| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RARA-positive acute myeloid leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Untreated adult patients with acute myeloid leukemia who have high levels of the RARA biomarker in their blood |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000880 |
| E.1.2 | Term | Acute myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Part 1
Characterize the safety and tolerability of tamibarotene/venetoclax/azacitidine combination
in RARA-positive, previously untreated AML patients to inform Part 2 dose and regimen of the
tamibarotene/venetoclax/azacitidine therapy
Part 2
Characterize and compare the CR/CRi rate of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine |
|
| E.2.2 | Secondary objectives of the trial |
Part 1
• Characterize the ORR of tamibarotene/venetoclax/azacitidine combination
• Characterize PK of tamibarotene when administered as a part of tamibarotene/venetoclax/azacitidine therapy
Part 2
• Characterize the safety and tolerability of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine in RARA-positive, previously untreated AML patients
• Characterize and compare CR rate and CR/CRh rate of tamibarotene/venetoclax/azacitidine versus
venetoclax/azacitidine
• Characterize duration of CR, duration of CR/CRi, and duration of CR/CRh of tamibarotene/venetoclax/azacitidine combination versus venetoclax/azacitidine
• Characterize time to CR, time to CR/CRi, and time to CR/CRh of tamibarotene/venetoclax/azacitidine
combination versus venetoclax/azacitidine
• Characterize and compare the ORR of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must be at least 18 years old at the time of signing of an informed consent.
2. Patients must be RARA-positive based on the investigational assay (Section 8.6.1).
3. Patients must have ND, previously untreated non-APL AML with a bone marrow or peripheral blood blast count ≥20% and must be unlikely to tolerate standard intensive chemotherapy at the time of study entry due to age, performance status, or comorbidities based on at least one of the following criteria (Ferrara 2013):
a. age ≥75 years old
OR
b. age <75 years old, with at least one of the following:
o Eastern Cooperative Oncology Group (ECOG) performance status of 3
o cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ≤50%
o pulmonary disease with diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume in one second (FEV1) ≤65%
o creatinine clearance ≥30 mL/min to <45 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation
o hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of normal (ULN)
o any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the sponsor prior to enrollment
4. Patients must have ECOG of 0 to 3 (if <75 years old) or 0 to 2 (if ≥75 years old).
5. Patients must have a white blood cell (WBC) count <25,000/μL at the time of initiation of study drug (leukapheresis may be performed and/or hydroxyurea may be administered to decrease the WBC count to <25,000/μL)
6. Patients must have adequate organ function, as defined by:
a. total bilirubin ≤3.0 × ULN (if <75 years old) or ≤1.5 × ULN (if ≥75 years old)
b. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN or ≤5 × ULN (if documented liver infiltration with leukemia cells)
c. creatinine clearance ≥30 mL/min (if <75 years old) or ≥45 mL/min (if ≥75 years old) based on the Cockcroft-Gault glomerular filtration rate estimation
7. Patients must have a serum/urine pregnancy test (for females of childbearing potential) that is negative at the Screening Visit and immediately prior to initiation of treatment (first dose of study drug).
8. Patients must be willing and able to comply with the scheduled study visits, treatment plans, laboratory tests, use of 2 methods of birth control (including a barrier method) for women of childbearing potential (WOCBP) and male patients (as described in Appendix 4), and other procedures.
9. Patients must be capable of giving signed and dated Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent |
|
| E.4 | Principal exclusion criteria |
1. Patients have APL.
2. Patients have known active central nervous system involvement with AML.
3. Patients currently receiving treatment for a malignancy (not including basal cell carcinoma, non-melanoma skin cancer, cervical carcinoma in situ, or localized prostate cancer treated with hormone therapy). Patients with history of other cancers should be free of disease for at least 2 years prior to the Screening Visit.
4. Patients have an active, life-threatening, or clinically-significant uncontrolled systemic infection requiring hospitalization.
5. Patients have a known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy).
6. Immunocompromised patients with increased risk of opportunistic infections, including known human immunodeficiency virus (HIV)-positive patients with CD4 counts ≤350 cells/mm3 or history of opportunistic infection in the last 12 months. Note: To ensure that effective anti-retroviral therapy (ART), when used in eligible HIV-positive patients, is tolerated and that toxicities are not confused with investigational drug toxicities, patients should be on an established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to the Screening Visit.
7. Patients have a known active or chronic hepatitis B or active hepatitis C virus (HCV) infection. Patients with a history of HCV infection who have completed curative therapy for HCV at least 12 weeks before the Screening Visit and have a documented undetectable viral load at the Screening Visit are eligible for enrollment.
8. Patients have other severe acute or chronic medical conditions (and/or psychiatric conditions or laboratory abnormalities) that may increase the expected risk to the patient (i.e., the risk associated with the study participation or study drug administration) or that may interfere with the interpretation of study results or, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
9. Patients received prior treatment with all-trans retinoic acid (ATRA) or systemic retinoid for a hematologic malignancy.
10. Patients have not adequately recovered from a major surgery within 4 weeks of starting study drug administration.
11. Prior treatment for the diagnosis of AML, MDS, or antecedent hematologic malignancy with any hypomethylating agent, venetoclax, chemotherapy, or hematopoietic stem cell transplantation (HSCT), with the exception of prior treatment with hydroxyurea.
12. Patients receiving strong inducers of CYP3A4 (see Appendix 6) within 2 weeks of the first tamibarotene administration.
13. Patients with a diagnosis of hypervitaminosis A or patients taking vitamin A supplements >10,000 IU/day, unless treatment is discontinued at least 7 days prior to the first dose of the study drug.
14. Patients received any other investigational agents within 4 weeks of the Screening Visit or <5 half-lives since completion of previous investigational therapy have elapsed, whichever is shorter.
15. Patients require concurrent treatment with any investigational or approved oncology agent, except for hydroxyurea.
16. Patients with Grade ≥2 hypertriglyceridemia, defined as >300 mg/dL (Common Terminology Criteria for Adverse Events [CTCAE], version 5).
17. Patients with QTc interval >480 msec based on triplicate electrocardiogram (ECG) readings at the Screening Visit using the Fridericia formula (QTcF), with the exception of patients with right bundle branch block or left bundle branch block.
18. Pregnant females, breastfeeding females, and males not willing to comply with contraceptive requirements or females of childbearing potential not willing to comply with contraceptive requirements.
19. Patients who have a hypersensitivity to tamibarotene, azacitidine, venetoclax or to any of their excipients.
20. Patients for whom treatment with tamibarotene, azacitidine, or venetoclax is contraindicated |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
Incidence of AEs, changes in clinical laboratory values, ECGs, and vital sign measurements
Part 2
CR/CRi rate, defined as proportion of patients who achieve CR/CRi (as determined by the investigator) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the course of the study |
|
| E.5.2 | Secondary end point(s) |
Part 1
• ORR, defined as the proportion of patients who achieve CR, CRi, CRh, MLFS, or PR (as determined by the investigator)
• Tamibarotene PK parameters
Part 2
• Incidence of AEs, changes in clinical laboratory values, ECGs, and vital sign measurements
• CR rate, defined as proportion of patients who achieve CR (as determined by the investigator)
• CR/CRh rate, defined as proportion of patients who achieve CR/CRh (as determined by the investigator)
• Duration of CR, defined as duration from the date of first documented evidence of CR to the date of
relapse of disease (as determined by the investigator), or death due to any cause, whichever
occurs first
• Duration of CR/CRi, defined as duration from the date of first documented evidence of CR/CRi to
the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first
• Duration of CR/CRh, defined as duration from the date of first documented evidence of CR/CRh to
the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first
• Time to CR, defined as the duration from the date of randomization to the date of the first
documented evidence of CR as determined by the investigator
• Time to CR/CRi, defined as the duration from the date of randomization to the date of the first
documented evidence of CR/CRi as determined by the investigator
• Time to CR/CRh, defined as the duration from the date of randomization to the date of the first
documented evidence of CR/CRh as determined by the investigator
• ORR, defined as the proportion of patients who achieve CR, CRi, CRh, MLFS, or PR (as determined by the investigator) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the course of the study |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
|
| 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
|
| The end of the study is defined as the date of the last scheduled procedure shown in the Schedules of Activities (SoAs) of the protocol, for the last patient in the study |
|
| 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 | |
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