Trial from ClinicalTrials.gov

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Trial ID
NCT02203773
Ethics application status
Date submitted
10/07/2014
Date registered
10/07/2014
Date last updated
10/07/2017

Titles & IDs
Public title
Phase 1b Acute Myelogenous Leukemia (AML) Study With ABT-199 + Decitabine or Azacitidine (Chemo Combo)
Scientific title
A Phase 1b Study of ABT-199 (GDC-0199) in Combination With Azacitidine or Decitabine in Treatment-Naive Subjects With Acute Myelogenous Leukemia Who Are = 60 Years of Age and Who Are Not Eligible for Standard Induction Therapy
Secondary ID [1] 0 0
2014-000687-18
Secondary ID [2] 0 0
M14-358
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myelogenous Leukemia 0 0
Myelogenous Leukemia 0 0
Treatment Naive 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
Description of intervention(s) / exposure
Treatment: drugs - ABT-199
Treatment: drugs - Decitabine
Treatment: drugs - Azacitidine
Treatment: drugs - Posaconazole

Experimental: ABT-199 + Decitabine - Treatment Naive Acute Myelogenous Leukemia

Experimental: ABT-199 + Azacitidine - Treatment Naive Acute Myelogenous Leukemia

Experimental: ABT-199+Decitibine+Posaconazole - Treatment Naive Acute Myelogenous Leukemia


Treatment: drugs: ABT-199
ABT-199 is taken orally once daily starting on Day 2 of cycle 1 and begin on day 1 of every other cycle thereafter. This is a dose escalation study, therefore the dose of ABT-199 will change.

Treatment: drugs: Decitabine
Decitabine will be administered by IV infusion over 1 hour beginning on Day 1 thru Day 5 of each Cycle for a minimum of 4 Cycles

Treatment: drugs: Azacitidine
Azacitidine will be administered by IV infusion over 10 to 40 minutes or subcutaneously based on the institutional guidelines, beginning on Day 1 through Day 7 of each Cycle, for a minimum of 4 Cycles.

Treatment: drugs: Posaconazole
Posaconazole will be administered twice a day on Cycle 1 Day 21 and once daily from Cycle 1 Day 22 to Cycle 1 Day 28.

Intervention code [1] 0 0
Treatment: drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Adverse Event (AE) monitoring of ABT-199 in combination with decitabine and azacitidine - AE monitoring will be assessed by evaluation of study drug exposure, AEs , serious AEs, all deaths, as well as laboratory determinations and vital sign parameters.
Timepoint [1] 0 0
Measured from Day 1 up to 2 years after the last subject has enrolled
Primary outcome [2] 0 0
Maximum observed plasma concentration (Cmax) - Maximum observed concentration, occurring at Tmax.
Timepoint [2] 0 0
For approximately 5 days following a single dose of ABT-199.
Primary outcome [3] 0 0
The time to Cmax (peak time, Tmax), - The time at which maximum plasma concentration (Cmax) is observed.
Timepoint [3] 0 0
For approximately 5 days following a single dose of ABT-199.
Primary outcome [4] 0 0
The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) - The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration.
Timepoint [4] 0 0
For approximately 5 days following a single dose of ABT-199.
Primary outcome [5] 0 0
AUC from 0-24 (AUC0-24) - The area under the plasma concentration-time curve (AUC) over a 24-hour dose interval.
Timepoint [5] 0 0
For approximately 5 days following a single dose of ABT-199.
Primary outcome [6] 0 0
half-life (t1/2) - The time required for the concentration of the drug to reach half of its original value.
Timepoint [6] 0 0
For approximately 5 days following a single dose of ABT-199.
Primary outcome [7] 0 0
AUC from 0 to infinity (AUC8) - Area under the plasma concentration-versus-time curve from time zero to infinity.
Timepoint [7] 0 0
For approximately 5 days following a single dose of ABT-199.
Primary outcome [8] 0 0
Clearance (CL) - Clearance is defined as the rate at which drug is cleared from the blood.
Timepoint [8] 0 0
For approximately 5 days following a single dose of ABT-199.
Primary outcome [9] 0 0
Complete Remission Rate - Complete Remission Rate will be determined by the number of subjects who achieve a Complete Remission.
Timepoint [9] 0 0
Measured up to 2 years after the last subject enrolled has their last study visit.
Primary outcome [10] 0 0
Complete Remission with incomplete blood count recovery rate - Complete Remission with incomplete blood count recovery Rate will be determined by the number of subjects who achieve a Complete Remission with incomplete blood count recovery.
Timepoint [10] 0 0
Measured up to 2 years after the last subject has their last study visit.
Primary outcome [11] 0 0
Overall Response Rate - Overall response rate will be defined as the proportion of subjects who achieve a complete remission (CR), complete remission incomplete (CRi), or partial remission(PR) per the International Working Group criteria for AML.
Timepoint [11] 0 0
Measured up to 2 years after the last subject enrolled has their last study visit.
Secondary outcome [1] 0 0
Duration of Response - Duration of response will be defined as the number of days from the date of first response per the IWG criteria for AML to the earliest recurrence or progressive disease (PD).
Timepoint [1] 0 0
Measured up to 2 years after the last subject has enrolled in the study.
Secondary outcome [2] 0 0
Overall Survival - Overall survival will be defined as the number of days from the date of enrollment to the date of death.
Timepoint [2] 0 0
Measured up to 2 years after the last subject has enrolled in the study.
Secondary outcome [3] 0 0
Minimal Residual Disease (MRD) Negativity Rate - The presence of less than one AML cell per 10,000 leukocytes in either peripheral blood and/or bone marrow.
Timepoint [3] 0 0
Measured up to 2 years after the last subject has enrolled in the study.
Secondary outcome [4] 0 0
Changes in clinical laboratory test results - chemistry, hematology, and urinalysis
Timepoint [4] 0 0
Measured from Day 1 up to 2 years after the last subject has enrolled in the study.
Secondary outcome [5] 0 0
Changes in physical exam findings, including vital signs. - Body temperature, weight, blood pressure, heart rate, and respiratory rate
Timepoint [5] 0 0
Measured from Day 1 up to 2 years after the last subject has enrolled in the study.
Secondary outcome [6] 0 0
Percent of subjects who move on to stem cell transplant - The percent of subjects who move on to stem cell transplant will be summarized.
Timepoint [6] 0 0
Measure up to 2 years after the last subject has enrolled in the study.
Secondary outcome [7] 0 0
Event Free Survival - Event-free survival (EFS) will be defined as the number of days from the date of first dose to the date of earliest evidence of relapse, subsequent treatment other than stem cell transplant while in composite complete response (CR + CRi), or death.
Timepoint [7] 0 0
Measured up to 2 years after the last subject enrolled has their last study visit.

Eligibility
Key inclusion criteria
1. Subject must have confirmation of AML by WHO criteria25 and be ineligible for
treatment with a standard cytarabine and anthracycline induction regimen due to
co-morbidity or other factors.

2. Subject must have received no prior treatment for AML with the exception of
hydroxyurea.

3. Subject must be = 60 years of age.

4. Subject must have a projected life expectancy of at least 12 weeks.

5. Subject must be considered ineligible for induction therapy defined by the following:

- = 75 years of age; OR

- = 60 to 74 years with at least one of the following co-morbidities:

- ECOG Performance Status of 2 or 3;

- Cardiac history of CHF requiring treatment or Ejection Fraction = 50% or
chronic stable angina;

- DLCO = 65% or FEV1 = 65%;

- Creatinine clearance = 30 mL/min to < 45 ml/min Moderate hepatic impairment
with total bilirubin >1.5 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

6. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status:

- 0 to 2 for subjects = 75 years of age OR

- 0 to 3 for subjects = 60 to 74 years of age.

7. Subject must have adequate renal function as demonstrated by a calculated creatinine
clearance = 30 mL/min; determined via urine collection for 24-hour creatinine
clearance or by the Cockcroft Gault formula.

8. Subject must have adequate liver function as demonstrated by:

- aspartate aminotransferase (AST) = 3.0 × ULN*

- alanine aminotransferase (ALT) = 3.0 × ULN*

- bilirubin = 1.5 × ULN* ? Subjects > 60 to 74 years of age may have bilirubin =
3.0 × ULN* * unless considered due to leukemic organ involvement.

9. Non-sterile male subjects must use contraceptive methods with partner(s) prior to
beginning study drug administration and continuing up to 90 days after the last dose
of study drug. Male subjects must agree to refrain from sperm donation from initial
study drug administration until 90 days after the last dose of study drug.

10. Female subjects must be either:

- Postmenopausal; defined as Age > 55 years with 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
99 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subject has received treatment with the following:

- hypomethylating agent and/or chemo therapeutic agent for Myelodysplastic syndrome
[MDS])

- CAR-T cell therapy

- Other experimental therapies for AML.

2. Subject has history of Myloproliferative Neoplasm (MPN).

3. Subject has favorable risk cytogenetics as categorized by the NCCN Guidelines Version
2, 2016 for Acute Myeloid Leukemia (Appendix D).

4. Subject has t(8;21), inv(16), t(16;16) or t(15;17) karyotype abnormalities.

5. Subject has acute promyelocytic leukemia.

6. Subject has known active CNS involvement from AML.

7. Subject is known to be positive for HIV. Note: HIV testing is not required.

8. Subject is known to be positive for hepatitis B or C infection with the exception of
those with an undetectable viral load. Note: Hepatitis B or C testing is not required
and subjects with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-,
anti-HBs+ and anti-HBc-) may participate.

9. Subject has received a strong and/or moderate CYP3A inducer within 7 days prior to the
initiation of study treatment.

10. Subject has consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or Star fruit within 3 days prior to the
initiation of study treatment.

11. Subject has any history of clinically significant condition(s) that in the opinion of
the investigator would adversely affect his/her participating in this study including,
but not limited to:

- cardiovascular disability status of New York Heart Association Class = 2. Class 2
is defined as cardiac disease in which patients are comfortable at rest but
ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal
pain.

- renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic,
cardiovascular disease, or bleeding disorder independent of leukemia,

- chronic respiratory disease that requires continuous oxygen use.

12. Subject has a malabsorption syndrome or other condition that precludes enteral route
of administration.

13. Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral,
bacterial or fungal).

14. Subject 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.

15. Subject has a white blood cell count > 25 × 109/L. Note: Hydroxyurea is permitted to
meet this criterion.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
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
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
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
Current
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Centre /ID# 130352 - East Melbourne
Recruitment hospital [2] 0 0
St. George Hospital /ID# 130356 - Kogarah
Recruitment hospital [3] 0 0
Alfred Health /ID# 130353 - Melbourne
Recruitment postcode(s) [1] 0 0
3002 - East Melbourne
Recruitment postcode(s) [2] 0 0
2217 - Kogarah
Recruitment postcode(s) [3] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
Country [5] 0 0
United States of America
State/province [5] 0 0
Maryland
Country [6] 0 0
United States of America
State/province [6] 0 0
Massachusetts
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
North Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Texas
Country [10] 0 0
United States of America
State/province [10] 0 0
Washington
Country [11] 0 0
France
State/province [11] 0 0
Paris Cedex 10
Country [12] 0 0
France
State/province [12] 0 0
Pessac Cedex
Country [13] 0 0
France
State/province [13] 0 0
Toulouse, Cedex 09
Country [14] 0 0
Germany
State/province [14] 0 0
Dresden
Country [15] 0 0
Germany
State/province [15] 0 0
Leipzig
Country [16] 0 0
Germany
State/province [16] 0 0
Muenchen
Country [17] 0 0
Germany
State/province [17] 0 0
Ulm

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 is a Phase 1b, open-label, non-randomized, multicenter study to evaluate the safety of
orally administered ABT-199 combined with decitabine or azacitidine and the preliminary
efficacy of these combinations. In addition, there is a DDI sub-study only at a single site,
to assess the pharmacokinetics and safety of ABT-199 in combination with posaconazole.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Jalaja Potluri, MD
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
Contact person responsible for updating information