Carfilzomib-based Chemotherapy for Multiple Myeloma

(CarMob Trial)

Overseen By Geneva Khan

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Hackensack Meridian Health

Disqualifiers: Heart disease, Uncontrolled hypertension, HIV, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I study utilizes a 3+3 design with escalating cohorts of Carfilzomib at 20mg/m2, 27mg/m2, 36mg/m2, 45mg/m2, 56mg/m2, and 70mg/m2 to be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone and Granulocyte colony-stimulating factor (G-CSF)

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

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Carfilzomib for treating multiple myeloma?

Carfilzomib, when used in combination with other drugs like lenalidomide and dexamethasone, has been shown to significantly prolong the time patients live without their disease getting worse, compared to some other treatments. This combination also improved patients' overall health status, making it a valuable option for those with relapsed multiple myeloma. ^{1 2 3 4 5}

Is carfilzomib safe for humans?

Carfilzomib, also known as Kyprolis, has been associated with several side effects, including fatigue, anemia (low red blood cell count), nausea, and serious conditions like pneumonia and heart failure. Some patients have experienced severe lung issues, and it can also cause cardiovascular problems and kidney damage. While many side effects are mild, it's important to monitor for these risks during treatment. ^{2 6 7 8 9}

How is the drug Carfilzomib different from other treatments for multiple myeloma?

Carfilzomib is unique because it is a second-generation proteasome inhibitor that binds selectively and irreversibly to the proteasome, which helps stop cancer cell growth and leads to cell death. It is used in combination with other drugs like lenalidomide and dexamethasone, and is administered intravenously, offering a different approach compared to some other standard treatments. ^{1 2 3 4 10}

Eligibility Criteria

This trial is for adults over 18 with multiple myeloma who have had some treatment but not a complete response. They should expect to live more than 12 weeks, be in fairly good health with normal liver function and heart performance, and have an acceptable blood count. Women must test negative for pregnancy and agree to use contraception, as must men.

Inclusion Criteria

You need to have had a heart scan showing that your heart is pumping well within the last 6 months.

Participants must have detectable levels of specific proteins in their blood or urine that can be measured.

I have multiple myeloma with measurable indicators.

Exclusion Criteria

I have not had radiation therapy in the last 3 weeks.

I do not have any uncontrolled illnesses like high blood pressure, diabetes, infections, or liver disease.

I have undergone stem cell transplant or preparation for it.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive escalating doses of Carfilzomib in combination with Cyclophosphamide, Dexamethasone, and G-CSF for mobilization of peripheral blood stem cells

4 weeks

Weekly visits for dose administration

Stem Cell Collection

Peripheral blood stem cell collection begins after high dose G-CSF injections

1 week

Daily visits for stem cell collection

Autologous Stem Cell Transplant

Patients proceed to a melphalan-based autologous stem cell transplant

1 week

Follow-up

Participants are monitored for safety and effectiveness after the transplant

24 months

Monthly visits for disease parameter assessment

Treatment Details

Interventions

• Carfilzomib

Trial Overview The study tests different doses of Carfilzomib (20-70mg/m2) combined with Cyclophosphamide, Dexamethasone, and G-CSF in escalating groups using a '3+3 design' to find the best dose for stem cell transplant preparation in multiple myeloma patients.

Participant Groups

Group I: Carfilzomib Mobilization - Dose Level 5 Experimental Treatment 4 Interventions

Carfilzomib at 70mg/m2 over 30 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing.

Group II: Carfilzomib Mobilization - Dose Level 4 Experimental Treatment 4 Interventions

Carfilzomib at 56mg/m2 over 30 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing.

Group III: Carfilzomib Mobilization - Dose Level 3 Experimental Treatment 4 Interventions

Carfilzomib at 45mg/m2 over 30 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing.

Group IV: Carfilzomib Mobilization - Dose Level 2 Experimental Treatment 4 Interventions

Carfilzomib at 36mg/m2 over 30 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing.

Group V: Carfilzomib Mobilization - Dose Level 1 Experimental Treatment 4 Interventions

Carfilzomib at 27mg/m2 over 10 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing.

Group VI: Carfilzomib Mobilization - Dose Level 0 Experimental Treatment 4 Interventions

Carfilzomib at 20mg/m2 over 10 minutes will be administered concomitantly with Cyclophosphamide 2 gm/m2, Dexamethasone 40mg and G-CSF. For patients who are naïve to carfilzomib based therapy a priming dose of Carfilzomib (20mg/m2) will be administered 1 week prior to the cohort dosing.

Carfilzomib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Kyprolis for:

• Multiple myeloma

Approved in European Union as Kyprolis for:

• Multiple myeloma

Approved in Canada as Kyprolis for:

• Multiple myeloma

Approved in Japan as Kyprolis for:

• Multiple myeloma

Who Is Running the Clinical Trial?

Hackensack Meridian Health

Lead Sponsor

Trials

141

Recruited

42,900+

Amgen

Industry Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

Findings from Research

Carfilzomib-containing combinations as frontline therapy for multiple myeloma showed a high overall response rate of 94% and a complete response rate of 21% across 13 trials involving 704 subjects.

