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

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ClinicalTrials.gov Identifier: NCT04887857
Recruitment Status : Not yet recruiting
First Posted : May 14, 2021
Last Update Posted : May 14, 2021
Sponsor:
Collaborator:
AbbVie
Information provided by (Responsible Party):
Celgene

Brief 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.


Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Drug: CC-486 Drug: Venetoclax Phase 1

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 136 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2, Open-label, Global, Multicenter, Dose Determination, Dose Expansion Study to Evaluate Safety, Tolerability, and Preliminary Efficacy of CC-486 (ONUREG®) in Combination Therapy in Subjects With Acute Myeloid Leukemia (AML)
Estimated Study Start Date : September 24, 2021
Estimated Primary Completion Date : February 15, 2026
Estimated Study Completion Date : August 31, 2027


Arm Intervention/treatment
Experimental: CC-486 in combination with Venetoclax in AML participants
Phase 1b dose-finding is designed to explore up to 4 combined dose levels of CC-486 (ONUREG, oral azacitidine) with venetoclax, using dose determination rules based on a Modified Toxicity Probability Interval (mTPI)-2 method. Phase 2 will open when MTD/RP2D has been reached in Phase 1b.
Drug: CC-486
CC-486 (oral azaciditine) 200 mg or 300 mg will be given orally (PO) once daily (QD) for 14 (or 21) days in a 28-day cycle.
Other Name: ONUREG®, oral azacitidine

Drug: Venetoclax
Venetoclax 400 mg is administered PO QD on Days 1 to 28 per 28-day cycle. A brief dose ramp-up occurs for Cycle 1 with 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and beyond.
Other Name: VENCLEXTA®, VENCLYXTO®




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) - Phase 1b (Parts I and II) [ Time Frame: Up to 42 days after first dose ]
    Highest dose safely administered from each part.

  2. Recommended Phase 2 Dose (RP2D) - Phase 1b (Part II) [ Time Frame: From first dose to the end of Cycle 1 (each cycle is 28 days) ]
    Dose that is chosen for both safety and tolerability to progress to Phase 2, dose expansion phase of the study.

  3. Safety and tolerability, incidence of adverse events (AEs) - Phase 1b [ Time Frame: : From informed consent form (ICF) signature to 28 days after last dose of study drug ]
    Type, frequency, seriousness and severity of AEs (using NCI CTCAE), relationship of AEs to study treatment, clinical laboratory evaluations. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-existing condition) should be considered an AE.

  4. Rate of CR/CRh - Phase 2 [ Time Frame: Up to approximately 12 months ]
    Defined as the rate of achieving complete remission (CR) or complete remission with partial hematologic recovery (CRh).


Secondary Outcome Measures :
  1. Rate of CR/CRh - Phase 1b [ Time Frame: Up to approximately 12 months ]
    Defined as the rate of achieving CR or CRh.

  2. Overall Response Rate (ORR) - Phase 1b and Phase 2 [ Time Frame: Up to approximately 12 months ]
    Defined as the rate of responses including CR, CR with incomplete blood recovery (CRi), morphologic leukemia-free state (MLFS), and partial remission (PR) according to the European Leukemia Network (ELN) AML Response Criteria.

  3. Safety and tolerability, incidence of adverse events (AEs) - Phase 2 [ Time Frame: From ICF signature to 28 days after last dose of study drug ]
    Type, frequency, seriousness and severity of AEs (using NCI CTCAE), relationship of AEs to study treatment, clinical laboratory evaluations. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-existing condition) should be considered an AE.

  4. Time to CR/CRh - Phase 2 [ Time Frame: Up to approximately 12 months ]
    Time from first dose to first response (CR/CRh).

  5. Time to response (CR/CRi/PR/MLFS) - Phase 2 [ Time Frame: Up to approximately 12 months ]
    Time from first dose to first response (CR/CRi/PR/MLFS).

  6. Duration of Response (CR/CRh)- Phase 2 [ Time Frame: Up to approximately 24 months ]
    Time from first response (CR/CRh) to first relapse or death, whichever occurs first.

  7. Duration of Response (CR/CRi/PR/MLFS)- Phase 2 [ Time Frame: Up to approximately 24 months ]
    Time from first response (CR/CRi/PR/MFLS) to first relapse, disease progression, or death due to any cause, whichever occurs first.

  8. Event Free Survival (EFS) - Phase 2 [ Time Frame: Up to approximately 24 months ]
    Time from first dose to first confirmed relapse, disease progression, treatment failure, or death from any cause, whichever occurs first.

  9. Overall Survival (OS)- Phase 2 [ Time Frame: Up to approximately 24 months ]
    Time from first dose to death due to any cause.

  10. One-year survival rate - Phase 2 [ Time Frame: Up to approximately 12 months ]
    Defined as the probability of survival at 1 year from first dose.

  11. MRD Response Rate - Phase 1b and Phase 2 [ Time Frame: Up to approximately 12 months ]
    Rate of having at least a one log reduction in disease burden or an MRD negative (10^3) test result.

  12. MRD Conversion Rate - Phase 1b and Phase 2 [ Time Frame: Up to approximately 12 months ]
    Rate of achieving MRD negativity (10^3) at any time on therapy.

  13. Duration of MRD Response - Phase 1b and Phase 2 [ Time Frame: Up to approximately 12 months ]
    Durability of MRD response by serial bone marrow aspirate assessment for MRD.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04887857


Contacts
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Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@bms.com

Sponsors and Collaborators
Celgene
AbbVie
Investigators
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Study Director: Kimberley Dilley, MD/MPH Celgene Corporation
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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT04887857    
Other Study ID Numbers: CC-486-AML-004
2020-004941-35 ( EudraCT Number )
First Posted: May 14, 2021    Key Record Dates
Last Update Posted: May 14, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Information relating to our policy on data sharing and the process for requesting data can be found at the following link:

https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: See Plan Description
Access Criteria: See Plan Description
URL: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Celgene:
Acute Myeloid Leukemia
CC-486
Onureg
oral azacitidine
venetoclax
Venclexta
Venclyxto
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors