A Phase III, Randomized Study of Daratumumab, Cyclophosphamide, Bortezomib and Dexamethasone (Dara-VCD) Induction Followed by Autologous Stem Cell Transplant or Dara-VCD Consolidation and Daratumumab Maintenance in Patients With Newly Diagnosed AL Amyloidosis
Summary
This phase III trial compares the effect of adding a stem cell transplant with melphalan after completing chemotherapy with daratumumab, cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) versus chemotherapy with Dara-VCD alone for treating patients with newly diagnosed amyloid light chain (AL) amyloidosis. Melphalan is a chemotherapy given prior to a stem cell transplant. Giving chemotherapy before a peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. The stem cells are then returned to the patients to replace the blood forming cells that were destroyed by the chemotherapy. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Chemotherapy drugs, such as cyclophosphamide and bortezomib, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Dexamethasone is in a class of medications called corticosteroids. It is used to lower the body's immune response to help stop the growth of cancer cells. Giving a stem cell transplant with melphalan after Dara-VCD may kill more cancer cells in patients with newly diagnosed AL amyloidosis.
Detailed description
PRIMARY OBJECTIVE: I. To compare major organ deterioration progression-free survival between participants randomized to the autologous stem cell transplant (ASCT) and non-ASCT arms of this study. SECONDARY OBJECTIVES: I. To compare overall survival (OS) between participants randomized to the ASCT and non-ASCT arms of this study. II. To compare rates of cardiac and renal organ responses between participants randomized to the ASCT and non-ASCT arms of this study. III. To compare rates of cardiac and renal organ progression between participants randomized to the ASCT and non-ASCT arms of the study. IV. To compare the frequency and severity of toxicities between participants randomized to the ASCT and non-ASCT arms of this study. V. To compare minimal residual disease (MRD) negativity rates between participants randomized to the ASCT and non-ACST arms of this study. ADDITIONAL OBJECTIVES: I. To compare the best overall hematologic response rates between participants randomized to the ASCT and non-ASCT arms of this study. II. To compare rates of hematologic complete response (CR) and very good partial response, following completion of consolidation therapy between participants randomized to the ASCT and non-ASCT arms of this study, post-consolidation. III. To compare hematologic progression-free survival between participants randomized to the ASCT and non-ASCT arms of this study. IV. To compare time to next treatment between participants randomized to the ASCT and non-ASCT arms of the study. V. To evaluate utilization of delayed ASCT in participants randomized to the non-ASCT arm of the study. TRANSLATIONAL MEDICINE PRIMARY OBJECTIVES: I. To compare MRD negativity rates from bone marrow aspirates via next generation flow cytometry (NGF) between the ASCT and non-ASCT arms of this study post-consolidation. II. To bank specimens for future use. TRANSLATIONAL MEDICINE EXPLORATORY OBJECTIVES: I. To evaluate MRD negativity rates at post-induction, and compare MRD negativity rates at 12 months post-consolidation from bone marrow aspirates via NGF between participants randomized to the ASCT and non-ASCT arms of this study. II. To investigate the association of achieving MRD negativity at any point (post-induction, post-consolidation, or 12 months post-consolidation) via NGF from bone marrow aspirates with major organ deterioration-progression free survival (MOD-PFS). III. To investigate the association of achieving sustained MRD negativity (MRD negative at two consecutive measurements -- post-induction, post-consolidation, and 12 months post-consolidation) via NGF from bone marrow aspirates with MOD-PFS. QUALITY OF LIFE (QOL) PRIMARY OBJECTIVE: I. To compare patient-reported physical function following consolidation treatment between participants randomized to the ASCT and non-ASCT arms using the Patient Reported Outcomes Measurement Information System (PROMIS)-29+2 Profile version (v) 2.1 physical function sub-scale. QOL SECONDARY OBJECTIVES: I. To compare patient-reported fatigue following consolidation treatment between participants randomized to the ASCT and non-ASCT arms using the PROMIS-29 fatigue subscale. II. To compare longitudinal changes in physical function using the PROMS-29+2 between participants randomized to the ASCT and non-ASCT arms. QOL EXPLORATORY OBJECTIVES: I. To assess baseline symptom burden in AL amyloidosis patients prior to induction therapy using the PROMIS-29+2. II. To compare mean scores of symptom scales