A Safety and Preliminary Efficacy Study of CC-99282 in Combination With Obinutuzumab in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Study Overview
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Brief Summary
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CC-99282-CLL-001 study is a Phase IB dose escalation and expansion clinical study of CC-99282 administered in combination with Obinutuzumab in subjects with relapsed or refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Detailed Description
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All eligible subjects must be relapsed or refractory to at least 2 prior lines of therapy, one of which must have included an inhibitor of B-cell receptor signaling (approved Bruton's tyrosine kinase inhibitor [BTKi] or Phosphoinositide 3-kinase inhibitor [PI3Ki]) or venetoclax. The dose escalation (Part A) will evaluate the safety, tolerability, and PK of escalating doses of CC-99282 given in combination with intravenous obinutuzumab to determine the MTD and RP2D of CC-99282 when given in combination with obinutuzumab. The dose expansion (Part B) may occur at the MTD established in the dose escalation phase, or at an alternative tolerable dosing schedule, based on review of safety, PK and PD data from Part A.

Official Title
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A Phase 1B, Multicenter, Open-label Study to Determine the Safety, Pharmacokinetics and Preliminary Efficacy of CC-99282 in Combination With Obinutuzumab in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: CC-99282
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥18 years of age Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Must have a documented diagnosis of CLL/SLL requiring treatment (IwCLL Guidelines for the Diagnosis and Treatment of CLL). In addition presence of clinically measurable disease determined by at least one of the factors listed: nodal lesion that measures ≥ 1.5 cm in longest dimension (LD) and ≥ 1.0 cm in longest perpendicular dimension (LPD), or spleen that measures ≥ 14 cm in longest vertical dimension (LVD) with a minimum of 2 cm enlargement, or liver that measures ≥ 20 cm in LVD with a minimum of 2 cm enlargement, or peripheral blood B lymphocyte count > 5000/uL All eligible subjects must be relapsed after or be refractory to >2 prior lines of therapy one of which must have included an approved BTK inhibitor. Must meet the following laboratory parameters: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3 or ≥ 1000 cells/mm^3 if secondary to bone marrow involvement by disease, without growth factor support for 7 days (14 days if pegfilgastrim). Platelet count ≥ 75,000 cells/mm^3 (100 x 10^9/L) or ≥ 50,000 cells/mm^3 (50 x 10^9/L) if secondary to bone marrow involvement by disease, without transfusion for 7 days. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) < 3.0 x upper limit of normal (ULN). Serum bilirubin < 1.5 x ULN unless due to Gilbert's syndrome. Calculated creatinine clearance of ≥ 60 ml/min. Exclusion Criteria: Presence of any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. Prior allogeneic stem cell transplant (SCT)/bone marrow transplant within 12 months of signing the ICF. Subjects who received allogeneic SCT ≥ 12 months before signing the ICF may be eligible provided there is no ongoing graft-versus-host disease and no ongoing immune suppression therapy. Subject has received prior CAR-T or other T-cell targeting treatment (approved or investigational) ≤ 4 weeks prior to starting CC-99282. Subject has received prior therapy with CRBN-modulating drug (eg, lenalidomide, avadomide/CC-122, pomalidomide) ≤ 4 weeks prior to starting CC-99282. History of second malignancies with life expectancy of ≤ 2 years or requirement of therapy that would confound study results. Peripheral neuropathy ≥ Grade 2. History of hypersensitivity to lenalidomide, pomalidomide, thalidomide. Impaired cardiac function or clinically significant cardiac disease. Persistent diarrhea or malabsorption ≥ NCI CTCAE Grade 2, despite medical management. Active disease transformation (ie, Richter's Syndrome) Uncontrolled/active autoimmune hemolytic anemia or thrombocytopenia

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-99282 + obinutuzumab<br>Escalating doses of CC-99282 administered orally once daily on intermittent schedules with obinutuzumab IV infusion 1000 mg up to 2 years in Part A. CC-99282 administered orally once daily at MTD or alternative tolerating dosing schedule with obinutuzumab IV infusion 1000 mg up to 2 years in Part B. | Drug: CC-99282<br>* CC-99282<br>Drug: Obinutuzumab<br>* Obinutuzumab<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 subjects with a DLT | Up to Cycle 2 Day 14 (each cycle is 28 days) | 
| Maximum tolerated dose (MTD) | The highest dose of CC-99282 in combination with obinutuzumab associated with acceptable safety and tolerability | Up to Cycle 2 Day 14 (each cycle is 28 days | 
| Adverse Events (AEs) | An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject 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 subject'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. | From first subjects first visit until 28 days after last subject discontinued study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Cmax | Maximum observed plasma concentration | Up to Cycle 2 Day 14 (each cycle is 28 days) | 
| Pharmacokinetics - AUC | Area under the plasma concentration-time curve | Up to Cycle 2 Day 14 (each cycle is 28 days) | 
| Pharmacokinetics - Tmax | Time to Cmax | Up to Cycle 2 Day 14 (each cycle is 28 days) | 
| Pharmacokinetics - T-HALF | Terminal-phase elimination half-life | Up to Cycle 2 Day 14 (each cycle is 28 days) | 
| Pharmacokinetics - CLT/F | Apparent total clearance of the drug from plasma after oral administration | Up to Cycle 2 Day 14 (each cycle is 28 days) | 
| Pharmacokinetics - Vz/F | Apparent volume of distribution during terminal phase after non-intravenous administration | Up to Cycle 2 Day 14 (each cycle is 28 days) | 
| Objective response rate (ORR) | Sum of complete response (CR), complete response with incomplete marrow recovery (CRi), nodular partial response (nPR), partial response (PR), partial response with lymphocytosis (PRL) determined by iwCLL criteria | Up to approximately 3 years | 
| Duration of response (DoR) | Time from first documentation of response (≥ PR) to the first documentation of PD or death | Up to approximately 3 years | 
| Progression free survival | Time from first dose of CC-99282 to the first occurrence of disease progression or death from any cause | Up to approximately 3 years | 
| Overall survival | Time from first dose of CC-99282 to death from any cause | Up to approximately 3 years | 
| Complete response with incomplete marrow recovery (CRi) | As assessed by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria | Up to approximately 3 years | 
| Nodular partial response (nPR) | As assessed by iwCL and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria | Up to approximately 3 years | 
| Partial response (PR) | As assessed by iwC and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria | Up to approximately 3 years | 
| Partial response with lymphocytosis (PRL) | As assessed by iwCLL and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria | Up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Safety, Efficacy, CC-99282, Obinutuzumab, Relapsed, Refractory