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

Sponsor

Celgene (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04434196

Collaborator

(none)

Enrollment

Locations

Arm

52.7

Anticipated Duration (Months)

2.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Non-Hodgkin	Drug: CC-99282 Drug: Obinutuzumab	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 21, 2020

Anticipated Primary Completion Date :

Nov 15, 2024

Anticipated Study Completion Date :

May 13, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CC-99282 + obinutuzumab 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 CC-99282 Drug: Obinutuzumab Obinutuzumab

Arm

Intervention/Treatment

Experimental: CC-99282 + obinutuzumab

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

CC-99282

Drug: Obinutuzumab

Obinutuzumab

Outcome Measures

Primary Outcome Measures

Dose Limiting Toxicity (DLT) [Up to Cycle 2 Day 14 (each cycle is 28 days)]
Number of subjects with a DLT
Maximum tolerated dose (MTD) [Up to Cycle 2 Day 14 (each cycle is 28 days]
The highest dose of CC-99282 in combination with obinutuzumab associated with acceptable safety and tolerability
Adverse Events (AEs) [From first subjects first visit until 28 days after last subject discontinued study treatment]
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.

Secondary Outcome Measures

Pharmacokinetics - Cmax [Up to Cycle 2 Day 14 (each cycle is 28 days)]
Maximum observed plasma concentration
Pharmacokinetics - AUC [Up to Cycle 2 Day 14 (each cycle is 28 days)]
Area under the plasma concentration-time curve
Pharmacokinetics - Tmax [Up to Cycle 2 Day 14 (each cycle is 28 days)]
Time to Cmax
Pharmacokinetics - t1/2 [Up to Cycle 2 Day 14 (each cycle is 28 days)]
Terminal-phase elimination half-life
Pharmacokinetics - CL/F [Up to Cycle 2 Day 14 (each cycle is 28 days)]
Apparent total clearance of the drug from plasma after oral administration
Pharmacokinetics - V/F [Up to Cycle 2 Day 14 (each cycle is 28 days)]
Apparent volume of distribution during terminal phase after non-intravenous administration
Objective response rate (ORR) [Up to approximately 3 years]
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
Duration of response (DoR) [Up to approximately 3 years]
Time from first documentation of response (≥ PR) to the first documentation of PD or death
Progression free survival [Up to approximately 3 years]
Time from first dose of CC-99282 to the first occurrence of disease progression or death from any cause
Overall survival [Up to approximately 3 years]
Time from first dose of CC-99282 to death from any cause
Complete response with incomplete marrow recovery (CRi) [Up to approximately 3 years]
As assessed by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
Nodular partial response (nPR) [Up to approximately 3 years]
As assessed by iwCL and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
Partial response (PR) [Up to approximately 3 years]
As assessed by iwC and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
Partial response with lymphocytosis (PRL) [Up to approximately 3 years]
As assessed by iwCLL and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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/mm3 or ≥ 1000 cells/mm3 if secondary to bone marrow involvement by disease.
Platelet count ≥ 100,000 cells/mm3 (100 x 109/L) or ≥ 50,000 cells/mm3 (50 x 109/L) if secondary to bone marrow involvement by disease.
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 ICD. Subjects who received allogeneic SCT ≥ 12 months before signing the ICD 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
3	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
4	University Of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
5	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
6	Oregon Health and Science University	Portland	Oregon	United States	97201-3098
7	Southwestern Medical Center- Harold C Simmons Comprehensive Cancer Center	Dallas	Texas	United States	75390
8	Local Institution - 403	Innsbruck		Austria	6020
9	Universitaetsklinik fuer Innere Medizin V	Innsbruck		Austria	6020
10	Landeskrankenhaus Salzburg	Salzburg		Austria	5020
11	Allgemeinen Krankenhaus (AKH) Wien - Medizinische Universitaet Wien	Wien		Austria	1090
12	Princess Margaret Hospital University Health Network	Toronto	Ontario	Canada	M5G 2M9
13	Sir Mortimer B. Davis - Jewish Genl	Montreal	Quebec	Canada	H3T 1E2
14	Hospital Universitario Vall D hebron - PPDS	Barcelona		Spain	08035
15	Clinica Universidad de Navarra	Madrid		Spain	28027
16	Hospital 12 de Octubre	Madrid		Spain	28041
17	Clinica Universidad de Navarra	Pamplona		Spain	31008
18	Hospital Universitario de Salamanca	Salamanca		Spain	37007
19	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010