Clinical trial NCT02848001: A Dose-finding Study of CC-90009 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-risk Myelodysplastic Syndromes
Official title: A Phase 1, Open-label, Dose Finding Study of CC-90009, a Novel Cereblon E3 Ligase Modulating Drug, in Subjects With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Keywords: CC-90009
Hematologic Cancers
Leukemia
Acute Myeloid Leukemia
Myelodysplastic Syndrome
AML
MDS
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2016-07-28
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: CC-90009-AML-001 is a phase 1, open-label, dose escalation and expansion, study in subjects with relapsed or refractory acute myeloid leukemia and relapsed or refractory higher-risk myelodysplastic syndrome.

Detailed description: Study CC-90009-AML-001 is an open-label, Phase 1, dose escalation and expansion, first-in-human clinical study of CC-90009 in subjects with relapsed or refractory acute myeloid leukemia (AML) and relapsed or refractory higher-risk myelodysplastic syndrome.

The dose escalation part (Part A) of the study will evaluate the safety and tolerability of escalating doses of CC-90009 in relapsed and refractory AML. The expansion part, (Part B), will further evaluate the safety and efficacy of CC-90009 administered at or below the maximum tolerated dose (MTD) in selected expansion cohorts of one or more dosing regimens in order to determine the recommended Phase 2 dose (RP2D) for subjects with relapsed or refractory AML and relapsed or refractory higher-risk myelodysplastic syndrome.

Eligibility criteria: Inclusion Criteria:

1. Men and women ≥ 18 years of age, at the time of signing the ICD (Informed Consent Document).
2. Subject must understand and voluntarily sign an ICD prior to any study-related assessments/procedures being conducted.
3. Relapsed or refractory AML (Acute Myeloid Leukemia) (Parts A and B) or relapsed or refractory (R/R) higher-risk MDS (Myelodysplastic Syndrome) (HR-MDS) (Part B only) as defined by World Health Organization criteria who are not suitable for other established therapies.

   1. In Part A, R/R AML
   2. In Part B, R/R AML including

      * Relapsed after allogeneic HSCT or
      * In second or later relapse or
      * Refractory to initial induction or re-induction treatment or
      * Refractory or relapse after HMA treatment (HMA failure defined as primary progression or lack of clinical benefit after a minimum of 6 cycles or unable to tolerate HMA due to toxicity) or
      * Refractory within 1 year of initial treatment (excluding those with favorable risk based on cytogenetics)
   3. In Part B, R/R HR-MDS (Revised International Prognostic Scoring System score (IPSS-R) \> 3.5 points, IPSS-R calculated during screening period):

      * IPSS-R intermediate risk (in combination with more than 10% bone marrow blasts or poor or very poor IPSS-R cytogenetic risk) or
      * IPSS-R high or
      * IPSS-R very high risk
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2.
5. At least 4 weeks (from first dose) has elapsed from donor lymphocyte infusion (DLI) without conditioning.
6. Subjects must have the following screening laboratory values:

   * Corrected serum Ca or free (ionized) serum Ca within normal limits (WNL).

     o Corrected Ca (mg/dL) = Total Ca (mg/dL) - 0.8 (albumin \[g/dL\] - 4)
   * Total White Blood Cell count (WBC) \< 25 x 10\^9/L prior to first infusion. Prior or concurrent treatment with hydroxyurea to achieve this level is allowed.
   * Potassium and magnesium within normal limits or correctable with supplements.
   * Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamate pyruvic transaminase (ALT/SGPT) ≤ 2.5 x Upper Limit of Normal (ULN).
   * Uric acid ≤ 7.5 mg/dL (446 μmol/L). Prior and/or concurrent treatment with hypouricemic agents (eg, allopurinol, rasburicase) are allowed.
   * Selected electrolytes within normal limits or correctable with supplements.
   * Serum bilirubin ≤ 1.5 x ULN (upper limit of normal).
   * Estimated serum creatinine clearance of ≥ 60 mL/min using the Cockcroft-Gault equation. Measured creatinine clearance from a 24-hour urine collection is acceptable if clinically indicated.
   * International normalized ratio (INR) \< 1.5 x ULN and Partial thromboplastin time (PTT) \< 1.5 x ULN.

Exclusion Criteria:

