Dose Escalation, First-in-human Clinical Trial to Evaluate the Safety, Pharmacokinetics and Preliminary Antitumor Activity of PEP-010, Administered as Single Agent and in Combination With Paclitaxel or With Gemcitabine in Patients With Metastatic Solid Cancer
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 入组人数
- 77
- 试验地点
- 8
- 主要终点
- Part 2 Cohort 1: The primary endpoint is the ORR (objective response rate), based on local investigator assessment, per RECIST 1.1.
研究概览
简要总结
This is an open-label, non-controlled, multicenter, dose escalation, first-in-human phase I clinical trial with an expansion phase designed to assess the safety, tolerability, PK and PD parameters, and preliminary antitumor activity of intravenous dosing of PEP-010 as single agent and in combination with paclitaxel or with gemcitabine
PEP-010 will be administered, in a Part 1, as single agent in patients with solid cancers who are not amenable to standard treatment, or in combination in patients who are eligible for the paclitaxel therapy, and in a Part 2 only in combination in:
Cohort 1 (expansion cohort, phase 1b): metastatic pancreatic ductal carcinoma (PDAC) who received at least one previous systemic chemotherapy and eligible for paclitaxel therapy.
Cohort 2 (dose escalation cohort, phase 1a): metastatic pancreatic ductal carcinoma or advanced/metastatic ovarian cancer (OC) eligible for gemcitabine-based therapy
详细描述
Part 1 : PEP-010 was administered on days 1, 2 and 3 every week. Treatment was administered until disease progression, unacceptable toxicity, death or withdrawal of consent, whichever occured first. Each cycle was of 21 days duration.
The initial starting dose of PEP-010, DL1 was selected based on pre-clinical data at 0.15 mg/kg. The other doses per injection from DL2 to DL7 are 0.3, 0.6; 1.2; 2.5; 5; 10 and 15 mg/kg.
For patients in Arm B, PEP-010 was combined with Paclitaxel, at a dose of 80 mg/m², weekly until disease progression or unacceptable toxicity. Paclitaxel will be administered according to local guidelines.
Main objective for Dose escalation cohorts was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of PEP-010 when administered as single agent (MTD1/RP2D1), and in combination with paclitaxel (MTD2/RP2D2) by recording the dose-limiting toxicities (DLTs).
Secondary objectives were
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
- •Part 1 Arms A and B:
- •Arm A: Patients must have histologically confirmed diagnosis of recurrent and/or metastatic solid tumors, who are not amenable to standard therapy, with exceptions as defined in the non-inclusion criteria,
- •Arm B: Patients must have histologically confirmed diagnosis of recurrent and/or metastatic solid tumors. Patients must be eligible for a treatment with paclitaxel as single agent. Patients who are eligible for standard of care paclitaxel-based combination therapy should not be included in the trial unless they have been previously exposed to that specific combination therapy. Specifically :
- •Patients with ovarian cancer must have received prior therapy with paclitaxel as part of standard of care in combination with carboplatin.
- •Patients with triple negative breast cancer are eligible for the trial since paclitaxel as single agent is standard of care in this disease.
- •Age ≥ 18 years,
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1,
- •Patients must have measurable disease (as per RECIST version 1.1),
- •Patient ability to comply with the collection of tumor biopsies, and tumors must be accessible for biopsy,
- •Adequate bone marrow function as defined by: Absolute Neutrophil Count (ANC) of ≥ 1.5 x 109/L, platelet count of ≥ 100 x 109/L, and hemoglobin of ≥ 9 g/dL),
- •Adequate liver function, as determined by a serum total bilirubin ≤ 1.5 Upper Limit of Normal (ULN), AST and ALT ≤ 3 x ULN (≤ 5 x ULN if liver metastases),
- •Adequate renal function, as determined by a serum creatinine ≤ 1.5 x ULN,
- •Provision of signed written informed consent,
- •Patient ability to comply with protocol requirements,
- •If the patient is female:
- •Patient must be postmenopausal, surgically sterile, or they must agree to use a physical barrier method of contraception in addition to either an intrauterine device or hormonal contraception until at least 6 months after termination of study drug or must refrain from heterosexual activity during this same period.
- •Patients of childbearing potential must have a negative pregnancy test within the seven days prior to the first study drug administration.
- •If the patient is male:
- •- Patient must abstain from heterosexual activity or must agree to use an acceptable method of contraception (e.g., condom) during the study for at least 6 months after termination of study drug.
