A Proof of Concept Pilot Study of the Addition of Venetoclax to Standard Remission Induction Chemotherapy Fludarabine or Cladrabine, Cytarabine, and Granulocyte Colony Stimulating Factor (G-CSF) (FLAG or CLAG) for Frontline Therapy of Secondary Acute Myeloid Leukemia

NCT05780879 | Suspended Phase 2 FDA Drug

• 2 other identifiers: UMCC 2021.145HUM00227799
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The primary purpose of this study is to determine complete remission rate of a novel combination induction chemotherapy treatment based upon 20 patients with newly diagnosed secondary AML.

Conditions

Secondary Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Morphologic complete remission (CR)

  If at least 12/20 (60%) of patients achieve a CR (based upon a bone marrow aspiration, biopsy, and peripheral blood studies according to the International Working Group criteria for AML), the combination treatment will be considered successful. If the true CR rate is 40%, then the trial will be considered successful with probability 0.06 (type I error). Conversely, if the true CR rate is 70%, then the trial will be considered successful with probability 0.89 (power).

  up to 43 days (+/- 2 days)

Secondary Outcomes (9)

• Overall response rate (ORR)

  28 days (+/- 7 days) days post remission marrow collection

• Progression-free survival (PFS)

  6 months and 1 year following the conclusion of study enrollment

• Overall survival (OS)

  6 months and 1 year following the conclusion of study enrollment

• Event free survival (EFS)

  6 months and 1 year following the conclusion of study enrollment

• Mortality rate

  30 days post study treatment start

Study Arms (1)

Venetoclax + FLAG or CLAG induction chemotherapy

EXPERIMENTAL

Induction chemotherapy with FLAG starting on day 1 and venetoclax given on days 3-16. The G-CSF component of FLAG will continue until count recovery (ANC at least \> 1000). FLAG dosing will be standard and uniform for all patients and venetoclax dosing will be determined according to institutional guidelines based on the prophylactic antifungal therapy chosen for use during induction therapy. Given the national shortage of Fludarabine, Cladrabine (5mg/m2/day IV over 2 hours) has been substituted (CLAG) with similar toxicity profile.

Drug: Venetoclax; Drug: FLAG or CLAG Protocol

Interventions

Venetoclax DRUG

Venetoclax administered orally once daily on days 3-16.

Venetoclax + FLAG or CLAG induction chemotherapy

FLAG or CLAG Protocol DRUG

FLAG consists of daily infusions of Fludarabine (30mg/m2/day over 30 minutes) and Ara-C (2g/m2/day over 4 hours) for 5 days with daily subcutaneous injections of G-CSF until count recovery. Tbo-filgrastim will be administered as follows: WBC count \>50,000 - 5mcg/kg; WBC count \<50,000 - hold Tbo-filgrastim. Given the national shortage of Fludarabine, Cladrabine (5mg/m2/day IV over 2 hours) has been substituted (CLAG) with similar toxicity profile.

Venetoclax + FLAG or CLAG induction chemotherapy

Eligibility Criteria

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

You may qualify if:

• Patients have an established, pathologically confirmed diagnosis of newly diagnosed secondary acute myeloid leukemia (sAML) as defined by the 2016 World Health Organization criteria. Secondary AML includes:
• AML arising after an antecedent hematologic neoplasm including aplastic anemia (AA), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and overlap syndromes (MDS/MPN)
• AML with MDS defining cytogenetic changes as defined in Vardiman et al. Blood 2009 114 (5): 937-951 - Table 6. Please see appendix 14.6 for full table.
• Therapy-related AML
• Patients must not have received prior treatment for the diagnosis of secondary acute myeloid leukemia, with the exception of hydroxyurea and/or leukopheresis which are permitted until day 1 of study participation. Prior treatment for a diagnosis of MDS, MPN, or MDS/MPN overlap syndrome is allowed.
• Patients ≥ 18 years of age.
• ECOG PS ≤ 2
• Patient has ability to understand and the willingness to sign a written informed consent.
• Adequate organ function as defined by:
• serum creatinine level ≤ 2.0 mg/dL or a CrCl ≥ 30 ml/min (Cockcroft-Gault equation using actual body weight)
• alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 3 times the institutional upper limit of normal (ULN) unless considered due to leukemic involvement
• total bilirubin level ≤1.5 times the institutional upper limits of normal (ULN) (unless secondary to Gilbert syndrome, hemolysis, or suspected leukemic involvement).
• Patients must be non-fertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate during and for at least 6 months after completion of study therapy.
• Patients must be able to comply with the requirements for the entire duration of the study.

You may not qualify if:

• Diagnosed with acute promyelocytic leukemia (acute leukemia with recurrent genetic abnormalities - APL with t(15;17)(q22;q12);PML-RARA).
• Diagnosed with myeloid blast phase of chronic myeloid leukemia.
• Diagnosed with isolated extramedullary AML
• Diagnosed with acute leukemia of ambiguous lineage, acute biphenotypic or acute bilineal acute leukemia per the 2016 World Health Organization classification system.
• Patients with a white blood cell count (WBC) \>50,000 at the time of initiation of therapy will be excluded. Patients can consent and screen with a WBC \> 50,000 but will require cytoreduction (hydrea or leukopheresis) prior to day 1 of therapy.
• Receiving antileukemic therapy other than hydroxyurea. Patients may have received therapy with a hypomethylating agent (azacitidine or decitabine) for a prior diagnosis of myelodysplastic syndrome (MDS) or chemotherapy for a prior diagnosis of a myeloproliferative neoplasm or an MDS/MPN overlap syndrome. Likewise, patients may have received chemotherapy for a prior non-leukemic oncologic malignancy.
• Any prior therapy with a Bcl-2 antagonist.
• Any known allergy to the chemotherapeutic agents being investigated including fludarabine,cladribine, cytarabine, G-CSF and venetoclax.
• Patients with known history of HIV, Hepatitis B, or Hepatitis C with the exception of those with an undetectable viral load within 3 months of screening. (Hepatitis B or C testing is not required). Subjects with serologic evidence of prior vaccination to HBV \[i.e., HBs Ag-, and anti-HBs+\] may participate.
• Having an active second malignancy requiring treatment--other than AML--within 3 months prior to the start of treatment, with the exception of basal cell carcinoma or squamous cell carcinoma of the skin, colon polyp, carcinoma in situ of the cervix, or DCIS/LCIS of the breast.
• Having an active uncontrolled infection (viral, bacterial or fungal), any other concurrent disease, or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator.
• Pregnant women or women who are breastfeeding. Women must be willing to not breast feed up until 30 days following the end of trial therapy.
• Men or women of childbearing potential must be willing to practice an effective method of birth control during treatment and up until 6 months following the end of trial therapy.
• Having received any live vaccines within 28 days prior to first study drug administration.
• Patient has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.

Sponsors & Collaborators

• University of Michigan Rogel Cancer Center: lead
• Genentech, Inc.: collaborator

Study Sites (1)

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Interventions

venetoclax; CLAG protocol

Study Officials

• Dale Bixby, MD, PhD

  University of Michigan Rogel Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2023
• First Posted: March 23, 2023
• Study Start: June 3, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: March 23, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)