Nutritional and Metabolic Diseases

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Amyloidosis

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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.

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.

Patients receive daratumumab and hyaluronidase-fihj 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 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 CT, MRI or 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.

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.

Autologous Hematopoietic Stem Cell Transplantation

Biopsy

Undergo blood and urine specimen collection

Biospecimen Collection

Bone Marrow Aspiration

Bone Marrow Biopsy

Computed Tomography

Daratumumab and Hyaluronidase-fihj

Echocardiography

Magnetic Resonance Imaging

Positron Emission Tomography

Stem Cell Isolation

Survey Administration

Patrick A Hagen

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.

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.

Comparing Dara-VCD Chemotherapy Plus Stem Cell Transplant to Dara-VCD Chemotherapy Alone for People Who Have Newly Diagnosed AL Amyloidosis

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

Comparisons of MRD negativity rates between arms will be made using a stratified Cochran-Mantel-Haenszel test, with analyses stratified according to European modification of the Mayo Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3a), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).

Analysis will be conducted using multiple linear regression analysis, adjusting for the clinical study-specified stratification factors (which are also anticipated to influence QOL endpoints), and the baseline score as covariates.

Analysis will be conducted using linear regression, adjusting for the clinical study-specified stratification factors and the baseline PROMIS-29 fatigue domain score as covariates. Additionally, will conduct longitudinal modeling of the physical function domain score over time (through 12 months from registration Step 3). For longitudinal modeling, linear mixed models will be used.

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.

Will be performed using a stratified log-rank test for comparison between arms, with stratification according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. \[VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).

Will be performed using a stratified log-rank test for comparison between arms, with stratification according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).

Progression will be defined based on objective evidence of worsening of organ dysfunction due to AL amyloid. Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).

Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).

Will be analyzed using the cumulative incidence competing risks method.

Will use the PROMIS-29+2 (version 2.1) to compare the physical function between participants in the ASCT vs. non-ASCT arm.

Participant-reported toxicity will be examined using Patient Reported Outcome-Common Terminology Criteria for Adverse Events.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comparing Dara-VCD Chemotherapy Plus Stem Cell Transplant to Dara-VCD Chemotherapy Alone for People Who Have Newly Diagnosed AL Amyloidosis	NCT06022939	AL Amyloidosis	Autologous Hema... Biopsy Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Bortezomib Computed Tomogr... Cyclophosphamid... Daratumumab and... Dexamethasone Echocardiograph... Magnetic Resona... Melphalan Positron Emissi... Stem Cell Isola... Survey Administ...	18 Years -	SWOG Cancer Research Network
Comparing Dara-VCD Chemotherapy Plus Stem Cell Transplant to Dara-VCD Chemotherapy Alone for People Who Have Newly Diagnosed AL Amyloidosis	NCT06022939	AL Amyloidosis	Autologous Hema... Biopsy Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Bortezomib Computed Tomogr... Cyclophosphamid... Daratumumab and... Dexamethasone Echocardiograph... Magnetic Resona... Melphalan Positron Emissi... Stem Cell Isola... Survey Administ...	18 Years -	SWOG Cancer Research Network
Comparing Dara-VCD Chemotherapy Plus Stem Cell Transplant to Dara-VCD Chemotherapy Alone for People Who Have Newly Diagnosed AL Amyloidosis	NCT06022939	AL Amyloidosis	Autologous Hema... Biopsy Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Bortezomib Computed Tomogr... Cyclophosphamid... Daratumumab and... Dexamethasone Echocardiograph... Magnetic Resona... Melphalan Positron Emissi... Stem Cell Isola... Survey Administ...	18 Years -	SWOG Cancer Research Network

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