1. Subjects with acute promyelocytic leukemia (APL)
2. Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is clinical suspicion of CNS involvement by leukemia during screening.
3. Patients with prior autologous hematopoietic stem cell transplant who, in the investigator's judgment, have not fully recovered from the effects of the last transplant (e.g., transplant related side effects).
4. Prior allogeneic hematopoietic stem cell transplant (HSCT) with either standard or reduced intensity conditioning ≤ 6 months prior to starting CC-90009.
5. Subjects on systemic immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD).
6. Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half lives or 4 weeks prior to starting CC-90009, whichever is shorter. Hydroxyurea is allowed to control peripheral leukemia blasts.
7. Leukapheresis ≤ 2 weeks prior to starting CC-90009.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicity (DLTs)
timeFrame: From first dose to at least 28 days and up to 42 days post first dose (Up to 42 days)
Secondary outcomes:
measure: Non-Tolerated Dose (NTD) of CC-90009
timeFrame: From first dose to at least 28 days and up to 42 days post first dose (Up to 42 days)
measure: Maximum Tolerated Dose (MTD) of CC-90009
timeFrame: From first dose to at least 28 days and up to 42 days post first dose (Up to 42 days)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From first dose until 28 days post last dose (Up to 25 months)
measure: Change From Baseline by Laboratory Test - Chemistry Parameters 1
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Change From Baseline by Laboratory Test - Chemistry Parameters 2
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Change From Baseline by Laboratory Test - Chemistry Parameters 3
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Change From Baseline for Vital Signs by Test - Parameters 1
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Change From Baseline for Vital Signs by Test - Parameters 2
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Change From Baseline for Vital Signs by Test - Parameters 3
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Change From Baseline for Vital Signs by Test - Parameters 4
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Change From Baseline for Electrocardiogram (ECG) by Test - Parameters 1
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Change From Baseline for Electrocardiogram (ECG) by Test - Parameters 2
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Eastern Cooperative Oncology Group (ECOG) Performance Status
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Left Ventricular Ejection Fraction (LVEF) Percent Change From Baseline
timeFrame: From baseline until 28 days post last dose (Up to 25 months)
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 25 months after the last dose
measure: Overall Survival (OS)
timeFrame: Up to approximately 25 months after the last dose
measure: Relapse-free Survival (RFS)
timeFrame: Up to approximately 25 months after the last dose
measure: Progression-free Survival (PFS)
timeFrame: Up to approximately 25 months after the last dose
measure: Event-free Survival (EFS)
timeFrame: Up to approximately 25 months after the last dose
measure: Duration of Remission/Response (DOR)
timeFrame: Up to approximately 25 months after the last dose
measure: Time to Remission/Response (TTR)
timeFrame: Up to approximately 25 months after the last dose
measure: Complete Remission Rate (CRR)
timeFrame: Up to approximately 88 months
measure: Time to Acute Myeloid Leukemia (AML) Transformation
timeFrame: Up to approximately 88 months
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Cycle 1 Day 1(C1D1), C1D5, C1D7, C1D8, C1D10,
measure: Time to Peak Plasma Concentration (Tmax)
timeFrame: Cycle 1 Day 1(C1D1), C1D5, C1D7, C1D8, C1D10. 1 cycle = 28 days
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose (AUC 0 - 24)
timeFrame: Cycle 1 Day 1(C1D1), C1D5, C1D7, C1D8, C1D10. 1 cycle = 28 days
measure: Terminal Phase Elimination Half-life (T1/2)
timeFrame: Cycle 1 Day 1(C1D1) and C1D5. 1 cycle = 28 days
measure: Total Body Clearance (CL)
timeFrame: Cycle 1 Day 1(C1D1), C1D5, C1D7, C1D8, C1D10. 1 cycle = 28 days
measure: Volume of Distribution (Vz)
timeFrame: Cycle 1 Day 1(C1D1) and C1D5. 1 cycle = 28 days
measure: Renal Clearance (CLr)
timeFrame: Cycle 1 Day 1(C1D1). 1 cycle = 28 days
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: New Haven
country: United States
facility: Local Institution - 105
state: Connecticut
city: Chicago
country: United States
facility: Local Institution - 102
state: Illinois
city: Boston
country: United States
facility: Local Institution - 103
state: Massachusetts
city: Saint Louis
country: United States
facility: Local Institution - 101
state: Missouri
city: Hackensack
country: United States
facility: Local Institution - 104
state: New Jersey
city: Toronto
country: Canada
facility: Local Institution - 201
state: Ontario
city: Lillie Cedex
country: France
facility: Local Institution - 505
city: Marseille Cedex 9
country: France
facility: Institut Paoli Calmettes
city: Pierre Benite
country: France
facility: Hopital Lyon Sud
city: Toulouse
country: France
facility: Local Institution - 502
city: Bergen
country: Norway
facility: Local Institution - 700
city: Oslo
country: Norway
facility: Local Institution - 701
city: Badalona
country: Spain
facility: Local Institution - 603
city: Barcelona
country: Spain
facility: Local Institution - 602
city: Madrid
country: Spain
facility: Local Institution - 604
city: Pamplona
country: Spain
facility: Local Institution - 605
city: Salamanca
country: Spain
facility: Local Institution - 601
city: Valencia
country: Spain
facility: Local Institution - 600
city: Oxford
country: United Kingdom
facility: Local Institution - 301
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Surka C, Jin L, Mbong N, Lu CC, Jang IS, Rychak E, Mendy D, Clayton T, Tindall E, Hsu C, Fontanillo C, Tran E, Contreras A, Ng SWK, Matyskiela M, Wang K, Chamberlain P, Cathers B, Carmichael J, Hansen J, Wang JCY, Minden MD, Fan J, Pierce DW, Pourdehnad M, Rolfe M, Lopez-Girona A, Dick JE, Lu G. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood. 2021 Feb 4;137(5):661-677. doi: 10.1182/blood.2020008676.