Phase 1/2 Trial of the MEK Inhibitor Selumetinib and Bromodomain Inhibitor ZEN-3694 With Durvalumab (MEDI4736), a PD-L1 Antibody for Sarcomas Including Malignant Peripheral Nerve Sheath Tumors
概览
- 阶段
- 2 期
- 干预措施
- Selumetinib + ZEN-3694 ± Durvalumab
- 疾病 / 适应症
- MPNST
- 发起方
- University of Alabama at Birmingham
- 入组人数
- 41
- 试验地点
- 1
- 主要终点
- Part A: Safety and Tolerability Selumetinib with ZEN-3694
- 状态
- 尚未招募
- 最后更新
- 2个月前
概览
简要总结
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.
详细描述
A multi-institutional open-label phase 1/2 trial of selumetinib in combination with bromodomain inhibitor (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. 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. Statistical Plan Phase 1: Conventional dose escalation schema. Cohorts of 3 to 6 participants will be treated per dose level. At the RP2D or last dose level, the cohort may be expanded to up to an additional six participants for further pharmacokinetic and tolerability experience. The MTD/RP2D will be defined as the dose level immediately below the level at which ≥33% of participants in a cohort experience a DLT based on toxicities observed in the first drug therapy cycle. Phase 2: A Simon's two-stage phase 2 trial of selumetinib, ZEN-3694, and durvalumab to determine the safety and clinical benefit in patients with unresectable or metastatic MPNST Maximum Total Number of Subjects Phase 1: 6-24 participants Phase 2: 9 participants in first stage with additional 8 participants in stage 2. Target Population Individuals ≥ 18 years of age with relapsed or refractory histologically confirmed sarcoma including MPNST. This may be amended when tolerability is established. Anticipated Length of Study Maximum enrollment number for entire study is 41participants. It is expected that 15-25 participants will be enrolled per year, and enrollment is expected to be completed in 3 years with follow up after last participant accrual to be approximately 12 months.
研究者
Girish Dhall, MD
PI, NFCTC
University of Alabama at Birmingham
入排标准
入选标准
- •Inclusion Criteria AGE: ≥ 18 years of age Weight: \>30 kg Life expectancy of at least 12 weeks
- •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)
排除标准
- •History of another primary malignancy except for
- •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:
研究组 & 干预措施
Phase 1 and 2 Study of Selumentinib, ZEN-3694 and Durvalumab
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.
干预措施: Selumetinib + ZEN-3694 ± Durvalumab
结局指标
主要结局
Part A: Safety and Tolerability Selumetinib with ZEN-3694
时间窗: From first dose through the end of the first treatment cycle for each participant at each dose level (up to 28 days).
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
时间窗: From first dose through the end of the first treatment cycle for each participant at each dose level (up to 28 days).
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
时间窗: From first dose through completion of 4 treatment cycles for each participant (up to 112 days).
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.