Phase 1b/2a Multicenter, Open-label, Dose-escalation Study to Determine the Maximum Tolerated Dose, Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of CC-220 As Monotherapy and in Combination With Other Treatments in Subjects With Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Celgene
- 入组人数
- 466
- 试验地点
- 162
- 主要终点
- Number of Participants With Dose Limiting Toxicities in Part 1.
研究概览
简要总结
This is a multicenter, multi-country, open-label, Phase 1b/2a dose-escalation study consisting of two parts: dose escalation (Part 1) for CC-220 monotherapy, CC-220 in combination with DEX, CC-220 in combination with DEX and DARA, CC-220 in combination with DEX and BTZ and CC-220 in combination with DEX and CFZ; and the expansion of the RP2D (Part 2) for CC-220 in combination with DEX for Relapsed Refractory Multiple Myeloma and CC-220 in combination with DEX and BTZ for Newly Diagnosed Multiple Myeloma.
详细描述
Subjects assigned to CC-220 monotherapy, who develop progressive disease (PD) will have the option to receive DEX in addition to CC-220 after consultation with the Medical Monitor. The dose of CC-220 will not be higher than the dose of CC-220 used in combination with dexamethasone in Cohort B that has been determined to be safe. Progressive disease must be confirmed in accordance with international myeloma working group (IMWG) criteria.
The starting dose of DEX will be 40 mg for subjects who are ≤75 years of age and 20 mg for subjects who are >75 years of age, given once weekly. This treatment will continue until PD, unacceptable toxicity or the subject withdraws consent.
For Cohorts A and B, the starting dose level of CC-220, dose level 1, is 0.3 mg. A dose level -1, of 0.15 mg, may also be evaluated if the starting dose level of 0.3 mg for 21 days of a 28-day cycle is not tolerated. For Cohorts E and F, the starting dose level of CC-220, dose level 1, is one dose level below the maximum dose for Cohort B that has been determined to be safe by the dose escalation committee (DEC) at the start of enrollment for both cohorts. For Cohort E in addition to CC-220 and DEX, daratumumab will be administered intravenously (IV) at a 16mg/kg dose. For Cohort F in addition to CC-220 and DEX, bortezomib will be administered subcutaneous (SC) at a 1.3mg/m2 dose.
All subjects with a minimal response (MR) or better who discontinue study treatment in Part 1 or Part 2 of the study for a reason other than PD or withdrawal of consent from the study will be followed for response assessment every 28 days (every 21 days for Cohort F) until PD.
The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •1. All subjects in RRMM cohorts must have a documented diagnosis of Multiple Myeloma and have measurable disease defined as:
- •M-protein (serum and/or urine protein electrophoresis (sPEP or uPEP)): sPEP ≥0.5 g/dL or uPEP ≥200 mg/24 hours and/or
- •Light chain Multiple Myeloma without measurable disease in the serum or urine: serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda free light chain ratio
- •All subjects in RRMM cohorts must have documented disease progression on or within 60 days from the last dose of their last myeloma therapy. Subjects who had CAR T therapy as their last myeloma therapy must have documented disease progression.
