Clinical trial NCT04748848: A Safety, Tolerability and Preliminary Efficacy Study of CC-90011 in Combination With Venetoclax and Azacitidine in R/R Acute Myeloid Leukemia and Treatment-naïve Participants Not Eligible for Intensive Therapy
Official title: A Phase 1/2, Open-label, Multicenter Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of CC-90011 in Combination With Venetoclax and Azacitidine in R/R Acute Myeloid Leukemia (AML) and Treatment-naïve Subjects With AML Who Are Not Eligible for Intensive Induction Chemotherapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Leukemia, Myeloid
Keywords: Acute Myeloid Leukemia
CC-90011
Venetoclax
Azacitidine
LSD-1 inhibitor
Minimal residual disease
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2021-02-10
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: CC-90011-AML-002 is a Phase 1/2, open-label, multicenter study to assess the safety, tolerability, and preliminary efficacy of CC-90011 given concurrently with Venetoclax and Azacitidine. This study will include 3 parts: a dose escalation part in R/R AML, a dose escalation part in ndAML (treatment-naïve participants with AML who are ≥ 75 years of age or are ≥ 18 to 74 years of age and otherwise not eligible for intensive induction chemotherapy), and a randomized dose expansion part in ndAML of Venetoclax and Azacitidine with or without CC-90011.


Eligibility criteria: Inclusion Criteria:

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

All participants (Parts I, II, and III):

1. Participant must understand and voluntarily sign an Informed Consent Form (ICF) prior to any study-related assessments/procedures being conducted.

3. Participant must have a projected life expectancy of at least 12 weeks. 4. Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

5. Participants must have the required protocol baseline laboratory values 6. Participant has adequate organ function 7. Participant must be able and willing to undergo hospitalization, hydration, and treatment with a uric acid-reducing agent prior to the first dose of venetoclax and during Cycle 1.

Part I only:

8. Relapsed and/or refractory acute myeloid leukemia (AML) as defined by the World Health Organization (WHO) Classification and is ≥ 18 years of age at the time of signing the ICF who are not eligible to receive further intensive therapy and:

1. Has failed to have a complete remission (CR) or CR with incomplete hematologic recovery (Cri) after induction plus reinduction with intensive chemotherapy (anthracycline plus cytarabine containing regimens) or 2 cycles of low intensity therapy (either 2 cycles of the same regimen or 1 cycle of 2 different regimens) OR
2. Has relapsed from CR from either intensive or low-intensity therapy. Participants with second relapse are also eligible

Part II and Part III only:

9. Histologically confirmed treatment naïve Acute myeloid leukemia (AML) as defined by the 2008 World Health Organization (WHO) Classification, including secondary AML and therapy related AML, and is ≥ 75 years of age at the time of signing the ICF, or is ≥ 18 to 74 years at the time of signing the ICF with comorbidities precluding the use of intensive induction chemotherapy 10. Participant has not received prior therapy for AML with the exception of hydroxyurea to treat hyperleukocytosis.

Exclusion Criteria:

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

All participants (Parts I, II, and III):

1. Participant is suspected or proven to have acute promyelocytic leukemia (APL) based on morphology, immunophenotype, molecular assay, or karyotype.
2. Participant has favorable risk cytogenetics
3. Participants with AML who may receive fms-like tyrosine kinase 3 (FLT3) inhibitor directed therapy.
4. Participant has or is suspected of having active central nervous system (CNS) involvement.
5. Participant has an active, uncontrolled infection except participants with infection under active treatment and controlled with antibiotics, antifungals, or antivirals are eligible.
6. Participant with prior autologous hematopoietic stem cell transplant (HSCT) who, in the investigator's judgment, have not fully recovered from the effects of the last transplant (eg, transplant related side effects).
7. Participant had prior allogeneic HSCT with either standard or reduced intensity conditioning ≤ 6 months prior to dosing.
8. Participants on systemic immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). The use of topical steroids for ongoing skin or ocular GVHD is permitted.
9. Participant has immediate life-threatening, severe complications of leukemia such as disseminated/uncontrolled infection, uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation. The participant should be afebrile for at least 72 hours.
10. Participants requiring treatment with strong or moderate CYP3A inhibitors/inducers.
11. Participant has ongoing treatment with chronic, therapeutic dosing of anticoagulants.
12. Participant has a history of concurrent secondary cancers requiring active, ongoing systemic treatment.
13. Participant has known human immunodeficiency virus (HIV) infection.
14. Participant has known chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV).

