A Study to Determine Dose, Safety, Tolerability and Efficacy of CC-220 Monotherapy, and in Combination With Other Treatments in Subjects With Multiple Myeloma

Phase 2Active Not RecruitingNCT02773030

Celgene466 enrolled

Overview

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.

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. The initiation of Part 2 will begin when the RP2D is established in Part 1 in either Cohort A or Cohort B. Either cohort may begin once the RP2D is determined for each cohort independently during Part 1. All expansion decisions will be determined by the DEC after review of all safety, PK, biomarker and preliminary efficacy data, as applicable. During Part 2, the Independent Expert Reviewer will review safety data and any other data deemed relevant so that subject safety is ensured.

Interventions

CC-220DRUG

CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.

DexamethasoneDRUG

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.

DaratumumabDRUG

Specified dose on specified days

BortezomibDRUG

Specified dose on specified days

CarfilzomibDRUG

Intravenous (IV) CFZ administered at a starting dose of 20 mg/m2 on C1D1 and C1D2; and at a dose level specified by cohort dose level thereafter Days 1, 2, 8, 9, 15, 16 of each 28-day cycle.

Daratumumab - 16mg/kgDRUG

Daratumumab (DARA) 16mg/kg by intravenous infusion 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.

Bortezomib (BTZ)DRUG

Bortezomib 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.

Daratumumab- 1800mgDRUG

Daratumumab (DARA) 1800 mg by subcutaneous injection 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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1\. All subjects in RRMM cohorts must have a documented diagnosis of Multiple Myeloma and have measurable disease defined as: 1. M-protein (serum and/or urine protein electrophoresis (sPEP or uPEP)): sPEP ≥0.5 g/dL or uPEP ≥200 mg/24 hours and/or 2. 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 2. 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 3. 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 4. 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. Exclusion Criteria: 1\. Subject has nonsecretory multiple myeloma 2. Subjects with Plasma Cell leukemia or amyloidosis 3. Any of the following laboratory abnormalities • Absolute neutrophil count (ANC) \<1,000/μL • Platelet count \< 75,000/μL for Part 1. 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 4. Subjects with peripheral neuropathy ≥Grade 2

Outcomes

Primary Outcomes

Number of Participants With Dose Limiting Toxicities in Part 1.

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.

Time frame: From first dose to 28 days post last dose (up to 28 days)

Overall Response Rate (ORR) in Cohort D and Cohort H2

Tumor response, including progressive disease (PD) according to the IMWG Uniform Response Criteria (Kumar, 2016) for subjects who achieved partial response (PR) or better.

Time frame: Approximately on average (Cohort D: 21.14 weeks, Cohort H2: 22.11 Weeks)

Secondary Outcomes

Number of Participants With Treatment Related Adverse Events

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 subject'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.

Time frame: 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)

An adverse event of special interest (AESI) is one of scientific and medical interest specific to understanding the safety profile of the Investigational Product, CC-220, and may require close monitoring and rapid communication by the Investigator to the Sponsor. An AESI may be serious or nonserious. The rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and understand their association with the use of this investigational product.

Very Good Partial Response Rate (ORR) in Cohort J1 and Cohort K

The very good partial response or better (≥ VGPR) rate is defined as the proportion of subjects with best response of VGPR or better during the trial without administration of myeloma therapy other than study treatment. The ≥ VGPR rate with 95% confidence interval (CI) together with the proportions in each response category based on the IMWG Uniform Response Criteria.

Time frame: On Average of (Cohort J: 86.21, Cohort K: 56.29) Weeks

Overall Response Rate (ORR)

Tumor response, including progressive disease (PD) according to the IMWG Uniform Response Criteria (Kumar, 2016) for subjects who achieved partial response (PR) or better.

Time frame: 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)

Time to response is defined as the time from the first dose date of study treatment to the first date of documented response (PR or better). Time to response will be summarized for responders using descriptive statistics by cohort and dose level.

Time frame: 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

Duration of response is defined as time from the earliest date of documented response (PR or better) to the earliest date of disease progression per IMWG Uniform Response Criteria or death, whichever occurred first. Participants who do not have progression of disease or death will be censored on the last adequate response assessment date. Duration of response for responders will be summarized using Kaplan-Meier estimates by cohort and dose level as appropriate. Data will be collected and analyzed per Cohort Totals.

Time frame: 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

Time from the first dose of investigational product (IP) to the first documentation of PD or death from any cause, whichever occurs first Data will be collected and analyzed per Cohort Totals.

Overall Survival for Cohort D, Cohort H2 and Cohort I

Time from first dose of IP to death due to any cause Data will be collected and analyzed per Cohort Totals.

Time frame: On Average of (Cohort D: 81.14 Cohort H2: 91.54 Cohort I: 74.20)Weeks

Auc(Tau)

Area under the plasma concentration time-curve. AUC over the dosing interval.

Time frame: From Cycle 1 Day 1 to Cycle 1 Day 15 (15 days)

Cmax

Cmax is defined as maximum plasma concentration of the drug.

Time frame: From Cycle 1 Day 1 to Cycle 1 Day 15 (15 days)

Tmax

Tmax is defined is the time to maximum plasma concentration.

Time frame: From Cycle 1 Day 1 to Cycle 1 Day 15 (15 days)

A Study to Determine Dose, Safety, Tolerability and Efficacy of CC-220 Monotherapy, and in Combination With Other Treatments in Subjects With Multiple Myeloma

Overview

Conditions

Interventions

Eligibility

Locations (162)

Outcomes

Primary Outcomes

Secondary Outcomes