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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT02287233
Ethics application status
Date submitted
6/11/2014
Date registered
10/11/2014
Date last updated
31/03/2020

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 Greater Than or Equal to 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: Venetoclax + Low-Dose Cytarabine (LDC) - Participants will receive various doses of Venetoclax


Treatment: Drugs: 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.

Treatment: Drugs: Cytarabine
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
Number of participants with adverse events - 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.
Timepoint [1] 0 0
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
Primary outcome [2] 0 0
Maximum tolerated dose (MTD) of venetoclax in combination with cytarabine - 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.
Timepoint [2] 0 0
Up to 28 days
Primary outcome [3] 0 0
Recommended phase two dose (RPTD) of venetoclax in combination with cytarabine - 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.
Timepoint [3] 0 0
Up to 28 days
Primary outcome [4] 0 0
Maximum observed plasma concentration (Cmax) of venetoclax - The highest concentration that a drug achieves in the blood after administration in a dosing interval.
Timepoint [4] 0 0
Pre-dose through 24 hours post-dose on Day 18
Primary outcome [5] 0 0
Time to maximum observed plasma concentration (Tmax) of venetoclax - The time at which the maximum plasma concentration (Cmax) is observed.
Timepoint [5] 0 0
Pre-dose through 24 hours post-dose on Day 18
Primary outcome [6] 0 0
Area Under the Plasma Concentration-Time Curve Over Time from 0 to Last Measurable Concentration (AUCt) of Venetoclax - Area Under the Plasma Concentration-time Curve (AUC) from 0 to last measurable concentration (AUCt) of Venetoclax.
Timepoint [6] 0 0
Pre-dose through 24 hours post-dose on Day 18
Primary outcome [7] 0 0
Area Under the Plasma Concentration-Time Curve Over Time from 0 to 24 hours (AUC0-24) of Venetoclax - Area Under the Plasma Concentration-time Curve (AUC) from 0 to 24 hours (AUC0-24) of venetoclax.
Timepoint [7] 0 0
Pre-dose through 24 hours post-dose on Day 18
Primary outcome [8] 0 0
Maximum observed plasma concentration (Cmax) of cytarabine - The highest concentration that a drug achieves in the blood after administration in a dosing interval.
Timepoint [8] 0 0
Pre-dose through 6 hours post-dose on Day 10
Primary outcome [9] 0 0
Time to maximum observed plasma concentration (Tmax) of cytarabine - The time at which the maximum plasma concentration (Cmax) is observed.
Timepoint [9] 0 0
Pre-dose through 6 hours post-dose on Day 10
Primary outcome [10] 0 0
Terminal Phase Elimination Half-life (t1/2) of Cytarabine In Plasma - Terminal Phase Elimination Half-life (t1/2) of cytarabine in plasma.
Timepoint [10] 0 0
Pre-dose through 6 hours post-dose on Day 10
Primary outcome [11] 0 0
Area Under the Plasma Concentration-Time Curve Over Time from 0 to Last Measurable Concentration (AUCt) of Cytarabine - Area Under the Plasma Concentration-time Curve (AUC) from 0 to last measurable concentration (AUCt) of Cytarabine.
Timepoint [11] 0 0
Pre-dose through 6 hours post-dose on Day 10
Primary outcome [12] 0 0
Area Under the Plasma Concentration-Time Curve Over Time from 0 to Infinity (AUCinf) of Cytarabine - Area Under the Plasma Concentration-time Curve (AUC) from 0 to infinity (AUCinf) of cytarabine.
Timepoint [12] 0 0
Pre-dose through 6 hours post-dose on Day 10
Primary outcome [13] 0 0
Apparent Oral Clearance of Cytarabine (CL/F) - Apparent Oral Clearance of Cytarabine (CL/F).
Timepoint [13] 0 0
Pre-dose through 6 hours post-dose on Day 10
Primary outcome [14] 0 0
Overall Response Rate (Phase 2) - 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.
Timepoint [14] 0 0
Measured up to 4 years after the last participant has enrolled in the study
Primary outcome [15] 0 0
Overall Response Rate- In Phase 2 Cohort C, for Participants Allowed Additional Supportive Medications (e.g Strong CYP3A Inhibitor) If Medically Indicated - 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.
Timepoint [15] 0 0
Measured up to 4 years after the last participant has enrolled in the study
Secondary outcome [1] 0 0
Percentage of Participants Achieving Leukemia Response - 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).
Timepoint [1] 0 0
Measured up to 4 years after the last participant has enrolled in the study
Secondary outcome [2] 0 0
Duration of response (DOR) - 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).
Timepoint [2] 0 0
Measured up to 4 years after the last participant has enrolled in the study
Secondary outcome [3] 0 0
Overall survival (OS) - Overall survival will be defined as the number of days from the date of first dose to the date of death.
Timepoint [3] 0 0
Measured up to 4 years after the last participant has enrolled in the study

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:

- 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 × 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 Eastern Cooperative Oncology Group (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.

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.

- Participant must have adequate liver function as demonstrated by:

- aspartate aminotransferase (AST) less than or equal to 2.5 × upper limit of
normal (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

- 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.

- 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
Gender
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 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
N/A
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
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
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 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.
Trial website
https://clinicaltrials.gov/show/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.
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
Other publications