E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Myelogenous Leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the blood and bone marrow |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001941 |
E.1.2 | Term | AML |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
● The primary objectives of the Phase 1 portion are to assess the safety profile, characterize pharmacokinetics (PK), determine the dose schedule, the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RPTD) of venetoclax (ABT-199/GDC-0199) in combination with LDC in treatment-naïve subjects with AML who are ≥ 65 years of age and who are not eligible for standard induction therapy due to co-morbidity or other factors.
● The primary objective of the initial Phase 2 portion of the study is to evaluate the leukemia response rate and duration and characterize the toxicities of the combination at the Recommended Phase 2 Dose (RPTD).
● The primary objective of Phase 2 Cohort C is to evaluate the ORR for subjects allowed additional supportive medications (strong CYP3A inhibitors) if medically indicated.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the initial Phase 2 portion and Phase 2 Cohort C are to evaluate leukemia response (rates of CR, CRi, PR, and MLFS), duration of response (DOR) and overall survival (OS).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 1. Subject must be ≥ 65 years of age in Phase 1 and initial Phase 2.
Subjects enrolled in Phase 2 Cohort C must be either:
- ≥ 75 years of age;
OR
- ≥ 60 to 74 years will be eligible if the subject has at least one of the following co-morbidities, which make the subject unfit for intensive chemotherapy:
o ECOG Performance Status of 2 – 3;
o Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina;
o DLCO ≤ 65% or FEV1 ≤ 65%;
o Creatinine clearance ≥ 30 mL/min to < 45 mL/min (calculated by
Cockcroft-Gault formula);
o Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 ×ULN;
o 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..
2. Subject must have a projected life expectancy of at least 12 weeks.
3. Subject 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.
4. Subject must have received no prior treatment for AML with the exception of hydroxyurea, allowed through first cycle of treatment. NOTE: Subject may have been treated for prior Myelodysplastic Syndrome.
5. Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance.
6. Subject must have adequate liver function as demonstrated by:
- aspartate aminotransferase (AST) ≤ 2.5 × ULN*
- alanine aminotransferase (ALT) ≤ 2.5 × ULN*
- bilirubin ≤ 1.5 × ULN for subjects who are < 75 years of age must have a bilirubin of < 3.0 × ULN
*Unless considered due to leukemic organ involvement.
Note: Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN per discussion between the investigator and AbbVie medical monitor.
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E.4 | Principal exclusion criteria |
1. Subject has received treatment with cytarabine for a pre-existing myeloid disorder.
2. Subject has acute promyelocytic leukemia .
3. Subject has known active CNS involvement with AML.
4. Subject has tested positive for HIV (due to potential drug-drug interactions between antiretroviral medications and venetoclax, as well as anticipated venetoclax mechanism-based lymphopenia that may potentially increase the risk of opportunistic infections). Note: HIV testing is not required.
5. Subject 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.
6. Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
7. Subject has a cardiovascular disability status of New York Heart Association Class > 2. Class 2 is defined as cardiac disease in which subjects are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
8. Subject has a white blood cell count > 25 × 10 9/L. Note: Hydroxyurea is permitted to meet this criterion.
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E.5 End points |
E.5.1 | Primary end point(s) |
● Phase 1: Safety profile, characterize PK, maximum tolerated dose (MTD) and recommended phase 2 dose (RPTD)
● Phase 2: Overall response rate (ORR), Event Free Survival (EFS), and to characterize the toxicities of the combination at the RPTD.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
First week of treatment (MTD); throughout the study (Safety); Cycle 1 Day 1, Cycle 1 Day 10 and Cycle 1 Day 18 (PK); Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, every 12 Weeks thereafter and as clinically indicated and final visit (MRD and other phase 2 primary end points) |
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E.5.2 | Secondary end point(s) |
Phase 2: Response rates of CR, CRi, PR, RD, and HR, and Duration of Response (DOR) and overall survival (OS). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, every 12 Weeks thereafter and as clinically indicated and final visit (MRD and other phase 2 primary end points) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
safety, pharmacodynamic and pharmacokinetic |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Germany |
Italy |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is defined as the date of the last subject's last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |