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

• ClinicalTrials.gov Identifier: NCT04434196
• Recruitment Status: Recruiting
• First Posted: June 16, 2020
• Last Update Posted: January 20, 2021
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

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 (Clinical Trial)
• Estimated Enrollment: 50 participants
• 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: December 21, 2020
• Estimated Primary Completion Date: June 10, 2024
• Estimated 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

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity (DLT) [ Time Frame: Up to Cycle 2 Day 14 (each cycle is 28 days) ]
   Number of subjects with a DLT
2. Maximum tolerated dose (MTD) [ Time Frame: 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
3. Adverse Events (AEs) [ Time Frame: 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 :

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

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Subject is ≥18 years of age
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

3. 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
4. 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.

5. Must meet the following laboratory parameters:

   1. Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 or ≥ 1000 cells/mm3 if secondary to bone marrow involvement by disease.
   2. 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.
   3. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) < 3.0 x upper limit of normal (ULN).
   4. Serum bilirubin < 1.5 x ULN unless due to Gilbert's syndrome.
   5. Calculated creatinine clearance of ≥ 60 ml/min.

Exclusion Criteria:

1. Presence of any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. 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.
3. Subject has received prior CAR-T or other T-cell targeting treatment (approved or investigational) ≤ 4 weeks prior to starting CC-99282.
4. Subject has received prior therapy with CRBN-modulating drug (eg, lenalidomide, avadomide/CC-122, pomalidomide) ≤ 4 weeks prior to starting CC-99282.
5. History of second malignancies with life expectancy of ≤ 2 years or requirement of therapy that would confound study results.
6. Peripheral neuropathy ≥ Grade 2.
7. History of hypersensitivity to lenalidomide, pomalidomide, thalidomide.
8. Impaired cardiac function or clinically significant cardiac disease.
9. Persistent diarrhea or malabsorption ≥ NCI CTCAE Grade 2, despite medical management.
10. Active disease transformation (ie, Richter's Syndrome)
11. Uncontrolled/active autoimmune hemolytic anemia or thrombocytopenia

Contacts and Locations

Contacts

Contact: Associate Director Clinical Trial Disclosure; 1-888-260-1599; clinicaltrialdisclosure@celgene.com

Locations

United States, Massachusetts

Dana Farber Cancer Institute; Not yet recruiting

Boston, Massachusetts, United States, 02215

United States, New York

Memorial Sloan-Kettering Cancer Center; Not yet recruiting

New York, New York, United States, 10021

United States, Ohio

The Ohio State University Comprehensive Cancer Center; Recruiting

Columbus, Ohio, United States, 43210

United States, Oregon

Oregon Health and Science University; Recruiting

Portland, Oregon, United States, 97201-3098

United States, Texas

Southwestern Medical Center- Harold C Simmons Comprehensive Cancer Center; Not yet recruiting

Dallas, Texas, United States, 75390

Austria

Universitaetsklinik fuer Innere Medizin V; Not yet recruiting

Innsbruck, Austria, 6020

Landeskrankenhaus Salzburg; Recruiting

Salzburg, Austria, 5020

Allgemeinen Krankenhaus (AKH) Wien - Medizinische Universitaet Wien; Recruiting

Wien, Austria, 1090

Canada, Ontario

Princess Margaret Hospital University Health Network; Recruiting

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

Sir Mortimer B. Davis - Jewish Genl; Not yet recruiting

Montreal, Quebec, Canada, H3T 1E2

Spain

Hospital Universitario Vall D hebron; Recruiting

Barcelona, Spain, 08035

Hospital 12 de Octubre; Recruiting

Madrid, Spain, 28041

Clinica Universidad de Navarra; Recruiting

Pamplona, Spain, 31008

Universitario de Salamanca - Hospital Clinico; Recruiting

Salamanca, Spain, 37007

Hospital Clinico Universitario de Valencia; Recruiting

Valencia, Spain, 46010

Sponsors and Collaborators

Celgene

Investigators

• Study Director: Poliana Patah, MD, PhD; Bristol-Myers Squibb

More Information

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT04434196
• Other Study ID Numbers: CC-99282-CLL-001; U1111-1251-4261 ( Other Identifier: WHO ); 2019-003228-18 ( EudraCT Number )
• First Posted: June 16, 2020
• Last Update Posted: January 20, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Information relating to our policy on data sharing and the process for requesting data can be found at the following link:

https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: See Plan Description
• Access Criteria: See Plan Description
• URL: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Celgene:

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Safety; Efficacy; CC-99282; Obinutuzumab; Relapsed; Refractory

Additional relevant MeSH terms:

Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Obinutuzumab; Antineoplastic Agents, Immunological; Antineoplastic Agents