- •3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2
- •Subject must have documented diagnosis with previously untreated symptomatic MM as defined by the criteria below (Rajkumar, 2016): MM diagnostic criteria;
- •- Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma
- •- Any one or more of the following myeloma defining events:
- •One or more of the following myeloma-related organ dysfunction (at least one of the following);
- •[C] Calcium elevation (serum calcium > 0.25 mmol/L [> 1 mg/dL] higher than the upper limit of laboratory normal or > 2.75 mmol/L [> 11 mg/dL])
- •[R] Renal insufficiency (serum creatinine > 2 mg/dl [> 177 μmol/L] or creatinine clearance < 40 ml/min)
- •[A] Anemia (hemoglobin < 10 g/dl or > 2 g/dL below the lower limit of laboratory normal)
- •[B] Bone lesions (lytic or osteopenic) one or more bone lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)/CT
- •One or more of the following biomarkers of malignancy:
- •Clonal bone marrow plasma cell percentage* ≥ 60%
- •Abnormal serum free light-chain (FLC) ratio ≥ 100 (involved kappa) or <0.01 (involved lambda) and involved FLC level must be ≥ 100 mg/L
- •>1 focal lesion detected by magnetic resonance imaging (MRI) (at least 5 mm in size)
- •AND have measurable disease, as assessed by central laboratory, defined by any of the following:
- •- Immunoglobulin (Ig)G myeloma: serum M-protein level ≥ 1.0 g/dL or urine M-protein level ≥ 200 mg/24 hours; or
- •- IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL or urine M-protein level ≥ 200 mg/24 hours; or
- •- Light chain multiple myeloma without measurable disease in serum or urine: serum FLC ≥ 100 mg/L and abnormal kappa lambda (κ/λ) ratio
- •Subjects in Cohort J1 are not considered by the investigator as eligible for high-dose chemotherapy and autologous stem cell transplantation due to:
- •- Age ≥65 years, OR
- •- In subjects <65 years: presence of important comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with autologous stem cell transplantation.
- •5. Subjects in Cohort J2 are considered by the investigator as eligible for high-dose chemotherapy and autologous stem cell transplantation according to the institution's criteria based on age, medical history, cardiac and pulmonary status, overall health and condition, co-morbid condition(s), physical examination, and laboratory data.
排除标准
- •1. Subject has nonsecretory multiple myeloma
- •Subjects with Plasma Cell leukemia or amyloidosis
- •Any of the following laboratory abnormalities
- •Absolute neutrophil count (ANC) <1,000/μL
- •Platelet count < 75,000/μL for Part
- •For Part 2; platelet count < 75,000/μL for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count < 50,000/μL (transfusions are not permitted to achieve minimum platelet counts
- •Corrected serum calcium >13.5 mg/dL (>3.4 mmol/L)
- •Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) or serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT)≥2.0 x upper limit of normal (ULN)
- •Serum total bilirubin and alkaline phosphatase >1.5 x ULN
- •Subjects with serious renal impairment creatinine clearance ([CrCl] <45 mL/min) or requiring dialysis would be excluded
- •Subjects with peripheral neuropathy ≥Grade 2
研究组 & 干预措施
Cohort A: CC-220 Monotherapy - Part 1
Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle
干预措施: CC-220 (Drug)
Cohort D: CC-220 in combination with Dexamethasone - Part 2
- Oral CC-220 at Recommended Phase 2 dose (RP2D) from Day 1-21 of each 28-day cycle
- Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: CC-220 (Drug)
Cohort D: CC-220 in combination with Dexamethasone - Part 2
- Oral CC-220 at Recommended Phase 2 dose (RP2D) from Day 1-21 of each 28-day cycle
- Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: Dexamethasone (Drug)
Cohort E: CC-220 with DEX and daratumumab (DARA) - Part 1
- Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
- Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
- Intravenous DARA at dose 16mg/kg on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
Once the MTD and/or RP2D is determined in Cohort E (CC-220Dd), subjects will be enrolled at this dose level using SC DARA.
- Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
- Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
- Subcutaneous DARA at dose 1800 mg over 3 to 5 minutes on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
干预措施: CC-220 (Drug)
Cohort E: CC-220 with DEX and daratumumab (DARA) - Part 1
- Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
- Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
- Intravenous DARA at dose 16mg/kg on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
Once the MTD and/or RP2D is determined in Cohort E (CC-220Dd), subjects will be enrolled at this dose level using SC DARA.
- Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
- Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
- Subcutaneous DARA at dose 1800 mg over 3 to 5 minutes on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
干预措施: Dexamethasone (Drug)
Cohort E: CC-220 with DEX and daratumumab (DARA) - Part 1
- Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
- Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
- Intravenous DARA at dose 16mg/kg on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
Once the MTD and/or RP2D is determined in Cohort E (CC-220Dd), subjects will be enrolled at this dose level using SC DARA.
- Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
- Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
- Subcutaneous DARA at dose 1800 mg over 3 to 5 minutes on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
干预措施: Daratumumab (Drug)
Cohort F: CC-220 with DEX and bortezomib - Part 1
- Oral CC-220 at dose specified by cohort dose level from Day 1-14 of each 21-day cycle.
- Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, and 15 of each 21-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, and 15 of each 21-day cycle.
- Subcutaneous BTZ at dose 1.3 mg/m^2 on Days 1, 4, 8 and 11 at cycle 1-8, and Days 1, 8 at cycle ≥9 of each 21-day cycle.
干预措施: CC-220 (Drug)
Cohort F: CC-220 with DEX and bortezomib - Part 1
- Oral CC-220 at dose specified by cohort dose level from Day 1-14 of each 21-day cycle.
- Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, and 15 of each 21-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, and 15 of each 21-day cycle.
- Subcutaneous BTZ at dose 1.3 mg/m^2 on Days 1, 4, 8 and 11 at cycle 1-8, and Days 1, 8 at cycle ≥9 of each 21-day cycle.
干预措施: Dexamethasone (Drug)
Cohort F: CC-220 with DEX and bortezomib - Part 1
- Oral CC-220 at dose specified by cohort dose level from Day 1-14 of each 21-day cycle.
- Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, and 15 of each 21-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, and 15 of each 21-day cycle.
- Subcutaneous BTZ at dose 1.3 mg/m^2 on Days 1, 4, 8 and 11 at cycle 1-8, and Days 1, 8 at cycle ≥9 of each 21-day cycle.
干预措施: Bortezomib (Drug)
Cohort G2 - CC-220 in combination with CFZ and DEX - Part 1
- Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle
- Intravenous (IV) CFZ administered at a starting dose of 20 mg/m2 on C1D1; and at a dose level specified by cohort dose level thereafter Days 1, 2, 8, 9, 15, 16 of each 28-day cycle
- Oral DEX on Days 1, 2, 8, 9, 15, 16, 22, 23 of each 28-day cycle. The DEX dose will be 20 mg
干预措施: CC-220 (Drug)
Cohort G2 - CC-220 in combination with CFZ and DEX - Part 1
- Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle
- Intravenous (IV) CFZ administered at a starting dose of 20 mg/m2 on C1D1; and at a dose level specified by cohort dose level thereafter Days 1, 2, 8, 9, 15, 16 of each 28-day cycle
- Oral DEX on Days 1, 2, 8, 9, 15, 16, 22, 23 of each 28-day cycle. The DEX dose will be 20 mg
干预措施: Dexamethasone (Drug)
Cohort G2 - CC-220 in combination with CFZ and DEX - Part 1
- Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle
- Intravenous (IV) CFZ administered at a starting dose of 20 mg/m2 on C1D1; and at a dose level specified by cohort dose level thereafter Days 1, 2, 8, 9, 15, 16 of each 28-day cycle
- Oral DEX on Days 1, 2, 8, 9, 15, 16, 22, 23 of each 28-day cycle. The DEX dose will be 20 mg
干预措施: Carfilzomib (Drug)
Cohort K: CC-220 with DEX and DARA in NDMM and not autologous stem cell transplant eligible - Part 2
Oral CC-220 at 1.0mg, 1.3mg or 1.6mg from Days 1-21 of each 28-day cycle.
Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
Subcutaneous DARA at 1800 mg over 3 to 5minutes on Days 1, 8, 15, and 22 at cycle 1-2 of a 28-day cycle, Days1, and 15 at cycle 3-6 of a 28-day cycle, and Day1 at cycle ≥7 of each 28-day cycle.
干预措施: Daratumumab (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities in Part 1.
