CC-220 Combination Therapy for Multiple Myeloma

Recruiting at 177 trial locations

Overseen By First line of the email MUST contain the NCT# and Site #.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Celgene

Disqualifiers: Nonsecretory multiple myeloma, other malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 49

466 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, CC-220, alone and with other drugs for patients with multiple myeloma who haven't responded to other treatments or are newly diagnosed. The drugs work by controlling cancer cell growth and killing cancer cells through different mechanisms.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug combination therapy for multiple myeloma?

Research shows that adding daratumumab to bortezomib and dexamethasone significantly improves progression-free survival (the time during which the disease does not get worse) and overall response rates in patients with relapsed or refractory multiple myeloma compared to using bortezomib and dexamethasone alone. ^{1 2 3 4 5}

Is the combination therapy of CC-220, bortezomib, daratumumab, and dexamethasone safe for humans?

The combination of daratumumab, bortezomib, and dexamethasone has been shown to be generally safe in humans, with a consistent safety profile over time. Iberdomide (CC-220) combined with dexamethasone has also been evaluated for safety in patients with multiple myeloma, indicating it is tolerable in heavily pretreated patients. ^{1 2 3 4 6}

What makes the CC-220 combination therapy for multiple myeloma unique?

The CC-220 combination therapy for multiple myeloma is unique because it includes daratumumab, a monoclonal antibody that targets CD38, which can be administered subcutaneously, offering a more convenient option compared to traditional intravenous methods. This combination aims to improve patient outcomes by enhancing immune responses and prolonging progression-free survival. ^{1 2 4 7 8}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for adults with Multiple Myeloma, either newly diagnosed and untreated (NDMM) or those whose disease has returned after treatment (RRMM). They must be in fairly good health overall, as indicated by an ECOG score of 0-2. People who have had other cancers within the last 5 years or have a significant medical condition that could interfere with the study cannot participate.

Inclusion Criteria

I have been diagnosed with multiple myeloma and have not received any treatment.

I am not planned for or eligible for stem cell transplant as my initial treatment.

My multiple myeloma has worsened within 2 months after my last treatment.

Exclusion Criteria

My multiple myeloma does not produce detectable levels of M protein.

I do not have any health issues that would stop me from joining the study.

I have been cancer-free for over 5 years, except for multiple myeloma or certain non-invasive cancers.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive CC-220 monotherapy or in combination with other treatments to determine the maximum tolerated dose

3 years

Visits every 28 days

Expansion

Participants receive CC-220 at the recommended phase 2 dose in combination with other treatments

Approximately 5 years

Visits every 21-28 days depending on cohort

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 5 years

Treatment Details

Interventions

• Bortezomib
• Carfilzomib
• CC-220
• Daratumumab
• Dexamethasone

Trial Overview The trial is testing different doses and combinations of a drug called CC-220 alone or with other treatments like Dexamethasone, Daratumumab, Bortezomib, and Carfilzomib. It's divided into two parts: finding the right dose and then expanding to more patients at that dose to see how well it works for both new and returning cases of Multiple Myeloma.

Participant Groups

Group I: Cohort K: CC-220 with DEX and DARA in NDMM and not autologous stem cell transplant eligible - Part 2 Experimental Treatment 3 Interventions

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.

Group II: Cohort J2: CC-220 in combination with DEX and BTZ in NDMM - Part 2 Experimental Treatment 3 Interventions

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.

Group III: Cohort J1: CC-220 in combination with DEX and BTZ in NDMM - Part 2 Experimental Treatment 3 Interventions

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.

Group IV: Cohort I: CC-220 in combination with DEX in post BCMA RRMM - Part 2 Experimental Treatment 2 Interventions

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.

Group V: Cohort G2 - CC-220 in combination with CFZ and DEX - Part 1 Experimental Treatment 3 Interventions

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.

Group VI: Cohort G1: CC-220 in combination with CFZ and DEX - Part 1 Experimental Treatment 3 Interventions

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

Group VII: Cohort F: CC-220 with DEX and bortezomib - Part 1 Experimental Treatment 3 Interventions

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.

Group VIII: Cohort E: CC-220 with DEX and daratumumab (DARA) - Part 1 Experimental Treatment 3 Interventions

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.

Group IX: Cohort D: CC-220 in combination with Dexamethasone - Part 2 Experimental Treatment 2 Interventions

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

Group X: Cohort C: CC-220 Monotherapy in RRMM - Part 2 Experimental Treatment 1 Intervention

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

Group XI: Cohort B: CC-220 in combination with Dexamethasone (DEX) - Part 1 Experimental Treatment 2 Interventions

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.

