Venetoclax Add in Combination With Fludarabine, Cyratabine and Idarubicine in Induction for Acute Myelid Leukemia

Phase 2

Active, not recruiting

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Venetoclax

• Registration Number: NCT03455504
• Lead Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto

Brief Summary

This study will test the effectiveness and safety of Venetoclax in combination with standard induction regimen for patients with acute leukemia and poor prognosis.

Detailed Description

Intensive treatment of Acute Leukemia, multidrug based chemotherapy induction, achieves complete remission (CR) rates ranging from 50% to 80%. Nonetheless, the majority (60- 70%) of responding patients will eventually relapse.

Patients with non-low risk leukemia according most diffuse risk scores have a poor prognosis and a short survival. For these patient traditional chemotherapy seems to be ineffective, even with BMT consolidation, probably due to activation of survival pathways in Leukemia cells, so that novel therapeutic interventions should be attempted.

This study will test the effectiveness and safety of Venetoclax, a selective BCL2 inhibitor, in combination with standard induction regimen.

Inhibiting anti-apoptotic pathway of BCL2, the investigators expect to improve success rate of standard chemotherapies.

Study Timeline

• Study First Submitted: 2018-02-28
• Study First Submitted QC: 2018-02-28
• Study First Posted: 2018-03-06
• Study Start: 2018-10-26
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-09
• Last Update Posted: 2024-04-10
• Primary Completion: 2025-01
• Study Completion: 2025-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 124

Inclusion Criteria

• Patients with documented/confirmed new onset non-m3 acute myeloid leukemia, according to WHO 2017 will be eligible for this study.

• Hematological illness has to be graded intermediate or high risk according ELN criteria

• Patients ≥ 18 years old and ≤ 65 years old

• ECOG performance status ≤ 2.

• Patients with a life expectancy >12 weeks

• Patients may have AML which has arisen from prior therapies or other antecedent disorder

• Adequate hepatic function

• Adequate pancreatic function

• Adequate renal function assessed by: Serum creatinine within reference laboratory ranges or creatinine clearance (by Cockcroft Gault formula, see Appendix 2) ≥ 50 mL/min for patients in whom, in the Investigator's judgment, serum creatinine level may not adequately reflect renal function.

• All non-hematological adverse events must have resolved to NCI-CTCAE Grade ≤ 2 prior to starting therapy.

• Patients must be considered by Investigator suitable to receive combination chemotherapy.

• Combination chemotherapy has not to be considered toxic without expectation of any benefit for the patient

• For females of childbearing potential, a negative pregnancy test must be documented within 72 hours prior to the first study drug administration.

• All patients must be willing to use effective methods of contraception, during the treatment period and for 100 days after the last dose of Venetoclax. Female patients must be postmenopausal (≥ 1 year of amenorrhea), surgically sterile, or they must agree to use 2 adequate methods of contraception with at least one method with a failure rate of

  ≤ 1% per year (e.g., hormonal implants, combined oral contraceptives, vasectomized partner) and the second preferably a physical barrier method of contraception. Oral or injectable contraceptive agents cannot be the sole method of contraception. Male patients must be surgically sterile or agree to use an acceptable method of contraception.

• Patient must be willing to submit the blood sampling and bone marrow sampling for the PK and PD analyses and exploratory biomarkers.

• Ability to understand and willingness to sign an informed consent form.

• Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

Exclusion Criteria

• Patients with low risk AML according ELN criteria
• Patients with current clinical evidence of CNS leukemia.
• Patients receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy with the exception of Hydroxyurea (HU) or 6-Mercaptopurine (6MP) in patients who need to continue this agent to maintain WBC count ≤10,000/mm3. HU and 6MP must be discontinued at the time of initiation of study medications.
• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study including but not limited at:
• unstable angina
• Patients who are on anti-microbial agents with therapeutic intent

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1	Venetoclax	FLAI + V400 mg
Cohort 2	Venetoclax	FLAI + V600 mg

Primary Outcome Measures

Name	Time	Method
Number of patients achieving complete response (CR) after course 1 or course 2 if course 2 is administered (CR + CRi + CRp)	At 24 months from study entry	Efficacy in new onset, non ELN Low risk AML (safety run-in, part1, and part2). Effectiveness of Venetoclax added in combination with chemotherapy in obtaining Complete remission in new onset, non ELN Low risk AML (safety run-in, part1, and part2).

Trial Locations

Locations (22)

Aou Senese - Uoc Ematologia E Trapianti; 🇮🇹 Siena, Italy

Spedali Civili - Azienda Ospedaliera U.O. Ematologia; 🇮🇹 Brescia, Italy

Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia; 🇮🇹 Pagani, Italy

U.O.C. Ematologia e CTMO Az Ospedaliero Universitaria; 🇮🇹 Parma, Italy

Fondazione Ircss Policlinico San Matteo - Pavia - Uo Ematologia; 🇮🇹 Pavia, Italy

Dipartimento Oncologico - Ospedale S. Maria delle Croci; 🇮🇹 Ravenna, Italy

Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia; 🇮🇹 Vicenza, Italy

Ististuto Clinico Humanitas - Rozzano - Uo Oncologia Medica Ed Ematologia; 🇮🇹 Rozzano, Italy

Università degli Studi "Sapienza" Dip. Biotecnologie Cellulari ed Ematologia; 🇮🇹 Roma, Italy

Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia; 🇮🇹 Roma, Italy

Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia - Università Degli Studi Di Torino; 🇮🇹 Torino, Italy

Dipartimento di Oncologia ed Ematologia S.C. -Città della Scienza di Torino San Giovanni Battista; 🇮🇹 Torino, Italy

Aou "San Giovanni Di Dio E Ruggi D'Aragona" - Salerno - Uoc Ematologia E Trapianti Di Cellule Staminali Emopoietiche; 🇮🇹 Salerno, Italy

Ematologia - ASST Papa Giovanni XXIII; 🇮🇹 Bergamo, Italy

Aou Di Bologna - Policlinico S. Orsola-Malpighi - Uoc Ematologia; 🇮🇹 Bologna, Italy

Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"; 🇮🇹 Catania, Italy

Irccs Aou San Martino - Genova - Uo Clinica Ematologica; 🇮🇹 Genova, Italy

A.O.U. Careggi - Ematologia; 🇮🇹 Firenze, Italy

Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori IRST; 🇮🇹 Meldola, Italy

Fondazione Irccs "Istituto Nazionale Tumori" - Milano - Sc Ematologia; 🇮🇹 Milano, Italy

Ospedale Niguarda "Ca Granda" SC Ematologia; 🇮🇹 Milano, Italy

U.O. Ematologia e Trapianto di Midollo Ist. Scientifico Ospedale San Raffaele; 🇮🇹 Milano, Italy