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Study to Evaluate Tolerability of Iberdomide (CC-220) in Combination With Polatuzumab Vedotin Plus Rituximab or Tafasitamab or Rituximab Plus Chemotherapy in B-cell Lymphoma

NCT04882163

Description:

This is a Phase 1b/2 randomized study of Iberdomide (CC-220) added to 3 different combination regimens (polatuzumab vedotin plus rituximab (Cohort A), tafasitamab (Cohort B), rituximab plus gemcitabine and platinum-based chemotherapy (Cohort C)) for participants with relapsed or refractory aggressive B-cell lymphoma (R/R a-BCL). All 3 cohorts will be open for enrollment at study start. Part 1 (dose escalation) will be followed by Part 2 (dose expansion), in which participants will be randomized to one of three cohorts, with CC-220 at the recommended Phase 2 Dose in combination with the Cohorts A, B and C treatment that is compared to their individual standard of care regimen.

Related Conditions:
  • Anaplastic Large Cell Lymphoma, ALK-Positive
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Grade 3b Follicular Lymphoma
  • High Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements
  • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
  • Primary Mediastinal B-Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study to Evaluate Tolerability of Iberdomide (CC-220) in Combination With Polatuzumab Vedotin Plus Rituximab or Tafasitamab or Rituximab Plus Chemotherapy in B-cell Lymphoma
  • Official Title: A Phase 1B/2 Randomized, Multicenter, Open-Label Study Of Iberdomide (CC-220) In Combination With Polatuzumab Vedotin Plus Rituximab Or Tafasitamab Or Rituximab Plus Chemotherapy For Subjects With Relapsed Or Refractory Aggressive B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: CC-220-DLBCL-002
  • SECONDARY ID: 2020-005333-32
  • NCT ID: NCT04882163

Conditions

  • Lymphoma, B-Cell

Interventions

DrugSynonymsArms
CC-220IberdomideCC-220 + Pola + Ritux vs Pola + Benda + Ritux (Cohort D)
Polatuzumab vedotinCC-220 + Pola + Ritux vs Pola + Benda + Ritux (Cohort D)
RituximabCC-220 + Pola + Ritux vs Pola + Benda + Ritux (Cohort D)
TafasitamabCC-220 + Tafasitamab- Cohort B
GemcitabineCC-220 + Rituximab + Chemo (Cohort C)
CisplatinCC-220 + Rituximab + Chemo (Cohort C)
DexamethasoneCC-220 + Rituximab + Chemo (Cohort C)
BendamustineCC-220 + Pola + Ritux vs Pola + Benda + Ritux (Cohort D)
LenalidomideCC-220 + tafasitamab vs Lenalidomide + Tafasitamab- Cohort E

Purpose

This is a Phase 1b/2 randomized study of Iberdomide (CC-220) added to 3 different combination regimens (polatuzumab vedotin plus rituximab (Cohort A), tafasitamab (Cohort B), rituximab plus gemcitabine and platinum-based chemotherapy (Cohort C)) for participants with relapsed or refractory aggressive B-cell lymphoma (R/R a-BCL). All 3 cohorts will be open for enrollment at study start. Part 1 (dose escalation) will be followed by Part 2 (dose expansion), in which participants will be randomized to one of three cohorts, with CC-220 at the recommended Phase 2 Dose in combination with the Cohorts A, B and C treatment that is compared to their individual standard of care regimen.

Trial Arms

NameTypeDescriptionInterventions
CC-220 + Polatuzumab vedotin + rituximab- Cohort AExperimentalSubjects with Relapsed or refractory (R/R) Aggressive B-cell lymphoma (a-BCL) will receive CC-220 at a dose specified by cohort dose level in combination with polatuzumab vedotin plus rituximab.
  • CC-220
  • Polatuzumab vedotin
  • Rituximab
CC-220 + Tafasitamab- Cohort BExperimentalSubjects with R/R a-BCL will receive CC-220 at a dose specified by cohort dose level in combination with tafasitamab.
  • CC-220
  • Tafasitamab
CC-220 + Rituximab + Chemo (Cohort C)ExperimentalSubjects with R/R a-BCL will receive CC-220 at a dose specified by cohort dose level in combination with rituximab plus chemotherapy (Gemcitabine, cisplatin, dexamethasone).
  • CC-220
  • Rituximab
  • Gemcitabine
  • Cisplatin
  • Dexamethasone
CC-220 + Pola + Ritux vs Pola + Benda + Ritux (Cohort D)ExperimentalSubjects will be randomized to receive either CC-220 + Pola (polatuzumab vedotin) + Ritux (rituximab) or polatuzumab vedotin + bendamustine + rituximab in 21-day treatment cycles. CC-220 will be given at the RP2D declared in Part 1 of this study. Polatuzumab vedotin and rituximab will be administered at the same levels as in part 1. Bendamustine will be given to subjects randomized in the control arm at a dose of 90 mg/m2 IV on Days 1 and 2 of each of the first 6 cycles.
  • CC-220
  • Polatuzumab vedotin
  • Rituximab
  • Bendamustine
CC-220 + tafasitamab vs Lenalidomide + Tafasitamab- Cohort EExperimentalSubjects will be randomized to receive either CC-220 + tafasitamab or lenalidomide + tafasitamab in 28-day treatment cycles. CC-220 will be given at the RP2D declared in Part 1 of this study and the tafasitamab will be at the same levels as in Part 1. Lenalidomide will be administered to subjects randomized in the control arm at a dose of 25 mg/day orally, for 21 days out of 28, for up to 12 cycles.
  • CC-220
  • Tafasitamab
  • Lenalidomide
CC-220 + Rituximab + Chemo vs Rituximab + Chemo (Cohort F)ExperimentalSubjects will be randomized to receive either CC-220 + rituximab + chemotherapy (Gemcitabine, Cisplatin, Dexamethasone) or rituximab + chemotherapy (Gemcitabine, Cisplatin, Dexamethasone) in 21-day treatment cycles. CC-220 will be administered at the RP2D declared in Part 1 of this study and the combination medicines will be at the same levels as in part 1.
  • CC-220
  • Rituximab
  • Gemcitabine
  • Cisplatin
  • Dexamethasone

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must satisfy the following criteria to be enrolled in the study:

               1. Participant 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,
                  aggressive B-cell lymphoma (a-BCL) according to 2016 WHO classification among the
                  following subtypes:

                    1. Diffuse large B-cell lymphoma (DLBCL), Not otherwise specified (NOS)
                       including Germinal center B-cell and Activated B-cell types;

                    2. High-grade B-cell lymphoma, with MYC and B-cell lymphoma 2 (BCL2) and/or
                       B-cell lymphoma 6 (BCL6) rearrangements;

                    3. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);

                    4. Primary cutaneous DLBCL-leg type;

                    5. Anaplastic lymphoma kinase positive (ALK+) large B-cell lymphoma;

                    6. Epstein Barr virus positive (EBV+) DLBCL, NOS;

                    7. Grade 3b Follicular lymphoma (FL).

               3. Participants must have relapsed or refractory disease after at least 2 prior
                  lines of therapy including Rituximab, cyclophosphamide, doxorubicin
                  hydrochloride, vincristine sulfate, and prednisone (R-CHOP)-like regimen OR after
                  one prior line of standard therapy and being not eligible for autologous stem
                  cell transplant (ASCT); participants previously treated with CAR-T therapy can be
                  enrolled.

               4. Participant must have measurable disease defined by at least one FDG-avid lesion
                  for FDGavid-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. Participant 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 pegylated granulocyte-colony
                       stimulating factor (peg-G-CSF))

                    2. Hemoglobin ≥ 8 g/dL

                    3. Platelets ≥ 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 glutamic pyruvic
                       transaminase (ALT/SGPT) ≤ 2.5 x ULN except in the case of documented liver
                       involvement by lymphoma, where ALT/SGPT and AST/SGOT must be ≤ 5.0 x ULN.

                    5. Serum total bilirubin ≤ 2.0 mg/dL (34 μmol/L) except in cases of Gilbert
                       syndrome, then ≤ 5.0 mg/dL (86 μmol/L)

                    6. Estimated serum creatinine clearance of ≥ 50 mL/minute using the
                       modification of diet in renal disease 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 Pregnancy Prevention Plan for Participants in Clinical Trials.

               8. A female of childbearing potential (FCBP) must:

                  a. Have two negative pregnancy tests as verified by the investigator prior to
                  starting study therapy. She must agree to ongoing pregnancy testing during the
                  course of the study, and after end of study therapy.

               9. Male participants must:

                    1. Practice true abstinence (which must be reviewed on a monthly basis and
                       source documented) 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. Participant has 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.

                  a. In the case of prior SARS-CoV-2 infection, symptoms must have completely
                  resolved

               2. Participant has 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. Participant has any other subtype of lymphoma.

               4. Participant has received systemic anti-cancer treatment, CAR-T or any T-cell
                  targeting treatment (approved or investigational) ≤ 5 half-lives or 4 weeks prior
                  to starting CC-220, whichever is shorter.