The combination of carfilzomib with lenalidomide and dexamethasone (CFZ-LEN-DEX) resulted in a significantly higher complete response rate of 49% compared to other combinations, indicating it may be the most effective regimen for newly diagnosed patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib-containing combinations as frontline therapy for multiple myeloma: A meta-analysis of 13 trials. Sheng, Z., Li, G., Li, B., et al.[2018]

Carfilzomib, a proteasome inhibitor approved for relapsing multiple myeloma, was associated with a case of fatal pulmonary toxicity in a 61-year-old male patient, highlighting a potential serious side effect of the drug.

The patient developed acute respiratory distress syndrome and diffuse alveolar hemorrhage shortly after starting carfilzomib, suggesting a direct link between the medication and the severe lung complications, which had not been previously reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatal pulmonary toxicity due to carfilzomib (Kyprolis™). Lataifeh, AR., Nusair, A.[2020]

In the ENDURANCE trial involving patients with newly diagnosed multiple myeloma, the combination of carfilzomib, lenalidomide, and dexamethasone (KRd) did not improve progression-free survival compared to the standard treatment of bortezomib, lenalidomide, and dexamethasone (VRd).

These findings suggest that KRd may not be a more effective treatment option than the current standard of care for patients with NDMM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib Triplet Fails to Induce Superior PFS in Newly Diagnosed Multiple Myeloma. Skarzynski, J.[2021]

Carfilzomib, when used in combination with lenalidomide and dexamethasone, significantly prolongs progression-free survival (PFS) by 8.7 months in patients with relapsed multiple myeloma, based on results from the phase III ASPIRE study involving a multinational patient population.

The combination therapy has a manageable safety profile, with low incidences of severe adverse events, suggesting it is a viable treatment option for patients who have received prior therapies, although overall survival data is still pending.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma. Hoy, SM.[2018]

Carfilzomib shows significant efficacy in treating multiple myeloma, with a 28% complete response rate and a 93% overall response rate among 2,487 patients analyzed across 12 clinical trials.

While carfilzomib improves survival rates (93% progression-free survival at 1 year), it is associated with a higher incidence of cardiotoxicity compared to traditional treatments, although it does not significantly increase the risk of peripheral neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Carfilzomib in the Treatment of Multiple Myeloma：A Systematic Evaluation]. Luo, T., Xia, HL.[2020]

Carfilzomib significantly improves progression-free survival, overall survival, and overall response rate in patients with relapsed/refractory multiple myeloma, based on evidence from 14 systematic reviews involving moderate quality data.

However, treatment with carfilzomib is associated with increased risks of cardiovascular events, nephrotoxicity, and serious infections, highlighting the need for careful monitoring and further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of carfilzomib for the treatment of multiple myeloma: An overview of systematic reviews. Georgoulis, V., Haidich, AB., Bougioukas, KI., et al.[2022]

In a study of 138 Korean patients with relapsed/refractory multiple myeloma, carfilzomib combined with lenalidomide and dexamethasone (KRd) was associated with a higher risk of specific adverse events, including dyspnea, muscle spasms, and thrombocytopenia, particularly during the early treatment cycles.

Despite the increased risk of these side effects, most adverse events were of low severity (grade 1-2), suggesting that while carfilzomib has notable side effects, it can still be used effectively and safely in real-world treatment settings for RRMM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib's Real-World Safety Outcomes in Korea: Target Trial Emulation Study Using Electronic Health Records. Jang, HY., Lee, HK., Kim, CJ., et al.[2023]

In patients with mild to moderate hepatic impairment, carfilzomib showed approximately 20-50% higher drug exposure compared to those with normal liver function, but this increase is not expected to be clinically significant due to the drug's pharmacokinetic variability.

The safety profile of carfilzomib in patients with advanced solid tumors was consistent with previous findings, although there was a noted increase in adverse events related to liver function abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study. Brown, J., Plummer, R., Bauer, TM., et al.[2020]

References

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

Carfilzomib-containing combinations as frontline therapy for multiple myeloma: A meta-analysis of 13 trials. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Fatal pulmonary toxicity due to carfilzomib (Kyprolis™). [2020]

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

Carfilzomib Triplet Fails to Induce Superior PFS in Newly Diagnosed Multiple Myeloma. [2021]

4. France pubmed.ncbi.nlm.nih.gov

Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma. [2018]

5. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Carfilzomib in the Treatment of Multiple Myeloma：A Systematic Evaluation]. [2020]

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

Incidence and management of adverse events in patients with relapsed and/or refractory multiple myeloma receiving single-agent carfilzomib. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of carfilzomib for the treatment of multiple myeloma: An overview of systematic reviews. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Carfilzomib's Real-World Safety Outcomes in Korea: Target Trial Emulation Study Using Electronic Health Records. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Carfilzomib: a novel agent for multiple myeloma. [2014]