Cyclophosphamide, Carfilzomib, Thalidomide, and Dexamethasone in Treating Patients With Newly Diagnosed Active Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Thalidomide may stop the growth of cancer cells by blocking blood flow to the tumor. Giving combination chemotherapy together with carfilzomib and thalidomide may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of carfilzomib when given together with cyclophosphamide, thalidomide, and dexamethasone in treating patients with newly diagnosed active multiple myeloma.

Detailed Description
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PRIMARY OBJECTIVES: I. To establish the maximum tolerated dose of carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone. (Phase I) II. In newly diagnosed myeloma to evaluate the response rate (CR, nCR, and VGPR) to carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone after four 28 day cycles. (Phase II) SECONDARY OBJECTIVES: I. Determine the overall response rate (CR, nCR, PR) after 4, 8, 12 cycles. II. Determine the duration of progression-free and overall survival for patients receiving this regimen. III. To evaluate the incidence of toxicities for this regimen. IV. To evaluate the ability to successfully collect peripheral blood stem cells following four months of combination therapy. OUTLINE: This is a phase I, dose escalation study of carfilzomib followed by a phase II study. Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 3 months, then every 3 months for 1 year, and then every 6 months for up to 3 years.

Official Title
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A Phase I/II Trial of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients With Newly Diagnosed Active Multiple Myeloma

Conditions
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Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

Intervention / Treatment
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* Drug: carfilzomib
* Drug: cyclophosphamide
* Drug: thalidomide
* Drug: dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Creatinine =< 2 mg/dL Calculated Creatinine Clearance >= 30 mL/min Total Bilirubin =< 2.0 mg/dL Alkaline Phosphatase =< 3 x ULN ALT =< 3 x ULN Absolute neutrophil count >= 1000/uL Platelet >= 75000/uL Hemoglobin >= 8.0 g/dL Untreated symptomatic myeloma: Prior non-systemic therapy for the treatment of solitary plasmacytoma is permitted, but >= 1 month should have elapsed from the last day of radiation; prior therapy with clarithromycin, DHEA, anakinra, pamidronate or zoledronic acid is permitted; any additional agents not listed must be approved by the Principal Investigator Prior high dose corticosteroid therapy for twelve days (480 mg total dose) or less is permitted for emergent complications from newly diagnosed multiple myeloma Measurable disease of multiple myeloma, as defined by at least ONE of the following: Serum monoclonal protein >= 1.0 g by protein electrophoresis OR > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis OR serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio; OR monoclonal bone marrow plasmacytosis >= 30% (evaluable disease) ECOG performance status (PS) 0, 1, 2; ECOG PS of 3 will be allowed if secondary to pain in the opinion of the Investigator Willingness and able to provide informed written consent Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only Willingness to return to Mayo Clinic enrolling institution for follow-up Exclusion MGUS or smoldering myeloma Peripheral sensory neuropathy >= Grade 2 as defined by CTEP Active Version of the CTCAE Active malignancy with the exception of non melanoma skin cancer or in situ cervical or breast cancer Pregnant women or women of reproductive ability who are unwilling to use effective contraception Nursing women Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 4 weeks after stopping treatment Known hypersensitivity, allergy or inability to tolerate any of the agents employed Active, uncontrolled infection Severe cardiac comorbidity New York Heart Association Class III or IV Heart Failure Recent history of myocardial infarction in the six months prior to registration Uncontrolled angina or electrocardiographic evidence of acute ischemia Severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of active conduction system abnormalities Cardiac amyloidosis with hypotension (systolic BP less than 100 mmHg) Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment The following medications are not permitted during the trial: any other investigational treatment; any cytotoxic chemotherapy; any other systemic anti-neoplastic therapy including, but not limited to, immunotherapy, hormonal therapy, or monoclonal antibody therapy Palliative radiation therapy is permitted if clinically indicated and not indicative of progressive disease

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: Arm I<br>Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28. | Drug: carfilzomib<br>* Given IV<br>* Other names: PR-171;Drug: cyclophosphamide<br>* Given orally<br>* Other names: Enduxan;Drug: thalidomide<br>* Given orally<br>* Other names: Thalomid;Drug: dexamethasone<br>* Given orally<br>* Other names: DXM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (Phase I) | To establish the maximum tolerated dose of carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone. For this protocol, dose-limiting toxicity (DLT) will be defined as an adverse event attributed (definitely, probably, possibly) in the first or second cycle for patients enrolled to Dose Levels -1 and 0 and in the first cycle only for patients enrolled to Dose Levels 1 and 2. We are reporting the number of DLTs | From baseline to end of active treatment, up to 12 28-day cycles. | 
| Percentage of Patients Who Have at Least a Confirmed Very Good Partial Response (Phase II) | The proportion of patients who have at least a confirmed very good partial response will be calculated by taking the number of patients with a very good partial response or a complete response divided by the total number of patients. A complete response is defined as: Negative immunofixation of the serum and urine If at on study, only the measurable non-bone marrow parameter was FLC, normalization of FLC ratio < 5% plasma cells in bone marrow Disappearance of any soft tissue plasmacytomas A very good partial response is defined as: Serum and urine M-component detectable by immunofixation but not on electrophoresis or If at on study, serum measurable, ≥ 90% or greater reduction in serum Mcomponent Urine M-component <100 mg per 24 hour | Following the first 4 cycles of treatment (28 day cycles) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (Phase II) | PFS was defined as the time from registration to progression or death due to any cause. Progression was defined as any one or more of the following: • Increase of 25% from lowest confirmed response in: Serum M-component (absolute increase must be ≥ 0.5 g/dl)c Urine M-component (absolute increase must be ≥ 200 mg/24 hour) If at on study, only the measurable non-bone marrow parameter was FLC, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dl) Bone marrow plasma cell percentage (absolute % must be 10%)d Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas • Development of hypercalcemia (corrected serum calcium >11.5 mg/dl) that can be attributed solely to the plasma cell proliferative disorder | From baseline to progression or death up to 3 years | 
| Time to Treatment Failure | The time from the date of registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a non-protocol failure, the patient will be censored on the date they were removed from treatment. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier | From baseline to end of active treatment | 
| Stem Cell Collection and Engraftment (Phase II) | For patients going on to stem cell collection, the total number of CD34 positive cells collected per collection, days to platelets over 20,000 without transfusion and ANC over 1000 will be recorded. If a patient fails to collect adequate stem cells for transplant, this will be recorded as such. The number of patients with successful stem cell mobilization are reported. | Following the first 4 courses of treatment | 
| Complete Response (Phase II) | In patients continuing beyond 4 cycles the ability to induce complete response will be evaluated at completion of planned therapy. | Following the first 4 courses of treatment | 
| Survival Time (Phase II) | Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier | From baseline to death | 
| Progression Free Survival (12 Month) | Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. This is reported as the percentage of patients alive and progression free at the 12 month mark. | 12 months | 
| Progession Free Survival (24 Month) | Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. This is reported as the percentage of patients alive and progression free at the 24 month mark. | 24 months | 
| Overall Survival (12 Month) | 12 Month Overall survival is defined as the proportion of patients to still be alive after 12 months. | From baseline to death | 
| Overall Survival (24 Month) | 24 Month Overall survival is defined as the proportion of patients to still be alive after 24 months. | From baseline to death |