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A Dose Finding and Safety Study of CC-220, Alone and in Combination With an Anti-CD20 Monoclonal Antibody (mAb) in Subjects With Relapsed or Refractory Lymphomas

  • Clinicaltrials.gov identifier

    NCT04464798

  • Recruitment Status

    Recruiting

  • First Posted

    July 9, 2020

  • Last update posted

    July 9, 2021

Study Description

Brief summary:

This Phase 1/2, multicenter, open-label study to evaluate CC-220 alone, as well as in combination with an anti-CD20 mAb (rituximab or obinutuzumab) in subjects with relapsed or refractory (R/R) lymphoma. Subjects must have received at least 2 prior lines of therapy, and have at least one measurable lesion according to Lugano 2014 classification. Study will consist of two parts: Part 1 (Dose Escalation) which will be followed by Part 2 (Dose Expansion).

  • Condition or Disease:Lymphoma
  • Intervention/Treatment: Drug: CC-220
    Drug: Rituximab
    Drug: Obinutuzumab
  • Phase: Phase 1

Detailed Description

N/A

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 152 participants
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase 1/2, Multicenter, Open-label Study to Assess Safety, Pharmacokinetics, and Preliminary Efficacy of CC-220, Alone and in Combination With an Anti-CD20 Monoclonal Antibody (mAb) in Subjects With Relapsed or Refractory Lymphomas.
  • Actual Study Start Date: November 2020
  • Estimated Primary Completion Date: January 2022
  • Estimated Study Completion Date: April 2025

Arms and interventions

Arm Intervention/treatment
Experimental: Cohort A- Monotherapy in R/R lymphoma subjects
Subjects with Relapsed or Refractory (R/R) lymphoma who have been allocated to Cohort A will receive CC-220 monotherapy (MonoT). Oral CC-220 at dose specified by cohort dose level from Day 1 to 21 of each 28-day cycle, up to PD or a maximum of 24 cycles.
Drug: CC-220
Oral
Experimental: Cohort B- CC-220 and rituximab in R/R B-Cell NHL subjects
Subjects with R/R B-cell Non Hodgkin Lymphoma (NHL) who have been allocated to Cohort B will receive CC-220 in combination with rituximab. Oral CC-220 at dose specified by cohort dose level from Day 1 to 21 of each 28-day cycle up to PD or maximum 24 cycles. Rituximab will be administered at 375 mg/m2 IV at C1D1 and then on D8, D15, and D22 of C1 and then every 28-day cycle at D1 from C2 to C5, either by SC infusion at a dose of 1400 mg or by IV infusion at a dose of 375 mg/m2.
Drug: CC-220
Oral

Drug: Rituximab
SC and IV infusion
Experimental: Cohort C - CC-220 and obinutuzumab in R/R FL or MZL subjects
Subjects with R/R FL (Grade 1 to 3a) or MZL who have been allocated to Cohort C will receive CC-220 in combination with obinutuzumab. Oral CC-220 at dose specified by cohort dose level from Day 1 to 21 of each 28-day cycle, up to PD or a maximum of 12 cycles. Obinutuzumab will be administered at 1000 mg at C1D1, D8, and D15, and on D1 of every 28-day cycle from C2 to C6.
Drug: CC-220
Oral

Drug: Obinutuzumab
IV Infusion
Experimental: Cohort D - Monotherapy in other lymphomas subtype subjects
Subjects with other lymphoma subtype who have been allocated to Cohort D will receive CC-220 monotherapy (MonoT). - Oral CC-220 at Recommended Phase 2 dose (RP2D) from Day 1 to 21 of each 28-day cycle, up to PD or a maximum of 24 cycles.
Drug: CC-220
Oral
Experimental: Cohort E - CC-220 and rituximab in B-cell lymphoma subjects
Subjects with aggressive B-cell lymphoma who have been allocated to Cohort E will receive CC-220 in combination with rituximab Oral CC-220 at RP2D from Day 1 to 21 of each 28-day cycle, up to PD or a maximum of 24 cycles. Rituximab will be administered at 375 mg/m2 IV at C1D1 and then on D8, D15, and D22 of C1 and then every 28-day cycle at D1 from C2 to C5, either by SC infusion at a dose of 1400 mg or by IV infusion at a dose of 375 mg/m2.
Drug: CC-220
Oral

Drug: Rituximab
SC and IV infusion
Experimental: Cohort F - CC-220 and rituximab in FL and MZL subjects
Subjects with follicular lymphoma (FL) (1 to 3a) and marginal zone lymphoma (MZL) who have been allocated to Cohort F Part 2 will receive CC-220 in combination with rituximab. Oral CC-220 at RP2D from Day 1 to 21 of each 28-day cycle, up to PD or a maximum of 12 cycles. Rituximab will be administered at 375 mg/m2 IV at C1D1 and then on D8, D15, and D22 of C1 and then every 28-day cycle at D1 from C2 to C5, either by SC infusion at a dose of 1400 mg or by IV infusion at a dose of 375 mg/m2
Drug: CC-220
Oral

