A Study of Carfilzomib Plus Dexamethasone in Adults With Relapsed or Refractory Multiple Myeloma at US Community Oncology Centers

Study Overview
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Brief Summary
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The primary objective was to describe the safety profile of carfilzomib plus dexamethasone regimen in adults with relapsed or refractory multiple myeloma (RRMM) with 1 to 3 prior lines of therapy at study entry.

Detailed Description
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This is a phase 2, multicenter, open-label study in adults with RRMM in US community oncology centers. Adults with 1-3 prior lines of therapy at study entry are eligible to be screened for participation. Patients refractory to their last line of treatment are eligible to participate as long as their last line of treatment did not include a proteasome inhibitor (PI). The study will consist of a screening period of up to 28 days for bone marrow assessments and up to 21 days for all other assessments, up to 12 cycles of treatment, and a 30-day safety follow-up period following the last dose of study drug.

Official Title
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An Open-label Phase 2 Study of Carfilzomib Plus Dexamethasone To Assess Tolerability and Adherence in Subjects With Relapsed or Refractory Multiple Myeloma at US Community Oncology Centers

Conditions
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Relapsed or Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Carfilzomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has provided informed consent prior to initiation of any study specific activities/procedures. Males or females greater than or equal to 18 years of age. Relapsed MM after last treatment or refractory while receiving non-proteasome inhibitor therapy. Measurable disease with at least 1 of the following assessed within 21 days prior to enrollment: Immunoglobulin G (IgG) MM: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL IgA, IgD, IgE multiple myeloma: serum M protein level ≥ 0.5 g/dL Urine M-protein ≥ 200 mg per 24 hours In subjects without measurable serum or urine M-protein, serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1. Subjects must have at least partial response (PR) to at least 1 line of prior therapy. Subjects must have received at least 1 but not more than 3 prior lines of therapy for MM (induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy). Prior therapy with a proteasome inhibitor (PI) is allowed as long as the subject had at least a PR to most recent therapy with PI, was not removed due to toxicity (except for neuropathy), did not relapse within 60 days from discontinuation of PI, and will have at least a 6-month PI treatment-free interval from last dose received until enrollment. (Subjects may receive maintenance therapy with drugs that are not PI during this 6-month PI treatment-free interval). Exclusion Criteria: Waldenström macroglobulinemia. Multiple myeloma of IgM subtype. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). History of plasma cell leukemia. Primary amyloidosis (patients with multiple myeloma with asymptomatic deposition of amyloid plaques found on biopsy would be eligible if all other criteria are met). Subjects with nephrotic range proteinuria (greater than or equal to 3 g albumin for 24 hours urine OR greater than or equal to 2 g albumin/1 g of creatinine on a random urine specimen). Myelodysplastic syndrome. History of other malignancy within the past 5 years, with the following exceptions: Malignancy treated with curative intent and with no known active disease present for greater than or equal to 3 years before enrollment and felt to be at low risk for recurrence by the treating physician. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. Adequately treated cervical carcinoma in situ without evidence of disease. Adequately treated breast ductal carcinoma in situ without evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer. Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ. Treated medullary or papillary thyroid cancer. Similar neoplastic conditions with an expectation of greater than 95% five-year disease-free survival. Known human immunodeficiency virus (HIV) infection, hepatitis C infection (subjects with hepatitis C that achieve a sustained virologic response following antiviral therapy are allowed), or hepatitis B infection (subjects with hepatitis B surface antigen or core antibody that achieve sustained virologic response with antiviral therapy directed at hepatitis B are allowed). Acute or chronic graft-versus-host disease (any grade). Acute active infection requiring systemic antibiotics, antifungal, antiviral (except antiviral therapy directed at hepatitis B) agents within 14 days prior to enrollment. Known cirrhosis. Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior to enrollment. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment. Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg. Subjects with controlled hypertension are eligible. Hepatic dysfunction within 21 days prior to enrollment: bilirubin 1.5 times the upper limit of normal (ULN) aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 3 times the ULN Active congestive heart failure with or without reduced ejection fraction (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant electrocardiogram (ECG) abnormalities, screening ECG with corrected QT interval (QTc) of greater than 470 msec, pericardial disease, myocardial infarction within 4 months prior to enrollment. Known chronic obstructive pulmonary disease. Known interstitial pneumonitis. Immunotherapy within 21 days prior to enrollment. Chemotherapy with approved anticancer therapeutic within 21 days prior to enrollment. Glucocorticoid therapy (prednisone greater than 30 mg/day or equivalent) within 14 days prior to enrollment. Focal radiation therapy within 7 days prior to enrollment. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to enrollment (ie, prior radiation must have been to less than 30% of the bone marrow). Major surgery (except kyphoplasty) within 28 days prior to enrollment. Autologous or allogeneic stem cell transplant within 90 days prior to enrollment. Contraindication to dexamethasone. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib). Intolerance to intravenous (IV) hydration. Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded. Hepatic dysfunction within 21 days prior to enrollment: bilirubin greater than or equal to 1.5 times the upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than or equal to 3 times the ULN. Left ventricular ejection fraction less than 40% assessed by transthoracic echocardiogram. Severe valvular disease assessed by transthoracic echocardiogram. Severe right-ventricular dysfunction assessed by transthoracic echocardiogram. Right-ventricular systolic pressure greater than 40 mm Hg assessed by transthoracic echocardiogram. Screening absolute neutrophil count (ANC) should be independent of growth factor support for greater than or equal to 1 week. Hemoglobin less than 80 g/L within 21 days prior to enrollment. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed, however most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin. Platelet count < 50 x 10^9/L (≤ 30 x 10^9/L if myeloma involvement in the bone marrow is > 50%) within 21 days prior to enrollment. Subjects should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count. Estimated glomerular filtration rate (GFR) less than 30 mL/min/1.73 m^2 (per the Chronic Kidney Disease Epidemiology Collaboration formula) within 21 days prior to enrollment.

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 Plus Dexamethasone<br>Participants received carfilzomib administered as an intravenous (IV) infusion twice-weekly for up to six 28-day cycles followed by once-weekly for another six 28-day cycles. The carfilzomib dose was 20 mg/m² on days 1 and 2 of cycle 1, 56 mg/m² for the remaining days of cycle 1 (days 8, 9, 15, and 16) and then on days 1, 2, 8, 9, 15, and 16 of each cycle for cycles 2 to 6, and 70 mg/m² on days 1, 8, and 15 of each cycle for cycles 7 to 12. Participants also received dexamethasone either orally or by IV infusion at a dose of 20 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles 1 to 6 and at a dose 40 mg once daily on days 1, 8, 15 of cycles 7 to 12. | Drug: Dexamethasone<br>* Dexamethasone will be taken orally or by IV infusion at a dose of 20 mg once-daily on days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles 1-6, and at a dose 40 mg once-daily on days 1, 8, 15 of cycles 7-12.<br>Drug: Carfilzomib<br>* Carfilzomib will be administered at 20 mg/m² on days 1 and 2 of the first cycle. After that, carfilzomib will be administered at 56 mg/m² on days 8, 9, 15, and 16 of the first cycle, and then on days 1, 2, 8, 9, 15, and 16 on each 28-day cycle for the cycles 2 through 6. Starting with cycle 7 through cycle 12, carfilzomib will be administered at 70 mg/m² on days 1, 8, and 15 of each 28-day cycle. All<br>* Other names: Kyprolis®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Completed 12 Cycles of Treatment |  | 12 cycles (each cycle is 28 days) | 
| Percentage of Expected Dose of Carfilzomib Received in Cycles 1 to 12 | Percentage of expected dose of carfilzomib is defined as the percentage of actual cumulative dose (mg/m²) received by the participant relative to the full intended cumulative dose (mg/m²). | Up to 12 cycles (each cycle is 28 days) | 
| Relative Dose Intensity of Carfilzomib in Cycles 1 to 12 | Relative dose intensity = actual dose intensity / planned dose intensity * 100, where dose intensity is the cumulative dose (mg) divided by the duration of the study drug administration (weeks). | Up to 12 Cycles (each cycle is 28 days) | 
| Number of Participants With Carfilzomib Dose Modifications During Cycles 1 to 12 | Dose modification includes dosage adjustments, delays or discontinuations. A participant is counted only once for a reason category if there were multiple occurrences for the same reason. Participants may be counted in more than one category. | Cycles 1 - 12 (each cycle is 28 days) | 
