A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Participants With Acute Myelogenous Leukemia
Study Details
Study Description
Brief Summary
This study consists of two portions: The first portion- Phase 1, or dose-escalation portion, that will evaluate the safety and pharmacokinetic profile of venetoclax in combination with low-dose cytarabine (LDC), 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). Second portion, initial Phase 2 that will evaluate if the RPTD has sufficient efficacy and acceptable toxicity to warrant further development of the combination therapy. Subsequently, Phase 2 Cohort C, will evaluate the overall response rate (ORR) for participants allowed additional supportive medications (strong Cytochrome P450 3A (CYP3A )inhibitors) if medically indicated.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Venetoclax + Low-Dose Cytarabine (LDC) Participants will receive various doses of Venetoclax |
Drug: Venetoclax
Venetoclax will be taken orally once daily on Days 1 through 28 of each cycle. This is a dose escalation study, therefore the dose of venetoclax will change.
Other Names:
Drug: Cytarabine
Cytarabine will be administered subcutaneously on Days 1 to 10 of each 28-day cycle.
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Outcome Measures
Primary Outcome Measures
- Number of participants with adverse events [From participant's first dose until 30 days after participant's last dose of study drug; up to 4 years following last participant first dose]
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 assessed each event as either having a reasonable possibility or no reasonable possibility of being related to the use of study drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs) are defined as any event that began or worsened in severity after the first dose of study drug.
- Maximum tolerated dose (MTD) of venetoclax in combination with cytarabine [Up to 28 days]
Venetoclax will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicity information from all participants.
- Recommended phase two dose (RPTD) of venetoclax in combination with cytarabine [Up to 28 days]
Venetoclax will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicity information from all participants.
- Maximum observed plasma concentration (Cmax) of venetoclax [Pre-dose through 24 hours post-dose on Day 18]
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
- Time to maximum observed plasma concentration (Tmax) of venetoclax [Pre-dose through 24 hours post-dose on Day 18]
The time at which the maximum plasma concentration (Cmax) is observed.
- Area Under the Plasma Concentration-Time Curve Over Time from 0 to Last Measurable Concentration (AUCt) of Venetoclax [Pre-dose through 24 hours post-dose on Day 18]
Area Under the Plasma Concentration-time Curve (AUC) from 0 to last measurable concentration (AUCt) of Venetoclax.
- Area Under the Plasma Concentration-Time Curve Over Time from 0 to 24 hours (AUC0-24) of Venetoclax [Pre-dose through 24 hours post-dose on Day 18]
Area Under the Plasma Concentration-time Curve (AUC) from 0 to 24 hours (AUC0-24) of venetoclax.
- Maximum observed plasma concentration (Cmax) of cytarabine [Pre-dose through 6 hours post-dose on Day 10]
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
- Time to maximum observed plasma concentration (Tmax) of cytarabine [Pre-dose through 6 hours post-dose on Day 10]
The time at which the maximum plasma concentration (Cmax) is observed.
- Terminal Phase Elimination Half-life (t1/2) of Cytarabine In Plasma [Pre-dose through 6 hours post-dose on Day 10]
Terminal Phase Elimination Half-life (t1/2) of cytarabine in plasma.
- Area Under the Plasma Concentration-Time Curve Over Time from 0 to Last Measurable Concentration (AUCt) of Cytarabine [Pre-dose through 6 hours post-dose on Day 10]
Area Under the Plasma Concentration-time Curve (AUC) from 0 to last measurable concentration (AUCt) of Cytarabine.
- Area Under the Plasma Concentration-Time Curve Over Time from 0 to Infinity (AUCinf) of Cytarabine [Pre-dose through 6 hours post-dose on Day 10]
Area Under the Plasma Concentration-time Curve (AUC) from 0 to infinity (AUCinf) of cytarabine.
- Apparent Oral Clearance of Cytarabine (CL/F) [Pre-dose through 6 hours post-dose on Day 10]
Apparent Oral Clearance of Cytarabine (CL/F).
- Overall Response Rate (Phase 2) [Measured up to 4 years after the last participant has enrolled in the study]
Overall response rate will be defined as the percentage of participants who achieve a complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) per the International Working Group (IWG) for AML.
- Overall Response Rate- In Phase 2 Cohort C, for Participants Allowed Additional Supportive Medications (e.g Strong CYP3A Inhibitor) If Medically Indicated [Measured up to 4 years after the last participant has enrolled in the study]
Overall response rate will be defined as the percentage of participants who achieve a complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) per the International Working Group (IWG) for AML.
