Clinical trial NCT02287233: A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Participants With Acute Myelogenous Leukemia
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Myelogenous Leukemia
AML
Keywords: Myelogenous Leukemia
Treatment Naive AML
Untreated AML
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
First posted: 2014-11-10
Enrollment: 94
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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)

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.

Primary outcomes:
measure: Phase 1: Number of Participants With Dose-limiting Toxicities
timeFrame: Up to 28 days (Cycle 1)
measure: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax
timeFrame: 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)
measure: Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
timeFrame: 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)
measure: Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax
timeFrame: 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)
measure: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine
timeFrame: Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
measure: Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine
timeFrame: Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
measure: Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine
timeFrame: Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
measure: Overall Response Rate
timeFrame: 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.
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: 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 outcomes:
measure: Complete Remission Rate
timeFrame: 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.
measure: Complete Remission Plus CR With Incomplete Blood Count Recovery (CRi) Rate
timeFrame: 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.
measure: CR Plus CRi Rate by Initiation of Cycle 2
timeFrame: Cycle 2, Day 1
measure: Time to First Response of CR + CRi
timeFrame: 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.
measure: Time to Best Response of CR + CRi
timeFrame: 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.
measure: Complete Remission With Partial Hematologic Recovery (CRh) Rate
timeFrame: 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.
measure: CR Plus CRh Rate
timeFrame: 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.
measure: CR Plus CRh Rate by Initiation of Cycle 2
timeFrame: Cycle 2, Day 1
measure: Time to First Response of CR Plus CRh
timeFrame: 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.
measure: Time to Best Response of CR Plus CRh
timeFrame: 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.
measure: Best Response Based on IWG Criteria
timeFrame: 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.
measure: Duration of Complete Response
timeFrame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
measure: Duration of CR Plus CRi
timeFrame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
measure: Duration of CRi
timeFrame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
measure: Duration of CR Plus CRh
timeFrame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
measure: Overall Survival (OS)
timeFrame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
measure: Post Baseline Transfusion Independence Rate
timeFrame: 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.
measure: Post Baseline Transfusion Independence Rate Among Participants Transfusion-dependent at Baseline
timeFrame: 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.
measure: Duration of Post Baseline Transfusion Independence
timeFrame: 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.
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: Univ Kansas Med Ctr /ID# 131175
state: Kansas
city: New York
country: United States
facility: Weill Cornell Medical College /ID# 131170
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh MC /ID# 131168
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center /ID# 131177
state: Tennessee
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center /ID# 131178
state: Washington
city: Waratah
country: Australia
facility: Calvary Mater Newcastle /ID# 136076
state: New South Wales
city: Melbourne
country: Australia
facility: Alfred Health /ID# 131180
state: Victoria
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf (UKE) /ID# 133979
city: Bologna
country: Italy
facility: Duplicate_A.O.U. Policlinico S.Orsola-Malpighi /ID# 131183
state: Emilia-Romagna
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.