A phase Ib clinical evaluation of Venetoclax in combination with chemotherapy in older patients with Acute Myeloid Leukemia

• Register: ANZCTR
• Last refreshed on: 13 January 2020
• Main ID: ACTRN12616000445471
• Date of registration: 06/04/2016
• Prospective Registration: Yes
• Primary sponsor: Alfred Health
• Public title: A phase Ib clinical evaluation of Venetoclax in combination with chemotherapy in older patients with Acute Myeloid Leukemia
• Scientific title: A phase Ib clinical evaluation of Venetoclax in combination with chemotherapy in older patients with Acute Myeloid Leukemia
• Date of first enrolment: 12/07/2016
• Target sample size: 48
• Recruitment status: Recruiting
• URL: https://anzctr.org.au/ACTRN12616000445471.aspx
• Study type: Interventional
• Study design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Other;Type of endpoint: Safety/efficacy;
• Phase: Phase 1 / Phase 2

Countries of recruitment

Australia

Contacts

• Name: A/Prof Andrew Wei

• Name: Ms Nola Kennedy

Key inclusion & exclusion criteria

Inclusion criteria: 1. De novo, secondary or therapy-related AML (except Acute Promyelocytic Leukaemia) without prior exposure to induction chemotherapy (not including hydroxyurea, low-dose cytarabine eg ~20mg bd, hypomethylating agents or non-chemotherapy-based investigational agents)
2. Age greater than or equal to 65
3. Or Age greater than or equal to 60 and monosomal karyotype
4. ECOG performance status 0-1
5. Adequate hepatic function as defined by bilirubin less than or equal to 1.5 x the upper limit of normal (ULN, excluding Gilbert’s syndrome) and AST & ALT less than or equal to 2.5 x ULN (unless due to leukemic involvement)
6. Adequate renal function as defined by eGFR>50ml/min as assessed by eCCr =(140 – Age) x (Weight in kg) x [1.23 if Male, 1.04 if Female]/Serum Creatinine (micromol/L)
7. WCC less than 25 x 109/L (hydroxyurea allowable to reduce WCC prior to day 1 of study)

Exclusion criteria: 1. Prior investigational anti-leukemia agents within 14 days of day 1 of study drug; demethylating agents within 14 days of day 1 of study drug; and hydroxyurea within 24 hrs prior to day 1 of study drug.
2. Prior exposure to Venetoclax or other BCL2 inhibitors
3. Prior anthracycline exposure for previous cancer
4. Any serious medical condition which the investigator feels may lead to an unacceptably high risk of treatment related death from 5+2 induction
5. Concurrent malignancy likely to affect treatment safety or study procedures
6. Known HIV infection
7. Uncontrolled viral hepatitis type B or C
8. Males with a female partner of childbearing potential must agree to use at least 2 effective contraceptive methods throughout the study and for 30 days following the date of last dose
9. Cardiac ejection fraction <45%
10. Subject has received the following within 7 days prior to the initiation of study treatment:
*Potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort;
*Warfarin or requires the use of warfarin (due to potential drug-drug interactions that may potentially increase the exposure of warfarin and complications of this effect).
11. Subject has received the following within 5 days prior to the initiation of study treatment:
* CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin.
12. Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
13. Subject has a history of other malignancies prior to study entry, with the exception of:
*Adequately treated in situ carcinoma of the breast or cervix uteri;
*Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
*Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
*Prior malignancy treated >4 years ago and no evidence of active disease


Age minimum: 60 Years
Age maximum: No limit
Gender: Both males and females

Health Condition(s) or Problem(s) studied

Cancer - Leukaemia - Acute leukaemia

Acute myeloid leukaemia;
Acute myeloid leukaemia

Intervention(s)

Dosage for Cohort 1

Induction cycle: Venetoclax 50mg oral tablet days 1-14 (of 28), Cytarabine 100mg/m2/d CIV days 8-12, Idarubicin 12mg/m2/d IV bolus days 9-10
Continuation (4 cycles) for patients achieving CR, Cri, PR, PRm: Venetoclax 50mg oral tablet days 1-14 (of 28), Cytarabine 100mg/m2/d CIV days 8-9, Idarubicin 12mg/m2/d IV bolus day 8
Maintenance (max 7 cycles at discretion of physician and patient): Venetoclax 50mg oral tablet days 1-14 (of 28)
Venetoclax monitoring through empty bottle return.

Subsequent Cohorts
Cytarabine and Idarubicin doses to remain the same for subsequent cohorts (up to 6). Venetoclax dosage increasing per cohort in increments of up to 100mg per day to a maximum possible dose of 800mg per day. Dose levels for each subsequent cohort to be determined following review by dose escalation committee.

Primary Outcome(s)

To assess the safety of Venetoclax in combination with idarubicin and cytarabine in frontline AML therapy through analysis of dose limiting toxicity during induction in each cohort. Fever, low red blood cell count, low white blood cell count, low platelet count, fever, tumor lysis syndrome and other adverse reactions/events to be assessed through review of peripheral blood examinations and other medical records.[Analysis during induction cycle]

Secondary Outcome(s)

Health resource utilization measured by reported days in hospital[At the end of induction and continuation cycles]

Response duration by review of medical records[Assessed at the end of each cycle of treatment and thereafter until last date of follow up or relapse/progression]

Composite rate of clinical & laboratory tumor lysis syndrome (severity determined using Cairo-Bishop criteria)[Upon reporting of adverse events at any point during the induction cycle.]

Patient reported outcomes through completion of EORTC-QlQ C30 and EQ5D quality of life questionnaires[At the end of each cycle of continuation therapy]

Time to partial hematopoietic recovery defined as median days from day 1 of investigational therapy until first day neutrophils 0.5 x 10^9/L and platelets 50 x 10^9/L (only evaluated in those with CRi).[Assessed days 1-8 and 28 of investigational therapy until end of induction cycle and thereafter at the end of each cycle until time of full hematopoietic recovery.]

Composite clinical response rate (LeukemiaNet criteria - Complete Response, Complete Response with Incomplete Recovery, Partial Response, Partial Marrow Response, Failure) assessed through review of bone marrow and peripheral blood examination and other medical records.[After completion of induction therapy]

Time to full hematopoietic recovery defined as median days from day 1 of investigational therapy until first day neutrophils 1 x 10^9/L and platelets 100 x 10^9/L (only evaluated in those with CR).[Assessed days 1-8 and 28 of investigational therapy until end of induction cycle and thereafter at the end of each cycle until time of full hematopoietic recovery.]

Overall survival as assessed through medical records[From day 1 of therapy until last date of follow-up or death]

Secondary ID(s)

Nil Known

Source(s) of Monetary Support

Victorian Cancer Agency

Abbvie

Ethics review

Status: Approved
Approval date:
Contact:

Alfred Health Human Research Ethic Committee