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

AbbVie

Status and phase: Completed; Phase 2; Phase 1

Conditions: AML; Acute Myelogenous Leukemia

Treatments: Drug: Venetoclax; Drug: Cytarabine

Study type: Interventional

Funder types: Industry

Identifiers

NCT02287233

2014-002610-23 (EudraCT Number)

M14-387

Details and patient eligibility

About

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.

Enrollment: 94 patients

Sex: All

Ages: 60+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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94 participants in 3 patient groups

Phase 1: 600 mg Venetoclax + LDAC

Experimental group

Description:

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.

Treatment:

Drug: Cytarabine

Drug: Venetoclax

Phase 1: 800 mg Venetoclax + LDAC

Experimental group

Description:

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.

Treatment:

Drug: Cytarabine

Drug: Venetoclax

Phase 2: 600 mg Venetoclax + LDAC

Experimental group

Description:

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:

Drug: Cytarabine

Drug: Venetoclax