IRB Study Number 20-246
Status Recruiting
Phases Phase 1, Phase 2
Institute Taussig Cancer Institute
Description
Primary Objectives
Phase 1b: To determine the safety and tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of the combination of Ivosidenib with venetoclax, with or without the addition of azacitidine, in IDH1-mutated patients with advanced hematologic malignancies.
Phase 2: To determine the overall response rate (ORR) including CR, CRi, MLFS, and PR of the combination of ivosidenib and venetoclax, with or without the addition of azacitidine, in IDH1-mutated patients with AML.
Secondary Objectives
Characterize the pharmacokinetic (PK) profiles of venetoclax and ivosidenib in combination in plasma samples (in Part 1b)
To evaluate molecular and cellular biomarkers that may be predictive of antitumor activity and/or resistance to treatment including evaluation of 2HG, IDH1 VAF levels before, during and after treatment
To determine time to event endpoints including duration of response (DOR), event free survival (EFS) and overall survival (OS)
Inclusion Criteria
Age > 18 years.
ECOG performance status of < 2.
IDH1-R132 mutated disease status as assessed by local laboratory. 2HG-producing IDH1 variants outside of R132 (i.e. R100) may be eligible after discussion with the PI.
Relapsed/refractory AML, or treatment-naïve patients with AML who are not eligible for standard induction chemotherapy. Patients with high-risk MDS or MPN (defined as > 10% bone marrow blasts, or intermediate or high risk by IPSS, R-IPSS or D-IPSS) may also be eligible after discussion with the PI.
Adequate hepatic function (direct bilirubin < 2 x ULN, ALT and/or AST < 3x ULN) unless deemed to be related to underlying leukemia.
Adequate renal function including creatinine clearance > 30 ml/min based on the Cockcroft-Gault equation.
Willing and able to provide informed consent
In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy) agents.
Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug.
Exclusion Criteria
Patients with known allergy or hypersensitivity to ivosidenib or venetoclax.
Patients who have previously received either ivosidenib or venetoclax.
Patients with any concurrent uncontrolled clinically significant medical condition including infection, laboratory abnormality, or psychiatric illness, which could place the patient at unacceptable risk of study treatment.
The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea and/or one dose of cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy.
Patients receiving concomitant treatment with strong CYP3A4 inhibitors within 3 days of start of study therapy (including posaconazole and voriconazole, see Appendix)
Patients receiving concomitant strong CYP3A inducers (avasimibe, carbamazepine, phenytoin, rifampin, rifabutin, St. John’s wort) within 3 days of start of study therapy.
Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI).
Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
Patients with a concurrent active malignancy under treatment.
QTc interval using Fridericia’s formula (QTcF) > 450 msec. Bundle branch block and prolonged QTc interval are permitted after discussion with the PI.
Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection.
Subject has a white blood cell count > 25 x 10⁹/L. (Note: Hydroxyurea is permitted to meet this criterion.)
Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception
a. Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, IUD, and double barrier methods (for example a condom in combination with a spermicide).