    1. Participant who is seropositive due to HBV vaccination is eligible.
    2. Participant who has no active viral infection and is under adequate prophylaxis against HBV reactivation is eligible.
15. Participant is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
16. Participant has impaired cardiac function or clinically significant cardiac diseases
17. Participant has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or Star fruit within 3 days prior to first venetoclax dose through last dose of venetoclax.
18. Pregnant women are excluded from this study due to potential teratogenic and/or abortifacient effect of this therapy. Nursing mothers should stop breastfeeding in order to be eligible due to potential risk for Adverse Events (AEs) in a nursing infant.
19. Participant has had previous treatment with a lysine-specific demethylase 1A (LSD1) inhibitor.
20. Participant has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study.
21. 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.
22. Participant has any condition that confounds the ability to interpret data from the study.
23. Participant received live COVID-19 vaccines within 30 days prior to initiation of study treatment
24. Participants currently in other interventional trials, including those for COVID-19, may not participate in BMS clinical trials until the protocol specific washout period is achieved. If a study participant has received an investigational COVID-19 vaccine or other investigational product designed to treat or prevent COVID-19 prior to screening, enrollment must be delayed until the biologic impact of the vaccine or investigational product is stabilized, as determined by discussion between the Investigator and the Medical Monitor.

    Part I only:
25. Participant had prior treatment with venetoclax for AML, either as monotherapy or in combination with other agents.

    Part II and Part III only:
26. Participant had prior treatment with hypomethylating agent (HMA) or chemotherapy for antecedent hematologic disorders. Prior treatment with hydroxyurea is permitted.
27. Participant has received systemic anticancer therapy (including investigational therapy), radiotherapy, or immunotherapy \< 14 days or 5 half-lives, whichever is shorter, prior to the first dose of CC-90011.

Primary outcomes:
measure: Adverse Events (AEs)
timeFrame: From ICF signature until 28 days after last dose of CC- 90011 and all combination agents
measure: Recommended Phase 2 dose (RP2D)
timeFrame: Up to approximately Cycle 1 (each cycle is 28 days)
Secondary outcomes:
measure: Complete remission (CR) Rate
timeFrame: Up to approximately 10 months
measure: Complete remission with partial hematologic recovery (CRh) Rate
timeFrame: Up to approximately 2 years
measure: Overall response rate (ORR)
timeFrame: Up to approximately 2 years
measure: Duration of response (CR)
timeFrame: Up to approximately 2 years
measure: Duration of response (CR/CRh)
timeFrame: Up to approximately 2 years
measure: Duration of response (CR/ CRMRD-/ CRi/ PR/MLFS)
timeFrame: Up to approximately 2 years
measure: Event-free survival (EFs)_Part III Only
timeFrame: Up to approximately 2 years
measure: Overall survival (OS)_Part III Only
timeFrame: Up to approximately 2 years
measure: Minimal residual disease (MRD) Response Rate_Part II and III only
timeFrame: Up to approximately 2 years
measure: Minimal residual disease (MRD) Conversion Rate_Part II and III Only
timeFrame: Up to approximately 2 years
measure: Complete response with incomplete hematologic recovery (CRi) rate
timeFrame: Up to approximately 2 years
measure: Duration of response (CR/CRi)
timeFrame: Up to approximately 2 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Local Institution - 110
state: California
city: New Haven
country: United States
facility: Local Institution - 103
state: Connecticut
city: Miami
country: United States
facility: Local Institution - 108
state: Florida
city: Chicago
country: United States
facility: Local Institution - 111
state: Illinois
city: New York
country: United States
facility: Local Institution - 121
state: New York
city: Durham
country: United States
facility: Local Institution - 118
state: North Carolina
city: Cleveland
country: United States
facility: Local Institution - 116
state: Ohio
city: Columbus
country: United States
facility: Local Institution - 115
state: Ohio
city: Dallas
country: United States
facility: Local Institution - 104
state: Texas
city: Houston
country: United States
facility: Local Institution - 101
state: Texas
city: Seattle
country: United States
facility: Local Institution - 120
state: Washington
city: Gent
country: Belgium
facility: Local Institution - 202
city: Villejuif CEDEX
country: France
facility: Local Institution - 401
city: Barcelona
country: Spain
facility: Local Institution - 803
city: Barcelona
country: Spain
facility: Local Institution - 800
city: Madrid
country: Spain
facility: Local Institution - 802
city: Sevilla
country: Spain
facility: Local Institution - 801
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: