A Safety Study of Carfilzomib, Cyclophosphamide & Dexamethasone Prior to ASCT in Patients With Newly Diagnosed Myeloma

Study Overview
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Brief Summary
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This is a dose finding pilot study to evaluate the safety and determine the maximum tolerated dose of the combination of carfilzomib and cyclophosphamide with dexamethasone (Car-Cy-Dex) prior to autologous stem cell transplant (ASCT) in patients with newly diagnosed transplant eligible multiple myeloma.

Detailed Description
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This is a dose finding pilot study to evaluate the safety and determine the maximum tolerated dose of the combination of carfilzomib and cyclophosphamide with dexamethasone (Car-Cy-Dex) prior to autologous stem cell transplant (ASCT) in patients with newly diagnosed transplant eligible multiple myeloma. The study will also explore the efficacy of Car-Cy-Dex including overall response after induction therapy, overall response at 3 and 6 months post ASCT, and time to progression, progression free survival, and time to next therapy if it occurs within 6 months post ASCT.

Official Title
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A Multi-Center Phase Ib, Open-Label, Dose-Finding Pilot Study to Evaluate the Combination of Carfilzomib and Cyclophosphamide With Dexamethasone Prior to ASCT in Patients With Transplant Eligible Newly Diagnosed Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Cyclophosphamide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytopathologically or histologically confirmed diagnosis of MM Measurable disease, as indicated by one or more of the following: Serum M-protein ≥ 1.0 g/dL Urine Bence Jones protein ≥ 200 mg/24 hr Elevated Free Light Chain as per the International Myeloma Working Group (IMWG) criteria Males and females ≥ 18 years of age Life expectancy of more than 5 months Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.5 times ULN Serum Creatinine Clearance(CrCl) ≥ 30 mL/min, either measured or calculated using a standard formula (e.g. Cockcroft and Gault) Additional Laboratory Requirements Absolute neutrophil count (ANC) ≥1.0 x 109/L Hemoglobin ≥8 g/dL [transfusion permitted] Platelet count ≥50.0 x 109/L Screening ANC should be independent of granulocyte-and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for at least 2 weeks Patients may receive RBC or platelet transfusions, if clinically indicated, in accordance with institutional guidelines Written informed consent in accordance with federal, local, and institutional guidelines Patients must agree to practice contraception Male patients must agree not to donate semen or sperm. Exclusion Criteria: Patients with non-secretory or hyposecretory MM Prior treatment for MM (prior radiation therapy or dexamethasone up to 160 mg for spinal cord compression is allowed. Other limited field radiation involving ≤ 1/3 of the pelvic area is also allowed) Plasma cell leukemia Pregnant or lactating females Major surgery within 21 days prior to first dose Congestive heart failure (CHF) (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction in the previous six months Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 14 days prior to first dose Patients receiving active treatment or intervention for any other malignancy or patients who, at the Investigator's discretion, may require active treatment or intervention for any other malignancy within 8 months of starting study treatment. Serious psychiatric or medical conditions that could interfere with treatment Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose and/or within 14 days before study treatment Contraindication to any of the required concomitant drugs, including antiviral (e.g. Valacyclovir) and proton-pump inhibitor (e.g. lansoprazole). Corticosteroid therapy in a dose equivalent to dexamethasone ≥ 1.5 mg/day or prednisone ≥ 10 mg/day. (Steroid use is allowed if necessary to treat spinal cord compression and/or hypocalcaemia.) Patients in whom the required program of oral and IV fluid hydration is contraindicated, e.g. due to pre-existing pulmonary, cardiac, or renal impairment Patients with primary systemic amyloidosis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib, Cyclophosphamide, Dexamethasone<br>All eligible subjects will receive Carfilzomib, Cyclophosphamide, and Dexamethasone. | Drug: Carfilzomib<br>* IV over 30 minutes on Days 1,2,8,9,15, and 16 every 28 days<br>* Other names: Kyprolis;Drug: Cyclophosphamide<br>* PO on days 1, 8, and 15 every 28 days<br>* Other names: Cytoxan;Drug: Dexamethasone<br>* 40 mg weekly PO or IV on Days 1, 8, 15, and 22, every 28 days.<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events as a measure of safety and tolerability | Review of adverse events for safety and to determine the maximum tolerated dose of the combination treatment. | Throughout treatment, estimated to be 4-6 months per patients | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response after induction therapy | Overall response (PR, VGPR, CR, sCR) | Every 28 days during induction therapy, estimated to be 4-6 months | 
| Overall Response post ASCT | Overall Response (PR, VGPR, CR, sCR) at 3 and 6 months post ASCT. | 3 and 6 months post ASCT | 
| Time to Progression | Time to progression will be noted if it occurs within 6 months post ASCT. | Througout treatment and 3 and 6 months post ASCT | 
| Progression Free Survival |  | up to 6 months post ASCT | 
| Time to Next Therapy | Time to Next Therapy if occurs within 6 months post ASCT | up to 6 months post ASCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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newly diagnosed multiple myeloma, transplant eligible multiple myeloma