Assessing PI3K Gamma Inhibition With Azacitidine, Venetoclax and Eganelisib in Patients With Acute Myeloid Leukemia (GAVEL)

Safety of Targeting PI3Kgamma Signaling With Azacitidine, Venetoclax and Eganelisib in Acute Myeloid Leukemia: A Phase 1 Study (GAVEL)

This study is to evaluate the safety and preliminary efficacy of adding the PI3K-gamma inhibitor, eganelisib, to a standard of care treatment option with combination venetoclax and azacitidine in participants with acute myeloid leukemia (AML).

The names of the study drugs involved in this research study are:

• Venetoclax (a type of BCL-2 inhibitor)
• Azacitidine (a type of Demethylating Agent)
• Eganelisib (a type of PI3K-gamma inhibitor)

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia; Leukemia; Leukemia, Myeloid; Refractory Leukemia
• Intervention / Treatment: Drug: Eganelisib; Drug: Azacitidine; Drug: Venetoclax

Detailed Description

This phase 1 clinical trial is to evaluate the safety and preliminary efficacy of adding the PI3K-gamma inhibitor, eganelisib, to a standard of care treatment option with combination venetoclax and azacitidine in participants with acute myeloid leukemia (AML).

The dose-escalation portion of the trial will aim to establish the maximum tolerated dose of the drug, eganelisib, for the recommended phase 2 dose. The dose-expansion portion of the trial will aim to confirm the recommended phase 2 dose of the drug, eganelisib.

The U.S. Food and Drug Administration (FDA) has not approved eganelisib as a treatment for acute myeloid leukemia.

The FDA has approved azacitidine and venetoclax as a treatment option for AML. However, the combination of these two drugs with eganelisib (three drug or triplet regimen) has not been FDA approved.

The research study procedures include screening for eligibility, in-clinic visits, blood tests, urine tests, electrocardiograms (ECGs), and bone marrow biopsies and aspirations.

It is expected that up to 48 people will take part in this research study. Stelexis BioSciences, Inc. is supporting this study by providing funding and the study drug, eganelisib.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jaqueline Garcia, MD; Phone Number: 617-632-6577; Email: jacqueline_garcia@dfci.harvard.edu
• Study Contact Backup: Name: Jacqueline Garcia, MD; Phone Number: 617-632-6577; Email: jacqueline_garcia@dfci.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
      • Contact: Jacqueline S Garcia, MD; Phone Number: 617-632-6577; Email: Jacqueline_garcia@dfci.harvard.edu
      • Principal Investigator: Jacqueline Garcia, MD
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
      • Contact: Jacqueline S Garcia, MD; Phone Number: 617-632-6577; Email: Jacqueline_garcia@dfci.harvard.edu
      • Principal Investigator: Jacqueline Garcia, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects must have histologically confirmed AML that meets one of these categories of disease:

  • Group A: Relapsed or Refractory: Subjects with relapsed or refractory AML or relapsed/refractory AML, who are not recommended for any approved targeted therapy must meet any one of the following criteria: (1) morphologic relapse (at least 5% blasts), or (2) refractory to intensive chemotherapy (at least one cycle of cytarabine and anthracycline-based intensive regimen) or at least 2 cycles of prior HMA/venetoclax-based therapy (without CR/CRh/CRi). No limit to prior lines of AML therapy. OR
  • (Expansion only) Group B: Untreated AML with ELN 2022 adverse risk disease: Subjects with newly diagnosed or previously untreated AML must be ineligible for intensive chemotherapy based on Ferrara criteria (age ≥75 years or presence of co- morbidity).
• Evidence of marrow involved AML.
• Age 18-90 years. Because no dosing or adverse event data are currently available on the use of eganelisib in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Eastern Cooperative Oncology Group performance status ≤ 3 if 18 to 74 years of age or ECOG 0-2 if ≥ 75 years of age.

