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

Phase 1

Terminated

• Conditions: Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
• Interventions: Drug: CC-90009

• Registration Number: NCT02848001
• Lead Sponsor: Celgene

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.

Study Timeline

• Study First Submitted: 2016-06-22
• Study First Submitted QC: 2016-07-25
• Study First Posted: 2016-07-28
• Study Start: 2016-11-14
• Primary Completion: 2023-04-11
• Study Completion: 2024-04-11
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-13
• Last Update Posted: 2024-05-14

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 101

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CC-90009 - Part A	CC-90009	Will be administered intravenously per dosing schedule in a 28-day cycle.
CC-90009 - Part B - AML and MDS patients	CC-90009	Relapsed or refractory AML and MDS subjects. IP will be administered intravenously per dosing schedule determined in Part A

Primary Outcome Measures

Name	Time	Method
Dose- limiting toxicity (DLT)	Up to 42 days	Number of participants with a DLT
Maximum tolerated dose (MTD)	Up to 42 days	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
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
Non-tolerated dose (NTD)	Up to 42 days	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.
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

Secondary Outcome Measures

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

Trial Locations

Locations (20)

Local Institution - 104; 🇺🇸 Hackensack, New Jersey, United States

Local Institution - 201; 🇨🇦 Toronto, Ontario, Canada

Local Institution - 701; 🇳🇴 Oslo, Norway

Local Institution - 700; 🇳🇴 Bergen, Norway

Stanford Cancer Center; 🇺🇸 Stanford, California, United States

Local Institution - 105; 🇺🇸 New Haven, Connecticut, United States

Local Institution - 101; 🇺🇸 Saint Louis, Missouri, United States

Local Institution - 505; 🇫🇷 Lillie Cedex, France

Local Institution - 502; 🇫🇷 Toulouse, France

Hopital Lyon Sud; 🇫🇷 Pierre Benite, France

Institut Paoli Calmettes; 🇫🇷 Marseille Cedex 9, France

Local Institution - 605; 🇪🇸 Pamplona, Spain

Local Institution - 601; 🇪🇸 Salamanca, Spain

Local Institution - 602; 🇪🇸 Barcelona, Spain

Local Institution - 102; 🇺🇸 Chicago, Illinois, United States

Local Institution - 103; 🇺🇸 Boston, Massachusetts, United States

Local Institution - 603; 🇪🇸 Badalona, Spain

Local Institution - 604; 🇪🇸 Madrid, Spain

Local Institution - 301; 🇬🇧 Oxford, United Kingdom

Local Institution - 600; 🇪🇸 Valencia, Spain