0C-10-4: A Phase Ia/Ib Clinical Trial of PRI-724 in Patients with Advanced Solid Tumors
Description
Detailed Description
Despite recent progresses in directed chemotherapy, the modern anti-cancer armamentarium only eradicates the majority of drug-sensitive and differentiated tumor cells. Unfortunately, to date no effective therapeutic solution has been developed to treat cancer stem cells. Based on pre-clinical research utilizing CREB-binding proteins/ beta-catenin antagonists, it is hypothesized that such antagonists can target CSCs and thereby offer a novel anti-tumor therapeutic approach.This is a Phase Ia/Ib clinical trial of PRI-724 in patients with advanced solid tumors. It has 2 arms:Phase Ia Accelerated Phase/Dose Escalation and Phase Ib Dose Expansion: PRI-724 MTDThe primary objective of the study is to determine the maximally tolerated dose (MTD) of PRI-724 when administered as a continuous 7-day intravenous infusion to patients with solid tumors. This has been completed in Phase 1a of the study. The Phase 1b will determine the MTD of PRI-274 when combined with mFOLFOX6 in patients with colorectal carcinoma.The secondary objectives are to describe the side effects experienced in both parts of the study, determine the pharmacokinetic profile of PRI-724 and C-82, assess anti-tumor activity, assess the genetic expression of survivin and the effect PRI-724 has on survivin, and assess the affect of C-82 on hair follicle neogenesis and collagen expression. The study also has an exploratory objective to obtain matrix metalloproteinase-7 (MMP7) levels in serum via enzyme-linked immunosorbent assay (ELISA) testing.The starting dose and dose escalation scheme was selected to provide an adequate safety margin based on Good Laboratory Practices (GLP) 28-day continuous iv infusion nonclinical studies. The study consists of accelerated Phase Ia and dose escalation at standard 3+3 phase. Each cycle is defined as 7-day continuous intravenous (iv) infusion followed by a 7-day rest period. At the Maximally Tolerated Dose (MTD), Phase Ib will commence where 18 patients with advanced colorectal cancer who have progressed or whose tumors are no longer responsive to standard therapies will be enrolled.The exact number of patients enrolled will depend on the toxicity observed in each dose escalation cohort and the number of cohorts required to reach MTD.The mRNA level of surviving will be measured in both Phase Ia and Ib. If mRNA level of surviving at day 8 of PRI-724 treatment is decreased 30% or more compared to the level prior to PRI-724 treatment, it suggests that PRI-724 inhibits surviving. In addition to this, assessment will be made of clinical endpoints including tumor response by RECIST and progression-free survival by tumor specimen and circulating tumor cells in every cohort.A typical electronic data capture (EDC) system will be used for data collection.Statistical analysis will be carried out by USC Norris Comprehensive Cancer Center Biostatistics core using SAS Version 9.0 or later.
Phase
N/AInclusion and Exclusion Criteria
- Inclusion Criteria Patients must fulfill all of the following criteria:
- In the dose-escalation part of the study (Phase Ia), patients mu have histological or cytological evidence of solid tumor malignancy; in the tumor-specific, dose-escalation/MTD-expansion part of the study (Phase Ib), patients must have histological or cytological evidence of colorectal cancer.
- Patients must have neoplastic disease that is metastatic or unresectable, that has recurred or progressed following standard therapy, not be candidates for standard therapy, or have a malignancy for which no standard therapy exists. In Phase Ib,patients must have colorectal cancer with tumor sites safely accessible for biopsy, and they must have measurable disease according to the response evaluation criteria in solid tumors (RECIST 1.1) criteria.
- In Phase Ib patients must have received and either relapsed from or failed at least two but no more than three prior regimens of chemotherapy, and be eligible to receive third- or fourth-line therapy for their malignancy.
- Patients must agree, as part of the informed consent, to provide blood samples for molecular correlative studies. In the Phase Ib cohorts, patients must agree to pre- and post-treatment biopsies of their malignant disease.
- Patients must be > 18 years of age.
- Patients must have a Karnofsky Performance Score of 70% - 100%.
- Patients must have a life expectancy of at least 12 weeks.
- Patients or their legal representatives must be able to comprehend and provide written informed consent.
- Patients must have adequate bone marrow reserve as evidenced by: - White blood cell (WBC) count> 3,000/µL - Absolute neutrophil count (ANC) > 1,500/µL - Platelet count> 100,000/µL
- Patients must have adequate renal function as evidenced by a serum creatinine value less than the upper limit of normal (< ULN) for the reference lab or creatinine clearance (CrCl) of > 60 mL/min (as calculated by Cockcroft-Gault formula).
- Patients must have adequate hepatic function as evidenced by a serum bilirubin < 1.5 mg/dL and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels < 3X the ULN for the reference lab (< 5X the ULN if there is evidence of hepatic involvement by malignant disease).
- Patients must be recovered to Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies. In Phase Ib patients must have no peripheral sensory neuropathy > Grade 1.
- Women of childbearing potential (WOCBP) and male patients with WOCBP partner must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Postmenopausal is defined as: - Amenorrhea ≥12 consecutive months without another cause or - For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level> 35 mIU/mL. Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to the start of investigational product. Exclusion Criteria: 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-724.
- Known hypersensitivity to any of the components of PRI-724.
- 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-724.
- 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.
Sites
Please contact Anayansi Miloud to learn more about where you can participate in this trial. Please use the contact form on the right side.
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