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Trial registered on ANZCTR


Registration number
ACTRN12616000445471
Ethics application status
Approved
Date submitted
29/03/2016
Date registered
6/04/2016
Date last updated
8/10/2019
Date data sharing statement initially provided
8/10/2019
Type of registration
Prospectively registered

Titles & IDs
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
Secondary ID [1] 288854 0
Nil Known
Universal Trial Number (UTN)
U1111-1181-3420
Trial acronym
CAVEAT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute myeloid leukaemia 298148 0
Condition category
Condition code
Cancer 298312 298312 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 294319 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 297789 0
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.
Timepoint [1] 297789 0
Analysis during induction cycle
Secondary outcome [1] 322252 0
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.
Timepoint [1] 322252 0
After completion of induction therapy
Secondary outcome [2] 322253 0
Response duration by review of medical records
Timepoint [2] 322253 0
Assessed at the end of each cycle of treatment and thereafter until last date of follow up or relapse/progression
Secondary outcome [3] 322254 0
Overall survival as assessed through medical records
Timepoint [3] 322254 0
From day 1 of therapy until last date of follow-up or death
Secondary outcome [4] 322255 0
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).
Timepoint [4] 322255 0
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.
Secondary outcome [5] 322256 0
Composite rate of clinical & laboratory tumor lysis syndrome (severity determined using Cairo-Bishop criteria)
Timepoint [5] 322256 0
Upon reporting of adverse events at any point during the induction cycle.
Secondary outcome [6] 322257 0
Patient reported outcomes through completion of EORTC-QlQ C30 and EQ5D quality of life questionnaires
Timepoint [6] 322257 0
At the end of each cycle of continuation therapy
Secondary outcome [7] 322258 0
Health resource utilization measured by reported days in hospital
Timepoint [7] 322258 0
At the end of induction and continuation cycles
Secondary outcome [8] 322305 0
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).
Timepoint [8] 322305 0
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.

Eligibility
Key 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)
Minimum age
60 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Up to 6 dose escalation cohorts with each subsequent cohort dose determined by dose escalation committee following analysis of dose limiting toxicity during induction.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is a Baysesian study design. Up to 8 patients will be included in each cohort with the aim of demonstrating DLT to be <33% at each dose. 6 dosing cohorts will be examined with the total number of participants not exceeding 48.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5503 0
The Alfred - Prahran
Recruitment hospital [2] 5504 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 5505 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 12984 0
3004 - Melbourne
Recruitment postcode(s) [2] 12986 0
3084 - Heidelberg
Recruitment postcode(s) [3] 12987 0
3050 - Royal Melbourne Hospital

Funding & Sponsors
Funding source category [1] 293214 0
Government body
Name [1] 293214 0
Victorian Cancer Agency
Address [1] 293214 0
50 Lonsdale St, Melbourne, VIC, 3001
Country [1] 293214 0
Australia
Funding source category [2] 293220 0
Commercial sector/Industry
Name [2] 293220 0
Abbvie
Address [2] 293220 0
1 North Waukegan Road North Chicago, IL 60064
Country [2] 293220 0
United States of America
Primary sponsor type
Hospital
Name
Alfred Health
Address
Commercial Road, Melbourne, Victoria, 3004
Country
Australia
Secondary sponsor category [1] 292012 0
None
Name [1] 292012 0
Address [1] 292012 0
Country [1] 292012 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294695 0
Alfred Health Human Research Ethic Committee
Ethics committee address [1] 294695 0
Commercial Road, Melbourne, VIC, 3004
Ethics committee country [1] 294695 0
Australia
Date submitted for ethics approval [1] 294695 0
04/09/2015
Approval date [1] 294695 0
16/02/2016
Ethics approval number [1] 294695 0

Summary
Brief summary
The primary purpose of this trial is to evaluate the safety and efficacy of venetoclax in combination with chemotherapy for the treatment of acute myeloid leukaemia (AML) in elderly patients.
Who is it for?
You may be eligible to participate in this trial if you are aged 60 or over with monosomal karyotype, or aged 65 or over with any karyotype, and have been diagnosed with AML for which you have received no induction chemotherapy.
Study details
All participants enrolled in this trial will be administered Venetoclax in combination with modified-dose chemotherapy. The dose provided will depend on the time of enrolment - each sequentially enrolled group of participants will be administered with a slightly higher dose than the previous group, pending a review of the safety of the previous dose. Participants will have an induction treatment consisting of 14 days Venetoclax tablets, 5 days IV Cytarabine and 2 days IV Idarubicin. For participant achieving a response to treatment there will be up to 4 further cycles of 14 days Venetoclax, 2 days Cytarabine and 1 day Idarubicin or until adequate blood count recovery.
Participants will be assessed through blood samples taken daily during initial hospitalisation and then at the end of each cycle of treatment, bone marrow samples taken 3 times during induction and then every other cycle as well as a physical exam every cycle in order for researchers to monitor whether the treatment is safe and whether it is effectively treating the AML.
It is hoped that the findings of this trial will provide information on the optimal dose of Venetoclax in combination with chemotherapy for the safe and effective treatment of AML in elderly patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64694 0
A/Prof Andrew Wei
Address 64694 0
Alfred Hospital, Commercial Road, Melbourne, VIC, 3004
Country 64694 0
Australia
Phone 64694 0
+61 3 90763451
Fax 64694 0
+61 3 90762298
Email 64694 0
a.wei@alfred.org.au
Contact person for public queries
Name 64695 0
Ms Nola Kennedy
Address 64695 0
Malignant Haematology & Stem Cell Transplantation Service, Alfred Hospital, Commercial Road, Melbourne, VIC, 3004
Country 64695 0
Australia
Phone 64695 0
+61 3 90762217
Fax 64695 0
+61 3 90765531
Email 64695 0
n.kennedy@alfred.org.au
Contact person for scientific queries
Name 64696 0
A/Prof Andrew Wei
Address 64696 0
Alfred Hospital, Commercial Road, Melbourne, VIC, 3004
Country 64696 0
Australia
Phone 64696 0
+61 3 90763451
Fax 64696 0
+61 3 90762298
Email 64696 0
a.wei@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results