using the PROMIS-29+2 following consolidation treatment, and at 6 months and 12 months from step 3 registration between treatment arms. III. To compare mean scores of functional scales using the PROMIS-29+2, following consolidation treatment, and at 6 months and 12 months from step 3 registration between treatment arms. IV. To explore whether longitudinal changes in symptoms, functioning, and overall heath related quality of life (HRQoL) as assessed by the PROMIS-29 +2 (version 2.1) differ according to treatment group and, separately, according to baseline cardiac or renal involvement using interaction tests between participants randomized to the ASCT and non-ASCT arms. V. To compare health utility indices using the PROMIS preference score (PROPr) between patients randomized to the ASCT and non-ASCT arms. PATIENT REPORTED OUTCOME (PRO)-COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) PRIMARY OBJECTIVE: I. To compare patient reported symptoms regarding treatment emergent adverse events of interest using the Patient Reported Outcome CTCAE (PRO-CTCAE) Measurement System between patients randomized to the ASCT and non-ASCT arms of this study. OUTLINE: INDUCTION: Patients receive daratumumab and hyaluronidase-fihj subcutaneously (SC) over 3-5 minutes on days 1, 8, 15 and 22 for 2 cycles and then days 1 and 15 for cycle 3. Patients receive bortezomib SC over 3-5 minutes, cyclophosphamide orally (PO) or intravenously (IV), and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET)-CT and fat pad aspiration at screening. Patients undergo echocardiography at screening, the completion of induction, and at progression. Patients undergo bone marrow aspiration and biopsy at screening, post induction treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression. CONSOLIDATION: Patients who achieve an overall response of partial response or better after 3 cycles of Dara-VCD are randomized to 1 of 2 arms. ARM I: Patients receive daratumumab and hyaluronidase-fihj SC over 3-5 minutes on days 1 and 15 as well as bortezomib SC over 3-5 minutes, cyclophosphamide PO or IV, and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within14-28 days post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression. ARM II: Patients undergo collection of peripheral blood stem cells. Patients receive melphalan IV for 1 cycle and then 2 days later receive the stem cell transplant IV in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within 60-90 days post initiation of stem cell transplant. Patients undergo blood and urine sample collection at screening, during treatment, and the end of treatment and during follow up or at progression. MAINTENANCE: Patients receive maintenance daratumumab and hyaluronidase-fihj SC over 3-5 minutes on day 1 of each cycle. Cycles repeat every 28 days for up 18 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening, 12 months post consolidation treatment and at progression. Patients undergo bone marrow aspiration and biopsy 12 months post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, during treatment, 12 months post consolidation treatment and during follow up or at progression. After completion of study treatment, patients are followed up every 3 or 6 months up to 4 years after registration.
Arms & interventions
- ProcedureAutologous Hematopoietic Stem Cell Transplantation
Given IV
- ProcedureBiopsy
Undergo fat pad biopsy
- ProcedureBiospecimen Collection
Undergo blood and urine specimen collection
- ProcedureBone Marrow Aspiration
Undergo bone marrow aspiration
- ProcedureBone Marrow Biopsy
Undergo bone marrow biopsy
- DrugBortezomib
Given SC
- ProcedureComputed Tomography
Undergo CT scan
- DrugCyclophosphamide
Given PO or IV
- DrugDaratumumab and Hyaluronidase-fihj
Given SC
- DrugDexamethasone
Given PO or IV
- ProcedureEchocardiography
Undergo echocardiography
- ProcedureMagnetic Resonance Imaging
Undergo MRI
- DrugMelphalan
Given IV
- ProcedurePositron Emission Tomography
Undergo PET-CT
- ProcedureStem Cell Isolation
Undergo stem cell collection
- OtherSurvey Administration
Ancillary study
Outcome measures
Primary
Major organ deterioration progression-free survival (PFS)
Will be performed using a stratified log-rank test for comparison between study arms. The analyses will be stratified according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 versus \[vs.\] 2-3), hematological response following 2 cycles of daratumumab, cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) induction (partial response \[PR\] or worse vs. very good partial response \[VGPR\] or better), and presence of t(11;14) by interphase fluorescence in situ hybridization \[iFISH\] (yes vs. no). All eligible participants will be considered in analyses of the primary endpoint, according to their assigned arm at randomization.
