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

Celgene

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Multiple Myeloma

Treatments: Drug: Carfilzomib; Drug: Dexamethasone; Drug: CC-220; Drug: Bortezomib; Drug: Daratumumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT02773030

2016-000860-40 (EudraCT Number)

U1111-1182-9200 (Registry Identifier)

CC-220-MM-001

Details and patient eligibility

About

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 monotherapy and CC-220 in combination with DEX for Relapsed Refractory Multiple Myeloma (RRMM), CC-220 in combination with DEX and BTZ, and CC-220 in combination with DEX and DARA for Newly Diagnosed Multiple Myeloma (NDMM).

Full description

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.

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 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 recommended phase 2 dose (RP2D) is established in Part 1 in either Cohort A, Cohort B, Cohort E or Cohort F. The cohorts 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.

Enrollment: 466 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2
• Relapsed and refractory multiple myeloma (RRMM) participants must have documented disease progression on or within 60 days from the last dose of their last myeloma therapy
• Newly diagnosed multiple myeloma (NDMM) participants must have documented diagnosis with previously untreated symptomatic multiple myeloma (MM)
• Participants in Cohorts J1 and K are those for whom autologous stem cell transplantation is not planned for initial therapy or are not considered by the investigator as eligible for high-dose chemotherapy and autologous stem cell transplantation

Exclusion criteria

• Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study
• Nonsecretory multiple myeloma
• Prior history of malignancies, other than MM and select non-invasive malignancies, unless the participant has been free of the disease for ≥ 5 years

Other protocol-defined inclusion/exclusion criteria apply

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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466 participants in 12 patient groups

Cohort A: CC-220 Monotherapy - Part 1

Experimental group

Description:

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

Treatment:

Drug: CC-220

Cohort B: CC-220 in combination with Dexamethasone (DEX) - Part 1

Experimental group

Description:

Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle. For subjects ≤ 75 years old, 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. Subjects who surpass the age of 75 years while on treatment may be switched to the 20 mg QD dosage based on the investigator's best judgment.

Treatment:

Drug: CC-220

Drug: Dexamethasone

Cohort D: CC-220 in combination with Dexamethasone - Part 2

Experimental group

Description:

Oral CC-220 at Recommended Phase 2 dose (RP2D) from Day 1-21 of each 28-day cycle For subjects ≤ 75 years old, 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

Treatment:

Drug: CC-220

Drug: Dexamethasone

Cohort E: CC-220 with DEX and daratumumab (DARA) - Part 1

Experimental group

Description:

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 a dose of 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.

Treatment:

Drug: Daratumumab

Drug: CC-220

Drug: Dexamethasone

Cohort F: CC-220 with DEX and bortezomib - Part 1

Experimental group

Description:

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, and 8 at cycle ≥9 of each 21-day cycle.

Treatment:

Drug: Bortezomib

Drug: CC-220

Drug: Dexamethasone

Cohort G1: CC-220 in combination with CFZ and DEX - Part 1

Experimental group

Description:

Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle Intravenous (IV) CFZ (Carfilzomib)administered at a starting dose of 20 mg/m2 on C1D1; and at a dose specified by cohort dose level thereafter on days 1, 8, and 15 of each 28-day cycle. Oral DEX (Dexamethasone) on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects ≤ 75 years old, the DEX dose will be 40 mg. For subjects \> 75 years old, the DEX dose will be 20 mg

Treatment:

Drug: CC-220

Drug: Dexamethasone

Drug: Carfilzomib

Cohort G2 - CC-220 in combination with CFZ and DEX - Part 1

Experimental group

Description:

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 C1D2; 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, and 23 of each 28-day cycle. The DEX dose will be 20 mg.

Treatment:

Drug: CC-220

Drug: Dexamethasone

Drug: Carfilzomib

Cohort I: CC-220 in combination with DEX in post BCMA RRMM - Part 2

Experimental group

Description:

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, oral DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.

Treatment:

Drug: CC-220

Drug: Dexamethasone

Cohort J1: CC-220 in combination with DEX and BTZ in NDMM - Part 2

Experimental group

Description:

Oral CC-220 at 1.0mg, 1.3mg or 1.6mg administered at cycles 1 to 8 on Days 1 to 14 of each 21-day cycle and cycles ≥ 9 on Days 1 to 21 of each 28-day cycle. Oral DEX at Cycles 1 to 8, 20 mg (≤ 75 years old) or 10 mg (\> 75 years old) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each 21-day cycle and Cycles ≥ 9, 40 mg (≤ 75 years old) or 20 mg (\> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle. Subcutaneous BTZ at dose 1.3 mg/m2 on Days 1, 4, 8 and 11 at Cycle 1-8 of each 21-day cycle.

Treatment:

Drug: Bortezomib

Drug: CC-220

Drug: Dexamethasone

Cohort J2: CC-220 in combination with DEX and BTZ in NDMM - Part 2

Experimental group

Description:

Oral CC-220 at Recommended Phase 2 Dose from Day 1-14 of each 21-day cycle. Oral DEX at 20 mg/day (≤ 75 years old) or 10 mg/day (\> 75 years old) for Cycles 1 to 6 on Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle. Subcutaneous BTZ at dose 1.3 mg/m2 on Days 1, 4, 8 and 11 at Cycle 1-6 of each 21-day cycle.

Treatment:

Drug: Bortezomib

Drug: CC-220

Drug: Dexamethasone

Cohort K: CC-220 with DEX and DARA in NDMM and not autologous stem cell transplant eligible - Part 2

Experimental group

Description:

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.

Treatment:

Drug: Daratumumab

Drug: CC-220

Drug: Dexamethasone

Cohort C: CC-220 Monotherapy in RRMM - Part 2

Experimental group

Description:

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

Treatment:

Drug: CC-220