• Subjects must meet the following organ and marrow function as defined below:

  • total serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) or

    ≤ 3 x ULN in case of Gilbert's disease

  • AST(SGOT)/ALT(SGPT) ≤ 2.5 x × institutional ULN
  • Creatinine clearance (CrCl) ≥ 30 L/min (Cockcroft-Gault formula)
• Prior history of CNS leukemia that has been treated, asymptomatic and controlled are eligible. CNS evaluation is not required for screening if asymptomatic.
• Subjects with a prior or concurrent malignancy (other than MDS, MPN, MDS/MPN, or AML) whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Treatment must be at least 12 months from last dose of chemotherapy or immunotherapy (except no window is required for palliative radiation or supportive or hormonal therapies). Concurrent malignancy must be considered not active or requiring therapy.
• Male subjects and female subjects/women of childbearing potential (WCBP) must agree to the following: The effects of eganelisib on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. When eganelisib is being used alone, the duration of contraception after the last dose should be 3 months for both males and females of childbearing potential. When eganelisib is being used with azacitidine + venetoclax, according to the USPI for azacitidine, females of reproductive potential should use effective contraception during treatment with azacitidine and for 6 months after the last dose and males with female partners of reproductive potential should use effective contraception during treatment with azacitidine and for 3 months after the last dose. WCBP must have negative serum beta human chorionic gonadotropin test measured within 7 days prior to the first dose of eganelisib and consent to ongoing pregnancy testing during the study.
• Willingness to practice adequate sun protection (i.e. use of sunscreen or sun-protective clothing, limitation of sun and artificial ultraviolet [UV] exposure) for the study duration and for 30 days after the last dose of eganelisib.
• Agree to the protocol-required bone marrow biopsies.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Prior systemic cancer therapy is allowed as long as >14 days prior to study treatment start. Hormonal therapy may be allowed if approved by Sponsor-Investigator.
• Major surgery within 28 days prior to study treatment start.
• Allogeneic stem cell transplant within 100 days prior to study treatment start.
• Active graft-versus-host disease (GVHD) after allogeneic stem cell transplantation or chronic GVHD requiring systemic steroid administration. Topical therapies are allowed for controlled GVHD.
• Receiving systemic immunosuppressive therapy such as steroids or calcineurin inhibitors.
• Participants who have not recovered from adverse events due to prior anti-cancer therapy with the exception of alopecia.
• Participants who are receiving any other investigational AML directed-agents for this condition.
• White blood cell count > 25x109/L prior to first dose of study treatment.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to eganelisib, venetoclax, or azacitidine.

• Participants receiving any medications or substances within 14 days prior to first dose of study drug and for duration of the study:

  • Moderate or strong inhibitors or inducers of CYP2C8 and CYP3A4, including grapefruit, grapefruit juice, Seville oranges, St. John's wort and herbal supplements, except for antibiotics, antifungals, or antivirals that are moderate or strong inhibitors of CYP3A (preference for moderate CYP3A inhibitors if antifungal therapy is recommended when clinically acceptable).
  • P-glycoprotein (P-gp) inhibitors except for azole antifungals.
  • Breast cancer resistance protein (BCRP) inhibitors.
• Administration of any of the following as of Cycle 1 Day 1 and for the study duration: Substrates with a narrow therapeutic index for P-gp, or Warfarin, phenytoin, or other substrates with a narrow therapeutic index for CYP2C8 or CYP2C9
• Pregnant women are excluded from this study because eganelisib is an agent without known fertility and developmental toxicity studies. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with eganelisib, breastfeeding should be discontinued if the mother is treated with eganelisib. These potential risks may also apply to other agents used in this study.
• History or current evidence of any acute or chronic condition, therapy, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or might confound the results of the trial, interfere with participation for the full duration of the trial, or render trial participation not compatible with the participant's best interest, in the opinion of the Investigator.
• Participant must be able to swallow pills and not have any known gastrointestinal abnormality that would affect drug absorption (examples include gastric bypass, gastrectomy, chronic diarrhea).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose-Escalation Eganelisib; Dose-Escalation with triplet azacitidine D1-7, venetoclax D1-28 and eganelisib D1-28 (dose-escalated); Baseline visit; Treatment in 28 day cycles; End of treatment visit; Follow up every 4 months for up to 1 year after end of treatment (for survival).	Drug: Eganelisib; PI3K-gamma inhibitor, capsule taken orally per protocol.; Other Names: IPI-549; Drug: Azacitidine; Demethylating Agent, single use vial, via subcutaneous (under the skin) injection or intravenous (into the vein) infusion per standard of care.; Drug: Venetoclax; BCL-2 inhibitor, tablet taken orally per standard of care.; Other Names: C45H50ClN7O7S
Experimental: Dose-Expansion Eganelisib; Dose-Escalation with triplet azacitidine D1-7, venetoclax D1-28 and eganelisib D1-28 (dose-expansion at MTD/RP2D); Baseline visit; Treatment in 28 day cycles; End of treatment visit; Follow up every 4 months for up to 1 year after end of treatment (for survival).	Drug: Eganelisib; PI3K-gamma inhibitor, capsule taken orally per protocol.; Other Names: IPI-549; Drug: Azacitidine; Demethylating Agent, single use vial, via subcutaneous (under the skin) injection or intravenous (into the vein) infusion per standard of care.; Drug: Venetoclax; BCL-2 inhibitor, tablet taken orally per standard of care.; Other Names: C45H50ClN7O7S

