A Phase Ib/II Trial of Zunsemetinib in Combination With Capecitabine in Patients With Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer With Bone Metastasis
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 152
- 试验地点
- 3
- 主要终点
- Number of participants with adverse events (Phase Ib only)
研究概览
简要总结
This is a phase Ib/II study evaluating the safety and efficacy of zunsemetinib (ATI-450) with capecitabine in patients with hormone receptor-positive and HER2-negative (HR+/HER2-) metastatic breast cancer (MBC).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •for both Phase Ib and Phase II:
- •Hormone receptor-positive, HER2-negative metastatic breast cancer.
- •Measurable or non-measurable but evaluable disease by RECIST v1.
- •Candidate for capecitabine treatment per physician decision. See below phase-specific eligibility criteria for further guidance.
- •No more than one prior chemotherapy for metastatic disease.
- •Patient must have received prior endocrine therapy with CDK4/6 inhibitor.
- •If patient is on denosumab or zoledronic acid prior to enrollment, patient must have been on the regimen for at least 6 months prior to study. However, a washout of 3 weeks is required prior to C1D
- •At least 18 years of age.
- •ECOG performance status 0, 1, or 2
- •Life expectancy of at least 12 weeks.
- •Adequate bone marrow and organ function as defined below:
- •Leukocytes ≥ 3 K/cumm
- •Absolute neutrophil count (ANC) ≥ 1.5 K/cumm
- •Platelets ≥ 100 K/cumm
- •Total bilirubin ≤ 1.5 x IULN (or total bilirubin ≤ 3 mg/dL if patient has known Gilbert Syndrome)
- •AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
- •Creatinine clearance > 60 mL/min by Cockcroft-Gault
- •Calcium within normal limits
- •Women of childbearing potential and men who are heterosexually active must agree to use adequate contraception as specified in the protocol. Contraception should continue for 6 months (for women) or 3 months (for men) after the end of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
- •Ability to understand and willingness to sign an IRB approved written informed consent document.
- •Patients must have archival tissue sample available from prior metastatic biopsy. If no tissue is available, patient may still be able to enroll with PI approval.
- •Inclusion Criteria for both Phase Ib:
- •Presence of bone metastasis is not required.
- •Candidate for, or currently on stable doses of capecitabine, defined as capecitabine: 1000 mg/m^2 BID, 14 days on and 7 days off. A stable dose of capecitabine is defined as no more than grade 1 AEs related to capecitabine on the 1000 mg/m^2 BID, 14 days on and 7 days off dose for at least 1 cycle. Capecitabine is not counted as a prior chemotherapy regimen in these patients.
- •Inclusion Criteria for Phase II:
- •Progressive bone metastasis per the most recent tumor imaging studies by RECIST 1.1 or clinical progression (such as worsening bone pain, elevation of tumor marker) per treating physician.
排除标准
- •for both Phase Ib and Phase II:
- •Patients may not have received the following investigational or SOC therapies within the below specified time frames prior to C1D1:
- •Radiation therapy within 1 week
- •Systemic chemotherapy, including antibody drug conjugates with chemotherapy payload, within 3 weeks.
- •Immunotherapy within 3 weeks
- •Oral chemotherapy or molecularly targeted therapy within 5 half-lives of the agent.
- •Endocrine therapies do not have a required washout and may be continued until C1D
- •Strong and moderate CYP3A4 and CYP2C8 inhibitors (including grapefruit), strong and moderate CYP3A and CYP2C8 inducers, and drugs with QT prolonging potential within 5 half-lives of the agent.
- •Untreated brain metastases. Patients with treated brain metastases are eligible if they show no evidence of progression and are off steroids.
- •A history of allergic reactions attributed to compounds of similar chemical or biologic composition to zunsemetinib or other agents used in the study.
- •History of acute, untreated skeletal related events (SRE) or active untreated SRE or a change or an anticipated change in the SOC anti-resorptive agents after entering the study.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
- •Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of C1D
- •Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to Cycle 1 Day
- •Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.
- •Screening resting QTcF above 470 msec.
- •Exclusion Criteria for Phase Ib:
- •Capecitabine within 2 weeks prior to C1D
- •Patients may be currently taking capecitabine, but must not have dosed within 2 weeks prior to C1D1 for study correlative purposes.
- •Exclusion Criteria for Phase II:
- •Prior capecitabine in the metastatic setting.
- •History of other malignancy, unless all treatment was completed and patient had no evidence of disease within 2 years of C1D1.
研究组 & 干预措施
Phase Ib: Zunsemetinib + Capecitabine
Patients will receive zunsemetinib by mouth (PO) twice per day (BID) at an assigned dose along with capecitabine (1000 mg/m^2 PO BID on Days 1-14 an every 21-day cycle). For patients enrolled in phase Ib, capecitabine is dosed on days 2-15 during cycles 1-2. Dose escalation of zunsemetinib will utilize a 3+3 design. A maximum of 3 dose levels of zunsemetinib will be tested, and the two highest dose levels which did not lead to more than 1 of 6 patients with DLT in cycle 1 will be chosen as the RP2D-L1 and RP2D-L2 for Phase II. If only one dose level of zunsemetinib was found tolerable, then only one RP2D will be chosen for Phase II.
