visible on CT scan). participants with third space fluid (for example pleural effusions) as only site of disease will not be eligible. Subjects in Arm 3 must have measurable disease according to RECIST 1.1 Design: Arm 1 is a phase I, open-label, 3+3 sequential dose escalation trial with short term, 2-week SX-682 monotherapy lead-in followed by treatment with M7824 and CV301 vaccine series in advanced solid tumors (Q2W dosing schedule) for the duration of treatment. Arm 2 is a phase I, open-label, 3+3 combination dose escalation trial with short term SX- 682 monotherapy lead in followed by SX-682 combination with M7824 and CV301 vaccine series in advanced solid tumors (Q2W dosing schedule). Each enrolled participant will receive SX-682 as monotherapy for 2 weeks then will receive SX-682, M7824 and CV301 for the duration of treatment Arm 3 has two expansion cohorts. Following identification of the MTD or R2PD for the combination of SX-682, M7824 and CV301 vaccine, disease-specific phase 2 expansion cohorts will open in 1) advanced/metastatic triple negative breast cancer and 2) advanced/metastatic, platinum-refractory HPV negative head and neck squamous cell carcinoma.

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