| Number of Participants With Treatment-emergent Adverse Events | Treatment-emergent adverse events are defined as any adverse event with an onset date from the first dose through 30 days after the last dose of any study drug. Treatment-emergent related adverse events are adverse events considered related to at least one study drug by the investigator. Adverse events were graded using Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03, where Grade 1: Mild (asymptomatic or mild symptoms) Grade 2: Moderate (minimal, local or noninvasive intervention indicated) Grade 3: Severe (severe) or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated) Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. | From the first dose of study drug until 30 days after the last dose (12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Expected Dose of Carfilzomib Received in Cycles 1 to 6 and 7 to 12 | Percentage of expected dose of carfilzomib is defined as the percentage of actual cumulative dose (mg/m²) received by the participant relative to the full intended cumulative dose (mg/m²). | Cycles 1-6 and 7-12 (each cycle is 28 days) | 
| Relative Dose Intensity of Carfilzomib in Cycles 1 to 6 and 7 to 12 | Relative dose intensity = actual dose intensity / planned dose intensity * 100, where dose intensity is the cumulative dose (mg) divided by the duration of the study drug administration (weeks). | Cycles 1 - 6 and 7 - 12 (each cycle is 28 days) | 
| Number of Participants With Carfilzomib Dose Modifications During Cycles 1 to 6 | Dose modification includes dosage adjustments, delays or discontinuations. A participant is counted only once for a reason category if there were multiple occurrences for the same reason. Participants may be counted in more than one category. | Cycles 1 - 6 (each cycle is 28 days) | 
| Number of Participants With Carfilzomib Dose Modifications During Cycles 7 to 12 | Dose modification includes dosage adjustments, delays or discontinuations. A participant is counted only once for a reason category if there were multiple occurrences for the same reason. Participants may be counted in more than one category. | Cycles 7 - 12 (each cycle is 28 days) | 
| Number of Participants Who Discontinued Carfilzomib in Cycles 1 to 6 and 7 to 12 | Treatment discontinuation for all reasons in cycles 1 - 6 and cycles 7 - 12 | Cycles 1 - 6 and 7 - 12 (each cycle is 28 days) | 
| Change From Baseline to Last Cycle of Treatment in European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire (EORTC QLQ)-Core 30 (C30) | The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-item questionnaire used to assess the overall quality of life in cancer patients. EORTC QLQ-C30 was administered on day 1 of each treatment cycle. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact). For each of these scales, scores range from 0 to 100. For the GHS and 5 functional scales a high score indicates better global health status/functioning and a positive change from baseline indicates improvement. For the 9 symptom scales, a high score indicates a higher level of symptoms, and a negative change from Baseline indicates an improvement in symptoms. | Baseline (cycle 1 day 1) to cycle 12 day 1 | 
| Change From Baseline in Average EORTC QLQ-C30 Scores During Cycles 2 to 6 in Participants Who Completed 12 Cycles of Treatment | EORTC QLQ-C30 was administered on day 1 of each treatment cycle. EORTC QLQ-C30 is a 30-item questionnaire used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact). For each of these scales, scores range from 0 to 100. For the GHS and 5 functional scales a high score indicates better global health status/functioning and a positive change from baseline indicates improvement. For the 9 symptom scales, a high score indicates a higher level of symptoms, and a negative change from Baseline indicates an improvement in symptoms. Change from baseline is the difference in the average score from cycles 2 to 6 and the score on cycle 1 day 1. | Baseline (cycle 1 day 1) and cycles 2 - 6 | 
| Change From Cycle 7 Day 1 in Average EORTC QLQ-C30 Scores During Cycles 8 to 12 in Participants Who Completed 12 Cycles of Treatment | EORTC QLQ-C30 was administered on day 1 of each treatment cycle. EORTC QLQ-C30 is a 30-item questionnaire used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact). For each of these scales, scores range from 0 to 100. For the GHS and 5 functional scales a high score indicates better global health status/functioning and a positive change from baseline indicates improvement. For the 9 symptom scales, a high score indicates a higher level of symptoms, and a negative change from baseline indicates an improvement in symptoms. Change was calculated as the difference in the average score from cycles 8 to 12 and the score on cycle 7 day 1. | Cycle 7 day 1 and cycles 8 - 12 | 
| Change From Baseline to Last Cycle of Treatment in EORTC QLQ Multiple Myeloma Module (MY-20) Scores | EORTC QLQ-MY20 is a 20-item questionnaire used in clinical research to assess health-related quality of life in multiple myeloma patients. Questions are answered on a 4-point scale from 1 'Not at All' to 4 'Very Much'. The QLQ-MY20 includes four domains (Disease Symptoms, Side-Effects of Treatment, Body Image and Future Perspective). Domain scores are calculated as averages and transformed to range from 0 to 100. For the Disease symptoms and side-effects of treatments scales a higher score represents a higher level of symptoms/problems and a negative change from baseline value indicates reduction (i.e. improvement) in symptoms. For the body image and future perspectives scales a higher score represents a higher level of functioning, and a positive change from baseline indicates improvement. | Baseline (cycle 1 day 1) and cycle 12 day 1 | 
