A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Participants With Acute Myelogenous Leukemia

NCT02287233 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: M14-3872014-002610-23
• Study Type: interventional
• Target: 94
• Locations: 4 countries
• Sites: 9

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.

Conditions

Acute Myelogenous Leukemia; AML

Keywords

Myelogenous Leukemia; Treatment Naive AML; Untreated AML

Outcome Measures

Primary Outcomes (9)

• Phase 1: Number of Participants With Dose-limiting Toxicities

  Dose-limiting toxicities (DLTs) were determined during cycle 1 of the dose-escalation phase and defined as Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 grade 4 (life threatening requiring urgent intervention) or 5 (resulted in death) toxicity, excluding adverse events commonly caused by AML (eg, neutropenia, fever). Hematologic DLT was defined as failure of platelet recovery to 25 × 10\^9/L or greater and absolute neutrophil count (ANC) to 0.5 × 10\^9/L or greater within 14 days of the last dose of venetoclax in the absence of residual AML.

  Up to 28 days (Cycle 1)

• Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax

  The highest concentration that a drug achieves in the blood after administration in a dosing interval.

  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)

• Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax

  The time at which the maximum plasma concentration (Cmax) is observed.

  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)

• Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax

  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)

• Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine

  The highest concentration that a drug achieves in the blood after administration in a dosing interval.

  Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.

• Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine

  The time at which the maximum plasma concentration (Cmax) is observed.

  Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.

• Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine

  Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.

• Overall Response Rate

  Overall response rate (ORR) is defined as the percentage of participants who achieved a complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) per the International Working Group (IWG) for AML response criteria, per investigator assessment. CR: absolute neutrophil count (ANC) ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, red blood cell (RBC) transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with \< 5% blasts. CRi: lack of morphologic evidence of leukemia (blasts \< 5%), and platelet counts \< 10\^5 /µL or ANC \< 10\^3 /µL. PR: all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.

  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.

• Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator rated the severity of each AE according to the CTCAE Version 4.0 and the following: Grade 1: The AE is transient and easily tolerated (mild). Grade 2: The AE causes discomfort and interrupts usual activities (moderate). Grade 3: The AE causes considerable interference with usual activities and may be incapacitating (moderate to severe). Grade 4: The AE is life threatening requiring urgent intervention. Grade 5: The AE resulted in death. The investigator assessed each event as either having a reasonable possibility or no reasonable possibility of being related to the use of study drug. Treatment-emergent events are defined as events that began or worsened in severity after the first dose of study drug.

  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 (19)

• Complete Remission Rate

  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.

• Complete Remission Plus CR With Incomplete Blood Count Recovery (CRi) Rate

  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.

• CR Plus CRi Rate by Initiation of Cycle 2

  Cycle 2, Day 1

• Time to First Response of CR + CRi

  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.

• Time to Best Response of CR + CRi

  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.

Study Arms (3)

Phase 1: 600 mg Venetoclax + LDAC

EXPERIMENTAL

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.

Drug: Venetoclax; Drug: Cytarabine

Phase 1: 800 mg Venetoclax + LDAC

EXPERIMENTAL

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.

Drug: Venetoclax; Drug: Cytarabine

Phase 2: 600 mg Venetoclax + LDAC

EXPERIMENTAL

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.

Drug: Venetoclax; Drug: Cytarabine

Interventions

Venetoclax DRUG

Venetoclax will be taken orally once daily.

Also known as: GDC-0199, ABT-199, VENCLEXTA®

Phase 1: 600 mg Venetoclax + LDAC; Phase 1: 800 mg Venetoclax + LDAC; Phase 2: 600 mg Venetoclax + LDAC

Cytarabine DRUG

Low-dose cytarabine will be administered subcutaneously on Days 1 to 10 of each 28-day cycle.

Phase 1: 600 mg Venetoclax + LDAC; Phase 1: 800 mg Venetoclax + LDAC; Phase 2: 600 mg Venetoclax + LDAC

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• AbbVie: lead
• Genentech, Inc.: collaborator

Study Sites (9)

Univ Kansas Med Ctr /ID# 131175

Kansas City, Kansas, 66160, United States

Location

Weill Cornell Medical College /ID# 131170

New York, New York, 10065, United States

Location

University of Pittsburgh MC /ID# 131168

Pittsburgh, Pennsylvania, 15260, United States

Location

Vanderbilt University Medical Center /ID# 131177

Nashville, Tennessee, 37232-0011, United States

Location

Fred Hutchinson Cancer Research Center /ID# 131178

Seattle, Washington, 98109-1024, United States

Location

Calvary Mater Newcastle /ID# 136076

Waratah, New South Wales, 2298, Australia

Location

Alfred Health /ID# 131180

Melbourne, Victoria, 3004, Australia

Location

Universitaetsklinikum Hamburg-Eppendorf (UKE) /ID# 133979

Hamburg, 20246, Germany

Location

Duplicate_A.O.U. Policlinico S.Orsola-Malpighi /ID# 131183

Bologna, Emilia-Romagna, 40138, Italy

Location

Related Publications (3)

• 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.

  PMID: 30892988 BACKGROUND

• Wei AH, Panayiotidis P, Montesinos P, Laribi K, Ivanov V, Kim I, Novak J, Champion R, Fiedler W, Pagoni M, Bergeron J, Ting SB, Hou JZ, Yamauchi T, Wang J, Strickland SA, Savona MR, Lin TL, Enjeti AK, Tiong IS, Lee S, Roboz GJ, Popovic R, Jiang Q, Liu Z, Sun Y, Mendes WL, Chyla B, DiNardo CD. Risk stratification of low-dose cytarabine and venetoclax in patients with AML ineligible for intensive chemotherapy. Blood Adv. 2025 Nov 21:bloodadvances.2025017083. doi: 10.1182/bloodadvances.2025017083. Online ahead of print.

  PMID: 41269778 DERIVED

• 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.

  PMID: 35829925 DERIVED

Related Links

• This clinical study may be evaluating a usage that is not currently FDA approved. Please see US Prescribing Information for approved uses.

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Myeloid

Interventions

venetoclax; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Global Medical Services
• Organization: AbbVie

abbvieclinicaltrials@abbvie.com

800-633-9110

Study Officials

• ABBVIE INC.

  AbbVie

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 6, 2014
• First Posted: November 10, 2014
• Study Start: December 31, 2014
• Primary Completion: August 10, 2021
• Study Completion: August 10, 2021
• Last Updated: August 29, 2022
• Results First Posted: August 29, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
• Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research, and will be provided following review and approval of a research proposal and statistical analysis plan and execution of a data sharing statement. Data requests can be submitted at any time after approval in the US and/or EU and a primary manuscript is accepted for publication. For more information on the process, or to submit a request, visit the following link https://www.abbvieclinicaltrials.com/hcp/data-sharing/

Locations

AU (2); DE (1); IT (1); US (5)