- •Patients covered by a health insurance system;
- •Part 2 Cohort 1 Pancreatic Ductal adenocarcinoma (PDAC)
- •Age ≥ 18 years,
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1,
- •Patients must have measurable disease (as per RECIST version 1.1),
- •Patient ability to comply with the collection of tumor biopsies, and tumors must be accessible for biopsy,
- •Adequate bone marrow function as defined by: Absolute Neutrophil Count (ANC) of ≥ 1.5 x 109/L, platelet count of ≥ 100 x 109/L, and hemoglobin of ≥ 9 g/dL),
- •Adequate liver function, as determined by a serum total bilirubin ≤ 1.5 Upper Limit of Normal (ULN), AST and ALT ≤ 3 x ULN (≤ 5 x ULN if liver metastases),
- •Adequate renal function, as determined by a serum creatinine ≤ 1.5 x ULN,
- •Provision of signed written informed consent,
- •Patient ability to comply with protocol requirements,
- •If the patient is female:
- •Patient must be postmenopausal, surgically sterile, or they must agree to use a physical barrier method of contraception in addition to either an intrauterine device or hormonal contraception until at least 6 months after termination of study drug or must refrain from heterosexual activity during this same period.
- •Patients of childbearing potential must have a negative pregnancy test within the seven days prior to the first study drug administration.
- •If the patient is male:
- •- Patient must abstain from heterosexual activity or must agree to use an acceptable method of contraception (e.g., condom) during the study for at least 6 months after termination of study drug.
- •Patients covered by a health insurance system
- •Histologically confirmed metastatic pancreatic ductal adenocarcinoma (mixed histology is acceptable as long adenocarcinoma is the dominant histological subtype)
- •Patient should have received at least one previous line of systemic treatment in metastatic setting
- •No previous disease progression under taxane therapy or 12-month free interval since last taxane therapy.
- •Part 2 Cohort 2 Pancreatic Ductal adenocarcinoma (PDAC) or Ovarian Cancer (OC)
- •Age ≥ 18 years,
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1,
- •Patients must have measurable disease (as per RECIST version 1.1),
- •Patient ability to comply with the collection of tumor biopsies, and tumors must be accessible for biopsy,
- •Adequate bone marrow function as defined by: Absolute Neutrophil Count (ANC) of ≥ 1.5 x 109/L, platelet count of ≥ 100 x 109/L, and hemoglobin of ≥ 9 g/dL),
- •Adequate liver function, as determined by a serum total bilirubin ≤ 1.5 Upper Limit of Normal (ULN), AST and ALT ≤ 3 x ULN (≤ 5 x ULN if liver metastases),
- •Adequate renal function, as determined by a serum creatinine ≤ 1.5 x ULN,
- •Provision of signed written informed consent,
- •Patient ability to comply with protocol requirements,
- •If the patient is female:
- 另有 30 项未显示
排除标准
- 未提供
研究组 & 干预措施
Part 2 cohort 1 : PEP010 in combination with paclitaxel
Fort part 2 the Cohort 1 will include patients with PDAC treated with the combination of PEP-010 at the dose of 2.5 mg/kg and weekly paclitaxel 80 mg/m².
干预措施: Dose escalation, first-in-human phase I clinical trial with an Expansion phase (Combination Product)
Part 2 cohort 2 : PEP010 in combination with gemcitabine
In arm B, the dose escalation phase will begin with DL4 (1.2 mg/kg) and will follow a 3+3 design For part 2 Cohort 2 will include patients with PDAC or OC treated with the combination of PEP-010 in ascending doses, and gemcitabine at 1000 mg/m2.
Four doses of PEP-010 will be tested: 1.2 mg/kg, 2.5 mg/kg, 5 mg/kg and 10 mg/kg, according to a 3+3 dose escalation design.
Once a MTD is achieved, and in light of safety, PK, and PD data, two dosing schedules will be further explored based on TSC recommendations. Each dosing schedule will be evaluated in a separate cohort to generate more data and inform on the choice of the RP2D, as per the recommendations of the FDA (Project Optimus). Patients will be randomized simultaneously in the two dose cohorts, each would include approximately 6 - 10 patients.
干预措施: Dose escalation, first-in-human phase I clinical trial with an Expansion phase (Combination Product)
结局指标
主要结局
Part 2 Cohort 1: The primary endpoint is the ORR (objective response rate), based on local investigator assessment, per RECIST 1.1.
时间窗: 6 months after study treatment initiation
the ORR (objective response rate), defined as the proportion of patients who have achieved a complete response (CR) or partial response (PR) within the first 6 months
For Part 1 (Dose escalation) and Part 2 (Cohort 2), the primary endpoints are the rate of occurrence of DLT within cycle 1 (21 days) after initiation of the study treatment for both parts.
时间窗: 21 days after study treatment initiation
The DLT is defined as any clinically significant non-hematological toxicity ≥ grade 3 and any hematological toxicity ≥ grade 4 of treatment-related adverse event
次要结局
未报告次要终点