Time frame: From date of randomization (Step 2 registration) to date of first documentation of hematologic progression, cardiac organ progression, renal organ progression, or death due to any cause, assessed up to 4 years
Secondary
Overall survival
Time frame: From randomization to date of death due to any cause, assessed up to 4 years
Hematologic PFS
Time frame: From randomization (Step 2 registration) to date of first documentation of hematologic progression, or death due to any cause, assessed up to 4 years
Cardiac and renal organ response rates
Time frame: Up to 4 years
Measurable residual disease (MRD) negativity rate
Time frame: From baseline to off treatment follow-up (prior to progression) or 12 months post consolidation
Best overall hematologic response
Time frame: From date of initial registration (Step 1) and date of randomization (Step 2 registration) to date of first documentation of hematologic PR, VGPR, or CR, assessed up to 4 years
Overall hematologic response rate
Time frame: From date of initial registration (Step 1) and date of randomization (Step 2 registration) to date of first documentation of hematologic PR, VGPR, or CR, assessed up to 4 years
Rate of complete response
Time frame: Up to 4 years
Rate of very good complete response or better
Time frame: Up to 4 years
Time to next treatment
Time frame: From date of initial registration (Step 1) to date of initiation of next line of therapy, assessed up to 4 years
Change in patient reported health quality of life (QOL)
Time frame: From baseline to post-maintenance, approximately 24 months
Incidence of adverse events
Time frame: Up to the end of maintenance therapy, approximately 24 months
Eligibility criteria
Study locations (117)
CTCA at Western Regional Medical Center
Goodyear, Arizona, 85338
Banner University Medical Center - Tucson
Tucson, Arizona, 85719
University of Arizona Cancer Center-North Campus
Tucson, Arizona, 85719
City of Hope Comprehensive Cancer Center
Duarte, California, 91010
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612
City of Hope at Irvine Lennar
Irvine, California, 92618
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
Smilow Cancer Hospital-Derby Care Center
Derby, Connecticut, 06418
Smilow Cancer Hospital Care Center at Greenwich
Greenwich, Connecticut, 06830
Smilow Cancer Hospital Care Center - Guilford
Guilford, Connecticut, 06437
Smilow Cancer Hospital Care Center at Saint Francis
Hartford, Connecticut, 06105
Yale University
New Haven, Connecticut, 06520
Yale-New Haven Hospital North Haven Medical Center
North Haven, Connecticut, 06473
Smilow Cancer Hospital Care Center at Long Ridge
Stamford, Connecticut, 06902
Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, 06611
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, 20007
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura, Florida, 33180
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146
UM Sylvester Comprehensive Cancer Center at Coral Springs
Coral Springs, Florida, 33065
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442
UM Sylvester Comprehensive Cancer Center at Hollywood
Hollywood, Florida, 33021
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, 33176
University of Miami Sylvester Comprehensive Cancer Center at Sole Mia
North Miami, Florida, 33181
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, 33324
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Rush-Copley Medical Center
Aurora, Illinois, 60504
University of Illinois
Chicago, Illinois, 60612
Carle at The Riverfront
Danville, Illinois, 61832
Carle Physician Group-Effingham
Effingham, Illinois, 62401
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois, 61938
Loyola University Medical Center
Maywood, Illinois, 60153
Carle Cancer Center
Urbana, Illinois, 61801
UI Health Care Mission Cancer and Blood - Ankeny Clinic
Ankeny, Iowa, 50023
UI Health Care Mission Cancer and Blood - West Des Moines Clinic
Clive, Iowa, 50325
Iowa Methodist Medical Center
Des Moines, Iowa, 50309
UI Health Care Mission Cancer and Blood - Des Moines Clinic
Des Moines, Iowa, 50309
UI Health Care Mission Cancer and Blood - Laurel Clinic
Des Moines, Iowa, 50314
UI Health Care Mission Cancer and Blood - Waukee Clinic
Waukee, Iowa, 50263
University of Kansas Cancer Center
Kansas City, Kansas, 66160
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
Walter Reed National Military Medical Center
Bethesda, Maryland, 20889-5600
Boston Medical Center
Boston, Massachusetts, 02118
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan, 48109
Henry Ford Cancer Institute-Downriver
Brownstown, Michigan, 48183
Henry Ford Macomb Hospital-Clinton Township
Clinton Township, Michigan, 48038
Henry Ford Medical Center-Fairlane
Dearborn, Michigan, 48126
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201
Henry Ford Hospital
Detroit, Michigan, 48202
Weisberg Cancer Treatment Center
Farmington Hills, Michigan, 48334
Allegiance Health
Jackson, Michigan, 49201
Karmanos Cancer Institute at McLaren Greater Lansing
Lansing, Michigan, 48910
Henry Ford Medical Center-Columbus
Novi, Michigan, 48377
Henry Ford West Bloomfield Hospital
West Bloomfield, Michigan, 48322
Henry Ford Wyandotte Hospital
Wyandotte, Michigan, 48192
Mercy Hospital
Coon Rapids, Minnesota, 55433
Fairview Southdale Hospital
Edina, Minnesota, 55435
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, 55416
Regions Hospital
Saint Paul, Minnesota, 55101
United Hospital
Saint Paul, Minnesota, 55102
Baptist Memorial Hospital and Cancer Center-Oxford
Oxford, Mississippi, 38655
Baptist Memorial Hospital and Cancer Center-Desoto
Southhaven, Mississippi, 38671
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
Nebraska Medicine-Bellevue
Bellevue, Nebraska, 68123
Nebraska Medicine-Village Pointe
Omaha, Nebraska, 68118
University of Nebraska Medical Center
Omaha, Nebraska, 68198
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, 07748
Memorial Sloan Kettering Bergen
Montvale, New Jersey, 07645
Memorial Sloan Kettering Commack
Commack, New York, 11725
Memorial Sloan Kettering Westchester
Harrison, New York, 10604
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
University of Rochester
Rochester, New York, 14642
Novant Health Presbyterian Medical Center
Charlotte, North Carolina, 28204
Duke University Medical Center
Durham, North Carolina, 27710
Novant Health Cancer Institute - Huntersville
Huntersville, North Carolina, 28078
Novant Health Cancer Institute - Mooresville
Mooresville, North Carolina, 28117
Novant Health Forsyth Medical Center
Winston-Salem, North Carolina, 27103
Case Western Reserve University
Cleveland, Ohio, 44106
Riverside Methodist Hospital
Columbus, Ohio, 43214
Providence Newberg Medical Center
Newberg, Oregon, 97132
Providence Willamette Falls Medical Center
Oregon City, Oregon, 97045
Providence Portland Medical Center
Portland, Oregon, 97213
Providence Saint Vincent Medical Center
Portland, Oregon, 97225
Oregon Health and Science University
Portland, Oregon, 97239
Geisinger Medical Center
Danville, Pennsylvania, 17822
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, 19104
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107
Geisinger Wyoming Valley/Henry Cancer Center
Wilkes-Barre, Pennsylvania, 18711
Baptist Memorial Hospital and Cancer Center-Collierville
Collierville, Tennessee, 38017
Baptist Memorial Hospital and Cancer Center-Memphis
Memphis, Tennessee, 38120
Houston Methodist San Jacinto Hospital
Baytown, Texas, 77521
Houston Methodist Cypress Hospital
Cypress, Texas, 77429
Houston Methodist Hospital
Houston, Texas, 77030
M D Anderson Cancer Center
Houston, Texas, 77030
Methodist Willowbrook Hospital
Houston, Texas, 77070
Houston Methodist West Hospital
Houston, Texas, 77094
Houston Methodist Saint John Hospital
Nassau Bay, Texas, 77058
Houston Methodist Sugar Land Hospital
Sugar Land, Texas, 77479
Houston Methodist The Woodlands Hospital
The Woodlands, Texas, 77385
Saint Vincent Hospital Cancer Center Green Bay
Green Bay, Wisconsin, 54301
Saint Vincent Hospital Cancer Center at Saint Mary's
Green Bay, Wisconsin, 54303
Gundersen Lutheran Medical Center
La Crosse, Wisconsin, 54601
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Madison, Wisconsin, 53718
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Saint Vincent Hospital Cancer Center at Oconto Falls
Oconto Falls, Wisconsin, 54154
Saint Vincent Hospital Cancer Center at Sheboygan
Sheboygan, Wisconsin, 53081
Sheboygan Physicians Group
Sheboygan, Wisconsin, 53081
Saint Vincent Hospital Cancer Center at Sturgeon Bay
Sturgeon Bay, Wisconsin, 54235-1495