A Phase 1b/2, Dose-escalation, Randomized, Multicenter Study of Maintenance Ivaltinostat Plus Capecitabine or Capecitabine in Patients With Metastatic Pancreatic Adenocarcinoma Whose Disease Has Not Progressed on FOLFIRINOX
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 70
- 试验地点
- 16
- 主要终点
- Progression-Free Survival (PFS) in Phase 2
研究概览
简要总结
This study is a Phase 1b/2, dose-escalation, randomized, multicenter study to assess the efficacy, safety, tolerability, and PK of ivaltinostat in combination with capecitabine and capecitabine monotherapy in patients with metastatic pancreatic adenocarcinoma whose disease has not progressed on a first line fluoropyrimidine-based chemotherapy (e.g., FOLFIRINOX).
In Phase 1b, 3 dose levels of ivaltinostat will be studied in combination with a fixed dose of capecitabine to determine the RP2D of ivaltinostat.
In Phase 2, patients will be randomized in a 1:1 ratio to the combination of ivaltinostat and capecitabine or to capecitabine monotherapy. A fixed dose for capecitabine 1000 mg/m2 orally twice daily will be taken on Days 1 to 14, and the RP2D of ivaltinostat will be administered intravenously once a week for 2 weeks, followed by 1 week of rest. One cycle consists of 21 days. Tumor response during study treatment will be assessed every 6 weeks up to Cycle 10, then every 9 weeks afterwards using RECIST v1.1 criteria.
详细描述
There will be approximately 70 (18 Phase 1b dose-escalation, 52 Phase 2 randomized) patients in the study. In Phase 1b, 3 dose levels of ivaltinostat will be studied in combination with a fixed dose of capecitabine to determine the RP2D of ivaltinostat. In Phase 2, patients will be randomized in a 1:1 ratio to the combination of ivaltinostat and capecitabine or to capecitabine monotherapy as specified below:
Arm A
- Ivaltinostat (the dose will be selected after reviewing the results of Phase 1b among 3 dose levels of 60, 125, or 250 mg/m2) intravenous infusion over 60 minutes (±10 minutes) once on Days 1 and 8 of a 21-day cycle
- Capecitabine 1000 mg/m2 orally twice daily on Days 1 to 14 of a 21-day cycle OR Arm B
- Capecitabine 1000 mg/m2 orally twice daily on Days 1 to 14 of a 21-day cycle Study Assessments In Phase 1b, patients will attend clinic visits in Cycle 1 on Days 1, 2, 3, 5, 8, and 15 for assessments, with treatment on Days 1 and 8. After Cycle 1, patients will attend clinic visits on a weekly schedule for treatment (Days 1 and 8) and assessments (Days 1, 8, and 15) during 21-day cycles for the remainder of time receiving study treatment. In Phase 2, patients will attend clinic visits on a weekly schedule for treatment (Days 1 and 8) and assessments (Days 1, 8, and 15) during 21-day cycles.
The Phase 1b will enroll up to 18 patients (6 patients each of 3 dose levels of ivaltinostat [60, 125, and 250 mg/m2] + 1000 mg/m2 capecitabine BID) to assess the combination of ivaltinostat and capecitabine for safety and tolerability as well as to determine the ivaltinostat RP2D, assess the PDy of ivaltinostat, and assess PK parameters of both ivaltinostat and capecitabine. Data from the Phase 1b will be used in safety analyses but not in efficacy analyses.
Tumor response during study treatment will be assessed using RECIST v1.1 criteria. Baseline and on-treatment tumor assessments will be performed using CT or MRI scans with contrast of the chest, abdomen, and pelvis, with other regions as clinically indicated for the assessment of disease. Baseline evaluation should be performed within the 28-day screening period prior to the start of study treatment, as close as possible to randomization. Follow-up assessment consistent with baseline radiologic evaluation (i.e., if CT scan was performed for baseline assessment, then CT scan should be done for the follow-up evaluation) should be performed approximately every 6 weeks (±1 week) until objective disease progression as defined by RECIST v1.1. In addition to the imaging listed above, any other sites with known disease, or at which new disease is suspected, should also be appropriately imaged. Safety evaluations will occur at each protocol-specified study visit.