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Eganelisib Recommended Phase 2 Dose (RP2D)	The eganelisib (daily) RP2D in combination with azacitidine 75 mg/m^2/day on days 1-7 and venetoclax 400 mg daily (28 days) is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The RP2D is based on the Bayesian optimal interval design (BOIN). The RP2D may also be based on available pharmacokinetic (PK) and pharmacodynamic (PD) data.	1 cycle=28 days
Recommended Phase 2 Dose (RP2D)	Number of Participants experiencing protocol-defined DLT	1 cycle=28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-Related Grade 3-4 Adverse Event (AE) Rate	Percentage of participants who experience an AE of grade 3 or 4 with treatment attribution of possible, probable or definite per Common Toxicity Adverse Event Criteria (CTCAE) version 5.	through study completion, an average of 2 years
Eganelisib Feasibility Rate	Percentage of participants completing >/= 75% of planned doses of eganelisib.	First 28 days
Eganelisib Area Under the Plasma Concentration versus Time Curve (AUC)	Eganelisib AUC exposure is quantified by the integral of the plasma drug concentration-time curve over a specified time interval associated with pharmacokinetic sampling.	Up to 4 months
Complete Remission (CR) Rate	Percentage of participants achieving CR on treatment per established criteria for adult acute myeloid leukemia: European Leukemia Network (ELN) 2022	Up to 4 months
CR with Partial Hematologic Recovery (CRh) Rate	Percentage of participants achieving CRh on treatment per established criteria for adult acute myeloid leukemia: European Leukemia Network (ELN) 2022	Up to 4 months
CR with incomplete count recovery (CRi) with Minimal Residual Disease (MRD) Negative Rate	Percentage of participants achieving CRi on treatment per established criteria for adult acute myeloid leukemia: European Leukemia Network (ELN) 2022 as well as MRD negativity per ELN 2021 criteria	Up to 4 months
Partial Remission (PR) Rate	Percentage of participants achieving PR on treatment per established criteria for adult acute myeloid leukemia: European Leukemia Network (ELN) 2022	Up to 4 months
Duration of Remission (DOR)	DOR estimated with the Kaplan-Meier method is defined as the time from CR until disease relapse per established criteria for adult acute myeloid leukemia: European Leukemia Network (ELN) 2022. Participants not experiencing disease relapse are censored at the date disease-free or end of follow-up.	through study completion, an average of 2 years
Subsequent Allogeneic Stem-Cell Transplant Rate	The proportion of participants who initiate allogeneic stem cell transplant as next line of therapy.	through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: Jacqueline Garcia, MD
• Collaborators: Stelexis BioSciences, Inc.
• Investigators: Principal Investigator: Jacqueline Garcia, MD, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: February 3, 2026
• First Submitted That Met QC Criteria: February 26, 2026
• First Posted (Actual): February 27, 2026

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 28, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; AML; Leukemia; Relapsed Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Leukemia, Myeloid
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax; IPI-549
• Other Study ID Numbers: DFCI 25-820

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No