Carfilzomib, Oral Cyclophosphamide, and Dexamethasone for RRMM

Study Overview
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Brief Summary
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This study aims to study the efficacy and safety of oral cyclophosphamide in addition to carfilzomib and dexamethadone for RRMM patients who have been previously exposed to lenalidomide combination therapies.

Detailed Description
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The survival of multiple myeloma (MM) patients has been improved significantly owing to the adoption of immunomodulatory agents (IMiD) and proteasome inhibitors (PI). However, most of the MM patients finally experience relapse of refractoriness of the disease, of which patients who relapse after bortezomib and lenalidomide have very poor prognosis. Carfilzomib is an irreversible second generation PI which is approved by Korean FDA for RRMM in combination with dexamethasone and/or lenalidomide based on the landmark studies ASPIRE and ENDEAVOR studies. The addition of intravenous cyclophosphamide to carfilzomib has recently showed a promising result for RRMM patients after bortezomib and lenalidomide. In this study, cyclophosphamide 50mg orally will be added to carfilzomib once weekly schedule for 21 days daily every 4 weeks. The rationale for oral metronomic cyclophosphamide is based on previous experimental studies which has shown that it removes CD4+CD25+regulatory T cells preserving T and NK/T cell funtions.

Official Title
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A Phase II Study of Carfilzomib, Oral Cyclophosphamide, and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma in Relapse, Multiple Myeloma, Refractory

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: Subjects aged 19 years or older ECOG performance status 0 to 2 Diagnosed with multiple myeloma by IMWG criteria Subjects previously treated with 1 or more lines of therapy Subjects previously treated with lenalidomide-based combination or sigle drug therapy Subjects with relapsed and/or refractory multiple myeloma Subjects with measurable disease at the time of treatment initiation serum M protein >=0.5 g/dL, or 24h urine M protein >= 200mg/24h serum free light chain difference >=10mg/dL and abnormal FLC ratio Adequate organ function absolute neutrophil count >= 1.0 x 109/L platelelt count >= 50 x 109/L (plasmacytoma in the bone: >=30 x 109/L) Hb >=8g/dL serum creatinine < 3.0mg/dL or CCR >=15mL/min serum AST and ALT <=3 x ULN serum total bilirubin <= 3 x ULN Subjects able to swallow oral drugs Subjects who had experienced toxicities to previous therapies: resolved from previous toxicities or stabilized of the toxicity to grade 1 Subjects who had received allogenetic stem cell transplantation: no acitve graft-versus-host disease Subjects without clinically relevant bleeding Subjects who have informed consent to the study Females of childbearing potential (FCBP) must be negative to pregnancy testing and give consent to practice contraception before and during the treatment Exclusion Criteria: 1. Subjects who were previously exposed to carfilzomib 1. Subjects who were previously exposed to cyclophosphamide 3. Subjects diagnosed with POEMS SD, Waldenstrom macroglobulinemia, Plasma cell leukemia 4. Subjects with concurrent heart conditions Myocardial infarction within 6 months prior to treatment, New York Heart Association class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, Uncontrolled arrythmias (CVDAE version4 grade 2 or more) or symptomatic EKG abnormalities 12-lead EKG : baseline ATcF > 470msec 2D Echocardiography or MUGA scan : systolic EF < 40% with clinically significant symptoms Uncontrolled hypertension ( with medication: systolic BP >= 160 mmHg or diastolic BP >= 100 mmHg) 5. Chronc obstructive pulmonary disease (FEV1 < 60%), history of asthma within 2 years 6. Surgery under general anesthesia withing 2 weeks 7. Subjects diagnosed with malignancies within 5 years (except for cured skin cancer, cervical cancer, intraepithelial gastrointestinal tract cancer after curative procedures or surgery for more than 3 years) 8. 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 9. Pregnant or breatfeeding subjecs

Ages Eligible for Study
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Minimum Age: 19 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: Weekly carfilzomib-oral cyclophosphamide-dexamethasone<br>Weekly carfilzomib-oral cyclophosphamide-dexamethasone | Drug: Carfilzomib<br>* 70 mg/m2 IV days 1, 8 and 15, every 4 weeks<br>* Other names: Kyprolis;Drug: Cyclophosphamide<br>* 50 mg PO days 1 to 21, every 4 weeks<br>* Other names: Alkyloxan;Drug: Dexamethasone<br>* 40mg PO or IV days 1, 8, 15, and 22, every 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Very good partial response | Reduction of serum M-protein > 90% | from the first date of KCd to the day 30 after KCd stop date | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response | sCR+CR+VGPR+PR | from the first date of KCd to the day 30 after KCd stop date | 
| Progression-free survival | the time from the first date of KCd to the date of disease progression or death or censored date | from the first date of KCd until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months | 
| Overall survival | the time from the first date of KCd to the date of death or censored date | from the first date of KCd until the date of death from any cause, assessed up to 48 months | 
| Duration of response | the time from the first date of PR to the date of disease progression or death or censord date | from the first date of PR to the date of disease progression or death or censord date, which ever came first, assessed up to 48 months | 
| Time to response | the time from the first date of KCd to the first date of partial response | from the first date of KCd to the date of first date of equal or more than partial response, which ever came first, assessed up to 48 months | 
| Safety profile | Adverse events after KCd | from the first date of KCd to day 30 after KCd stop date |