Clinical trial NCT03455504: Venetoclax Add in Combination With Fludarabine, Cyratabine and Idarubicine in Induction for Acute Myelid Leukemia
Official title: Study Investigating Safety, Tolerability and Effectiveness of Venetoclax Add in Combination With Fludarabine, Cyratabine and Idarubicine in Induction of New Onset Non-M3 Acute Myelid Leukemia
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: Acute myeloid leukemia
Venetoclax
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2018-03-06
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Study run-in and phase II
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of patients achieving complete response (CR) after course 1 or course 2 if course 2 is administered (CR + CRi + CRp)
timeFrame: At 24 months from study entry
Secondary outcomes:
Other outcomes:
Locations:
city: Bergamo
country: Italy
facility: Ematologia - ASST Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Aou Di Bologna - Policlinico S. Orsola-Malpighi - Uoc Ematologia
city: Brescia
country: Italy
facility: Spedali Civili - Azienda Ospedaliera U.O. Ematologia
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Firenze
country: Italy
facility: A.O.U. Careggi - Ematologia
city: Genova
country: Italy
facility: Irccs Aou San Martino - Genova - Uo Clinica Ematologica
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori IRST
city: Milano
country: Italy
facility: Fondazione Irccs "Istituto Nazionale Tumori" - Milano - Sc Ematologia
city: Milano
country: Italy
facility: Ospedale Niguarda "Ca Granda" SC Ematologia
city: Milano
country: Italy
facility: U.O. Ematologia e Trapianto di Midollo Ist. Scientifico Ospedale San Raffaele
city: Pagani
country: Italy
facility: Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia
city: Parma
country: Italy
facility: U.O.C. Ematologia e CTMO Az Ospedaliero Universitaria
city: Pavia
country: Italy
facility: Fondazione Ircss Policlinico San Matteo - Pavia - Uo Ematologia
city: Ravenna
country: Italy
facility: Dipartimento Oncologico - Ospedale S. Maria delle Croci
city: Roma
country: Italy
facility: Università degli Studi "Sapienza" Dip. Biotecnologie Cellulari ed Ematologia
city: Roma
country: Italy
facility: Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia
city: Rozzano
country: Italy
facility: Ististuto Clinico Humanitas - Rozzano - Uo Oncologia Medica Ed Ematologia
city: Salerno
country: Italy
facility: Aou "San Giovanni Di Dio E Ruggi D'Aragona" - Salerno - Uoc Ematologia E Trapianti Di Cellule Staminali Emopoietiche
city: Siena
country: Italy
facility: Aou Senese - Uoc Ematologia E Trapianti
city: Torino
country: Italy
facility: Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia - Università Degli Studi Di Torino
city: Torino
country: Italy
facility: Dipartimento di Oncologia ed Ematologia S.C. -Città della Scienza di Torino San Giovanni Battista
city: Vicenza
country: Italy
facility: Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia
Study officials:
affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) Meldola
name: Giovanni Martinelli
role: STUDY_CHAIR
affiliation: Istituto S. Raffaele, Milan
name: Fabio Ciceri
role: STUDY_DIRECTOR
References: