| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To evaluate if venetoclax in combination with azacitidine will improve overall survival (OS) and composite complete remission rate (complete remission + complete remission with incomplete marrow recovery; CR/CRi) versus placebo in combination with azacitidine, in treatment naïve subjects with acute myeloid leukemia (AML). |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate if venetoclax in combination with azacitidine will improve the rate of CR.
•To evaluate if venetoclax in combination with azacitidine will improve the rate of CR and complete remission with partial hematologic recovery rate (CRh).
•To evaluate if venetoclax in combination with azacitidine:
-will improve the proportion of subjects achieving composite complete remission (CR or CRi) by initiation of Cycle 2.
-will improve the transfusion independence rate.
-will improve the MRD response rate
-will improve the response rates and overall survival in molecular subgroups.
-reduces fatigue and improves global health status/quality of life (GHS/QoL) based on patient reported outcome (PRO) assessments (Patient Reported Outcomes Measurement Information System [PROMIS], Cancer Fatigue Short Form [SF] 7a and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core [EORTC QLQ-C30]).
-will improve, event-free survival (EFS). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for study participation if he/she meets the following criteria within 21 days prior to randomization.
● Subject must have confirmation of AML by WHO criteria and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due age or comorbidities.
● Subject must be ≥ 18 years of age.
● Subject must have a projected life expectancy of at least 12 weeks.
● Subject must be considered ineligible for induction therapy defined by the following:
- ≥ 75 years of age; OR
- ≥ 18 to 74 years of age 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 AbbVie TA MD before study enrollment.
● 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 ≥ 18 to 74 years of age.
● Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.
● 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*
* Unless considered to be due to leukemic organ involvement
o Subjects who are < 75 years of age may have a bilirubin of ≤ 3.0 × ULN
● Female subjects must be either postmenopausal defined as:
- Age > 55 years with no menses for 12 or more months without an alternative medical cause
- Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an FSH level > 40 IU/L.
OR
- Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
OR
- Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control, starting at Study Day 1 through at least 90 days after the last dose of study drug.
● Male subjects who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice the protocol specified contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 90 days after the last dose of study drug.
● Female subjects of childbearing potential must have negative results for pregnancy test performed:
- At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and
- Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy test results.
● Subject 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.
|
|
| E.4 | Principal exclusion criteria |
● Subject has received treatment with the following:
- A hypomethylating agent, venetoclax and/or chemo therapeutic agent for Myelodysplastic syndrome (MDS).
- CAR-T cell therapy
- Experimental therapies for MDS or AML.
-Current participation in another research or observational study.
● Subject has history of myeloproliferative neoplasm (MPN).
● Subject has the following:
- Favorable risk cytogenetics such as t(8;21), inv(16) or t(16;16) or t(15;;17) as per the NCCN Guidelines Version 2, 2016 for Acute Myeloid Leukemia.
● Subject has acute promyelocytic leukemia
● Subject has known active CNS involvement with AML.
● Subject has known HIV infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax) HIV testing will be performed at
Screening, only if required per local guidelines or institutional standards.
● Subject is known to be positive for hepatitis B or C infection [HCV Ab indicative of a previous or current infection; and/or positive HBs Ag or detected sensitivity on
HBV-DNA PCR test for HBc Ab and/or HBs Ab positivity] with the exception of those with an undetectable viral load within 3 months of screening. (Hepatitis B or C testing is not required). Subjects with serologic evidence of prior vaccination to HBV [i.e., HBs Ag-, and anti-HBs+] may participate.
● Subject has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
-Chinese AML subjects participating in the safety cohort per Appendix K are also excluded from receiving strong and/or moderate CYP3A inhibitors from 7 days prior to the initiation of study treatment through the entire dose limiting toxicity (DLT)/safety evaluation period.
● 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.
● Subject has a 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.
● Subject has chronic respiratory disease that requires continuous oxygen, or 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.
● Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
● Subject exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).
● Subject has a history of other malignancies within 2 years prior to study entry, with the exception of:
- Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
- 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 ;requires discussion with TA MD.
● Subject has a white blood cell count > 25 × 109/L. (Hydroxyurea or leukapheresis are permitted to meet this criterion.)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Rate of complete remission (CR) or complete remission with incomplete marrow recovery (CRi)
2. Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Every 2 months for 1 year after the last subject has been enrolled into the study
2. Measured up to 2 years after the last participant is randomized |
|
| E.5.2 | Secondary end point(s) |
1. Event-Free Survival (EFS)
2. CR + CRi rate by the initiation of Cycle 2
3. Patient Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue Short Form [SF] 7a and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core [EORTC QLQ-C30]).
4. CR rate
5. CR + CRh rate
6. post-baseline transfusion independence rate
7. MRD response rate
8. Response rates and OS in molecular subgroups
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Measured up to 2 years after the last participant is randomized
2. 6 months after the last participant is randomized
3. Measured at participant's Day 1 of Cycle 1 and at Day 1 of every Cycle thereafter for up to 2 years following the last subject last visit
4. Measured up to 2 years after the last participant is randomized
5. 6 months after the last participant is randomized
6. Measured up to 2 years after the last participant is randomized
7. Measured up to 2 years after the last participant is randomized
8. Measured up to 2 years after the last participant is randomized
|
|
| 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 | No |
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 82 |
| 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 |
| Brazil |
| Canada |
| China |
| European Union |
| Israel |
| Japan |
| Korea, Republic of |
| Norway |
| Puerto Rico |
| Russian Federation |
| South Africa |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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