| Change From Baseline in Average EORTC QLQ-MY20 Scores During Cycles 2 to 6 in Participants Who Completed 12 Cycles of Treatment | EORTC QLQ-MY20 is a 20-item questionnaire used in clinical research to assess health-related quality of life in multiple myeloma patients. Questions are answered on a 4-point scale from 1 'Not at All' to 4 'Very Much'. The QLQ-MY20 includes four domains (Disease Symptoms, Side-effects of Treatment, Body Image and Future Perspective). Domain scores are calculated as averages and transformed to range from 0 to 100. For the disease symptoms and side-effects of treatment scales a higher score represents a higher level of symptoms/problems and a negative change from baseline value indicates reduction (i.e. improvement) in symptoms. For the body image and future perspectives scales a higher score represents a higher level of functioning, and a positive change from baseline indicates improvement. Change from baseline is the difference in the average score from cycles 2 to 6 and the score on cycle 1 day 1. | Baseline (cycle 1 day 1) and cycles 2 - 6 | 
| Change From Cycle 7 Day 1 in Average EORTC QLQ-MY20 Scores Over Cycles 8 to 12 in Participants Who Completed 12 Cycles of Treatment | EORTC QLQ-MY20 is a 20-item questionnaire used in clinical research to assess health-related quality of life in multiple myeloma patients. Questions are answered on a 4-point scale from 1 'Not at All' to 4 'Very Much'. The QLQ-MY20 includes four domains (Disease Symptoms, Side- Effects of Treatment, Body Image and Future Perspective). Domain scores are calculated as averages and transformed to range from 0 to 100. For the disease symptoms and side effects of treatments scales a higher score represents a higher level of symptoms/problems and a negative change from baseline value indicates reduction (i.e. improvement) in symptoms. For the body image and future perspectives scales a higher score represents a higher level of functioning, and a positive change from baseline indicates improvement. Change was calculated as the difference in the average score from cycles 8 to 12 and the score on cycle 7 day 1. | Cycle 7 day 1 and cycles 8 - 12 | 
| Overall Response Rate (ORR) | Disease response and progression were determined using International Myeloma Working Group Uniform Response Criteria (IMWG-URC) 2016, assessed by the Investigator. Per IMWG, determination of disease response requires: serum free light chain (SFLC), serum and urine protein electrophoresis (SPEP, UPEP, respectively), serum and urine immunofixation (SIFE, UIFE, respectively), bone marrow aspirate (for complete response confirmation), corrected calcium (cCa), and plasmacytoma evaluation, if present at screening. Best overall response is defined as a participant's best response during the study. Overall response rate is defined as the percentage of participants achieving a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). | Disease assessments were performed every 28 days up to 12 months from enrollment. | 
| Overall Response Rate (ORR) After 6 Cycles | Disease response and progression were determined using International Myeloma Working Group Uniform Response Criteria (IMWG-URC) 2016, assessed by the Investigator. Per IMWG, determination of disease response requires: serum free light chain (SFLC), serum and urine protein electrophoresis (SPEP, UPEP, respectively), serum and urine immunofixation (SIFE, UIFE, respectively), bone marrow aspirate (for CR confirmation), corrected calcium, and plasmacytoma evaluation, if present at screening. Overall response rate after 6 cycles is defined as the percentage of participants achieving a best overall response during the first 6 treatment cycles of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). | Disease assessments were performed every 28 days up to 6 cycles of treatment (each cycle was 28 days) | 
| Overall Response Rate (ORR) by Prior Lines of Therapy | Disease response and progression were determined using International Myeloma Working Group Uniform Response Criteria (IMWG-URC) 2016, assessed by the Investigator. Per IMWG, determination of disease response requires: serum free light chain (SFLC), serum and urine protein electrophoresis (SPEP, UPEP, respectively), serum and urine immunofixation (SIFE, UIFE, respectively), bone marrow aspirate (for CR confirmation), corrected calcium, and plasmacytoma evaluation, if present at screening. Best overall response is defined as a participant's best response during the study. Overall response rate is defined as the percentage of participants achieving a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). | Disease assessments were performed every 28 days up to 12 months from enrollment. | 
| Percentage of Participants With Progression-free Survival (PFS) Events at 12 Months | Progression-free survival events include disease progression or death due to any cause. Disease progression was determined by the Investigator according to IMWG criteria. | 12 months | 
| Percentage of Participants With PFS Events by Prior Lines of Therapy | Progression-free survival (PFS) events include disease progression or death due to any cause. Disease progression was determined by the Investigator according to IMWG criteria. | Disease assessments were performed every 28 days up to 12 months from enrollment. |