时间窗: From first dose to 28 days post last dose (up to 28 days)
The dose-limiting toxicity (DLT) population includes subjects who missed no more than 4 doses of CC-220, 2 doses of DEX, 1 dose of IV DARA (Cohort E), 1 dose of BTZ (Cohort F), or 1 dose of CFZ (Cohort G1 or G2) during Cycle 1 for reasons other than DLT. This population will be used for analyzing the primary endpoint regarding the determination of the MTD. Hematologic DLTs: Grade 4 neutropenia (ANC \<500/μL for \>5 days) Grade 3 neutropenia (ANC \<1,000/μL) with fever ≥38.5°C Grade 4 thrombocytopenia (platelet count \<25,000/μL) or Grade 3 thrombocytopenia with bleeding or need for platelet transfusion Any other grade 4 hematologic toxicity, except anemia, not resolving to pretreatment baseline within 72 hours. Non-hematologic DLT: Any non-hematological toxicity ≥ Grade 3, except alopecia and nausea controlled by medical management.
Overall Response Rate (ORR) in Cohort D and Cohort H2
时间窗: Approximately on average (Cohort D: 21.14 weeks, Cohort H2: 22.11 Weeks)
Tumor response, including progressive disease (PD) according to the IMWG Uniform Response Criteria (Kumar, 2016) for subjects who achieved partial response (PR) or better.
次要结局
- Number of Participants With Treatment Related Adverse Events(Approximately on average of (Cohort A: 16.23 Cohort B: 10.32 Cohort D: 18.68 Cohort E: 15.65 Cohort F: 12.66 Cohort G: 16.03 Cohort H1: 17.22 Cohort H2: 21.07 Cohort I: 17.10 Cohort J: 20.56 Cohort K: 13.56) Months)
- Number of Participants With Treatment Emergent Adverse Events of Special Interest (AESI)(Approximately on average of (Cohort A: 16.23 Cohort B: 10.32 Cohort D: 18.68 Cohort E: 15.65 Cohort F: 12.66 Cohort G: 16.03 Cohort H1: 17.22 Cohort H2: 21.07 Cohort I: 17.10 Cohort J: 20.56 Cohort K: 13.56) Months)
- Very Good Partial Response Rate (ORR) in Cohort J1 and Cohort K(On Average of (Cohort J: 86.21, Cohort K: 56.29) Weeks)
- Overall Response Rate (ORR)(On Average of (Cohort A: 44.96, Cohort B: 32.79, Cohort D: 21.14, Cohort E: 53.74, Cohort F: 46.34, Cohort G: 63.26, Cohort H1: 58.10, Cohort H2: 22.11, Cohort I: 20.96, Cohort J: 86.21, Cohort K: 56.29) Weeks)
- Time to Response (TTR)(On Average of (Cohort A:19.14, Cohort B: 12.39, Cohort D: 7.54, Cohort E: 5.44, Cohort F: 4.97, Cohort G: 12.30, Cohort H: 4.14, Cohort I: 8.79, Cohort J: 4.76, Cohort K: 6.51) Weeks)
- Duration of Response(On Average of (Cohort A:161.33, Cohort B: 63.74, Cohort D: 39.16, Cohort E: 89.56, Cohort F: 69.24, Cohort G: 80.93, Cohort H1: 77.11, Cohort H2: 42.71, Cohort I: 36.80, Cohort J: 92.36, Cohort K: 51.85) Weeks)
- Progression Free Survival(On Average of (Cohort A: 44.96, Cohort B: 32.79, Cohort D: 21.14, Cohort E: 53.74, Cohort F: 46.34, Cohort G: 63.26, Cohort H1: 58.10, Cohort H2: 22.11, Cohort I: 20.96, Cohort J: 86.21, Cohort K: 56.29) Weeks)
- Overall Survival for Cohort D, Cohort H2 and Cohort I(On Average of (Cohort D: 81.14 Cohort H2: 91.54 Cohort I: 74.20)Weeks)
- Auc(Tau)(From Cycle 1 Day 1 to Cycle 1 Day 15 (15 days))
- Cmax(From Cycle 1 Day 1 to Cycle 1 Day 15 (15 days))
- Tmax(From Cycle 1 Day 1 to Cycle 1 Day 15 (15 days))