Drug: Rituximab
SC and IV infusion
Experimental: Cohort G -CC-220 and obinutuzumab in FL and MZL subjects
Subjects with FL (1 to 3a) and MZL who have been allocated to Cohort G will receive CC-220 in combination with obinutuzumab. Oral CC-220 at RP2D from Day 1 to 21 of each 28-day cycle, up to PD or a maximum of 12 cycles. Obinutuzumab will be administered at 1000 mg at C1D1, D8, and D15 and on D1 of every 28-day cycle from C2 to C6.
Drug: CC-220
Oral

Drug: Obinutuzumab
IV Infusion

Outcome Measures

  • Primary Outcome Measures: 1. Maximum Tolerated Dose (MTD) [ Time Frame: During the First cycle (each cycle is 28 days) ]
    is defined as the dose that satisfies the escalation with overdose control (EWOC) criterion that the posterior probability to have excessive toxicity is less than 25% and has the highest probability of dose-limiting toxicity (DLT) rate being in the target interval (0.16 to 0.33)
  • 2. Recommended Phase 2 Dose (RR2D) [ Time Frame: During the first Cycle (each cycle is 28 days) ]
    is defined as the dose that will be selected for dose expansion based on PK/Pd and MTD
  • Secondary Outcome Measures: 1. Progression-free Survival (PFS) [ Time Frame: Approximately 5 years ]
    is defined as the time from enrollment date to the first occurrence of disease progression or death from any cause
  • 2. Overall Survival (OS) [ Time Frame: Approximately 5 years ]
    is defined as the time from enrollment date to death from any cause
  • 3. Complete Response Rate (CRR) [ Time Frame: Approximately 5 years ]
    is defined as the proportion of subjects experiencing CR before receiving any subsequent anti-lymphoma therapy
  • 4. Time to Response (TTR) [ Time Frame: Approximately 5 years ]
    is defined as the time from enrollment dose date to the date of first documented response (≥ PR)
  • 5. Duration of Response (DOR) [ Time Frame: Approximately 5 years ]
    is defined as the time from first dose date to the date of first documented response (≥ PR)
  • 6. Adverse Events (AEs) [ Time Frame: From first dose to 28 days after last subject discontinues 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.
  • 7. Pharmacokinetics - Cmax [ Time Frame: At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days) ]
    Maximum plasma concentration
  • 8. Pharmacokinetics - Ctrough [ Time Frame: At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days) ]
    Observed plasma concentration at the end of the dosing interval
  • 9. Pharmacokinetics - AUC [ Time Frame: At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days) ]
    Area under the concentration-time curve
  • 10. Pharmacokinetics - tmax [ Time Frame: At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days) ]
    Time to maximum plasma concentration
  • 11. Pharmacokinetics - CL/F [ Time Frame: At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days) ]
    Apparent total plasma clearance
  • 12. Pharmacokinetics - V/F [ Time Frame: At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days) ]
    Apparent total volume of distribution
  • 13. Overall Response Rate (ORR) [ Time Frame: Approximately 5 years ]
    is defined as the proportion of subjects with best overall response as either CR or partial response (PR) before subsequent anti-lymphoma therapy

