Study of Enasidenib and Venetoclax in IDH2-Mutated Blood Cancers

NCT04092179 | Terminated Phase 1 DMC

• 2 other identifiers: 19-5939ENAVEN-AML
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this research study is to see how safe and tolerable, and to find the highest or best dose, of an investigational combination of drugs called enasidenib and venetoclax, in patients with relapsed (the cancer has come back) or refractory (the cancer does not respond or have stopped responding to treatment) acute myeloid leukemia (AML, a type of blood cancer). This study will also see how useful the combination of enasidenib and venetoclax is in the treatment of patients with relapsed or refractory AML.

Conditions

Acute Myeloid Leukemia; Relapsed Cancer; Refractory Cancer; IDH2 Gene Mutation

Outcome Measures

Primary Outcomes (4)

• Overall response rate (ORR)

  3 years

• Dose Limiting Toxicity

  28 days

• Maximum tolerated dose or Recommended Phase 2 Dose

  Dose indicated by the mTPI decision

  3 years

• Duration of Response

  The time from the date of first response until progression, relapse, death, or last follow-up.

  3 years

Secondary Outcomes (2)

• Overall Survival

  3 years

• Event Free Survival

  3 years

Study Arms (1)

Venetoclax and Enadisenib

EXPERIMENTAL

Enasidenib and venetoclax will be taken by mouth (orally), once a day, every day, continuously. Every 28-day period will be called a cycle. Participants will start venetoclax alone on Cycle 1 Day 1 and continue the study drug alone until Day 15. On Day 15, participants will take enasidenib and venetoclax together and will continue to take the combination of study drugs until intolerable side effects or disease worsening.

Drug: Enasidenib; Drug: Venetoclax

Interventions

Enasidenib DRUG

Enasidenib is a drug that blocks a protein called isocitrate dehydrogenase (IDH) 2 from working. The family of IDH proteins have been indicated in the development of leukemia. By blocking IDH2, enasidenib may help stop cancer cells from growing. It is believed that the drug may be more useful in patients with a change (mutation) in their IDH 2 protein. The IDH2 gene (substances in the body that contain instructions for the proper development and function of cells) makes IDH2 proteins. As such, only patients with IDH 2 mutated gene are eligible for this study. Enasidenib is currently approved for the treatment of IDH2 mutated AML.

Also known as: IDHIFA

Venetoclax and Enadisenib

Venetoclax DRUG

Venetoclax is a drug that blocks a protein called B-cell lymphoma (BCL2) protein from working. BCL2 is a protein that helps control whether a cell lives or dies and is thought to help cancer cells to live. Blocking BCL2 is believed to help kill cancer cells. Venetoclax is currently approved for the treatment of type of blood cancer called chronic lymphocytic leukemia (CLL) who have received prior treatment.

Also known as: VENCLEXTA

Venetoclax and Enadisenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance score of ≤2
• IDH2 (R140 or IDH R172) mutated AML disease status as determined by local laboratory
• Relapsed and/or refractory acute myeloid leukemia (AML). Treatment-naïve patients who are not eligible for standard induction chemotherapy or high-risk myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) may also be eligible.
• Adequate hepatic function
• Adequate renal function
• 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 and non-cytotoxic (immunotherapy) agents

You may not qualify if:

• Known allergy or hypersensitivity to enasidenib or venetoclax
• Previously received either an IDH2 inhibitor or BCL2 inhibitor
• With any uncontrolled clinically significant medical conditions
• The use of other chemotherapeutic agents or anti-leukemic agents, radiotherapy or other investigational therapy is not permitted during study with exceptions
• Receiving concomitant treatment with strong cytochrome P450 2A (CYP3A4) inhibitors within 3 days of start of study therapy
• Receiving concomitant strong CYP3A inducers (avasimibe, carbamazepine, phenytoin, rifampin, rifabutin, St. John's Wort) within 3 days of start of study therapy.
• Taking the following sensitive CYP substrate medications that have a narrow therapeutic range are excluded from the study unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment: paclitaxel and docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2)
• Active graft-versus-host-disease (GVHD) status post stem cell transplant
• Severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
• Concurrent active malignancy under treatment
• Administration or consumption of any of the following within 3 days prior to first dose of study drug: grapefruit or grapefruits products, Seville oranges (including marmalade containing Seville oranges) and start fruit
• Heart-rate corrected QT (QTc) interval ≥480 msec (Fridericia's formula) except for underlying right-bundle branch block (RBBB).
• Positive for HIV
• Subject has an unacceptable white blood cell count
• Positive urine pregnancy test,

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Celgene: collaborator
• AbbVie: collaborator

Study Sites (2)

University of Alberta Hospital

Edmonton, Alberta, T6G 2B7, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 1Z5, Canada

Location

Related Publications (1)

• Richard-Carpentier G, Gupta G, Koraksic C, Cathelin S, Wang L, Bankar A, Davidson M, Gupta V, Maze D, Minden MD, Murphy T, Schimmer AD, Schuh AC, Sibai H, Yee K, DiNardo CD, Brandwein J, McNamara CJ, Chan SM. Enasidenib plus venetoclax in patients with IDH2-mutated relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome (ENAVEN-AML): a multicentre, single-arm, phase 1b/2 trial. Lancet Haematol. 2025 Nov;12(11):e887-e897. doi: 10.1016/S2352-3026(25)00254-6. Epub 2025 Oct 8.

  PMID: 41075807 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence; Neoplasms

Interventions

enasidenib; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Steven Chan, M.D.

  Princess Margaret Cancer Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2019
• First Posted: September 17, 2019
• Study Start: November 5, 2020
• Primary Completion: October 26, 2023
• Study Completion: October 26, 2023
• Last Updated: January 24, 2024

Record last verified: 2024-01

Locations

CA (2)