Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02287233




Registration number
NCT02287233
Ethics application status
Date submitted
6/11/2014
Date registered
10/11/2014
Date last updated
29/08/2022

Titles & IDs
Public title
A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Participants With Acute Myelogenous Leukemia
Scientific title
A Phase 1/2 Study of Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia Who Are = 60 Years of Age and Who Are Not Eligible for Standard Anthracycline-Based Induction Therapy
Secondary ID [1] 0 0
2014-002610-23
Secondary ID [2] 0 0
M14-387
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myelogenous Leukemia 0 0
AML 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - Venetoclax
Treatment: Drugs - Cytarabine

Experimental: Phase 1: 600 mg Venetoclax + LDAC - Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg (Day 2) and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received low-dose cytarabine (LDAC; 20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.

Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.

Experimental: Phase 1: 800 mg Venetoclax + LDAC - Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 100 mg (Day 2) and increased up to 800 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.

Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.

Experimental: Phase 2: 600 mg Venetoclax + LDAC - Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.

Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.


Treatment: Drugs: Venetoclax
Venetoclax will be taken orally once daily.

Treatment: Drugs: Cytarabine
Low-dose cytarabine will be administered subcutaneously on Days 1 to 10 of each 28-day cycle.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 1: Number of Participants With Dose-limiting Toxicities
Timepoint [1] 0 0
Up to 28 days (Cycle 1)
Primary outcome [2] 0 0
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax
Timepoint [2] 0 0
Cycle 1, Day 10 at predose and 2, 4, 6, 8, and 24 hours postdose (venetoclax with LDAC); Cycle 1, Day 18 at predose, 2, 4, 6, 8, and 24 hours postdose (venetoclax alone)
Primary outcome [3] 0 0
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
Timepoint [3] 0 0
Cycle 1, Day 10 at predose and 2, 4, 6, 8, and 24 hours postdose (venetoclax with LDAC); Cycle 1, Day 18 at predose, 2, 4, 6, 8, and 24 hours postdose (venetoclax alone)
Primary outcome [4] 0 0
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax
Timepoint [4] 0 0
Cycle 1, Day 10 at predose and 2, 4, 6, 8, and 24 hours postdose (venetoclax with LDAC); Cycle 1, Day 18 at predose, 2, 4, 6, 8, and 24 hours postdose (venetoclax alone)
Primary outcome [5] 0 0
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine
Timepoint [5] 0 0
Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
Primary outcome [6] 0 0
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine
Timepoint [6] 0 0
Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
Primary outcome [7] 0 0
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine
Timepoint [7] 0 0
Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
Primary outcome [8] 0 0
Overall Response Rate
Timepoint [8] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Primary outcome [9] 0 0
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Timepoint [9] 0 0
From first dose of study drug until 30 days after last dose of study drug; median (minimum, maximum) duration of treatment was 4.1 (0.2, 62.8) months overall.
Secondary outcome [1] 0 0
Complete Remission Rate
Timepoint [1] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Secondary outcome [2] 0 0
Complete Remission Plus CR With Incomplete Blood Count Recovery (CRi) Rate
Timepoint [2] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Secondary outcome [3] 0 0
CR Plus CRi Rate by Initiation of Cycle 2
Timepoint [3] 0 0
Cycle 2, Day 1
Secondary outcome [4] 0 0
Time to First Response of CR + CRi
Timepoint [4] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Secondary outcome [5] 0 0
Time to Best Response of CR + CRi
Timepoint [5] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Secondary outcome [6] 0 0
Complete Remission With Partial Hematologic Recovery (CRh) Rate
Timepoint [6] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Secondary outcome [7] 0 0
CR Plus CRh Rate
Timepoint [7] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Secondary outcome [8] 0 0
CR Plus CRh Rate by Initiation of Cycle 2
Timepoint [8] 0 0
Cycle 2, Day 1
Secondary outcome [9] 0 0
Time to First Response of CR Plus CRh
Timepoint [9] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Secondary outcome [10] 0 0
Time to Best Response of CR Plus CRh
Timepoint [10] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Secondary outcome [11] 0 0
Best Response Based on IWG Criteria
Timepoint [11] 0 0
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Secondary outcome [12] 0 0
Duration of Complete Response
Timepoint [12] 0 0
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Secondary outcome [13] 0 0
Duration of CR Plus CRi
Timepoint [13] 0 0
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Secondary outcome [14] 0 0
Duration of CRi
Timepoint [14] 0 0
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Secondary outcome [15] 0 0
Duration of CR Plus CRh
Timepoint [15] 0 0
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Secondary outcome [16] 0 0
Overall Survival (OS)
Timepoint [16] 0 0
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Secondary outcome [17] 0 0
Post Baseline Transfusion Independence Rate
Timepoint [17] 0 0
From the first dose of study drug to the last dose of study drug plus 30 days, disease progression (including clinical progression), or death, whichever was earlier; median duration of treatment was 4.2 months.
Secondary outcome [18] 0 0
Post Baseline Transfusion Independence Rate Among Participants Transfusion-dependent at Baseline
Timepoint [18] 0 0
From the first dose of study drug to the last dose of study drug plus 30 days, disease progression (including clinical progression), or death, whichever was earlier; median duration of treatment was 4.2 months.
Secondary outcome [19] 0 0
Duration of Post Baseline Transfusion Independence
Timepoint [19] 0 0
From the first dose of study drug to the last dose of study drug plus 30 days, disease progression (including clinical progression), or death, whichever was earlier; median duration of treatment was 4.2 months.

