Trial of Selumetinib and Bromodomain Inhibitor With Durvalumab for Sarcomas

NCT05253131 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 300006373W81XWH-17-2-0037 NF160012
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 1

Brief Summary

A multi-institutional open-label phase 1/2 trial of selumetinib in combination with ZEN-3694 and durvalumab in refractory/unresectable sarcomas including MPNST. The phase 1 portion will be separated in two parts and will be open to all patients with refractory/relapsed sarcomas. The phase 2 portion will be for patients with refractory/unresectable NF1-associated MPNST.

Conditions

MPNST; NF1; Sarcoma

Keywords

MPNST; Neurofibromatosis 1; NF1; sarcoma

Outcome Measures

Primary Outcomes (3)

• 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.

  From first dose through the end of the first treatment cycle for each participant at each dose level (up to 28 days).

• 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.

  From first dose through the end of the first treatment cycle for each participant at each dose level (up to 28 days).

• 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.

  From first dose through completion of 4 treatment cycles for each participant (up to 112 days).

Study Arms (1)

Phase 1 and 2 Study of Selumentinib, ZEN-3694 and Durvalumab

EXPERIMENTAL

Part A will be a phase 1 dose escalation study of the combination with selumetinib and ZEN-3694. Part B will be phase 1 study combining the determined dose of selumetinib and ZEN-3694 from Part A with durvalumab. Part C will be a phase 2 study combining selumetinib, ZEN-3694 with durvalumab in MPNST patients at the recommended doses from part B. A Simon's two-stage design will be used in the phase 2 trial to determine the clinical benefit in patients with unresectable or metastatic NF associated MPNST.

Combination Product: Selumetinib + ZEN-3694 ± Durvalumab

Interventions

Selumetinib + ZEN-3694 ± Durvalumab COMBINATION_PRODUCT

Selumetinib and ZEN-3694 administered per protocol, with durvalumab added in later study parts.

Phase 1 and 2 Study of Selumentinib, ZEN-3694 and Durvalumab

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A and B (Phase 1): Patients with histologically confirmed soft tissue or bone sarcoma of the following subtypes:
• MFH/ undifferentiated pleomorphic sarcoma
• Unclassified sarcoma
• Rhabdomyosarcoma
• Malignant peripheral nerve sheath tumor (MPNST)
• Osteosarcoma
• Ewing or Ewing-like sarcoma
• Synovial sarcoma
• Desmoplastic small round blue cell tumor (DSRCT)
• Patients must have progressed or demonstrated disease that is refractory to standard therapies.
• Patients for whom no standard of care treatments exist are eligible.
• Part C (Phase 2): Patients with progressive, relapsed, unresectable or metastatic NF associated MPNST.
• MEASURABLE DISEASE:
• Patients must have evaluable or measurable disease (Phase 1) and measurable disease by RECISTv1.1 (Phase 2).
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering on this study excluding chronic grade 1 toxicities and alopecia.

You may not qualify if:

• A malignancy treated with curative intent and with no known active disease ≥5 years prior to study entry
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
• Stable optic pathway glioma or low grade glioma not receiving active therapy
• History of leptomeningeal carcinomatosis.
• Patients receiving other anti-cancer agents are not eligible.
• Patients who cannot swallow whole pills.
• History of allogeneic organ transplantation.
• Current or prior use of immunosuppressive medications within 14 days prior to study entry. The following are exceptions to this criterion:
• intranasal, inhaled, topical steroids or local steroid injection (e.g., intra-articular injection)
• Systemic corticosteroids used at physiologic doses not to exceed 10mg/day of prednisone or its equivalent.
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Patients should not receive immunizations with attenuated live vaccines within four weeks of study entry or during study period.
• Any recent major surgery within a minimum of 4 weeks prior to starting drug therapy. Placement of vascular access device, percutaneous tumor biopsy, or bone marrows are not considered major surgical procedures and no minimum time frame prior to starting study drug.
• Patients who have any known severe and/or uncontrolled medical therapy is required.

Sponsors & Collaborators

• Congressionally Directed Medical Research Programs: collaborator
• University of Alabama at Birmingham: lead
• Children's Hospital of Philadelphia: collaborator

Study Sites (1)

The University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

MeSH Terms

Conditions

Neurofibrosarcoma; Sarcoma; Neurofibromatosis 1

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

Fibrosarcoma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Neurofibromatoses; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PI, NFCTC

Model Details: Part A will be a phase 1 dose escalation study of the combination with selumetinib and BI. Part B will be phase 1 study combining the determined dose of selumetinib and BI from Part A with durvalumab. Part C will be a phase 2 study combining selumetinib, BI with durvalumab in MPNST patients at the recommended doses from part B. A Simon's two-stage design will be used in the phase 2 trial to determine the clinical benefit in patients with unresectable or metastatic NF associated MPNST.

Study Record Dates

• First Submitted: February 3, 2022
• First Posted: February 23, 2022
• Study Start (Estimated): May 15, 2026
• Primary Completion (Estimated): May 15, 2031
• Study Completion (Estimated): May 15, 2032
• Last Updated: February 11, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)