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A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis

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ClinicalTrials.gov Identifier: NCT03201965
Recruitment Status : Recruiting
First Posted : June 28, 2017
Last Update Posted : August 27, 2018
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Brief Summary:
The purpose of this study is to evaluate the efficacy and safety of daratumumab plus cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared with CyBorD alone in treatment of newly diagnosed amyloid light chain (AL) amyloidosis participants.

Condition or disease Intervention/treatment Phase
Amyloidosis Drug: Cyclophosphamide Drug: Bortezomib Drug: Dexamethasone, 40 mg Drug: Daratumumab Phase 3

Detailed Description:
Participant involved in study for approx. 8 years duration includes Screening Phase (complete clinical evaluation will be done), Treatment Phase (monitoring of adverse events (AEs), laboratory abnormalities and clinical response), Post-Treatment Observation Phase (disease evaluations will be done) and a Long-term Follow-up Phase (Subsequent anticancer treatment, response to subsequent treatment, date of progression and survival status will be obtained every 16 weeks).The primary hypothesis is that daratumumab in combination with CyBorD will improve the overall complete hematological response rate compared to CyBorD alone in AL amyloidosis participants. Safety will be assessed by AEs, laboratory test results, electrocardiogram, vital sign measurements, physical examination, and Eastern Cooperative Oncology Group (ECOG) performance status.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 370 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis
Actual Study Start Date : October 5, 2017
Estimated Primary Completion Date : January 22, 2021
Estimated Study Completion Date : October 30, 2025


Arm Intervention/treatment
Active Comparator: CyBorD alone (cyclophosphamide/bortezomib/dexamethasone)
Participants will receive dexamethasone (40 milligrams [mg] orally or intravenous [IV] dose), followed by cyclophosphamide (300 milligram per meter square [mg/m^2] orally or IV dose), then bortezomib (1.3 mg/m^2 subcutaneous injection) weekly on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles.
Drug: Cyclophosphamide
Participants will receive 300 mg/m^2 of cyclophosphamide as an oral or IV dose.

Drug: Bortezomib
Participants will receive 1.3 mg/m^2 of bortezomib as an subcutaneous (SC) injection.

Drug: Dexamethasone, 40 mg
Participants of CyBorD alone arm will receive 40 mg dexamethasone orally or IV dose. Participants of CyBorD plus daratumumab arm will receive dexamethasone 20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing to make a total of 40 mg.

Experimental: CyBorD plus Daratumumab
Participants will receive dexamethasone (20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing) followed by 1800 mg of daratumumab subcutaneously followed by cyclophosphamide (300 mg/m^2 orally or IV dose weekly) and bortezomib (1.3 mg/m^2 subcutaneous injection weekly) on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles. Daratumumab will be administered weekly for the first 8 weeks (2 cycles), then every 2 weeks for 4 cycles (cycles 3-6), and then every 4 weeks until progression of disease or subsequent therapy for a maximum of 2 years.
Drug: Cyclophosphamide
Participants will receive 300 mg/m^2 of cyclophosphamide as an oral or IV dose.

Drug: Bortezomib
Participants will receive 1.3 mg/m^2 of bortezomib as an subcutaneous (SC) injection.

Drug: Dexamethasone, 40 mg
Participants of CyBorD alone arm will receive 40 mg dexamethasone orally or IV dose. Participants of CyBorD plus daratumumab arm will receive dexamethasone 20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing to make a total of 40 mg.

Drug: Daratumumab
Participants will receive 1800 mg of daratumumab subcutaneously.




Primary Outcome Measures :
  1. Percentage of Participants With Overall Complete Hematologic Response [ Time Frame: Approximately 3 years ]
    Overall complete hematologic response rate will be defined as percentage of participants who achieve Complete Hematologic Response (CHR), according to the International Amyloidosis Consensus Criteria. CHR: normalization of free light chain levels and ratio, negative serum and urine immunofixation.


Secondary Outcome Measures :
  1. Major Organ Deterioration Progression-Free Survival (MOD-PFS) [ Time Frame: Approximately 5 years ]
    MOD-PFS is defined from randomization to any one of following events, whichever comes first: death; clinical manifestation of cardiac/renal failure; development of hematologic progression of disease. Clinical manifestation of cardiac failure: development of dyspnea at rest (for at least 3 consecutive days) and due solely to amyloidosis cardiac deterioration, or need for cardiac transplant, left ventricular assist device, or intraaortic balloon pump or clinical manifestation of renal failure: development of end-stage renal disease (need for hemodialysis or renal transplant). Hematologic progression of disease: from CHR, abnormal free light chain ratio (light chain must be double), or from CHR/ VGPR (very good partial response) /PR (partial response), 50 percent (%) increase in serum M-protein to greater than (>) 0.5 gram per deciliter (g/dL) or 50% increase in urine M-protein to >200 milligram per day (mg/day); free light chain increase of 50% to > 100 mg/L.

