A Study to Assess Safety and Tolerability of CC-486 (ONUREG®, Oral Azacitidine) in Combination Therapy in Participants With Acute Myeloid Leukemia (AML)

• Status: Not yet recruiting
• Trial end date: 2027-08-31
• Target enrollment: 0
• Participant gender: All

Summary

The Phase 1b, dose-finding parts of the study is to determine safety, tolerability, and preliminary efficacy of CC-486 (Onureg, oral azacitidine) in combination with venetoclax initially in the relapsed and/or refractory (R/R) AML participants who are ≥ 18 years of age, not eligible to receive further intensive therapy (Phase 1b, Part I); then in newly diagnosed AML participants who are ≥ 75 years of age, or ≥ 18 to 74 years of age with comorbidities that preclude the use of intensive induction chemotherapy or hematopoietic stem cell transplant (HSCT) (Phase 1b, Part II).

Primary objective in Phase 1b is to establish maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) by evaluating safety and tolerability of CC-486 in combination with venetoclax. Key secondary objective is to assess the preliminary efficacy. Up to 4 dose levels of CC-486 with venetoclax may be explored.

Once MTD is established in the R/R AML population, then safety and tolerability of this MTD will be evaluated in the newly diagnosed AML population. When MTD/RP2D is determined in the newly diagnosed AML population, then Phase 2 dose expansion part of the study will open for enrollment.

Primary objective in Phase 2 is to assess efficacy of the RP2D of CC-486 and venetoclax in eligible newly diagnosed AML participants who are ≥ 75 years of age; or ≥ 18 to 74 years of age with comorbidities that preclude the use of intensive induction chemotherapy or HSCT. Key secondary objectives include evaluation of safety, overall response rate, time to response, duration of response, event-free survival, etc of this CC-486 and venetoclax combination in the frontline setting.

This study is designed with the goal of developing CC-486 (oral azacitidine) as backbone for combination therapy to treat AML patients in the frontline setting.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Celgene
• Collaborator: AbbVie
• Treatments: Azacitidine; Cc-486; Venetoclax

Criteria

Inclusion Criteria:

-Participants must satisfy the following criteria to be enrolled in the study:

1. Participant is ≥ 18 years of age at the time of signing the informed consent form (ICF).

2. Confirmation of the following for AML as defined by the updated 2016 World Health Organization (WHO) Classification

Phase 1b, Part I:

• Relapsed and/or refractory AML participants ≥ 18 years of age who are not eligible to receive further intensive therapy and:

• Has failed to achieve remission with at least 5% bone marrow blasts after at least 2 cycles intensive chemotherapy, ie anthracycline plus cytarabine, or at least 1 cycle of high-dose cytarabine based induction; or at least 2 cycles of low-intensity therapy (either 2 cycles of the same regimen or 1 cycle of 2 different regimens); OR

• Has relapsed with BM blasts ≥ 5% after previously achieving remission from either intensive or low-intensity therapy. Participants with second relapse are also eligible.

Phase 1b, Part II and Phase 2:

• Newly diagnosed, histologically confirmed de novo AML including secondary AML to prior myelodysplastic disease or CMML, or therapy related AML participants ≥ 75 years of age, or ≥ 18 to 74 years of age with comorbidities precluding the use of intensive induction chemotherapy defined by the following:

• ≥ 18 to 74 years of age old with any of the following comorbidities:

o Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3

o Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50%, or chronic stable angina

o Any other comorbidity that the Investigator judges to be incompatible with intensive chemotherapy must be reviewed by the Sponsor during screening and before study enrollment

• Intermediate or poor risk cytogenetics status for newly diagnosed AML

3. ECOG performance status of 0, 1, or 2. ECOG 3 is allowed if participants are 18 to 74 years old with comorbidities (Inclusion criterion number #2)

4. Participants must have the following baseline laboratory values:

• White blood cell (WBC) count of ≤ 25 x 109/L. Use of hydroxyurea, or leukapheresis or fixed dose ara-C (eg 100 to 500 mg IV) are permitted to meet this criterion.

Note: hydroxyurea is allowed up to 24 hours prior to the starting treatment and limited use only during Cycle 1 for cytoreduction (to control high white blood cell count).

• Potassium and magnesium within normal limits or correctable with supplements

• Uric acid ≤ 7.5 mg/dL (446 μmol/L). Prior and/or concurrent treatment with hypouricemic agents (eg, allopurinol, rasburicase) are allowed. Rasburicase is contraindicated in participants with baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency.

