J1369, A phase I study of SGI-110 combined with irinotecan followed by a randomized phase II study of SGI-110 combined with irinotecan versus regorafenib in previously treated metastatic colorectal cancer patients
This study is being done to test the safety of an investigational drug called SGI-110 together with irinotecan to see what effects (good and bad) this chemotherapy combination has on people with metastatic colorectal cancer. The study is being done in 2 parts. The first part is the dose escalation part where the dose of SGI-110 is increased until the highest safe dose of SGI-110 together with irinotecan is defined. Special blood tests and biopsies are done so that the effects of SGI-110 and irinotecan can be studied. Blood tests will also be used to find out how much of the study drugs are in a personâ??s blood at given times. The second part will use these defined doses of SGI-110 andirinotecan to look at the effects that these study drugs have on metastatic colorectal cancer in comparison to regorafenib.
Inclusion Criteria: Participants must have histologically or cytologically confirmed adenocarcinoma of the colon or rectumPatients in the phase I cohort must have biopsiable disease and be amenable to having two research biopsiesArchival tissue must be procured if available Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as greater than 20 mm with conventional techniques or as greater than 10 mm with spiral CT scan. Patients must have received irinotecan therapy in the metastatic setting. There are no limitation on number of prior therapies in the metastatic setting. Age minimum of 18 years. Life expectancy of greater than 12 weeks.ECOG performance status less than 1 Participants must have normal organ and marrow function .Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Ability to understand and sign a written informed consent document.Exclusion Criteria:Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.Participants may not be receiving any other study agents.Participants with known brain metastases History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, decitabine or SGI-110.Subjects who have received prior therapy with any hypomethylating agents.Uncontrolled intercurrent illness.Pregnant women are excluded from this study. Individuals with a history of a different malignancy are ineligible except for those who have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.HIV-positive individuals on combination antiretroviral therapy are ineligible.Previous treatment with regorafenib (This applies to phase II only.)
Stage 1: Stage 1 will be a traditional phase I study with a standard 3+3 design. Study drugs will be escalated per the schema to maximize the dose of drugs when given concurrently. Patients will be treated with combined therapy immediately. Each cycle will last 28 days. All patients enrolled at each dose level will be evaluated for dose limiting toxicities for the purpose of determining the maximum tolerated dose. The dose escalation scheme is shown below.Level -1: SGI-110 (SQ)30 mg/m2 days 1-5, Irinotecan (IV) 125 mg/m2 days 8 and 15 each cycle.Level 1 (starting dose):SGI-110 (SQ) 45 mg/m2 days 1-5, Irinotecan (IV) 125 mg/m2 days 8 and 15 each cycle.Level 2: SGI-110 (SQ) 60 mg/m2 days 1-5, Irinotecan (IV) 125 mg/m2 days 8 and 15 each cycle.Level 3: SGI-110 (SQ) 60 mg/m2 days 1-5,Irinotecan (IV) 125 mg/m2 days 1, 8 and 15 each cycle.Stage 2: The second stage of this study will be conducted as an open-label, randomized trial. Ninety-six eligible subjects will be randomized in a 2:1 ratio to receive either (1) SGI-110+irinotecan combination treatment in 28-day cycles or (2) regorafenib 160 mg QD days 1-21 in 28-day cycles.
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