Secondary Outcome Measures
- Percentage of Participants Achieving Leukemia Response [Measured up to 4 years after the last participant has enrolled in the study]
Leukemia response is defined as percentage of participants achieving Complete Remission (CR), Complete Remission with incomplete blood count recovery (CRi), partial remission (PR), or Morphologically Leukemia Free Status (MLFS).
- Duration of response (DOR) [Measured up to 4 years after the last participant has enrolled in the study]
Duration of response will be defined as the number of days from the date of first response (CR, CRi, or PR) per the IWG criteria for AML to the earliest recurrence or progressive disease (PD).
- Overall survival (OS) [Measured up to 4 years after the last participant has enrolled in the study]
Overall survival will be defined as the number of days from the date of first dose to the date of death.
Eligibility Criteria
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:
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greater than or equal to 75 years of age; OR
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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:
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ECOG Performance Status of 2 - 3;
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Cardiac history of congestive heart failure (CHF) requiring treatment or Ejection Fraction less than or equal to 50% or chronic stable angina;
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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%;
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Creatinine clearance greater than or equal to 30 mL/min to less than 45 ml/min (calculated by Cockcroft-Gault formula)
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Moderate hepatic impairment with total bilirubin greater than 1.5 to less than or equal to 3.0 × ULN
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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
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Participant must have a projected life expectancy of at least 12 weeks.
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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.
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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.
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Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status;
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of 0 to 2 for participants greater than equal to 75 years of age
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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.
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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.
Note: Investigators should consider measuring a 24-hour creatinine clearance for subjects who are morbidly obese, have fluctuating renal function, or who in the investigator's clinical judgment may yield a more accurate clearance when measured than when calculated.
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Participant must have adequate liver function as demonstrated by:
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aspartate aminotransferase (AST) less than or equal to 2.5 × upper limit of normal (ULN)*
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alanine aminotransferase (ALT) less than or equal to 2.5 × ULN*
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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
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Unless considered due to leukemic organ involvement. Note: Participants with Gilbert's Syndrome may have a bilirubin greater than 1.5 × ULN per discussion between the investigator and AbbVie medical monitor.
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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.
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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.
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If female, participant must be either:
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Postmenopausal defined as no menses for 12 or more months without an alternative medical cause OR
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Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
Exclusion Criteria:
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Participant has received treatment with cytarabine for a pre-existing myeloid disorder.
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Participant has acute promyelocytic leukemia (French-American-British Class M3 AML).
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Participant has known active central nervous system (CNS) involvement with AML.
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Participant has tested positive for human immunodeficiency virus (HIV).
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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.
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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.
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Participant has a cardiovascular disability status of New York Heart Association Class greater than 2.
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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.
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Participant has chronic respiratory disease that requires continuous oxygen use.
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Participant has a malabsorption syndrome or other condition that precludes enteral route of administration.
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Participant exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
-- Uncontrolled systemic infection requiring IV therapy (viral, bacterial or fungal).
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Participant has a history of other malignancies prior to study entry, with the exception of:
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Adequately treated in situ carcinoma of the breast or cervix uteri;
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Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
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Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
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Participant has a white blood cell count greater than 25 × 10^9/L. Note: Hydroxyurea is permitted to meet this criterion.
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Participant is a candidate for a bone marrow or stem cell transplant within 12 weeks after study enrollment.
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Participant has a history of myeloproliferative neoplasm (MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Univ Kansas Med Ctr /ID# 131175 | Kansas City | Kansas | United States | 66160 |
| 2 | Weill Cornell Medical College /ID# 131170 | New York | New York | United States | 10065 |
| 3 | University of Pittsburgh MC /ID# 131168 | Pittsburgh | Pennsylvania | United States | 15260 |
| 4 | Vanderbilt University Medical Center /ID# 131177 | Nashville | Tennessee | United States | 37232-0011 |
| 5 | Fred Hutchinson Cancer Research Center /ID# 131178 | Seattle | Washington | United States | 98109-1024 |
| 6 | Calvary Mater Newcastle /ID# 136076 | Waratah | New South Wales | Australia | 2298 |
| 7 | Alfred Health /ID# 131180 | Melbourne | Victoria | Australia | 3004 |
| 8 | Universitaetsklinikum Hamburg-Eppendorf (UKE) /ID# 133979 | Hamburg | Germany | 20246 | |
| 9 | Duplicate_A.O.U. Policlinico S.Orsola-Malpighi /ID# 131183 | Bologna | Emilia-Romagna | Italy | 40138 |
Sponsors and Collaborators
- AbbVie
- Genentech, Inc.
Investigators
- Study Director: ABBVIE INC., AbbVie
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- M14-387
- 2014-002610-23