Acute Myeloid LeukemiaPhase 1/2NCT03471260
Ivosidenib and Venetoclax With or Without Azacitidine in Treating Patients With IDH1 Mutated Hematologic Malignancies
A Phase 1/2 study testing Azacitidine, Ivosidenib and Venetoclax in people with Acute Myeloid Leukemia and Hematopoietic and Lymphoid System Neoplasm, run by M.D. Anderson Cancer Center at 4 sites in United States.
Trial summary
This phase Ib/II trial studies the side effects and best dose of venetoclax and how well it works when given together with ivosidenib with or without azacitidine, in treating patients with IDH1-mutated hematologic malignancies. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Myeloid Leukemia, Hematopoietic and Lymphoid System Neoplasm, Myelodysplastic Syndrome
- What is being tested?
- Azacitidine, Ivosidenib and Venetoclax
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 96 participants
- Where
- 4 sitesUnited States
- Study dates
- 19 Mar 2018to 30 Sep 2027
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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, MDS/MPN or MPN (defined as > 10% bone marrow blasts, or intermediate or high risk by IPSS, R-IPSS or D-IPSS) that have failed standard therapy 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.
Show all 9Show fewer
- 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.
Who cannot join
- 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 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).
Show all 12Show fewer
- 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).
Trial locations and contacts
4 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States4 sites, 4 recruiting
- Recruiting
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Jacqueline S. Garcia, MD, 617-632-2168, Jacqueline_Garcia@DFCI.HARVARD.EDU
Jacqueline S. Garcia, MD
- Recruiting
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, 44195
Hetty Carraway, MD, 216-445-5899, carrawh@ccf.org
Hetty Carraway, MD
- Recruiting
M D Anderson Cancer Center
Houston, Texas, 77030
Courtney DiNardo, 713-794-1141, cdinardo@mdanderson.org
Courtney DiNardo
- Recruiting
Oregon Health and Science University
Portland, Oregon, 97239
Curtis Lachowiez, MD, 503-346-0010, lundbert@ohsu.edu
Curtis Lachowiez, MD
About this study
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
This phase Ib/II trial studies the side effects and best dose of venetoclax and how well it works when given together with ivosidenib with or without azacitidine, in treating patients with IDH1-mutated hematologic malignancies. Venetoclax and ivosidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ivosidenib and venetoclax with azacitidine may work better in treating patients with hematologic malignancies compared to ivosidenib and venetoclax alone.
Read the detailed description
PRIMARY OBJECTIVES:
- 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)
SECONDARY OBJECTIVES:
- 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).
EXPLORATORY OBJECTIVES:
- 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.
- Conditions
- Acute Myeloid Leukemia, Hematopoietic and Lymphoid System Neoplasm, Myelodysplastic Syndrome, Myeloproliferative Neoplasm, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia
- Being tested
- Azacitidine, Ivosidenib, Venetoclax
- Medical subject headings
- Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Myeloproliferative Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzacitidineDrug
Also called 5 AZC, 5-AC, 5-Azacytidine, 5-AZC
Given IV or SC
IvosidenibDrug
Also called AG-120, Tibsovo
Given PO
VenetoclaxDrug
Also called ABT-0199, ABT-199, ABT199, GDC-0199
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Treatment (venetoclax, ivosidenib, azacitidine) | Experimental | 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. Receives: Drug: Azacitidine; Drug: Ivosidenib; Drug: Venetoclax |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall response rate (ORR)
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.
Measured: Up to 3 years
Incidence of adverse events
Will be collected using leukemia adverse event guidelines.
Measured: Up to 3 years
Dose-limiting toxicity
Defined as any grade 3 or 4, clinically significant non-hematologic adverse event or abnormal laboratory value.
Measured: Up to 56 days
Secondary outcomes (4)
Response to therapy
Will be calculated.
Measured: Up to 3 years
Duration of response
Will be calculated.
Measured: From the date of initial response to first documented disease progression/relapse or death, assessed up to 3 years
Event-free survival
Will be calculated.
Measured: From treatment initiation to date of documented treatment failure, relapse, or death from any cause, assessed up to 3 years
Overall survival
Will be calculated.
Measured: Up to 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Mar 2018
- Study start19 Mar 2018
- Primary completion30 Sep 2027 (estimated)
- Study completion30 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- More trials run by M.D. Anderson Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 96 participants (estimated)
Sponsor and investigators
- Lead sponsor
- M.D. Anderson Cancer Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Courtney DiNardo, MD, Principal investigator, M.D. Anderson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03471260
- Sponsor's protocol ID
- 2017-0490
- Other IDs
- NCI-2018-00921, 2017-0490
- Status last verified
- Sep 2026
- First submitted
- 2 Mar 2018
- Last updated
- 14 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
DiNardo CD, Marvin-Peek J, Loghavi S, Takahashi K, Issa GC, Jen WY, Daver NG, Reville PK, Short NJ, Sasaki K, Mullin JK, Bradley CA, Borthakur G, Maiti A, Alvarado Y, Pemmaraju N, Abbas HA, Hammond DE, Haddad F, Bravo GM, Chien KS, Yilmaz M, Kornblau SM, Jabbour E, Ravandi F, Kadia T, Garcia-Manero G, Konopleva MY, Kantarjian HM. Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML. J Clin Oncol. 2025 Aug 20;43(24):2692-2699. doi: 10.1200/JCO-25-00640. Epub 2025 Jun 13.
PubMed 40513054Greenberg PL, Stone RM, Abaza Y, Al-Kali A, Anand S, Ball B, Bennett JM, Borate U, Brunner AM, Chai-Ho W, Curtin P, DeZern AE, Gaensler K, Gahvari Z, Garcia-Manero G, Griffiths EA, Haque T, Jacoby M, Jonas BA, Keel S, Khanal R, Kishtagari A, Madanat Y, Maness LJ, McCurdy SR, McMahon C, Odenike O, Osman A, Reddy VV, Sallman DA, Sayar H, Shallis R, Singh A, Tanaka T, Thota S, Kovach E, Nguyen J, Hochstetler C. NCCN Guidelines(R) Insights: Myelodysplastic Syndromes, Version 2.2025. J Natl Compr Canc Netw. 2025 Mar;23(3):66-75. doi: 10.6004/jnccn.2025.0013.
PubMed 40073835Wilde L, Kasner M. Whom should we treat with novel agents? Specific indications for specific and challenging populations. Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):24-29. doi: 10.1182/hematology.2021000228.
PubMed 34889407