Group XII: Cohort A: CC-220 Monotherapy - Part 1 Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

Celgene

Lead Sponsor

Trials

649

Recruited

130,000+

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Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Findings from Research

In a subgroup analysis of the CASTOR trial involving 498 patients, daratumumab combined with bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival (PFS) in patients with high cytogenetic risk (12.6 months) compared to bortezomib and dexamethasone alone (6.2 months).

D-Vd also demonstrated a higher rate of minimal residual disease (MRD) negativity, indicating deeper responses in treatment effectiveness, while maintaining a safety profile consistent with the overall study population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. Weisel, K., Spencer, A., Lentzsch, S., et al.[2021]

Intravenous daratumumab, when combined with bortezomib, thalidomide, and dexamethasone, significantly improves treatment outcomes for adults with newly diagnosed multiple myeloma, leading to higher rates of stringent complete response and prolonged progression-free survival, as shown in the phase III CASSIOPEIA trial.

The addition of daratumumab has a minimal impact on overall toxicity, with the most common serious side effects being blood-related issues, indicating it is a relatively safe option for patients undergoing treatment for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma. Lamb, YN.[2021]

In a phase 3 study (CASTOR) with a median follow-up of 19.4 months, the combination of daratumumab, bortezomib, and dexamethasone significantly improved progression-free survival (16.7 months) compared to bortezomib and dexamethasone alone (7.1 months), indicating its efficacy in treating relapsed/refractory multiple myeloma.

Daratumumab plus bortezomib and dexamethasone also showed a higher overall response rate (83.8% vs. 63.2%) and was particularly beneficial for patients with one prior line of therapy, demonstrating a favorable safety profile consistent over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Spencer, A., Lentzsch, S., Weisel, K., et al.[2019]

Daratumumab, a monoclonal antibody targeting CD38, has been approved in the USA for treating multiple myeloma in patients who have undergone at least three prior therapies, demonstrating its role as a treatment option for difficult-to-treat cases.

In a phase II trial, daratumumab monotherapy showed an overall response rate of about 30% in patients with relapsed or refractory multiple myeloma, indicating its efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: First Global Approval. McKeage, K.[2018]

Daratumumab, a monoclonal antibody targeting CD38, has shown significant efficacy as a monotherapy in relapsed/refractory multiple myeloma, achieving an overall response in about one-third of patients, with rapid and durable effects.

In combination with other treatments like bortezomib or lenalidomide, daratumumab significantly prolonged progression-free survival, although the overall survival benefit is still being evaluated, and it was generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. Blair, HA.[2018]

Iberdomide combined with dexamethasone demonstrated meaningful clinical activity in heavily pretreated patients with relapsed or refractory multiple myeloma, achieving an overall response rate of 32% in the dose-escalation cohort and 26% in the dose-expansion cohort, indicating its potential effectiveness even in difficult-to-treat cases.

The treatment was generally safe, with a recommended phase 2 dose established at 1.6 mg, although some patients experienced serious adverse events, including neutropenia and infections, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lonial, S., Popat, R., Hulin, C., et al.[2022]

The antibody-drug conjugate MEDI2228 enhances the effectiveness of immunotherapies for multiple myeloma by activating key signaling pathways that increase CD38 expression and improve immune response, even in drug-resistant cancer cells.

In combination with the CD38 monoclonal antibody daratumumab, MEDI2228 significantly boosts NK cell-mediated cytotoxicity against multiple myeloma cells, suggesting a promising strategy for improving treatment outcomes in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCMA-Specific ADC MEDI2228 and Daratumumab Induce Synergistic Myeloma Cytotoxicity via IFN-Driven Immune Responses and Enhanced CD38 Expression. Xing, L., Wang, S., Liu, J., et al.[2022]

C-CAR088, a novel anti-BCMA CAR T-cell therapy, demonstrated a high overall response rate of 96.4% in patients with relapsed or refractory multiple myeloma, with significant rates of complete response (10.7%) and stringent complete response (46.4%).

The therapy showed a favorable safety profile, with 93.5% of patients experiencing cytokine release syndrome (CRS) that was manageable and reversible, and no dose-limiting toxicities reported across the tested dosages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma. Qu, X., An, G., Sui, W., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. [2021]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma. [2021]

3. Italy pubmed.ncbi.nlm.nih.gov

Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. [2019]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Daratumumab: First Global Approval. [2018]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

BCMA-Specific ADC MEDI2228 and Daratumumab Induce Synergistic Myeloma Cytotoxicity via IFN-Driven Immune Responses and Enhanced CD38 Expression. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma. [2022]