干预措施: Zumsemetinib (Drug)
Phase Ib: Zunsemetinib + Capecitabine
Patients will receive zunsemetinib by mouth (PO) twice per day (BID) at an assigned dose along with capecitabine (1000 mg/m^2 PO BID on Days 1-14 an every 21-day cycle). For patients enrolled in phase Ib, capecitabine is dosed on days 2-15 during cycles 1-2. Dose escalation of zunsemetinib will utilize a 3+3 design. A maximum of 3 dose levels of zunsemetinib will be tested, and the two highest dose levels which did not lead to more than 1 of 6 patients with DLT in cycle 1 will be chosen as the RP2D-L1 and RP2D-L2 for Phase II. If only one dose level of zunsemetinib was found tolerable, then only one RP2D will be chosen for Phase II.
干预措施: Capecitabine (Drug)
Phase II Arm 1: Standard of care anti-resorptive + Capecitabine
Standard of care anti-resorptives will consist of bisphosphonate (zoledronic acid) is to be administered every 4-12 weeks, or denosumab is to be administered every 4-6 weeks, as per physician choice and institutional practice. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3.
干预措施: Denosumab (Drug)
Phase II Arm 1: Standard of care anti-resorptive + Capecitabine
Standard of care anti-resorptives will consist of bisphosphonate (zoledronic acid) is to be administered every 4-12 weeks, or denosumab is to be administered every 4-6 weeks, as per physician choice and institutional practice. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3.
干预措施: Zoledronic acid (Drug)
Phase II Arm 2: Zunsemetinib (RP2D-L1) + Capecitabine
Patients will receive zunsemetinib by mouth (PO) twice per day (BID) at an assigned dose. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3.
干预措施: Zumsemetinib (Drug)
Phase II Arm 2: Zunsemetinib (RP2D-L1) + Capecitabine
Patients will receive zunsemetinib by mouth (PO) twice per day (BID) at an assigned dose. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3.
干预措施: Capecitabine (Drug)
Phase II Arm 3: Zunsemetinib (RP2D-L2) + Capecitabine
Patients will receive zunsemetinib by mouth (PO) twice per day (BID) at an assigned dose. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3. If only one dose level of zunsemetinib plus capecitabine was found tolerable in phase Ib testing, the phase II trial will proceed with 2:1 two-arm randomization with Arm 2 of capecitabine plus zunsemetinib and Arm 1 of capecitabine plus standard of care anti-resorptive agent.
干预措施: Zumsemetinib (Drug)
Phase II Arm 3: Zunsemetinib (RP2D-L2) + Capecitabine
Patients will receive zunsemetinib by mouth (PO) twice per day (BID) at an assigned dose. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3. If only one dose level of zunsemetinib plus capecitabine was found tolerable in phase Ib testing, the phase II trial will proceed with 2:1 two-arm randomization with Arm 2 of capecitabine plus zunsemetinib and Arm 1 of capecitabine plus standard of care anti-resorptive agent.
干预措施: Capecitabine (Drug)
Phase II Arm 1: Standard of care anti-resorptive + Capecitabine
Standard of care anti-resorptives will consist of bisphosphonate (zoledronic acid) is to be administered every 4-12 weeks, or denosumab is to be administered every 4-6 weeks, as per physician choice and institutional practice. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3.
干预措施: Capecitabine (Drug)
结局指标
主要结局
Number of participants with adverse events (Phase Ib only)
时间窗: From start of treatment through 30 days after end of treatment (estimated to be 11 months)
Number of participants with dose-limiting toxicities (Phase Ib only)
时间窗: Through end of 1st cycle (each cycle is 21 days)
Recommended phase II dose of zunsemetinib (Phase Ib only)
时间窗: Through end of 1st cycle (each cycle is 21 days)
Percent change in serum CTX (Phase II only)
时间窗: Baseline and Day 1 of week 7
Progression-free survival (PFS) (Phase II only)
时间窗: From start of treatment through completion of follow-up (estimated to be 3 years and 10 months)
次要结局
- Clinical benefit rate (Phase II only)(Through completion of treatment (estimated to be 10 months))
- Treatment-induced changes in pain as measured by Brief Pain Inventory (BPI) (Phase II only)(Prior to start of 1st treatment, cycle 5 day 1, every 4 cycles thereafter (each cycle is 21 days), and at the time of progression (estimated to be 3 years and 10 months))
- Treatment-induced changes in sCTX by clinical assay (Phase II only)(Baseline, cycle 1 day 1 pre-dose, cycle 1 day 8 pre-dose, cycle 1 day 15 pre-dose, day 1 of subsequent cycles (each cycle is 21 days), and end of treatment (estimated to be 10 months))
- Objective response rate (ORR) (Phase II only)(Through completion of treatment (estimated to be 10 months))
- Overall survival (OS) (Phase II only)(From start of treatment through completion of follow-up (estimated to be 3 years and 10 months))
- Treatment-induced changes in DEXA BMD (g/cm^2) at hip and spine (Phase II only)(Baseline, end of cycle 8, and end of treatment (estimated to be 10 months))
- Number of participants with adverse events (Phase II only)(From start of treatment through 30 days after end of treatment (estimated to be 11 months))
- Treatment-induced changes in DEXA BMD (g/cm^2) at hip and spine (Phase Ib only)(Baseline, end of cycle 8 (each cycle is 21 days), and end of treatment (estimated to be 10 months))
- Treatment-induced changes in quality of life as measured by EORTC QLQ-C30 (Phase II only)(Prior to start of 1st treatment, cycle 5 day 1, every 4 cycles thereafter (each cycle is 21 days), and at the time of progression (estimated to be 3 years and 10 months))