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

Sponsor

Celgene (Industry)

Overall Status

Completed

CT.gov ID

NCT04748848

Collaborator

(none)

Enrollment

Locations

Arms

4.8

Actual Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid	Drug: CC-90011 Drug: Venetoclax Drug: Azacitidine Drug: Venetoclax Drug: CC-90011	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

1 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 14, 2021

Actual Primary Completion Date :

Mar 9, 2022

Actual Study Completion Date :

Mar 9, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CC-90011 in combination with Venetoclax and Azacitidine in Dose Escalation CC-90011 in combination with venetoclax and azacitidine in dose escalation	Drug: CC-90011 CC-90011 will be given PO on Days 1, 8, and 15 of continuous 4-week (28-day) cycle. The dose escalation is designed to explore three dose levels of CC-90011, for example 20, 40, and 60 mg as determined by Bayesian design. Drug: Venetoclax Venetoclax is administered orally QD on Days 1 to 28 of each 28-day cycle with a brief dose ramp-up for Cycle 1 with the dosing of 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3. Venetoclax should be administered at 400 mg on subsequent days. Drug: Azacitidine Azacitidine is administered on Days 1 to 7 of each 28-day cycle as an IV infusion or SC injection at 75 mg/m2
Experimental: Venetoclax and Azacitidine Venetoclax and Azacitidine control arm in dose expansion. The participants will be randomized to the treatment arm or control arm at a 2:1 ratio.	Drug: Azacitidine Azacitidine is administered on Days 1 to 7 of each 28-day cycle as an IV infusion or SC injection at 75 mg/m2 Drug: Venetoclax Venetoclax is administered orally QD on Days 1 to 28 of each 28-day cycle
Experimental: CC-90011 in combination with Venetoclax and Azacitidine in Dose Expansion CC-90011 in combination with venetoclax and azacitidine in dose expansion	Drug: Venetoclax Venetoclax is administered orally QD on Days 1 to 28 of each 28-day cycle with a brief dose ramp-up for Cycle 1 with the dosing of 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3. Venetoclax should be administered at 400 mg on subsequent days. Drug: Azacitidine Azacitidine is administered on Days 1 to 7 of each 28-day cycle as an IV infusion or SC injection at 75 mg/m2 Drug: CC-90011 CC-90011 will be given PO on Days 1, 8, and 15 of continuous 4-week (28-day) cycle at the recommended phase to dose of CC-90011 confirmed in dose escalation.

Arm

Intervention/Treatment

Experimental: CC-90011 in combination with Venetoclax and Azacitidine in Dose Escalation

CC-90011 in combination with venetoclax and azacitidine in dose escalation

Drug: CC-90011

CC-90011 will be given PO on Days 1, 8, and 15 of continuous 4-week (28-day) cycle. The dose escalation is designed to explore three dose levels of CC-90011, for example 20, 40, and 60 mg as determined by Bayesian design.

Drug: Venetoclax

Venetoclax is administered orally QD on Days 1 to 28 of each 28-day cycle with a brief dose ramp-up for Cycle 1 with the dosing of 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3. Venetoclax should be administered at 400 mg on subsequent days.

Drug: Azacitidine

Azacitidine is administered on Days 1 to 7 of each 28-day cycle as an IV infusion or SC injection at 75 mg/m2

Experimental: Venetoclax and Azacitidine

Venetoclax and Azacitidine control arm in dose expansion. The participants will be randomized to the treatment arm or control arm at a 2:1 ratio.

Drug: Azacitidine

Azacitidine is administered on Days 1 to 7 of each 28-day cycle as an IV infusion or SC injection at 75 mg/m2

Drug: Venetoclax

Venetoclax is administered orally QD on Days 1 to 28 of each 28-day cycle

Experimental: CC-90011 in combination with Venetoclax and Azacitidine in Dose Expansion

CC-90011 in combination with venetoclax and azacitidine in dose expansion

Drug: Venetoclax

Drug: Azacitidine

Azacitidine is administered on Days 1 to 7 of each 28-day cycle as an IV infusion or SC injection at 75 mg/m2

Drug: CC-90011

CC-90011 will be given PO on Days 1, 8, and 15 of continuous 4-week (28-day) cycle at the recommended phase to dose of CC-90011 confirmed in dose escalation.

Outcome Measures

Primary Outcome Measures

Adverse Events (AEs) [From ICF signature until 28 days after last dose of CC- 90011 and all combination agents]
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 preexisting condition) should be considered an AE
Recommended Phase 2 dose (RP2D) [Up to approximately Cycle 1 (each cycle is 28 days)]
The RP2D will include evaluation of DLTs and MTD using NCI CTCAE criteria

Secondary Outcome Measures

Complete remission (CR) Rate [Up to approximately 10 months]
Defined as the rate of achieving CR (as assessed by the Investigator and by programmatic outputs by the Sponsor)
Complete remission with partial hematologic recovery (CRh) Rate [Up to approximately 2 years]
Defined as the rate of achieving CRh (as assessed by the Investigator and by programmatic outputs by the Sponsor)
Overall response rate (ORR) [Up to approximately 2 years]
Defined as the rate of achieving CR/CRMRD-/CRi/PR/MLFS
Duration of response (CR) [Up to approximately 2 years]
Time from the first CR to the date of documented disease relapse or death, whichever is earlier.
Duration of response (CR/CRh) [Up to approximately 2 years]
Time from the first CR or CRh to the date of documented disease relapse or death, whichever is earlier.
Duration of response (CR/ CRMRD-/ CRi/ PR/MLFS) [Up to approximately 2 years]
Time from the first CR, CRMRD-, CRi, PR or MLFS to the date of documented disease relapse, progression, or death, whichever is earlier.
Event-free survival (EFs)_Part III Only [Up to approximately 2 years]
Time from study randomization to the date of treatment failure, relapse from CR or death from any cause, whichever comes first.
Overall survival (OS)_Part III Only [Up to approximately 2 years]
Time from study randomization to the date of death due to any cause.
Minimal residual disease (MRD) Response Rate_Part II and III only [Up to approximately 2 years]
The rate of having at least a one log reduction in disease burden or an MRD negative (10-3) test result.
Minimal residual disease (MRD) Conversion Rate_Part II and III Only [Up to approximately 2 years]
The rate of participants achieving MRD negativity (10-3) at any time on therapy.
Complete response with incomplete hematologic recovery (CRi) rate [Up to approximately 2 years]
Defined as the rate of achieving CRi (as assessed by the Investigator and by programmatic outputs by the Sponsor)
Duration of response (CR/CRi) [Up to approximately 2 years]
Time from the first CR or CRi to the date of documented disease relapse or death, whichever is earlier.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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

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

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:
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
Has relapsed from CR from either intensive or low-intensity therapy. Participants with second relapse are also eligible

Part II and Part III only:

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):

Participant is suspected or proven to have acute promyelocytic leukemia (APL) based on morphology, immunophenotype, molecular assay, or karyotype.
Participant has favorable risk cytogenetics
Participants with AML who may receive fms-like tyrosine kinase 3 (FLT3) inhibitor directed therapy.
Participant has or is suspected of having active central nervous system (CNS) involvement.
Participant has an active, uncontrolled infection except participants with infection under active treatment and controlled with antibiotics, antifungals, or antivirals are eligible.
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).
Participant had prior allogeneic HSCT with either standard or reduced intensity conditioning ≤ 6 months prior to dosing.
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.
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.
Participants requiring treatment with strong or moderate CYP3A inhibitors/inducers.
Participant has ongoing treatment with chronic, therapeutic dosing of anticoagulants.
Participant has a history of concurrent secondary cancers requiring active, ongoing systemic treatment.
Participant has known human immunodeficiency virus (HIV) infection.
Participant has known chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV).
Participant who is seropositive due to HBV vaccination is eligible.
Participant who has no active viral infection and is under adequate prophylaxis against HBV reactivation is eligible.
Participant is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
Participant has impaired cardiac function or clinically significant cardiac diseases
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.
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.
Participant has had previous treatment with a lysine-specific demethylase 1A (LSD1) inhibitor.
Participant has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study.
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.
Participant has any condition that confounds the ability to interpret data from the study.
Participant received live COVID-19 vaccines within 30 days prior to initiation of study treatment
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:

Participant had prior treatment with venetoclax for AML, either as monotherapy or in combination with other agents.

Part II and Part III only:

Participant had prior treatment with hypomethylating agent (HMA) or chemotherapy for antecedent hematologic disorders. Prior treatment with hydroxyurea is permitted.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010-301
2	Local Institution - 110	Duarte	California	United States	91010-301
3	Yale University School of Medicine	New Haven	Connecticut	United States	06510
4	University of Miami Miller School of Medicine Jackson Memorial Hospital	Miami	Florida	United States	33136
5	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
6	Northwestern University Medical Center	Chicago	Illinois	United States	60611
7	Mount Sinai Medical Center	New York	New York	United States	10029
8	Duke University Medical Center	Durham	North Carolina	United States	27710
9	Cleveland Clinic	Cleveland	Ohio	United States	44195
10	Ohio State University Medical CenterJames Cancer Hospital	Columbus	Ohio	United States	43210
11	Baylor University Medical Center	Dallas	Texas	United States	75246
12	The University of Texas - MD Anderson Cancer Center	Houston	Texas	United States	77030
13	Swedish Medical Center	Seattle	Washington	United States	98104
14	Salzburger Landkliniken St. Johanns-Spital	Salzburg		Austria	5020
15	Medical University of Vienna	Vienna		Austria	1090
16	Krankenhaus Hietzing	Wien		Austria	1130
17	ZNA Stuivenberg Centrumziekenhuis	Antwerpen		Belgium	2060
18	UZ Gent	Gent		Belgium	9000
19	CHU de Liege	Liege		Belgium	4000
20	Hopital Aviecenne	BOBIGNY Cedex		France	93009
21	CHRU Nantes	Nantes		France	44093
22	Centre Hospitalier Lyon Sud - Hospices Civils de Lyon Groupement Hospitalier Sud	Pierre-Benite		France	69495
23	Institut Claudius Regaud, IUCT-Oncopole	Toulouse		France	31059
24	Gustave Roussy	Villejuif CEDEX		France	94805
25	Local Institution - 401	Villejuif CEDEX		France	94805
26	Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi	Bologna		Italy	40138
27	IRST Meldola	Meldola		Italy	40 - 47014
28	Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Milano		Italy	20122
29	Ospedale Santa Maria Della Misericordia Di Perugia	Perugia PG		Italy	06129
30	Haukeland University Hospital	Bergen		Norway	N-5053
31	Oslo Universitetssykehus	Oslo		Norway	0310
32	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
33	Hospital de Bellvitge	Barcelona		Spain	08907
34	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
35	Hospital Universitario Virgen del Rocio - PPDS	Sevilla		Spain	41013