A Phase 1b, Open Label, Global, Multicenter, Dose Determination, Randomized Dose Expansion Study to Determine the Maximum Tolerated Dose, Assess the Safety and Tolerability, Pharmacokinetics and Preliminary Efficacy of Iberdomide (CC-220) in Combination With R-CHOP-21 and CC-99282 in Combination With R-CHOP-21 for Subjects With Previously Untreated Aggressive B-cell Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Celgene
- 入组人数
- 224
- 试验地点
- 59
- 主要终点
- Maximum Tolerated Dose (MTD) - Part 1
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants 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).
- •Participant has histologically confirmed (per local evaluation) diagnosis of de novo, previously untreated, a-BCL according to 2016 WHO classification.
- •Participant has International Prognostic Index (IPI) score 0-5 in Part 1 and IPI 2-5 in Part
- •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.
- •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).
- •Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
- •Participants must have the following laboratory values:
- •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)
- •Hemoglobin (Hb) ≥ 8 g/dL
- •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
- •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.
- •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).
- •Estimated serum creatinine clearance (CrCl) of ≥ 50 mL/min using the modification of diet in renal disease (MDRD) formula.
- •All participants 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 or CC-99282 Pregnancy Prevention Plan for Participants in Clinical trials.
- •Females of childbearing potential (FCBP) must:
- •a. Have two negative pregnancy tests as verified by the investigator prior to starting study therapy.
- •Male participants must:
- •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.
排除标准
- •The presence of any of the following will exclude a participant from enrollment:
- •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.
- •Any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study.
- •Any other subtype of lymphoma.
- •Documented or suspected CNS involvement by lymphoma.
- •Persistent diarrhea or malabsorption ≥ Grade 2 (NCI CTCAE v5.0), despite medical management.
- •Peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0).
- •Subjects with a history of progressive multifocal leukoencephalopathy.
- •Chronic systemic immunosuppressive therapy or corticosteroids
- •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)
- •Major surgery ≤ 2 weeks prior to starting CC-220 or CC-99282; participant must have recovered from any clinically significant effects of recent surgery.
- •Any condition causing inability to swallow tablets.
- •Known seropositivity for or active viral infection with human immunodeficiency virus (HIV)
- •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
- •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:
- •Localized nonmelanoma skin cancer
- •Carcinoma in situ of the cervix
- •Carcinoma in situ of the breast
- •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.
- •Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients of rituximab or polatuzumab vedotin.
- •Known hypersensitivity to any component of CHOP/CHP regimen.
- •Known allergy to thalidomide, pomalidomide, or lenalidomide.
研究组 & 干预措施
Administration of CC-220 with R-CHOP-21
CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: CC-220 (Drug)
Administration of CC-220 with R-CHOP-21
CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Rituximab (Drug)
Administration of CC-220 with polatuzumab-R-CHP
CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Rituximab (Drug)
Administration of CC-99282 with polatuzumab-R-CHP
CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Prednisone (Drug)
Administration of CC-99282 with polatuzumab-R-CHP
CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Polatuzumab vedotin (Drug)
Administration of CC-99282 with polatuzumab-R-CHP
CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: CC-99282 (Drug)
Administration of CC-220 with polatuzumab-R-CHP
CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Polatuzumab vedotin (Drug)
Administration of CC-99282 with R-CHOP-21
CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: CC-99282 (Drug)
Administration of CC-220 with polatuzumab-R-CHP
CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: CC-220 (Drug)
Administration of CC-220 with R-CHOP-21
CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Prednisone (Drug)
Administration of CC-220 with R-CHOP-21
CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Doxorubicin (Drug)
Administration of CC-220 with R-CHOP-21
CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Vincristine (Drug)
Administration of CC-220 with R-CHOP-21
CC-220 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Cyclophosphamide (Drug)
Administration of CC-99282 with R-CHOP-21
CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Rituximab (Drug)
Administration of CC-99282 with R-CHOP-21
CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Cyclophosphamide (Drug)
Administration of CC-99282 with R-CHOP-21
CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Doxorubicin (Drug)
Administration of CC-99282 with R-CHOP-21
CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Vincristine (Drug)
Administration of CC-99282 with R-CHOP-21
CC-99282 to be administered orally in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP-21) for 6 cycles of treatment
干预措施: Prednisone (Drug)
Administration of CC-220 with polatuzumab-R-CHP
CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Cyclophosphamide (Drug)
Administration of CC-220 with polatuzumab-R-CHP
CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Doxorubicin (Drug)
Administration of CC-220 with polatuzumab-R-CHP
CC-220 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Prednisone (Drug)
Administration of CC-99282 with polatuzumab-R-CHP
CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Cyclophosphamide (Drug)
Administration of CC-99282 with polatuzumab-R-CHP
CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Doxorubicin (Drug)
Administration of CC-99282 with polatuzumab-R-CHP
CC-99282 to be administered orally in combination with Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (polatuzumab-R-CHP) for 6 cycles of treatment
干预措施: Rituximab (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) - Part 1
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
次要结局
- Pharmacokinetics - Cmax for CC-220(At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days))
- Pharmacokinetics - Ctrough for CC-99282(At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days)
- Best overall response rate (ORR)(Up to 4 years)
- Duration of Response (DOR)(Up to 4 years)
- Complete Metabolic Response Rate (CMRR)(Up to 4 years)
- Time to Response (TTR)(Up to 4 years)
- Overall Survival (OS)(Up to 4 years)
- Progression-free Survival (PFS)(Up to 4 years)
- Pharmacokinetics - Ctrough for CC-220(At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days)
- Pharmacokinetics - Cmax for CC-99282(At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days)
- Pharmacokinetics - Tmax for CC-220(At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days)
- Pharmacokinetics - Tmax for CC-99282(At Cycle 1 Day 7, Cycle 1 Day 15, and Cycle 2 Day 7 (each cycle is 21 days)