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

Sponsor

Celgene (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04464798

Collaborator

(none)

232

Enrollment

Locations

Arms

53.6

Anticipated Duration (Months)

6.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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	Intervention/Treatment	Phase
Lymphoma	Drug: CC-220 Drug: Rituximab Drug: Obinutuzumab	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

232 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 :

Nov 11, 2020

Anticipated Primary Completion Date :

Aug 31, 2023

Anticipated Study Completion Date :

Apr 30, 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 Other Names: Iberdomide
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 administration at a dose of 1400 mg or by IV infusion at a dose of 375 mg/m2.	Drug: CC-220 Oral Other Names: Iberdomide 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 Other Names: Iberdomide Drug: Obinutuzumab IV Infusion
Experimental: Cohort D -CC-220 monotherapy in participants with aggressive B-cell lymphoma and follicular lymphoma	Drug: CC-220 Oral Other Names: Iberdomide
Experimental: Cohort E - CC-220 and rituximab in participants with aggressive B-cell lymphoma	Drug: CC-220 Oral Other Names: Iberdomide Drug: Rituximab SC and IV infusion
Experimental: Cohort F - CC-220 and rituximab with follicular lymphoma grade 1-3a	Drug: CC-220 Oral Other Names: Iberdomide Drug: Rituximab SC and IV infusion
Experimental: Cohort G - CC-220 plus obinutuzumab in participants with follicular lymphoma grade 1-3a	Drug: CC-220 Oral Other Names: Iberdomide Drug: Obinutuzumab IV Infusion

Outcome Measures

Primary Outcome Measures

Maximum Tolerated Dose (MTD) [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)
Recommended Phase 2 Dose (RP2D) [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

Adverse Events (AEs) [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.
Pharmacokinetics - Cmax [At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days)]
Maximum plasma concentration
Pharmacokinetics - Ctrough [At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days)]
Observed plasma concentration at the end of the dosing interval
Pharmacokinetics - AUC(TAU) [At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days)]
Area under the plasma concentration-time curve from time zero to tau, where tau is the dosing interval
Pharmacokinetics - tmax [At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days)]
Time to maximum plasma concentration
Pharmacokinetics - CLT/F [At Cycle1 Day15 and Cycle2 Day15 (each cycle is 28 days)]
Apparent total plasma clearance
Best Overall Response Rate (ORR) [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
Complete Response Rate (CRR) [Approximately 5 years]
is defined as the proportion of subjects experiencing CR before receiving any subsequent anti-lymphoma therapy
Time to Response (TTR) [Approximately 5 years]
is defined as the time from enrollment dose date to the date of first documented response (≥ PR)
Duration of Response (DOR) [Approximately 5 years]
is defined as the time from first dose date to the date of first documented response (≥ PR)
Progression-free Survival (PFS) [Approximately 5 years]
is defined as the time from enrollment date to the first occurrence of disease progression or death from any cause
Overall Survival (OS) [Approximately 5 years]
is defined as the time from enrollment date to death from any cause

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

Is ≥ 18 years of age at the time of signing the informed consent form (ICF).
Has histologically confirmed (per local evaluation) diagnosis of lymphoma according to 2016 World Health Organization (WHO) classification including:
Cohort A: all subtypes including B-cell, T-cell and Natural killer (NK)-cell Non-Hodgkin lymphoma (NHL), and Classical Hodgkin lymphoma (cHL).
Cohort B: all B-cell NHL.
Cohort C: FL Grade 1-3a and MZL including extranodal marginal zone lymphoma (ENMZL) of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma (NMZL) and splenic marginal zone lymphoma (SMZL)
Cohort D: aggressive B-cell lymphoma and FL grade 1-3a
Cohort E: aggressive B-cell lymphoma including DLBCL NOS, high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements, Grade 3b FL and PMBCL
Cohorts F and G: FL Grade 1 to 3a
Relapsed or refractory disease according to the following definitions:
Aggressive B-cell lymphoma
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).
Mantle cell lymphoma (MCL): following at least 2 prior lines of therapy including at least 1 immunochemotherapy and 1 bruton tyrosine kinase (BTK) inhibitor.
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.
Classical Hodgkin lymphoma (cHL): following at least 2 prior systemic lines of therapy and previously exposed to brentuximab vedotin and anti-PD1.
All other subtypes: following at least 2 prior lines of therapy.
Subjects previously treated with CAR-T therapy can be enrolled (irrespective of the indication).
Subjects must not be eligible for any other approved treatment for their underlying lymphoma as assessed by the Investigator.
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.
Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
Must have the following laboratory values:
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L or ≥ 1.0 x 109/L
Hemoglobin (Hb) ≥ 8 g/dL.
Platelets (Plt) ≥ 75 x 109/L or ≥ 50 x 109/L
Aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase / serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 2.5 x ULN.
Serum total bilirubin ≤ 1.5 ULN except in cases of Gilbert's syndrome, then ≤ 3.0 ULN.
Estimated serum creatinine clearance of ≥ 50 mL/min
All subjects must:
Have an understanding that the study drug could have a potential teratogenic risk.
Agree to follow all requirements defined in the Pregnancy Prevention Program for CC-220 Pregnancy Prevention Plan for Subjects in Clinical Trials.
Females of childbearing potential (FCBP1) must:

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.

Male subjects must:
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:

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.
Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
Life expectancy ≤ 3 months.
Diagnosis of lymphoblastic lymphoma.
Aggressive lymphoma relapse requiring immediate cytoreductive therapy to avoid potential life-threatening consequences (eg, due to tumor location).
Prior Grade 3 or 4 infusion related reaction with rituximab (for Cohorts B, E and F) or obinutuzumab (for Cohorts C and G).
Prior therapy with the cereblon-modulating drug CC-99282.
Chronic systemic immunosuppressive therapy or corticosteroids.
Prior ASCT ≤ 3 months prior to starting CC-220 or > 3 months AND with unresolved, Grade > 1, treatment-related toxicity.
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.

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients of rituximab or obinutuzumab.
Known allergy to thalidomide, pomalidomide or lenalidomide.
Inability or unwilling to undergo protocol required thromboembolism prophylaxis.
Major surgery ≤ 2 weeks prior to starting CC-220;
Peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0).
Documented or suspected central nervous system (CNS) involvement of disease.
Subject with clinically significant cardiac disease.
Known seropositivity for or active viral infection with human immunodeficiency virus (HIV).
Known chronic active hepatitis B
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:
Incidental histologic finding of prostate cancer (or prostate cancer that has been treated with curative intent

Other protocol defined inclusion/exclusion criteria could apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Phoenix	Phoenix	Arizona	United States	85054
2	UCSF Fresno	Houston	California	United States	93701
3	Lake Mary DDU Florida Cancer	Lake Mary	Florida	United States	32746
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Weill Cornell Medical College - New York Presbyterian Hospital	New York	New York	United States	10065
6	University of Rochester Cancer Center	Rochester	New York	United States	14642
7	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
8	Hopital Henri Mondor	Creteil		France	94010
9	CHRU de Lille - Hopital Claude Huriez	Lillie Cedex		France	59037
10	CHU Montpellier - Hôpital Saint Eloi	Montpellier CEDEX 5		France	34295
11	CHU Nantes Hotel Dieu	Nantes cedex 1		France	44093
12	Hopital Saint Louis	Paris		France	75010
13	Local Institution - 204	Paris		France	75010
14	Pitié-Salpêtriere Hospital Paris	Paris		France	75013
15	CHRU - Hopital du Haut Leveque	Pessac		France	33604
16	Charite - Universitaetsmedizin Berlin Charité - Campus Benjamin Franklin	Berlin		Germany	12203
17	Universitatsklinikum Essen	Essen		Germany	45147
18	University Hospital Leipzig	Leipzig		Germany	4103
19	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz	Mainz		Germany	55131
20	Local Institution - 403	Munster		Germany	48149
21	Universitaetsklinikum Muenster	Munster		Germany	48149
22	Universitaetsklinikum Wuerzburg	Wuerzburg		Germany	97080
23	A.O.U. di Bologna Policlinico S.Orsola-Malpighi	Bologna		Italy	40138
24	AO Spedali Civili di Brescia	Brescia		Italy	25123
25	Local Institution - 300	Brescia		Italy	25123
26	AO di Rilievo Nazionale e di Alta Secializzazione Garibaldi	Catania		Italy	95122
27	Istituto Nazionale Dei Tumori	Milano		Italy	20133
28	I.R.C.C.S. Policlinico San Matteo	Pavia		Italy	27100
29	AOU Integrata Verona - Ospedale Policlinico Giambattista Rossi di Borgo Roma	Verona		Italy	37134
30	Severance Hospital	Seoul		Korea, Republic of	03722
31	Local Institution - 501	Seoul		Korea, Republic of	06351
32	Samsung Medical Center	Seoul		Korea, Republic of	06351
33	Asan Medical Center	Seoul		Korea, Republic of	5505
34	Local Institution - 500	Seoul		Korea, Republic of	5505
35	Chang Gung Memorial Hospital - Kaohsiung	Niaosong District Kaohsiung City		Taiwan	83301
36	Chang Gung Memorial Hospital- Linkou	Taoyuan City		Taiwan	33305
37	China Medical University Hospital	Taoyuan City		Taiwan	40447