  2. Progression-Free Survival (PFS) [ Time Frame: Approximately 5 years ]
    Progression-free survival (PFS) is defined as time from date of randomization to date of first documentation of hematologic disease progression, or organ (cardiac, renal, or liver) progression, or death due to any cause, whichever occurs first. Hematologic disease progression: from CHR, any detectable monoclonal protein or abnormal free light chain ratio (light chain must be double), from PR, 50% increase in serum M-protein to > 0.5 g/dL or 50% increase in urine M-protein to > 200 mg/day; free light chain increase of 50% to > 100 mg/L. Organ progression for heart: NT-proBNP progression [> 30%; > 300 ng/l increase] or cardiac troponin (cTn) progression [greater than or equal to (>=) 33% increase] or ejection fraction progression [>= 10% decrease]; for kidney: renal progression is defined as a >=25% estimated glomerular filtration rate (eGFR) decrease.

  3. Organ Response Rate (OrRR) [ Time Frame: Approximately 5 years ]
    Organ response rate (OrRR) for kidney, heart, liver is defined as the proportion of baseline organ involved participants who achieve organ response in each corresponding organ. Organ response defined for heart :N-terminal brain pronatriuretic peptide (NT-proBNP) response (> 30% and > 300 nanogram per liter [ng/L] decrease in participants with baseline NT-proBNP >= 650 ng/L) or New York Heart Association (NYHA) class response (>= 2 class decrease in participants with baseline NYHA class 3 or 4); for kidney: decrease in proteinuria by >=30% or below 0.5 grams /24 hours without renal progression; for liver: 50% decrease in abnormal alkaline phosphatase value.

  4. Overall Survival (OS) [ Time Frame: Approximately 8 years ]
    Overall survival (OS) is measured from the date of randomization to the date of the participant's death.

  5. Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Fatigue Scale Score [ Time Frame: Baseline, up to end of study (approximately 5 years) ]
    The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 is a 30-question tool used in clinical research 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, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate reduction in fatigue (i.e. improvement in symptom) and positive values indicate increases in fatigue (i.e. worsening of symptom).

  6. Change From Baseline in the 36-Item Short Form Survey version 2 (SF-36v2) Mental Component Summary (MCS) [ Time Frame: Baseline, up to end of study (approximately 5 years) ]
    The 36-Item Short Form Survey version 2 (SF-36v2) is a survey of participant health. It consists of 8 individual domains, which are weighted sums of the questions in their section. The 8 domains are: vitality (VT), physical functioning (PF), bodily pain (BP), general health (GH), Role-Physical (RP), Role-Emotional (RE), social functioning (SF) and mental health (MH). Each of these 8 scales (domains) is scored from 0 to 100 with higher scores indicating better health. Based on the scale scores, the summary mental component score (MCS) is derived. Scales contributing most to the scoring of the SF-36 MCS include the VT, SF, RE and MH. Other domains not noted contribute to the scoring but to a lesser degree. The scoring is derived based on an algorithm that has been developed in a software provided by the developer. The summary MCS score is also scaled from 0 to 100 with higher scores indicating better health.

  7. Change From Baseline in the EORTC QLQ-C30 Global Health Status Scale Score [ Time Frame: Baseline, up to end of study (approximately 5 years) ]
    The European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ)-C30 is a 30-question tool 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, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in QOL or functioning and positive values indicate improvement.

  8. Time to Next Treatment (TNT) [ Time Frame: Approximately 5 years ]
    Time to next treatment (TNT) defined as the time from the date of randomization to the start date of subsequent treatment for AL amyloidosis treatment.

  9. Hematologic Very Good Partial Response or Better Rate [ Time Frame: Approximately 3 years ]
    Hematologic very good partial response or better rate is defined as the percentage of participants who achieve hematologic complete response or very good partial response. Complete response: normalization of free light chain levels and ratio, negative serum and urine immunofixation; Very good partial response: reduction in the dFLC less than 40 mg/L.

  10. Time to Complete Hematologic Response [ Time Frame: Approximately 3 years ]
    Time to complete hematologic response is defined as the time between the date of randomization and the first efficacy evaluation at which the participant has met the criteria for hematologic complete response.

  11. Time to Hematologic Very Good Partial Response (VGPR) or Better Response [ Time Frame: Approximately 3 years ]
    Time to hematologic VGPR or better response is defined as the time between the date of randomization and the first efficacy evaluation at which the participant has met the criteria for hematologic VGPR or better response.

  12. Duration of Complete Hematologic Response [ Time Frame: Approximately 5 years ]
    Duration of complete hematologic response is defined as the time between the date of initial documentation of complete hematologic response to the date of first documented evidence of hematologic progressive disease.

  13. Duration of Hematologic Very Good Partial Response (VGPR) or Better Response [ Time Frame: Approximately 5 years ]
    Duration of hematologic VGPR or better response is defined as the time between the date of initial documentation of hematologic VGPR or better response to the date of first documented evidence of hematologic progressive disease.

  14. Time to Organ Response [ Time Frame: Approximately 5 years ]
    Time to organ response is defined as the time between the date of randomization and the first efficacy evaluation at which the participant has each corresponding organ response.

  15. Duration of Organ Response [ Time Frame: Approximately 5 years ]
    Duration of organ response is defined as the time between the date of initial documentation of each corresponding organ response to the date of first documented evidence of the corresponding organ progressive disease.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent material in congo red stained tissue specimens (in an organ other than bone marrow) or characteristic electron microscopy appearance
  • Measurable disease of amyloid light-chain (AL) amyloidosis as defined by at least one of the following:

    1. serum monoclonal (M)-protein greater than or equal (>=) 0.5 grams/deciliter (g/dL) by protein electrophoresis (routine serum protein electrophoresis and immunofixation [IFE] performed at a central laboratory)
    2. serum free light chain greater than or equal to (>=) 5.0 milligram/deciliter (mg/dL) with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) >= 5 mg/ dL
  • One or more organs impacted by AL amyloidosis according to consensus guidelines
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2

Exclusion Criteria:

  • Prior therapy for AL amyloidosis or multiple myeloma including medications that target CD38, with the exception of 160 mg dexamethasone (or equivalent corticosteroid) maximum exposure prior to randomization
  • Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, >= 60 percent (%) plasma cells in the bone marrow, or hypercalcemia
  • Evidence of significant cardiovascular conditions as specified below:

    1. NT-ProBNP > 8500 nanogram per liter (ng/L)
    2. New York Heart Association (NYHA) classification IIIB or IV heart failure
    3. Heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (eg, prior myocardial infarction with documented history of cardiac enzyme elevation and electrocardiogram [ECG] changes) or uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy
    4. Inpatient admission to a hospital for unstable angina or myocardial infarction within the last 6 months prior to first dose or percutaneous cardiac intervention with recent stent within 6 months or coronary artery bypass grafting within 6 months
    5. For participants with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to randomization
    6. Participants with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/implantable cardioverter-defibrillators [ICD] is indicated but not placed (participants who do have a pacemaker/ICD are allowed on study)
    7. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) > 500 milliseconds (msec). Participants who have a pacemaker may be included regardless of calculated QTc interval
    8. Supine systolic blood pressure < 90 millimeter of mercury (mmHg), or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 20 mmHg despite medical management (eg, midodrine, fludrocortisones) in the absence of volume depletion
  • Planned stem cell transplant during the first 6 cycles of protocol therapy are excluded. Stem cell collection during the first 6 cycles of protocol therapy is permitted
  • Know to be seropositive for human immunodeficiency virus (HIV)
  • Any one of the following:

    1. Known to be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (ie, participants who are positive for antibodies to hepatitis B core antigen [antiHBc] and/or antibodies to hepatitis B surface antigen [antiHBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded
    2. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
  • Grade 2 sensory or Grade 1 painful peripheral neuropathy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03201965


Contacts
Contact: Study Contact 844-434-4210 JNJ.CT@sylogent.com

  Show 153 Study Locations
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Additional Information:
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT03201965     History of Changes
Other Study ID Numbers: CR108193
2016-001737-27 ( EudraCT Number )
54767414AMY3001 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: June 28, 2017    Key Record Dates
Last Update Posted: August 27, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Dexamethasone acetate
Dexamethasone
Daratumumab
Cyclophosphamide
Bortezomib
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists