A Dose-finding Study of CC-90009 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-risk Myelodysplastic Syndromes

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

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.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: CC-90009

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.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution - 201
• France
  • Lillie Cedex, France, 59037
    • Local Institution - 505
  • Marseille Cedex 9, France, 13273
    • Institut Paoli Calmettes
  • Pierre Benite, France, 69310
    • Hopital Lyon Sud
  • Toulouse, France, 31059
    • Local Institution - 502
• Norway
  • Bergen, Norway, N-5053
    • Local Institution - 700
  • Oslo, Norway, N-0027
    • Local Institution - 701
• Spain
  • Badalona, Spain, 8916
    • Local Institution - 603
  • Barcelona, Spain, 08036
    • Local Institution - 602
  • Madrid, Spain, 28033
    • Local Institution - 604
  • Pamplona, Spain, 31008
    • Local Institution - 605
  • Salamanca, Spain, 37007
    • Local Institution - 601
  • Valencia, Spain, 46009
    • Local Institution - 600
• United Kingdom
  • Oxford, United Kingdom, 0X3 7LE
    • Local Institution - 301
• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Cancer Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Local Institution - 105
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Local Institution - 102
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Local Institution - 103
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Local Institution - 101
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Local Institution - 104

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CC-90009 - Part A; Will be administered intravenously per dosing schedule in a 28-day cycle.	Drug: CC-90009; CC-90009
Experimental: CC-90009 - Part B - AML and MDS patients; Relapsed or refractory AML and MDS subjects. IP will be administered intravenously per dosing schedule determined in Part A	Drug: CC-90009; CC-90009

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose- limiting toxicity (DLT)	Number of participants with a DLT	Up to 42 days
Non-tolerated dose (NTD)	Dose level at which 2 or more of up to 6 evaluable subjects in any dose cohort experience a DLT in Cycle 1 during dose escalation.	Up to 42 days
Maximum tolerated dose (MTD)	Last dose level(s) below the NTD with 0 or 1 out of 6 evaluable subjects experiencing a DLT in Cycle 1 during dose escalation	Up to 42 days
Number of participants with Adverse Events (AEs)		Up to 42 days
Number of participants with laboratory abnormalities		Up to 42 days
Number of participants with vital sign abnormalities		Up to 42 days
Number of participants with electrocardiogram (ECG) abnormalities		Up to 42 days
Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status abnormalities		Up to 42 days
Number of participants with Left Ventricle Ejection Fraction (LVEF) assessment abnormalities		Up to 42 days
Number of participants with physical examination abnormalities		Up to 42 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preliminary efficacy of CC-90009 - acute myeloid leukemia (AML)	Determined by response rates of AML by disease response criteria	Up to 2.5 years
Overall survival		Up to 2.5 years
Relapse-free survival		Up to 2.5 years
Progression-free survival		Up to 2.5 years
Event-free survival		Up to 2.5 years
Duration of remission		Up to 2.5 years
Duration of response		Up to 2.5 years
Time to remission for AML participants		Up to 2.5 years
Time to response for AML participants		Up to 2.5 years
Preliminary efficacy of CC-90009 - Higher-risk myelodysplastic syndromes (HR-MDS)	Determined by response rates of HR-MDS by disease response criteria	Up to 2.5 years
Time to AML transformation		Up to 2.5 years
Time to remission for HR-MDS participants		Up to 2.5 years
Time to response for HR-MDS participants		Up to 2.5 years
Pharmacokinetics-Cmax	Maximum observed concentration in plasma	Up to Day 11
Pharmacokinetics - AUC24	Area under the plasma concentration time-curve from time 0 to 24 hours	Up to Day 11
Pharmacokinetics - tmax	Time to peak (maximum) plasma concentration	Up to Day 11
Pharmacokinetics - t 1/2	terminal half-life	Up to Day 11
Pharmacokinetics - CL	Total body clearance of the drug from plasma	Up to Day 11
Pharmacokinetics - Vss	Volume of distribution at steady-state	Up to Day 11

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

General Publications

• 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.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2016
• Primary Completion (Actual): April 11, 2023
• Study Completion (Actual): April 11, 2024

Study Registration Dates

• First Submitted: June 22, 2016
• First Submitted That Met QC Criteria: July 25, 2016
• First Posted (Estimated): July 28, 2016

Study Record Updates

• Last Update Posted (Estimated): May 14, 2024
• Last Update Submitted That Met QC Criteria: May 13, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; AML; Leukemia; MDS; CC-90009; Hematologic Cancers; Myelodysplastic Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia
• Other Study ID Numbers: CC-90009-AML-001; 2017-001535-39 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No