Carfilzomib With Bendamustine and Dexamethasone in Multiple Myeloma

Study Overview
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Brief Summary
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This study is designed to define dose-limiting toxicity and determine preliminary evidence of efficacy of carfilzomib (CFZ) in combination with bendamustine and dexamethasone for patients with newly diagnosed multiple myeloma (MM).

Detailed Description
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Multiple myeloma (MM) is a malignant plasma cell disorder resulting in approximately 11,000 deaths in the United States each year. It is estimated that between 60,000-80,000 people are currently under treatment for refractory or relapsed MM. Prognosis and survival have improved over the last 20 years, but the disease is still universally fatal despite efforts to develop new and more effective chemotherapeutic regimens. Therefore, new regimens need to be developed for patients prior to peripheral blood stem cell transplant and for those unable to tolerate the toxicity of transplant.

Official Title
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Phase I/II Study of Carfilzomib in Combination With Bendamustine and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma

Conditions
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Multiple Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Life expectancy ≥ 3 months. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Adequate hepatic function. Sufficient Absolute neutrophil count (ANC) within 14 days prior to randomization. Sufficient Hemoglobin within 14 days prior to randomization (subjects may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines). Sufficient platelet count 14 days prior to randomization. Creatinine Clearance ≥ 30 mL/minute within 7 days prior to randomization. Left Ventricular Ejection Fraction ≥ 40%. Written informed consent in accordance with federal, local, and institutional guidelines. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception. Male subjects must agree to practice contraception. Patients must have histologically or cytologically confirmed symptomatic multiple myeloma (MM). Patients should not have previously been treated. Prior kyphoplasty, vertebroplasty, local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture) are permitted. Patients are allowed up to two cycles of high dose steroids if needed for symptomatic disease before study enrollment. Exclusion Criteria: Patients who have had chemotherapy for Multiple Myeloma. Exception: local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture). Patients currently receiving high dose systemic steroids for treatment of Multiple Myeloma in excess of 320mg total dose of dexamethasone or equivalent, patients who received an investigational agent within 5 half-lives of the agent. Patients with non-measurable Multiple Myeloma or primary plasma cell leukemia. Pregnant or lactating females. Major surgery within 21 days prior to enrollment. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to enrollment. Known human immunodeficiency virus (HIV) infection. Known active hepatitis B or C infection. Unstable angina or myocardial infarction within 4 months prior to enrollment. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment. Uncontrolled, non-hematologic malignancy requiring active treatment. Patients with known brain metastases (treated or not) will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Significant neuropathy within 14 days prior to randomization. Known history of allergy to Captisol, or to other agents in the study. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.

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: CFZ with bendamustine and dexamethasone<br>Subjects will receive Carfilzomib on Days 1, 2, 8, 9, 15, and 16 every 28 days with dose escalation from 27, 36, 45 to 56 mg/ m2 . No matter what target dose the subject will receive, days 1 and 2 doses in the first cycle will always be 20 mg/m2, followed by target dose for all subsequent dates and cycles. Bendamustine will be given IV on days 1 and 2 with dose escalation up to 90 mg/m2 and dexamethasone 20 mg orally or intravenously on 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day cycle. Study treatment will be given until 8 cycles of treatment are completed or until disease progression, whichever comes first. | Drug: Bendamustine<br>* Bendamustine will be administered IV on days 1 and 2 with dose escalation up to 90 mg/m2 of each 28-day cycle. Dose escalation is as follows: -1 | 60 mg/m2 | 70 mg/m2 | 70 mg/m2 | 90 mg/m2 | 90mg/m2 | 90 mg/m2<br>* Other names: Treanda;Drug: Carfilzomib<br>* Carfilzomib will be administered IV on Days 1, 2, 8, 9, 15, and 16 every 28 days. Dose Escalation is as follows: -1 | 27 mg/m2 | 27 mg/m2 | 36 mg/m2 | 36 mg/m2 | 45 mg/m2 | 56 mg/m2<br>* Other names: CFZ;Drug: Dexamethasone<br>* Dexamethasone will be administered PO or IV, 20 mg, on 1, 2, 8, 9, 15, 16 and 22, 23 of each 28-day cycle.<br>* Other names: Dexpak Taperpak;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Carfilzomib in combination with bendamustine and dexamethasone | The primary endpoint of this study is dose-limiting toxicity (DLT), to define the recommended phase II dose. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Includes complete response and partial response. | 2 years | 
| Duration of response (DOR) | The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the study treatment started). | 2 years | 
| Progression free survival (PFS) | PFS is defined as the duration of time from start of study treatment to time of progression or death, whichever occurs first. | 2 years | 
| Time to best response | Time to the best response recorded. | 2 years | 
| Overall survival (OS) rate | The percentage of people who are still alive. | 2 years | 
| Number of adverse events (AEs) | Total number of AEs observed. | 2 years | 
| Number of adverse events in relation to carfilzomib maintenance | Total number of AEs observed that are determined to be related to carfilzomib. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Newly diagnosed, multiple myeloma, myeloma, bendamustine, Treanda, carfilzomib, dexamethasone, phase I, phase II, dose escalation, transplant, non-transplant, plasma cell, Kyprolis