A Phase Ia/Ib Clinical Trial of PRI-724 in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 23
- 试验地点
- 3
- 主要终点
- Maximum Therapeutic Dose, as defined by the highest dose identified in which ≤1/3 or ≤2/6 patients do not experience a dose limiting toxicity
研究概览
简要总结
PRI-724 is a new investigational drug being studied to treat subjects with cancer who have advanced solid tumors. PRI-724 is thought to work by blocking the Wnt signaling pathway that cancer cells need to grow and spread(metastasize).
Phase Ia: Patient cohorts with solid tumor malignancies will be treated with escalating doses (per cohort) of PRI-724 in order to identify the MTD of this single-agent regimen. PRI-724 dosing is to start at 40 mg/m2/day, CIV infusion over 24 hours × 7 days.
Phase Ib: This phase is to begin upon identification of the MTD in Phase 1a. Patient cohorts with CRC will be treated with escalating doses (per cohort) of PRI-724 administered in combination with a modified regimen of FOLFOX6 (mFOLFOX 6, standardized doses and schedule) in order to identify the MTD of this combined regimen. Up to 2 dose levels of PRI-724 are to be examined (640 and 905 mg/m2/day, CIV infusion over 24 hours × 7 days), with potential to evaluate a previously unexamined intermediate dose, if indicated, to more fully characterize tolerability. The MTD cohort (or maximum dose to be studied) will be expanded up to 12 patients.
详细描述
Primary Objectives
- Determine the MTD of PRI-724 when administered as a 7-day CIV intravenous infusion to patients with solid tumors (Phase Ia).
- Determine the MTD of PRI-724 when administered as a 7-day CIV infusion in combination with mFOLFOX6 in patients with colorectal carcinoma (Phase Ib).
Secondary Objectives
-
Describe the dose-limiting toxicities (DLTs) and adverse event profile of PRI-724 when administered as a 7-day CIV infusion either alone in patients with solid tumors, or in combination with mFOLFOX6 in patients with colorectal carcinoma.
-
Determine the pharmacokinetic (PK) profile of PRI-724 and C-82 when administered as a 7-day CIV infusion in these patient populations (In Phase 1b PK assessments will not be performed in expanded MTD cohort patients).
-
Obtain preliminary assessment of anti-tumor activity as manifested by responses to treatment in these patient populations.
-
Measure the mRNA expression of survivin by reverse transcriptase-polymerase chain reaction (RT-PCR), pre- and post-treatment with PRI-724:
-
In circulating tumor cells (CTC)
-
In tumor biopsy specimens from CRC patients (Phase Ib only) Also, evaluate whether survivin expression in CTC is consistent and reflective of expression in tumor specimens.
-
Obtain preliminary assessments of potential associations of survivin that may be impacted by the pharmacodynamic (PD) properties of PRI-724 and clinical outcome, toxicity and PK parameters
-
Assess the effects of Wnt inhibitor C-82 on the hair follicle neogenesis and the amount of collagen expression
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- 未提供
排除标准
- •Patients exhibiting any of the following will be excluded from the trial:
- •Infection requiring systemic antibiotics 72 hours prior to the first dose of PRI-
- •Known hypersensitivity to any of the components of PRI-
- •Women who are pregnant or lactating.
- •Untreated central nervous system (CNS) metastases; patients whose CNS metastases have been treated by surgery or radiotherapy, who are no longer on corticosteroids, and who are neurologically stable may be enrolled in the initial dose escalation portion of the trial (Phase Ia), but not in the Phase Ib portion of the trial.
- •Treatment with any investigational agent within a period of 28 days between the last dose of the investigational agent and the first dose of PRI-
- •QTcF intervals > 470 msec (females) or > 450 msec (males).
- •Active hepatitis B, hepatitis C.
- •New York Heart Association (NYHA) Class 3 or 4; myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contra-indicates treatment with PRI-724 or places the patient at undue risk for treatment-related complications.
- •Any other condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.
- •Patients with a current condition of osteopenia or osteoporosis via a Dual Energy X-ray Absorptiometry (DEXA) scan; patients with a history of either are allowed.
- •Patients on any dose of warfarin are excluded.
- •Given the potential interaction between C82, the metabolite of PRI-724, and CYP3A4 inhibitors, treating physicians should exercise caution and switch patients to equivalent drugs that are not potent CYP3A4 inhibitors when feasible. Medications which are sensitive substrates of CYP2C9 or CYP3A4 with a narrow therapeutic range should be used with caution.
- •In Phase 1b, patients with a history of poor FOLFOX tolerability as manifested by inability to tolerate standard therapeutic doses (i.e., at minimum patients must have tolerated an oxaliplatin dose of 85 mg/m2 and a 5FU dose of 2400 mg/m2).
- •Note: Patients are eligible for this trial if, during the previous FOLFOX administration, they underwent one dose reduction of oxaliplatin due to sensory neuropathy (provided the neuropathy has now resolved to Grade 1 or less), and/or one dose reduction of 5FU due to cumulative toxicity.
研究组 & 干预措施
PRI-724
干预措施: PRI-724 (Drug)
结局指标
主要结局
Maximum Therapeutic Dose, as defined by the highest dose identified in which ≤1/3 or ≤2/6 patients do not experience a dose limiting toxicity
时间窗: Assessed at the completion of each patient enrollment cohort. Each patient monitoring duration is 28 days.
Maximum Therapeutic Dose (MTD) will be the highest dose in which no dose limiting toxicity (DLT) is seen in a accelerated enrollment cohort (1 patient) and then subsequently a 3-6 patient cohort following a 3+3 study design. MTD may also be determined by evaluation of PK and PD results of patients.
次要结局
- Maximum Therapeutic Dose of combined regimen, as defined by the highest dose identified in which ≤1/3 or ≤2/6 patients do not experience a dose limiting toxicity(Assessed at the completion of each patient enrollment cohort. Each patient monitoring duration is 28 days)