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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: CC-90009


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 18 years of age, at the time of signing the ICD (Informed Consent Document). Subject must understand and voluntarily sign an ICD prior to any study-related assessments/procedures being conducted. 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. In Part A, R/R AML 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) 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 Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2. At least 4 weeks (from first dose) has elapsed from donor lymphocyte infusion (DLI) without conditioning. 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: Subjects with acute promyelocytic leukemia (APL) 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. 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). Prior allogeneic hematopoietic stem cell transplant (HSCT) with either standard or reduced intensity conditioning ≤ 6 months prior to starting CC-90009. Subjects on systemic immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). 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. Leukapheresis ≤ 2 weeks prior to starting CC-90009.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CC-90009, Hematologic Cancers, Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome, AML, MDS