Study of Safety and Efficacy of Iberdomide (CC-220) and CC-99282 Combined With R-CHOP to Treat Lymphoma

Phase 1

Recruiting

• Conditions: Lymphoma, B-Cell
• Interventions: Drug: CC-220; Drug: Rituximab; Drug: Cyclophosphamide; Drug: CC-99282; Drug: Doxorubicin; Drug: Vincristine; Drug: Polatuzumab vedotin; Drug: Prednisone

• Registration Number: NCT04884035
• Lead Sponsor: Celgene

Brief Summary

This is a Phase 1b study consisting of 2 parts: a dose escalation (Part 1) of CC-220 or CC-99282 added to the standard R-CHOP-21 regimen for first-line treatment of a-BCL. The dose escalation (Part 1) will consist of 2 parallel arms in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP-21); CC-220 and R-CHOP-21 or CC-99282 and R-CHOP-21. Part 1 will be followed by a randomized dose expansion (Part 2) with CC-220 and/or CC-99282 at the Recommended Phase 2 Dose (RP2D) in combination with R-CHOP-21. A polatuzumab-R-CHP regimen in combination with CC-220 or CC-99282 will be explored with the addition of a new cohort only after the RP2D for the CC-220 and/or CC-99282 and R-CHOP-21 combination has been defined.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-05-07
• Study First Submitted QC: 2021-05-07
• Study First Posted: 2021-05-12
• Study Start: 2021-09-15
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-21
• Last Update Posted: 2025-03-24
• Primary Completion: 2027-06-21
• Study Completion: 2027-06-21

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 174

Inclusion Criteria

• Participants 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. Participant has histologically confirmed (per local evaluation) diagnosis of de novo, previously untreated, a-BCL according to 2016 WHO classification.

  3. Participant has International Prognostic Index (IPI) score 0-5 in Part 1 and IPI 2-5 in Part 2. For the CELMoD and polatuzumab-R-CHP cohort, the subject must also have IPI score 0 to 5 in Part 2A and IPI 2 to 5 in Part 2B.

  4. Participants must have measurable disease defined by at least one FDG-avid lesion for FDG-avid subtype and one 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 (Cheson, 2014).

  5. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

  6. Participants must have the following laboratory values:

     1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L or ≥ 1.0 x 109/L in case of documented bone marrow involvement (> 50% or tumor cells), without growth factor support for 7 days (14 days if peg-G-CSF)
     2. Hemoglobin (Hb) ≥ 8 g/dL
     3. Platelets (PLT) ≥ 75 x 109/L or ≥ 50 x 109/L in case of documented bone marrow involvement (>50% or tumor cells), without transfusion for 7 days
     4. Aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase / serum glutamate pyruvic transaminase (ALT/SGPT) ≤ 2.5 x upper limit of normal (ULN). In the case of documented liver involvement by lymphoma, ALT/SGPT and AST/SGOT must be ≤ 5.0 x ULN.
     5. Serum total bilirubin ≤ 2.0 mg/dL except in cases of Gilbert's syndrome, then ≤ 5.0 mg/dl. Subjects receiving polatuzumab vedotin must have serum total bilirubin < 1.5 × ULN (26 μmol/L) (corresponding to mild degree as per National Cancer Institute Organ Dysfunction Working Group [NCI ODWG] criteria) except in cases of Gilbert's syndrome, then ≤ 3.0 mg/dl (51 μmol/L).
     6. Estimated serum creatinine clearance (CrCl) of ≥ 50 mL/min using the modification of diet in renal disease (MDRD) formula.

  7. All participants 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 or CC-99282 Pregnancy Prevention Plan for Participants in Clinical trials.

  8. Females of childbearing potential (FCBP) must:

     a. Have two negative pregnancy tests as verified by the investigator prior to starting study therapy.

  9. Male participants must:

     1. Practice true abstinence 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 participant from enrollment:

  1. Any significant medical condition, active infection (including SARS-CoV-2 suspected or confirmed), laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study.

  2. Any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study.

  3. Any other subtype of lymphoma.

  4. Documented or suspected CNS involvement by lymphoma.

  5. Persistent diarrhea or malabsorption ≥ Grade 2 (NCI CTCAE v5.0), despite medical management.

  6. Peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0).

  7. Subjects with a history of progressive multifocal leukoencephalopathy.

  8. Chronic systemic immunosuppressive therapy or corticosteroids

  9. Impaired cardiac function or clinically significant cardiac disease, including any of the following:

     a. Left ventricular ejection fraction (LVEF) < 45% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO)

  10. Major surgery ≤ 2 weeks prior to starting CC-220 or CC-99282; participant must have recovered from any clinically significant effects of recent surgery.

  11. Any condition causing inability to swallow tablets.

  12. Known seropositivity for or active viral infection with human immunodeficiency virus (HIV)

  13. Known chronic active hepatitis B (hepatitis B virus surface antigen [HBsAg] positive and/or hepatitis B core antibody [anti-HBc] positive with viral DNA positive) or C (positive serology requiring treatment and/or with evidence of liver damage) infection

  14. History of other malignancy, unless being free of the disease for ≥ 3 years; exceptions to the ≥ 3-year time limit include history of the following:

      1. Localized nonmelanoma skin cancer
      2. Carcinoma in situ of the cervix
      3. Carcinoma in situ of the breast
      4. Incidental histologic finding of prostate cancer (T1a or T1b as per Tumor Node Metastasis [TNM] staging system) or prostate cancer that has been treated with curative intent.

  15. Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients of rituximab or polatuzumab vedotin.

  16. Known hypersensitivity to any component of CHOP/CHP regimen.

  17. Known allergy to thalidomide, pomalidomide, or lenalidomide.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Administration of CC-220 with R-CHOP-21	Rituximab	CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-99282 with R-CHOP-21	Cyclophosphamide	CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-99282 with polatuzumab-R-CHP	CC-99282	CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-99282 with R-CHOP-21	CC-99282	CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-220 with R-CHOP-21	CC-220	CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-220 with polatuzumab-R-CHP	CC-220	CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-220 with R-CHOP-21	Prednisone	CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-220 with R-CHOP-21	Doxorubicin	CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-220 with R-CHOP-21	Vincristine	CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-220 with R-CHOP-21	Cyclophosphamide	CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-99282 with R-CHOP-21	Rituximab	CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-99282 with R-CHOP-21	Doxorubicin	CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-99282 with R-CHOP-21	Vincristine	CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-99282 with R-CHOP-21	Prednisone	CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
Administration of CC-220 with polatuzumab-R-CHP	Cyclophosphamide	CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-220 with polatuzumab-R-CHP	Doxorubicin	CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-220 with polatuzumab-R-CHP	Prednisone	CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-99282 with polatuzumab-R-CHP	Cyclophosphamide	CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-220 with polatuzumab-R-CHP	Polatuzumab vedotin	CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-220 with polatuzumab-R-CHP	Rituximab	CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-99282 with polatuzumab-R-CHP	Doxorubicin	CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-99282 with polatuzumab-R-CHP	Prednisone	CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-99282 with polatuzumab-R-CHP	Polatuzumab vedotin	CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
Administration of CC-99282 with polatuzumab-R-CHP	Rituximab	CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) - Part 1	During the first 2 cycles of treatment (each cycle is 21 days)	Frequency of dose-limiting toxicities (DLT) associated with addition of iberdomide (CC-220) to R-CHOP-21 therapy and the addition of CC-99282 to R-CHOP-21 therapy
Recommended Phase 2 Dose (RP2D) - Part 1	During the first cycle of treatment (each cycle is 21 days)	Defined as the dose that will be selected for dose expansion based on MTD
Safety and tolerability of CC-220 and CC-99282 at RP2D - Part 2	From the first dose of any IP until 28 days after the last dose of IP	AEs evaluated using NCI CTCAE criteria, v. 5.0, including treatment -emergent adverse events (TEAEs) and laboratory assessments
Maximum Tolerated Dose (MTD) - Part 2A	During the first cycle of treatment (each cycle is 21 days)	Frequency of DLTs associated with addition of iberdomide (CC-220) to polatuzumab-R-CHP therapy and the addition of CC-99282 to polatuzumab-R-CHP therapy
Recommended Phase 2 Dose (RP2D) - Part 2A	During the first cycle of treatment (each cycle is 21 days)	Defined as the dose that will be selected for dose expansion based on MTD

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics - Cmax for CC-220	At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days)	Maximum plasma concentration of drug
Pharmacokinetics - Ctrough for CC-99282	At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days	Minimum or trough concentration
Best overall response rate (ORR)	Up to 4 years	The proportion of participants with best overall response achieved during the study as either Complete Response or Partial Response before subsequent anti-lymphoma therapy
Duration of Response (DOR)	Up to 4 years	The time from the earliest date of documented response (≥ PR) to the first occurrence of relapse or progression
Complete Metabolic Response Rate (CMRR)	Up to 4 years	The proportion of participants experiencing complete metabolic response (CMR) before receiving any subsequent anti-lymphoma therapy
Time to Response (TTR)	Up to 4 years	The time from entry to the study (enrollment date for Part 1 and randomization date for Part 2) to the date of first documented response (≥ PR)
Overall Survival (OS)	Up to 4 years	The time from entry to the study (enrollment date for Part 1 and randomization date for Part 2) to death from any cause
Progression-free Survival (PFS)	Up to 4 years	The time from entry to the study (enrollment date for Part 1 and randomization date for Part 2) to the first occurrence of disease progression or death from any cause
Pharmacokinetics - Ctrough for CC-220	At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days	Minimum or trough concentration
Pharmacokinetics - Cmax for CC-99282	At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days	Maximum plasma concentration
Pharmacokinetics - Tmax for CC-220	At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days	Time to maximum plasma concentration
Pharmacokinetics - Tmax for CC-99282	At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days	Time to maximum plasma concentration

Trial Locations

Locations (34)

Local Institution - 703; 🇬🇷 Patras, Greece

Taichung Veterans General Hospital; 🇨🇳 Taichung City, Taiwan

Mayo Clinic - Arizona; 🇺🇸 Scottsdale, Arizona, United States

Mayo Clinic - Jacksonville; 🇺🇸 Jacksonville, Florida, United States

Mayo Clinic Jacksonville - PPDS; 🇺🇸 Jacksonville, Florida, United States

University Of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

Mayo Clinic - Rochester; 🇺🇸 Rochester, Minnesota, United States

University of Nebraska - Fred and Pamela Buffet Center; 🇺🇸 Omaha, Nebraska, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Local Institution - 501; 🇦🇺 Adelaide, South Australia, Australia

Local Institution - 503; 🇦🇺 Perth, Australia

Local Institution - 502; 🇦🇺 Waratah, Australia

Evangelismos General Hospital of Athens; 🇬🇷 Athens, Greece

General Hospital of Athens "Laiko"; 🇬🇷 Athens, Greece

Attikon University General Hospital; 🇬🇷 Athens, Greece

Georgios Papanikolaou General Hospital of Thessaloniki; 🇬🇷 Thessaloniki, Greece

Local Institution - 300; 🇰🇷 Seoul, Korea, Republic of

Local Institution - 302; 🇰🇷 Seoul, Korea, Republic of

Local Institution - 301; 🇰🇷 Seoul, Korea, Republic of

Uniwersyteckie Centrum Kliniczne; 🇵🇱 Gdansk, Poland

MCM Krakow - PRATIA - PPDS; 🇵🇱 Krakow, Poland

Centrum Medyczne Pratia Poznan; 🇵🇱 Poznan, Poland

Local Institution - 0706; 🇵🇱 Poznan, Poland

Local Institution - UNK0706; 🇵🇱 Poznan, Poland

SP ZOZ Szpital Uniwersytecki w Krakowie; 🇵🇱 Slomniki, Poland

Local Institution - 602; 🇵🇱 Warsaw, Poland

Local Institution - 604; 🇵🇱 Wroclaw, Poland

Hospital Universitari Germans Trias i Pujol ICO Badalona; 🇪🇸 Barcelona, Spain

Local Institution - 204; 🇪🇸 Madrid, Spain

H. Virgen de la Victoria; 🇪🇸 Málaga, Spain

Hospital Universitario de Salamanca - Complejo Asistencial Universitario de Salamanca; 🇪🇸 Salamanca, Spain

Local Institution - 403; 🇨🇳 Taichung, Taiwan

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan