Study to Evaluate Safety Tolerability & Efficacy of Kyprolis (Carfilzomib) in Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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To characterize safety associated with the use of Kyprolis under the locally approved label.

Detailed Description
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Kyprolis® (K; carfilzomib) was approved in India on 17 January 2017 as a prescription medication in combination with dexamethasone (Kd) or with lenalidomide (Revlimid®) plus dexamethasone (KRd) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) following 1 to 3 prior lines of therapy. This non-comparative, interventional phase 4 study is designed to fulfil the post-marketing requirement to assess safety, tolerability, and efficacy of Kyprolis on Indian subjects with RRMM as per the locally approved label.

Official Title
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Post-marketing Phase 4 Study to Evaluate Safety, Tolerability, and Efficacy of Kyprolis® (Carfilzomib) in Indian Patients With Relapsed or Refractory Multiple Myeloma: A Prospective, Open-label, Non-comparative, Multicenter Study

Conditions
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Relapsed Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Drug: Carfilzomib + Dexamethasone
* Drug: Drug: Carfilzomib + Lenalidomide + Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented RRMM after last treatment. Refractory is defined as meeting 1 or more of the following: Nonresponsive to most recent therapy (stable disease [SD] or progressive disease [PD]) while on treatment, or Disease progression within 60 days of discontinuation from the most recent therapy. Eligible to receive Kyprolis per the locally approved label. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Adequate hepatic function within 28 days prior to enrollment: bilirubin < 1.5 times the upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times the ULN. Absolute neutrophil count (ANC) ≥ 1.0 x 10^9 /L within 28 days prior to enrollment. (Screening ANC should be independent of granulocyte- and granulocyte macrophage-colony stimulating factor support for at least 1 week and of pegylated granulocyte stimulating factor for ≥ 2 weeks). Hemoglobin ≥ 80 g/L within 28 days prior to enrollment. Subjects should not have received red blood cell (RBC) transfusions for at least 7 days prior to obtaining the screening hemoglobin. Platelet count ≥ 75 x 10^9/L (≥ 50 x 10^9/L if myeloma involvement in the bone marrow is ≥ 50%) within 28 days prior to enrollment. Subjects should not have received platelet transfusions for at least 7 days prior to obtaining the screening platelet count. Adequate renal function within 28 days prior to enrollment (either measured or calculated using a standard formula such as the Cockcroft and Gault): calculated or measured creatinine clearance (CrCl) of ≥ 50 mL/min for subjects receiving KRd; calculated or measured CrCl of ≥ 15 mL/min for subjects receiving Kd. Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram (TTE) or multigated acquisition scan (MUGA). Females of childbearing potential (FCBP) must have a negative serum pregnancy test within the 10 to 14 days prior to enrollment and a negative urine pregnancy test within the 24 hours prior to day 1 of each cycle prior to dosing. Subject or legally acceptable representative has provided informed consent/assent prior to initiation of any study specific activities/procedures. Exclusion Criteria: Waldenström macroglobulinemia. Plasma cell leukemia (> 2.0 x 10^9/L circulating plasma cells by standard differentials). POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Myelodysplastic síndrome. Primary amyloidosis (subjects with multiple myeloma with asymptomatic deposition of amyloid plaques found on biopsy would be eligible if all other criteria are met). History of other malignancy within the past 5 years, with the following exception[s]: 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 cáncer. Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ. Known immediate or delayed hypersensitivity reaction to Captisol (a cyclodextrin derivative used to solubilize Kyprolis). Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs. Intolerance to hydration. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant echocardiogram (ECHO) abnormalities, screening ECG with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to enrollment. Infiltrative pulmonary disease and/or known pulmonary hypertension. Active infection within 14 days prior to enrollment requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents. Such infections must be fully resolved prior to initiating study treatment. Pleural effusions requiring thoracentesis within 14 days prior to enrollment. Ascites requiring paracentesis within 14 days prior to enrollment. Uncontrolled hypertension, defined as an average systolic blood pressure > 159 mmHg or diastolic > 99 mm/Hg despite optimal treatment (measured following European Society of Hypertension/European Society of Cardiology [ESH/ESC] 2013 guidelines. Active hepatitis B virus (HBV) infection. Subjects with positive hepatitis B surface antigen (HBsAg) or core antibody (anti-HBc) that achieve sustained virologic response with antiviral therapy directed at hepatitis B are allowed. Subjects with known history or resolved infection (negative for HBsAg but positive for antibodies to surface antigen, and/or core antigen) must be screened with HBV DNA levels. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (hepatitis B surface antibody [anti-HBs] positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA. Known human immunodeficiency virus (HIV) infection, hepatitis C infection (subjects with hepatitis C that achieve a sustained virologic response following antiviral therapy are allowed). Ongoing graft-versus-host disease. Subjects with grade 3 or worse neuropathy within 14 days prior to enrollment. Antitumor therapy (eg, chemotherapy, immunotherapy, antibody therapy) or investigational agent within 28 days before enrollment or not recovered from any acute toxicity. Subjects on immunosuppressive therapy for graft versus host disease, even if it has resolved. Glucocorticoid therapy within 14 days before first dose that exceeds a cumulative dose of 160 mg or dexamethasone or equivalent dose of other corticosteroids. Focal radiation therapy within 7 days before enrollment. Radiation therapy to an extended field involving significant volume of bone marrow within 28 days prior to enrollment (ie, prior radiation must have been to less than 30% of the bone marrow). Autologous stem cell transplant less than 100 days prior to enrollment. Prior treatment with Kyprolis (carfilzomib). 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. Other investigational procedures while participating in this study are excluded. Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment, during any breaks (interruptions) in the treatment, and for an additional 30 days after the last dose of Kyprolis. Females of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test. Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment, during any breaks (interruptions) in the treatment, and for an additional 30 days after the last dose of Kyprolis. NOTE: Female subjects of childbearing potential being treated with lenalidomide must agree to use 2 methods of contraception for at least 28 days before starting treatment, during treatment, during any breaks (interruptions) in the treatment, and for an additional 30 days after the last dose of treatment. • Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 90 days after the last dose of Kyprolis. NOTE: Male subjects being treated with lenalidomide must agree to use a male condom with spermicide even if they have undergone a successful vasectomy. Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 90 days after the last dose of Kyprolis. Male subjects unwilling to abstain from donating sperm during treatment and for an additional 90 days after the last dose of Kyprolis. Subject likely to not be available to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion. Active hepatitis B virus (HBV) infection. Subjects with positive hepatitis B surface antigen (HBsAg) or core antibody (anti-HBc) that achieve sustained virologic response with antiviral therapy directed at hepatitis B are allowed. Subjects with known history or resolved infection (negative for HBsAg but positive for antibodies to surface antigen, and/or core antigen) must be screened with HBV DNA levels. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (hepatitis B surface antibody [anti-HBs] positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib + Dexamethasone<br>Drug: Carfilzomib + Dexamethasone Carfilzomib 20 mg/m2 on days 1 and 2, and if tolerated, escalated to a target dose of 56 mg/m2 starting on day 8 of cycle 1 and thereafter. Dexamethasone 20 mg taken by mouth or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. An individual subject will receive study treatment for a maximum of 3 years if the subject has not yet experienced disease progression | Drug: Drug: Carfilzomib + Dexamethasone<br>* Drug: Carfilzomib + Dexamethasone Carfilzomib will be administered as a 30-minute infusion. Dexamethasone will be taken by mouth or intravenously.<br>* Other names: Kyprolis;|
| Experimental: Carfilzomib+Lenalidomide+Dexamethasone<br>Drug: Carfilzomib + Lenalidomide + Dexamethasone Carfilzomib is 20 mg/m2 on days 1 and 2, and if tolerated, escalated to a target dose of 27 mg/m2 starting on day 8 of cycle 1 and thereafter. From cycle 13, the day 8 and day 9 doses of Carfilzomib will be omitted. Lenalidomide 25 mg is taken orally on days 1 to 21. Dexamethasone 40 mg on days 1, 8, 15, and 22 of the 28-day cycles. An individual subject will receive study treatment for a maximum of 18 months consistent with the approved use in this combination. | Drug: Drug: Carfilzomib + Lenalidomide + Dexamethasone<br>* Drug: Carfilzomib + Lenalidomide + Dexamethasone Carfilzomib will be administered as a 10 minute infusion. Lenalidomide will be taken orally. Dexamethasone will be taken by mouth or intravenously.<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 with treatment-emergent adverse events as assessed by CTCAE v4.03 | Using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 | From enrollment up to the post treatment follow-up visit, which is 19 months for Carfilzomib + Lenolidamide + Dexamethasone arm or until disease progression or a maximum of 3 years for the Carfilzomib + Dexamethasone arm. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression Free Survival is defined as the time from first dose of study treatment until the earliest date of disease progression or death due to any cause | From enrollment up to the post treatment follow-up visit, which is 19 months for Carfilzomib + Lenolidamide + Dexamethasone arm or until disease progression or a maximum of 3 years for the Carfilzomib + Dexamethasone arm. | 
| Overall Response Rate | Overall Response Rate is defined as the proportion of subjects with either a best overall response of the stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) CBR is defined as the proportion of subjects with either a best overall response of sCR, CR, VGPR, PR, and minimal response (MR) | From enrollment up to the post treatment follow-up visit, which is 19 months for Carfilzomib + Lenolidamide + Dexamethasone arm or until disease progression or a maximum of 3 years for the Carfilzomib + Dexamethasone arm. | 
| Clinical Benefit Rate | Clinical Benefit Rate is defined as the proportion of subjects with either a best overall response of sCR, CR, VGPR, PR, and minimal response (MR) | From enrollment up to the post treatment follow-up visit, which is 19 months for Carfilzomib + Lenolidamide + Dexamethasone arm or until disease progression or a maximum of 3 years for the Carfilzomib + Dexamethasone arm. | 
| Time to Response | Time To Response is calculated only for subjects who achieve a best overall response of PR or better and is defined as the time from first dose of study treatment to the earliest date a response of PR or better is first achieved and subsequently confirmed | From enrollment up to the post treatment follow-up visit, which is 19 months for Carfilzomib + Lenolidamide + Dexamethasone arm or until disease progression or a maximum of 3 years for the Carfilzomib + Dexamethasone arm. | 
| Duration of Response | Duration of Response is defined as the time from initial response (sCR, CR, VGPR, or PR) to date of disease progression | From enrollment up to the post treatment follow-up visit, which is 19 months for Carfilzomib + Lenolidamide + Dexamethasone arm or until disease progression or a maximum of 3 years for the Carfilzomib + Dexamethasone arm. |