• International normalized ratio (INR) < 1.5 x upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) < 1.5 x ULN

5. Adequate organ function defined as:

• Renal function: Creatinine clearance ≥ 30 mL/minute, calculated by the Cockcroft-Gault formula or measured by 24 hours urine collection

• Hepatic function: aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 3.0 x ULN, bilirubin ≤ 1.5 x ULN, unless due to Gilbert's syndrome or leukemic organ involvement. Participants who are < 75 years of age may have a bilirubin of ≤ 3.0 x ULN

6. Agree to serial bone marrow aspirate/biopsies

7. Females of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) and must:

• Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the participant practices true abstinence from heterosexual contact.

• Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with highly effective contraception without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 6 months after last dose of CC-486, or at least 1 month after the last dose of venetoclax, whichever is later or longer if required by local regulations.

8. Male participants must practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 3 months after the last dose of CC-486, or at least 1 month after the last dose of venetoclax, whichever is later or longer if required by local regulations, even if he has undergone a successful vasectomy.

9. Participant must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.

10. Participant is willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

• The presence of any of the following will exclude a participant from enrollment:

1. Participant is suspected or proven to have acute promyelocytic leukemia (APML) (FAB M3) based on morphology, immunophenotype, molecular assay, or karyotype

2. Participant is BCR-ABL1 t(9;22)(q34;q11) positive.

3. Participant with prior history of myelofibrosis

4. Participant has received systemic anticancer therapy or radiotherapy < 28 days prior to the start of study treatment. Note that hydroxyurea is allowed prior to the start of study treatment for the control of leukocytosis.

5. Participant has received investigational agents < 28 days or 5 half-lives, whichever is longer, prior to the start of study treatment

6. Participant has received prior HMA therapy for MDS/CMML then develop AML within 4 months of discontinuing the HMA therapy

7. Participant has undergone HSCT within 90 days prior to the start of study treatment, or on immunosuppressive therapy post HSCT at the time of screening, or with graft-versus-host disease (GVHD). The use of a stable dose of oral steroid post-HSCT, or topical steroids for ongoing skin GVHD is permitted.

8. Participant has persistent, clinically significant non-hematologic toxicities from prior therapies which have not recovered to < Grade 2

9. Participant has or is suspected of having central nervous system (CNS) leukemia. Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is suspected during screening.

10. Participant has an active, uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment). The participant should be afebrile for at least 72 hours.

• In the case of prior SARS-CoV-2 infection, symptoms must have completely resolved and based on Investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the patient at a higher risk of receiving investigational treatment.

11. Participant has immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation

12. Participant has prior history of malignancy unless the participant has been free of the disease for ≥ 1 year prior to the start of study treatment. However, participants with the following history/concurrent conditions are allowed:

• Basal or squamous cell carcinoma of the skin

• Carcinoma in situ cancers, ie cervix, breast, bladder

13. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis clinical staging system) Participant is known seropositive or active infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)

14. Participant is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally

15. Participant has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg) or has not been stable for at least 1 month prior to treatment 16. Significant active cardiac disease within the previous 6 months prior to signing the ICF, including:

• New York Heart Association (NYHA) Class III or IV congestive heart failure

• Unstable angina or angina requiring surgical or medical intervention

• Significant cardiac arrhythmia; and/or

• Myocardial infarction

17. Participant is a pregnant or lactating female 18. Participant has known or suspected to have hypersensitivity to any of the components of the assigned study treatments 19. Participant has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study

• In the case of prior SARS-CoV-2 infection, symptoms must have completely resolved and based on Investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment.

• Participant who is excluded for SARS-CoV-2 infection could be re-screened.

• Additionally, a participant who is currently in another interventional trial for Coronavirus disease 2019 (COVID-19) may not participate in this clinical trial until the protocol-specific washout period is achieved.

20. Participant has any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study 21. Participant has any condition that confounds the ability to interpret data from the study 22. Received strong CYP3A inhibitors, moderate CYP3A inhibitors, strong CYP3A inducers, moderate CYP3A inducers within 7 days prior to initiation of study treatment.

23. Received live attenuated vaccines and live COVID-19 vaccines within 30 days prior to initiation of study treatment.

24. Consumption of grapefruit products, Seville oranges or starfruit within 3 days prior to first dose of venetoclax.