Trial of Selumetinib and Bromodomain Inhibitor With Durvalumab for Sarcomas

Part A: Safety and Tolerability Selumetinib with ZEN-3694

To determine the safety, tolerability, and recommended doses of selumetinib given in combination with ZEN-3694 in participants with refractory sarcomas including MPNST. The Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of selumetinib in combination with ZEN-3694 will be determined based on dose-limiting toxicities (DLTs) observed during the first cycle of therapy. DLTs are defined as grade ≥3 toxicities attributable to the study drugs, assessed according to CTCAE v5. Dose escalation will proceed in cohorts of 3-6 participants, with possible dose de-escalation if ≥33% of participants experience a DLT. At the RP2D, the cohort may be expanded to up to six additional participants to further evaluate pharmacokinetics and tolerability.

Part B: Safety and Tolerability of Durvalumab with Combination of Selumetinib and ZEN-3694

To determine the safety, tolerability, and recommended doses of durvalumab when given in combination with selumetinib and ZEN-3694 in participants with refractory sarcomas including MPNST. The Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of the combination of selumetinib, ZEN-3694, and durvalumab will be determined based on dose-limiting toxicities (DLTs) observed during the first cycle of therapy. DLTs are defined as grade ≥3 toxicities attributable to the study drugs, assessed according to CTCAE v5. Dose escalation will proceed in cohorts of 3-6 participants, with possible dose de-escalation if ≥33% of participants experience a DLT. At the RP2D, the cohort may be expanded to up to six additional participants to further evaluate pharmacokinetics and tolerability.

Part C: Determine the Clinical Benefit of Selumetinib, ZEN-3694 and Durvalumab

Clinical benefit rate defined as radiographic complete response, partial response, or stable disease, greater than or equal to four cycles. The primary endpoint is the clinical benefit rate, defined as the proportion of evaluable participants achieving a complete response (CR), partial response (PR), or stable disease (SD) for at least 4 treatment cycles. A Simon's optimal two-stage phase 2 design will be used to evaluate efficacy in participants with unresectable or metastatic NF1-associated MPNST. In the first stage, 9 participants will be enrolled; the trial will stop early if 0 participants respond. If the study continues to the second stage, a total of 17 participants will be enrolled, and the treatment will be considered ineffective if ≤2 participants respond. The target clinical benefit rate is 30% (p1 = 0.30), and a rate ≤5% (p0 = 0.05) is considered uninteresting.