Safety and Efficacy Study of PRI-724 in Subjects With Advanced Solid Tumors

Inclusion Criteria

Patients must fulfill all of the following criteria:

1. 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.
2. 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.
3. 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.
4. 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.
5. Patients must be > 18 years of age.
6. Patients must have a Karnofsky Performance Score of 70% - 100%.
7. Patients must have a life expectancy of at least 12 weeks.
8. Patients or their legal representatives must be able to comprehend and provide written informed consent.

9. 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
10. 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).
11. 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).
12. 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.

13. 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:

1. Infection requiring systemic antibiotics 72 hours prior to the first dose of PRI-724.
2. Known hypersensitivity to any of the components of PRI-724.
3. Women who are pregnant or lactating.
4. 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.
5. 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.
6. QTcF intervals > 470 msec (females) or > 450 msec (males).
7. Active hepatitis B, hepatitis C.
8. 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.
9. 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.
10. 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.
11. Patients on any dose of warfarin are excluded.
12. 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.
13. 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.