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

Celgene

Status and phase: Enrolling; Phase 1

Conditions: Lymphoma, B-Cell

Treatments: Drug: Doxorubicin; Drug: Prednisone; Drug: CC-220; Drug: Vincristine; Drug: CC-99282; Drug: Polatuzumab vedotin; Drug: Cyclophosphamide; Drug: Rituximab

Study type: Interventional

Funder types: Industry

Identifiers

NCT04884035

CC-220-DLBCL-001

2020-005705-71 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 174 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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174 participants in 4 patient groups

Administration of CC-220 with R-CHOP-21

Experimental group

Description:

CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment

Treatment:

Drug: Rituximab

Drug: Cyclophosphamide

Drug: Vincristine

Drug: Rituximab

Drug: Prednisone

Drug: Doxorubicin

Drug: CC-220

Administration of CC-99282 with R-CHOP-21

Experimental group

Description:

CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment

Treatment:

Drug: Rituximab

Drug: Cyclophosphamide

Drug: CC-99282

Drug: Vincristine

Drug: Rituximab

Drug: Prednisone

Drug: Doxorubicin

Administration of CC-220 with polatuzumab-R-CHP

Experimental group

Description:

CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment

Treatment:

Drug: Rituximab

Drug: Cyclophosphamide

Drug: Polatuzumab vedotin

Drug: Rituximab

Drug: Prednisone

Drug: Doxorubicin

Drug: CC-220

Administration of CC-99282 with polatuzumab-R-CHP

Experimental group

Description:

CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment

Treatment:

Drug: Rituximab

Drug: Cyclophosphamide

Drug: Polatuzumab vedotin

Drug: CC-99282

Drug: Rituximab

Drug: Prednisone

Drug: Doxorubicin