Ivosidenib and Venetoclax With or Without Azacitidine in Treating Patients With IDH1 Mutated Hematologic Malignancies
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|ClinicalTrials.gov Identifier: NCT03471260|
Recruitment Status : Recruiting
First Posted : March 20, 2018
Last Update Posted : December 15, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Acute Myeloid Leukemia Hematopoietic and Lymphoid System Neoplasm Myelodysplastic Syndrome Myeloproliferative Neoplasm Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia||Drug: Azacitidine Drug: Ivosidenib Drug: Venetoclax||Phase 1 Phase 2|
I. 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 Ib) II. To determine the overall response rate (ORR) including complete response (CR), CR with incomplete blood count recovery (CRi), morphologic leukemia-free state (MLFS), and partial response (PR) of the combination of ivosidenib and venetoclax, with or without the addition of azacitidine, in IDH1-mutated patients with acute myeloid leukemia (AML). (Phase II)
I. Characterize the pharmacokinetic (PK) profiles of venetoclax and ivosidenib in combination in plasma samples (in Part 1b).
II. 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.
III. To determine time to event endpoints including duration of response (DOR), event free survival (EFS) and overall survival (OS).
I. Evaluate minimal residual disease (MRD) using multiparameter flow cytometry, cytogenetics and molecular evaluation.
II. Evaluate global gene expression profiles, deoxyribonucleic acid (DNA) methylation profiles, BH3 profiling and other potential prognostic markers to explore predictors of antitumor activity and/or resistance to treatment.
OUTLINE: This is a phase Ib, dose-escalation study of venetoclax followed by a phase II study.
Patients receive venetoclax orally (PO) daily on days 1-14. Patients also receive ivosidenib PO daily on days 15-28 of cycle 1 and days 1-28 of subsequent cycles. Patients may also receive azacitidine intravenously (IV) over 30-60 minutes or subcutaneously (SC) on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, and then monthly for 3 years.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase Ib/II Investigator Initiated Study of the IDH1-Mutant Inhibitor Ivosidenib (AG120) With the BCL2 Inhibitor Venetoclax +/- Azacitidine in IDH1-Mutated Hematologic Malignancies|
|Actual Study Start Date :||March 19, 2018|
|Estimated Primary Completion Date :||September 30, 2023|
|Estimated Study Completion Date :||September 30, 2023|
Experimental: Treatment (venetoclax, ivosidenib, azacitidine)
Patients receive venetoclax PO daily on days 1-14. Patients also receive ivosidenib PO daily on days 15-28 of cycle 1 and days 1-28 of subsequent cycles. Patients may also receive azacitidine IV over 30-60 minutes or SC on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Given IV or SC
- Overall response rate (ORR) [ Time Frame: Up to 3 years ]Defined as complete response (CR), CR with incomplete blood count recovery (CRi), morphologic leukemia-free state (MLFS), and partial response (PR) based on revised International Working Group (IWG) response criteria. Analysis will be performed for enrolled subjects.
- Incidence of adverse events [ Time Frame: Up to 3 years ]Will be collected using leukemia adverse event guidelines.
- Dose-limiting toxicity [ Time Frame: Up to 56 days ]Defined as any grade 3 or 4, clinically significant non-hematologic adverse event or abnormal laboratory value.
- Response to therapy [ Time Frame: Up to 3 years ]Will be calculated.
- Duration of response [ Time Frame: From the date of initial response to first documented disease progression/relapse or death, assessed up to 3 years ]Will be calculated.
- Event-free survival [ Time Frame: From treatment initiation to date of documented treatment failure, relapse, or death from any cause, assessed up to 3 years ]Will be calculated.
- Overall survival [ Time Frame: Up to 3 years ]Will be calculated.
- Plasma concentrations and pharmacokinetic parameter [ Time Frame: Up to 3 years ]Will be tabulated for each subject, visit, and dose level, and summary statistics will be computed for each sampling time and each parameter.
- Peripheral blood and bone marrow aspirate samples [ Time Frame: Up to 3 years ]Biomarker assays may include, but are not limited to, BH3 profiling and characterization of BCL-2 and related proteins, IDH1 mutant status, serum R-2HG analysis, and assessment of the depth of response and monitoring of disease recurrence by assessment of minimal residual disease in the bone marrow.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Eastern Cooperative Oncology Group (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 principal investigator (PI).
- Relapsed/refractory AML, or treatment-naive patients with AML who are not eligible for standard induction chemotherapy. Patients with high-risk myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) (defined as >= 10% bone marrow blasts, or intermediate or high risk by International Prostate Symptom Score [IPSS], Revised [R]-IPSS or Dynamic [D]-IPSS) may also be eligible after discussion with the PI
- Direct bilirubin =< 2 x upper limit of normal (ULN) unless deemed to be related to underlying leukemia.
- Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =< 3 x ULN unless deemed to be related to underlying leukemia.
- 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.
- 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 central nervous system (CNS) leukemia. (2) use of hydroxyurea and/or one dose of cytarabine (up to 2 g/m^2) 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).
- 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.
- Corrected QT (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 human immunodeficiency virus (HIV) infection.
- Subject has a white blood cell count > 25 x 10^9/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.
- Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03471260
|Contact: Courtney DiNardofirstname.lastname@example.org|
|United States, Massachusetts|
|Dana-Farber Cancer Institute||Active, not recruiting|
|Boston, Massachusetts, United States, 02215|
|United States, New York|
|Roswell Park Cancer Institute||Not yet recruiting|
|Buffalo, New York, United States, 14263|
|Contact: Eunice S. Wang 716-845-2300 email@example.com|
|Principal Investigator: Eunice S. Wang|
|United States, Ohio|
|Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center||Recruiting|
|Cleveland, Ohio, United States, 44195|
|Contact: bhumika patel 216-444-8665 firstname.lastname@example.org|
|Principal Investigator: bhumika patel|
|United States, Texas|
|M D Anderson Cancer Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Courtney DiNardo 713-794-1141 email@example.com|
|Principal Investigator: Courtney DiNardo|
|Principal Investigator:||Courtney DiNardo||M.D. Anderson Cancer Center|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||M.D. Anderson Cancer Center|
|Other Study ID Numbers:||
NCI-2018-00921 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0490 ( Other Identifier: M D Anderson Cancer Center )
|First Posted:||March 20, 2018 Key Record Dates|
|Last Update Posted:||December 15, 2022|
|Last Verified:||December 2022|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Bone Marrow Diseases
Neoplasms by Site
Molecular Mechanisms of Pharmacological Action