Eligibility
Key inclusion criteria
* Participant must be greater than or equal to 65 years of age in Phase 1 and 2. Participants enrolled in Cohort C must be either:

* greater than or equal to 75 years of age; OR
* greater than or equal to 60 to 74 years will be eligible if the participants has at least one of the following co-morbidities, which make the participant unfit for intensive chemotherapy:

* Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 - 3;
* Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction less than or equal to 50% or chronic stable angina;
* Diffusion capacity of carbon monoxide (DLCO) less than or equal to 65% or forced expiratory volume in one second (FEV1) less than or equal to 65%;
* Creatinine clearance greater than or equal to 30 mL/min to less than 45 ml/min (calculated by Cockcroft-Gault formula)
* Moderate hepatic impairment with total bilirubin greater than 1.5 to less than or equal to 3.0 × upper limit of normal (ULN)
* Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the study medical monitor before study enrollment
* Participant must have a projected life expectancy of at least 12 weeks.
* Participant must have histological confirmation of AML and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidity or other factors.
* Participant must have received no prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Note: Participant may have been treated for prior Myelodysplastic Syndrome.
* Participant must have an ECOG performance status:

* of 0 to 2 for participants greater than equal to 75 years of age
* of 0 to 3 for participants greater than equal to 60 to 74 years of age, if 0 - 1 another co-morbidity is required to make participant eligible.
* Participant must have adequate renal function as demonstrated by a creatinine clearance greater than or equal to 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.
* Participant must have adequate liver function as demonstrated by:

* aspartate aminotransferase (AST) less than or equal to 2.5 × ULN
* alanine aminotransferase (ALT) less than or equal to 2.5 × ULN
* bilirubin less than or equal to 1.5 × ULN for all participants age 75 and older

* Participants who are less than 75 years of age must have a bilirubin of less than 3.0 × ULN.

Note: Participants with Gilbert's Syndrome may have a bilirubin greater than 1.5 × ULN per discussion between the investigator and AbbVie medical monitor.

* Male participants must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 180 days after the last dose of study drug.
* Participant 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.
* If female, participant must be either:

* Postmenopausal defined as no menses for 12 or more months without an alternative medical cause OR
* Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Participant has received treatment with cytarabine for a pre-existing myeloid disorder.
* Participant has acute promyelocytic leukemia (French-American-British Class M3 AML).
* Participant has known active central nervous system (CNS) involvement with AML.
* Participant has tested positive for human immunodeficiency virus (HIV).
* Participant has received the following within 7 days prior to the initiation of study treatment:

* Strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort.
* Participant has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
* Participant has a cardiovascular disability status of New York Heart Association Class greater than 2.
* Participant has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
* Participant has chronic respiratory disease that requires continuous oxygen use.
* Participant has a malabsorption syndrome or other condition that precludes enteral route of administration.
* Participant exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

* Uncontrolled systemic infection requiring intravenous (IV) therapy (viral, bacterial or fungal).
* Participant 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.
* Participant has a white blood cell count greater than 25 × 10^9/L. Note: Hydroxyurea is permitted to meet this criterion.
* Participant is a candidate for a bone marrow or stem cell transplant within 12 weeks after study enrollment.
* Participant has a history of myeloproliferative neoplasm (MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.

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
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
31/12/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
10/08/2021
Sample size
Target
Accrual to date
Final
94
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Calvary Mater Newcastle /ID# 136076 - Waratah
Recruitment hospital [2] 0 0
Alfred Health /ID# 131180 - Melbourne
Recruitment postcode(s) [1] 0 0
2298 - Waratah
Recruitment postcode(s) [2] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Kansas
Country [2] 0 0
United States of America
State/province [2] 0 0
New York
Country [3] 0 0
United States of America
State/province [3] 0 0
Pennsylvania
Country [4] 0 0
United States of America
State/province [4] 0 0
Tennessee
Country [5] 0 0
United States of America
State/province [5] 0 0
Washington
Country [6] 0 0
Germany
State/province [6] 0 0
Hamburg
Country [7] 0 0
Italy
State/province [7] 0 0
Emilia-Romagna

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AbbVie
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Genentech, Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This study consists of two parts: A Phase 1 dose-escalation part that will evaluate the safety and pharmacokinetic profile of venetoclax in combination with low-dose cytarabine (LDAC), define the maximum tolerated dose (MTD), and generate data to support a recommended Phase 2 dose (RPTD) in treatment-naïve participants with acute myelogenous leukemia (AML); and a Phase 2 part that will evaluate if the RPTD has sufficient efficacy and acceptable toxicity to warrant further development of the combination therapy.
Trial website
https://clinicaltrials.gov/study/NCT02287233
Trial related presentations / publications
Wei AH, Strickland SA Jr, Hou JZ, Fiedler W, Lin TL, Walter RB, Enjeti A, Tiong IS, Savona M, Lee S, Chyla B, Popovic R, Salem AH, Agarwal S, Xu T, Fakouhi KM, Humerickhouse R, Hong WJ, Hayslip J, Roboz GJ. Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study. J Clin Oncol. 2019 May 20;37(15):1277-1284. doi: 10.1200/JCO.18.01600. Epub 2019 Mar 20.
Badawi M, Chen X, Marroum P, Suleiman AA, Mensing S, Koenigsdorfer A, Schiele JT, Palenski T, Samineni D, Hoffman D, Menon R, Salem AH. Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet. Clin Drug Investig. 2022 Aug;42(8):657-668. doi: 10.1007/s40261-022-01172-4. Epub 2022 Jul 13.
Public notes

Contacts
Principal investigator
Name 0 0
ABBVIE INC.
Address 0 0
AbbVie
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02287233