               5. Participant has received prior therapy with a Cereblon-modulating drug (eg,
                  lenalidomide, avadomide) ≤ 4 weeks prior to starting CC-220.

               6. Participant has persistent diarrhea or malabsorption ≥ Grade 2 (NCI-CTCAE v5.0),
                  despite medical management.

               7. Participant has peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0).

               8. Participant is on chronic systemic immunosuppressive therapy or corticosteroids.

               9. Participant has impaired cardiac function or clinically significant cardiac
                  disease.

              10. Participant had major surgery ≤ 2 weeks prior to starting CC-220.

              11. Participant has known seropositivity for or active viral infection with human
                  immunodeficiency virus (HIV).

              12. Participant has known chronic active hepatitis B

              13. Participant has history of other malignancy, unless being free of the disease for
                  ≥ 3 years prior to starting study drug; exceptions to the ≥ 3-year time limit
                  include history of the following:

                    1. Localized non-melanoma 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.

              14. Participant has current treatment with strong CYP3A4/5 modulators.

              15. Participant has known hypersensitivity to any component of planned combination
                  medications in the regimen.

              16. Participant has known allergy to thalidomide, pomalidomide, lenalidomide or
                  avadomide.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:During the First cycle (each cycle is 28 days)
Safety Issue:
Description:Frequency of dose limiting toxicities (DLT) to define MTD of CC- 220 in combination with polatuzumab vedotin plus rituximab or tafasitamab or rituximab plus chemotherapy in subjects with R/R a-BCL.

Secondary Outcome Measures

Measure:Incidence of Adverse Events (AEs)
Time Frame:From enrollment until at least 28 days after last dose of study treatment
Safety Issue:
Description:An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant 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 participant'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.
Measure:Best ORR- Part 1
Time Frame:Up to 6 years
Safety Issue:
Description:The proportion of participants with best overall response achieved during the study as either Complete Response or Partial Response before subsequent anti-lymphoma therapy.
Measure:Complete Response Rate (CRR)- Part 2
Time Frame:Up to 7 years
Safety Issue:
Description:The proportion of participants experiencing Complete Response before receiving any subsequent anti-lymphoma therapy.
Measure:Time to Response (TRR)- Part 2
Time Frame:Up to 7 years
Safety Issue:
Description: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).
Measure:Duration of Response (DOR)- Part 2
Time Frame:Up to 7 years
Safety Issue:
Description:The time from the earliest date of documented response (≥ PR) to the first occurrence of relapse or progression.
Measure:Progression-free Survival (PFS)- Part 2
Time Frame:Up to 7 years
Safety Issue:
Description: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.
Measure:Overall Survival (OS)- Part 2
Time Frame:Up to 7 years
Safety Issue:
Description:The time from entry to the study (enrollment date for Part 1 and randomization date for Part 2) to death from any cause.
Measure:Pharmacokinetics (PK) - Cmax
Time Frame:Up to 4 weeks
Safety Issue:
Description:Observed maximum CC-220 serum concentration
Measure:EORTC QLQ-C30 - Part 2
Time Frame:Up to 7 years
Safety Issue:
Description:European Organization for Research and Treatment of Cancer - Quality of Life C30 questionnaire (EORTC QLQ-C30) consists of 30 questions incorporated into five functional domains (physical, role, cognitive, emotional, and social), nine symptom scales (fatigue, pain, nausea and vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a single global QoL/global health status score.
Measure:FACT-Lym LymS - Part 2
Time Frame:Up to 7 years
Safety Issue:
Description:Functional Assessment of Cancer Therapy-Lymphoma Lymphoma subscale (FACT-Lym LymS) is a 15-item subscale that addresses health-related quality of life symptoms for Non-Hodgkin's lymphoma participants (eg, swelling, night sweats). The FACT instruments use a 5-point intensity type of rating scale (from "not at all" to "very much").
Measure:FACT/GOG-NTX-4 - Part 2
Time Frame:Up to 7 years
Safety Issue:
Description:Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 40-item questionnaire (FACT/GOG-NTX-4) is a 4-item peripheral neuropathy subscale used to differentiate between participants with and without treatment-related neurotoxicity. The FACT instruments use a 5-point intensity type of rating scale (from "not at all" to "very much").
Measure:EQ-5D-5L - Part 2
Time Frame:Up to 7 years
Safety Issue:
Description:EQ-5D-5L has 2 components: a descriptive system and a visual analogue scale (VAS). The instrument's descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Celgene

Trial Keywords

  • CC-220
  • Phase 1B/2
  • B-Cell Lymphoma

Last Updated

June 9, 2021