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: Subjects must satisfy the following criteria to be enrolled in the study: 1. Is ≥ 18 years of age at the time of signing the informed consent form (ICF). 2. Has histologically confirmed (per local evaluation) diagnosis of lymphoma according to 2016 World Health Organization (WHO) classification including: 1. Cohort A and Cohort D: all subtypes including B-cell, T-cell and Natural killer (NK)-cell Non-Hodgkin lymphoma (NHL), and Classical Hodgkin lymphoma (cHL). 2. Cohort B: all B-cell NHL. 3. Cohort E: aggressive B-cell lymphoma 4. Cohorts C, F and G: FL Grade 1 to 3a and MZL 3. Relapsed or refractory disease according to the following definitions: 1. Aggressive B-cell lymphoma: after at least 2 prior lines of therapy including R-CHOP-like regimen. 2. Follicular lymphoma (FL) and Marginal zone lymphoma (MZL): following at least 2 prior lines of systemic therapy (being previously exposed to at least 1 anti-CD20 mAb and 1 alkylating agent). 3. Mantle cell lymphoma (MCL): following at least 2 prior lines of therapy including at least 1 immunochemotherapy and 1 bruton tyrosine kinase (BTK) inhibitor. 4. Peripheral T-cell lymphoma (PTCL): following at least 2 prior lines of therapy OR after 1 prior line of standard therapy and being not eligible for any other approved regimen. 5. Classical Hodgkin lymphoma (cHL): following at least 2 prior systemic lines of therapy and previously exposed to brentuximab vedotin and anti-PD1. 6. All other subtypes: following at least 2 prior lines of therapy. 7. Subjects previously treated with CAR-T therapy can be enrolled (irrespective of the indication). 4. Subjects must not be eligible for any other approved treatment for their underlying lymphoma as assessed by the Investigator. 5. Must have measurable disease defined by at least 1 fluorodeoxyglucose (FDG)-avid lesion for FDG-avid subtype and 1 bi-dimensionally measurable (> 1.5 cm in longest diameter) disease by computed tomography (CT) or magnetic resonance imaging (MRI), as defined by the Lugano classification. Site of measurable disease cannot be previously irradiated. 6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 7. Must have the following laboratory values: 1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L or ≥ 1.0 x 109/L 2. Hemoglobin (Hb) ≥ 8 g/dL. 3. Platelets (Plt) ≥ 75 x 109/L or ≥ 50 x 109/L 4. Aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase / serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 2.5 x ULN. 5. Serum total bilirubin ≤ 1.5 ULN except in cases of Gilbert's syndrome, then ≤ 3.0 ULN. 6. Estimated serum creatinine clearance of ≥ 50 mL/min 8. All subjects must: 1. Have an understanding that the study drug could have a potential teratogenic risk. 2. Agree to follow all requirements defined in the Pregnancy Prevention Program for CC-220 Pregnancy Prevention Plan for Subjects in Clinical Trials. 9. Females of childbearing potential (FCBP1) must: a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. 10. Male subjects must: 1. Practice true abstinence2 or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: 1. Any significant medical condition, active infection (including severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2) suspected or confirmed, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. 2. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. 3. Life expectancy ≤ 3 months. 4. Diagnosis of lymphoblastic lymphoma. 5. Aggressive lymphoma relapse requiring immediate cytoreductive therapy to avoid potential life-threatening consequences (eg, due to tumor location). 6. Prior Grade 3 or 4 infusion related reaction with rituximab (for Cohorts B, E and F) or obinutuzumab (for Cohorts C and G). 7. Prior therapy with the cereblon-modulating drug CC-99282. 8. Chronic systemic immunosuppressive therapy or corticosteroids. 9. Prior ASCT ≤ 3 months prior to starting CC-220 or > 3 months AND with unresolved, Grade > 1, treatment-related toxicity. 10. Prior allogeneic stem cell transplant with either standard or reduced intensity conditioning ≤ 6 months prior to starting CC-220 or > 6 months with unresolved, Grade > 1, treatment-related toxicity. 11. Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients of rituximab or obinutuzumab. 12. Known allergy to thalidomide, pomalidomide or lenalidomide. 13. Inability or unwilling to undergo protocol required thromboembolism prophylaxis. 14. Major surgery ≤ 2 weeks prior to starting CC-220; 15. Peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0). 16. Documented or suspected central nervous system (CNS) involvement of disease. 17. Subject with clinically significant cardiac disease. 18. Known seropositivity for or active viral infection with human immunodeficiency virus (HIV). 19. Known chronic active hepatitis B 20. History of other malignancy, unless the subject has been free of the disease for ≥ 3 years; exceptions to the ≥ 3-year time limit include history of the following: 1. Incidental histologic finding of prostate cancer (or prostate cancer that has been treated with curative intent.

Contacts and Locations

Contacts

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

Locations

United States, Arizona
Mayo Clinic Phoenix
Phoenix

United States, Florida
Lake Mary DDU Florida Cancer
Lake Mary

United States, Minnesota
Mayo Clinic
Rochester

United States, New York
Weill Cornell Medical College - New York Presbyterian Hospital
New York

United States, New York
University of Rochester Cancer Center
Rochester

United States, Tennessee
Sarah Cannon Research Institute
Nashville

France
Hopital Henri Mondor
Creteil

France
CHRU de Lille - Hopital Claude Huriez
Lillie Cedex

France
CHU Montpellier - Hôpital Saint Eloi
Montpellier CEDEX 5

France
CHU Nantes Hotel Dieu
Nantes cedex 1

France
Hopital Saint Louis
Paris

France
CHRU - Hopital du Haut Leveque
Pessac

Germany
Charite - Universitaetsmedizin Berlin Charité - Campus Benjamin Franklin
Berlin

Germany
University Hospital Leipzig
Leipzig

Germany
Universitaetsklinikum Muenster
Munster

Germany
Universitaetsklinikum Wuerzburg
Wuerzburg

Italy
AO Spedali Civili di Brescia
Brescia

Italy
Istituto Nazionale Dei Tumori
Milano

Italy
I.R.C.C.S. Policlinico San Matteo
Pavia

Italy
AOU Integrata Verona - Ospedale Policlinico Giambattista Rossi di Borgo Roma
Verona

Sponsors and Collaborators

Celgene

Investigators

Study Director: Vijaya Kesanakurthy, M.D Celgene/BMS

More Information

  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT04464798 History of Changes
  • Other Study ID Numbers: CC-220-NHL-001, U1111-1254-1772, 2020-000354-10
  • First Posted: July 9, 2020 Key Record Dates
  • Last Update Posted: July 9, 2021
  • Last Verified: July 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: Safety
    Pharmacokinetics
    Monoclonal Antibody
    Anti-CD20
    CC-220
    Lymphomas
    Relapsed or Refractory Lymphomas
  • Additional relevant MeSH terms: Lymphoma