| 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 | 20.0 |
| 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 when co-administered with low dose cytarabine (LDAC) improves overall survival (OS) versus LDAC and placebo, in treatment naïve subjects with acute myeloid leukemia (AML). |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate if venetoclax when co-administered with LDAC improves:
-composite complete remission rate (complete remission + complete remission with incomplete blood count recovery, CR + CRi).
-complete remission and complete remission with partial hematologic recovery rate (CR + CRh)
-the proportion of subjects achieving a composite CR (CR + CRi) by the initiation of Cycle 2
-complete remission rate (CR)
- Event-free survival (EFS)
-the transfusion independence rates
-the proportion of subjects achieving complete remission and complete remission with partial hematologic recovery (CR + CRh) by the Initiation of Cycle 2
-the MRD response rate
-the response rates and overall survival in molecular subgroups (e.g., IDH1/2,FLT3)
•To evaluate if venetoclax when co-administered with LDAC reduces fatigue based on patient reported outcome (PRO) assessment of the Patient Reported Outcomes Measurement Information System
(PROMIS), and Fatigue Short Form (SF) 7a. |
|
| 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 (bone marrow samples and peripheral blasts used for AML diagnosis can be collected within 30 days Prior to randomization).
• Subject must have histological confirmation of AML by WHO criteria, is ineligible for intensive induction chemotherapy and either is:
- ≥ 75 years of age
OR
- ≥ 18 to 74 years of age and fulfill at least one criteria associated with lack of fitness for intensive induction chemotherapy:
o Eastern Cooperative Oncology Group (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
o Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN
o Other comorbidity that the physician judges to be incompatible with conventional intensive chemotherapy which must be reviewed and approved by the study medical monitor before study enrollment
• Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status:
• of 0 to 2 for subjects ≥ 75 years of age OR
• of 0 to 3 for subjects between 18 to 74 years of age
• Subject must have a projected life expectancy of at least 12 weeks.
• 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*
o Subjects who are < 75 years of age may have bilirubin of ≤ 3.0 × ULN
* Unless considered to be due to leukemic organ involvement.
• 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
- 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
- A Woman of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control starting at Study Day 1 through at least 180 days after the last dose of study drug.
• Male subjects who are sexually active, must agree, from Study Day 1 through at least 180 days after the last dose of study drug, to practice the protocol-specified methods of contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 180 days after the last dose of study drug.
• Females 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 with borderline pregnancy tests at screening must have a serum pregnancy test ≥ 3 days later to document continued lack of a positive result.
• Subject must voluntarily sign and date an informed consent form, 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 any prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Note: Prior treatment for Myelodysplastic Syndrome is allowed except for use of cytarabine.
• Subject had an antecedent myeloproliferative neoplasm (MPN) including myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic myelogenous leukemia (CML) with or without BCR-ABL 1 translocation and AML with BCR-ABL1 translocation.
• Subjects that have acute promyelocytic leukemia (APL).
• Subject has known 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, if required per local guidelines or institutional standards.
• Subject is known to be positive for hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals (non-exclusionary medications) are not excluded.
• Subject has received strong or moderate CYP3A inducers 7 days prior to the initiation of study treatment.
- Chinese subjects are excluded from receiving strong and/or moderate CYP3A Inhibitors 7 days Prior to the Initiation of study Treatment through the end of intensive PK collection (24 hours post dose on Cycle 1 Day 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.
• Subject has cardiovascular disability status of New York Heart Association Class > 2. Class 2 is defined as cardiac disease which subjects are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain.
• Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medication including excipients of LDAC 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 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.
• Subject has a white blood cell count > 25 × 109/L. (Note: Hydroxyurea administration or leukapheresis is permitted to meet this criterion).
• Previous treatment with Venetoclay and/or current participation in any other research study with investigational product. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Measured up to 2 years after the last participant is randomized |
|
| E.5.2 | Secondary end point(s) |
- CR + CRi rate
- Event-Free Survival (EFS);
- CR + CRi rate by initiation of Cycle 2.
-Complete remission Rate (CR)
- Patient Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue Short Form [SF] 7a.
-Event-free survival
- Global Health Status/Quality of Life (GHS/QoL) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30)
-CR + CRh rate by the initiation of Cycle 2
-Transfusion independence rates for RBC or platelets
-CR + CRi and MRD response rate
-CR + CRh and MRD response rate |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- EFS: Measured up to 2 years after the last participant
- CR +CRi rate: 6 months after the last participant is randomized
- Fatigue based on the PROMIS Fatigue SF 7a: Measured up to 2 years after the last participant
- GHS/QoL scale from the EORTC QLQ-C30: Measured up to 2 years after the last the last participant
-CR + CRh rate by the initiation of Cycle 2: best one up to cycle 2
-Transfusion independence rates for RBC or platelets: during the treatment period
-CR + CRi and MRD response rate: best one up to cutoff, disease progression, blind broken by site, new post-treatment therapy, new post-treatment of radio therapy, new post-treatment of procedure whichever is earlier
-CR + CRh and MRD response rate: same as CR+CRI and MRD Response rate |
|
| 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 | 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 | 40 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| European Union |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Norway |
| Russian Federation |
| South Africa |
| Taiwan |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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