The objective of this study is to investigate the PK, PD, safety, and tolerability of ivosidenib in adult participants with IDH1-mutated malignancies and hepatic impairment (HI)/ renal impairment (RI). Participants will be enrolled into one of 5 groups based on their hepatic or renal function. During the treatment period participants will have study visits on days 1, 4, 8, 15, 22, and 28 of Cycle 1, on days 1 and 15 of Cycle 2 and 3, and on day 1 of each additional cycle. Each cycle is 28 consecutive days of treatment and cycles will be continuous until the end of the study. Approximately 30 days after treatment has ended, a safety follow-up visit will occur. Study visits may include blood tests, ECG, vital signs, and a physical examination.
Participants with hematologic malignancies (including but not limited to acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms, clonal cytopenia of unknown significance with a high-risk score [CHRS ≥12.5], chronic myelomonocytic leukemia, multiple myeloma, and non-Hodgkin's lymphoma) or solid tumors excluding glioma, with a locally confirmed IDH1 R132 mutation before Cycle 1 Day 1.
Blood total bilirubin ≤1.5 × ULN, unless due to Gilbert's disease, where participants should have blood total bilirubin ≤3 × ULN;
AST, alanine aminotransferase, and alkaline phosphatase ≤3.0 × ULN
Hepatic control group: Adequate hepatic function as evidenced by total bilirubin and AST ≤ULN, and normal to mild RI (CrCl ≥60 mL/min estimated according to the Cockcroft-Gault formula).
Have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of ivosidenib, or on immunosuppressive therapy post-HSCT at the time of screening, or with active acute or chronic graft-versus-host-disease (GVHD) requiring systemic therapy. (Participants with GVHD managed by minimal interventions [a physiologic dose of steroids] are permitted with the medical monitor's approval.)
Have received systemic anticancer therapy (with the exception of azacitidine), investigational agent treatment, or radiotherapy <14 days, or had surgery <4 weeks before planned Cycle 1 Day 1 of ivosidenib, and/or did not recover from the AEs associated with these therapies and/or surgeries. In addition, the first dose of ivosidenib should not occur before a period of ≥5 half-lives of the study drug has elapsed.
Have hematological diseases (other than AML or MDS) or solid tumors that are eligible for other treatments known to provide clinical benefit.
Have received calcineurin inhibitors within 4 weeks prior to enrollment.
Parallel
Ivosidenib Oral Tablet
Drug500mg Ivosidenib taken orally once daily for continuous 28-day cycles
Maximum observed steady-state concentration (Cmax,ss)
Area under the concentration time curve from 0 to 24 hours (AUC0-24hr)
Predose plasma concentration (Ctrough)
Time to maximum observed concentration (Tmax)
Area under the effect concentration-time curve from time point 0 (predose) up to 8 hours postdose (AUEC0-8hr)
Percent inhibition for AUEC0-8hr (%BAUEC0-8hr)
Single dose ivosidenib plasma concentrations, maximum observed concentration (Cmax)
Single dose ivosidenib plasma concentrations AUC0-24hr
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Servier Bio-Innovation LLC
Lead sponsor
Institut de Recherches Internationales Servier
Collaborator