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
- •Age: ≥18 years
- •For Phase 1b, histologically or cytologically confirmed pancreatic adenocarcinoma (locally advanced or metastatic) with at least 1 prior therapy in either the advanced or perioperative setting
- •For Phase 1b, measurable disease and/or non-measurable disease per RECIST v1.1
- •For Phase 2, histologically or cytologically confirmed pancreatic adenocarcinoma without evidence of disease progression while receiving initial chemotherapy for metastatic disease (e.g., must have had a demonstrated CR, PR, or SD following initial chemotherapy).
- •For Phase 2, measurable disease and/or non-measurable or no evidence of disease assessed by baseline CT (or MRI where CT is contraindicated). RECIST v1.1 will be used to allow for assessment of disease progression due to new lesions in patients with no evidence of disease at baseline. Patients with no evidence of disease following FOLFIRINOX chemotherapy will be deemed to have radiographic disease progression if new lesions are detected.
- •For Phase 2, treatment with FOLFIRINOX for metastatic pancreatic adenocarcinoma at full or modified doses, for a minimum of 16 weeks, and no evidence of progression based on the radiographic imaging.
- •a. Randomization must occur within 6 weeks of the last dose of chemotherapy.
- •b. Patients who have received at least 16 weeks of FOLFIRINOX combination regimen but had non-fluoropyrimidine chemotherapeutic agents discontinued prior to 16 weeks due to toxicity are eligible if they have no radiographic evidence of disease.
- •For Phase 2, patients who received prior chemotherapy or prior chemoradiation for a prior cancer or as adjuvant/neoadjuvant treatment for pancreatic adenocarcinoma are eligible provided at least 12 months have elapsed between the last dose of treatment and initiation of the FOLFIRINOX chemotherapy for metastatic pancreatic adenocarcinoma.
- •Prior radiation therapy is allowed, provided >14 days have elapsed since completion of radiation prior to randomization.
- •Adequate organ function
- •ECOG Performance Status 0-1 at the date of signing the informed consent.
排除标准
- •For Phase 2, radiographic progression of tumor per RECIST 1.1 between start of first line FOLFIRINOX chemotherapy for metastatic pancreatic adenocarcinoma and randomization.
- •Cytotoxic chemotherapy or non-hormonal targeted therapy within 28 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 14 or more days before Cycle 1 Day
- •The patient can receive a stable dose of bisphosphonates or RANKL directed therapy for bone metastases before and during the study as long as these were initiated at least 2 weeks prior to study treatment
- •For Phase 2, not receiving FOLFIRINOX as initial therapy for metastatic PDAC. Patients who received FOLFIRINOX initially and who needed to discontinue irinotecan or oxaliplatin due to toxicity are eligible, provided they received at least 4 weeks (2 cycles) of FOLFIRINOX
- •For Phase 2, more than 1 prior line of therapy for metastatic PDAC
- •Exposure to an investigational agent within 30 days or 5 half-lives (whichever is longer) prior to randomization
- •Any previous treatment with a HDAC inhibitor, including ivaltinostat
研究组 & 干预措施
Ivaltinostat plus Capecitabine
Ivaltinostat plus Capecitabine
干预措施: Ivaltinostat (Drug)
Ivaltinostat plus Capecitabine
Ivaltinostat plus Capecitabine
干预措施: Capecitabine (Drug)
Capecitabine Monotherapy
Capecitabine Monotherapy
干预措施: Capecitabine (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) in Phase 2
时间窗: 15 months
Investigator assessed PFS
Treatment emergent changes in clinical laboratory tests in phase 1
时间窗: 15 months
The number of subjects who experience a change in laboratory parameters that was possibly related to study drug.
Incidence of dose-limiting toxicities (DLTs) in phase 1
时间窗: 15 months
The percentage of subjects who experience a grade 3 or higher adverse event that qualifies as a DLT
Incidence of treatment emergent AEs in phase 1
时间窗: 15 months
The number of subjects who experience an adverse event that was possibly related to study drug
次要结局
- AUC of ivaltinostat in Phase 1 and 2(19 months)
- Objective response rate (ORR) in Phase 1 and 2(19 months)
- Cmax of ivaltinostat in Phase 1 and 2(19 months)
- Incidence of treatment emergent AEs in Phase 2(19 months)
- Half-life (T1/2) of ivaltinostat in Phase 1 and 2(19 months)