A Study of Daratumumab-Based Therapies in Participants With Amyloid Light Chain (AL) Amyloidosis

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT05250973
• Collaborator: (none)
• Enrollment: 150
• Locations: 47
• Arms: 3
• Anticipated Duration (Months): 44.6
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to characterize cardiac safety of Daratumumab, Cyclophosphamide, Bortezomib, and Dexamethasone (D-VCd) treatment regimens (Arm A: immediate daratumumab + VCd treatment and Arm B: daratumumab + deferred VCd) in newly diagnosed systemic amyloid light chain (AL) amyloidosis with cardiac involvement and to identify potential mitigation strategies for cardiac toxicity (cohort 1); to characterize the pharmacokinetics of subcutaneous (SC) daratumumab, among racial and ethnic minorities, including Black or African American, with newly diagnosed AL amyloidosis treated with D-VCd (cohort 2).

Condition or Disease	Intervention/Treatment	Phase
Amyloidosis	Drug: Daratumumab; Drug: Cyclophosphamide; Drug: Bortezomib; Drug: Dexamethasone	Phase 2

Detailed Description

AL amyloidosis is a rare disorder caused by clonal plasma cells that secrete immunoglobulin light chains that misfold into insoluble amyloid. The insoluble amyloid gets deposited in vital organs which results in serious and life-threatening organ dysfunction. Daratumumab is a human immunoglobulin (IgG1K) monoclonal antibody (mAb) that binds with high affinity to a unique epitope on cluster of differentiation 38 (CD38), a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor cells that overexpress CD38. Participants will be enrolled into 2 cohorts based on cardiac involvement at baseline for cohort 1 and racial or ethnic minority with at least one organ involved for cohort 2. This study aims to generate data on risk factors for cardiac toxicity and to evaluate the cardiac safety of the proposed treatment regimens and identify potential mitigation strategies for cardiac toxicity such as deferred VCd treatment, The study will consist of screening phase (up to 28 days) and treatment phase with up to 24 treatment cycles (each cycle is 28 days). Safety assessment will include adverse events (AEs), serious adverse events (SAEs), physical examinations, Eastern Cooperative Oncology Group (ECOG) criteria for performance status, laboratory tests and vital signs. The overall duration of the study will be up to 3 years and 8 months.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicohort Study of Daratumumab-Based Therapies in Participants With Amyloid Light Chain (AL) Amyloidosis
• Actual Study Start Date: Mar 1, 2022
• Anticipated Primary Completion Date: Nov 29, 2024
• Anticipated Study Completion Date: Nov 18, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort1 (Arm A): Immediate Daratumumab + Cyclophosphamide, Bortezomib and Dexamethasone (VCd) Participants with newly diagnosed systemic amyloid light chain (AL) amyloidosis with Mayo Cardiac Stage II and IIIa cardiac involvement will receive daratumumab 1800 milligrams (mg) subcutaneously (SC) starting on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (cyclophosphamide 300 milligrams per meter square [mg/m^2] either orally or intravenously [IV], bortezomib 1.3 mg/m^2 SC, dexamethasone 40 mg weekly either orally or IV) weekly starting at Cycle 1 Day 1 up to Day 22 in every 28-day cycle for a maximum of 6 cycles (Cycle 6 Day 22).	Drug: Daratumumab; Daratumumab will be administered subcutaneously.; Other Names: JNJ-54767414 ; Drug: Cyclophosphamide; Cyclophosphamide will be administered either orally or IV.; Drug: Bortezomib; Bortezomib will be administered by SC injection.; Drug: Dexamethasone; Dexamethasone will be administered orally or IV.
Experimental: Cohort1 (Arm B): Daratumumab + Deferred VCd Participants with newly diagnosed systemic AL amyloidosis with Mayo Cardiac Stage II and IIIa cardiac involvement will receive SC daratumumab 1800mg on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (Cyclophosphamide 300 mg/m^2 either orally or IV, Bortezomib 1.3 mg/m^2 SC, Dexamethasone 40 mg weekly either orally or IV) starting at Cycle 4 Day 1, weekly (Days 1, 8, 15, 22) in every 28-day cycle for a maximum of 6 cycles (Cycle 9 Day 22).	Drug: Daratumumab; Daratumumab will be administered subcutaneously.; Other Names: JNJ-54767414 ; Drug: Cyclophosphamide; Cyclophosphamide will be administered either orally or IV.; Drug: Bortezomib; Bortezomib will be administered by SC injection.; Drug: Dexamethasone; Dexamethasone will be administered orally or IV.
Experimental: Cohort 2: Daratumumab + VCd Participants with racial and ethnic minorities, including Black or African American participants, with newly diagnosed AL amyloidosis will receive SC injection of daratumumab 1800 mg SC on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (cyclophosphamide 300 milligrams per meter square [mg/m^2] either orally or intravenously [IV], bortezomib 1.3 mg/m^2 SC, dexamethasone 40 mg weekly either orally or IV) weekly starting at Cycle 1 Day 1 up to Day 22 in every 28-day cycle for a maximum of 6 cycles (Cycle 6 Day 22).	Drug: Daratumumab; Daratumumab will be administered subcutaneously.; Other Names: JNJ-54767414 ; Drug: Cyclophosphamide; Cyclophosphamide will be administered either orally or IV.; Drug: Bortezomib; Bortezomib will be administered by SC injection.; Drug: Dexamethasone; Dexamethasone will be administered orally or IV.

Outcome Measures

Primary Outcome Measures

1. Number of Participants with Cardiac Events of Any Toxicity Grade [Up to 12 months]

   Number of participants with cardiac events of any toxicity grade will be reported.

2. Observed Concentration Immediately Prior to the Next Study Treatment Administration (Ctrough) [Cycle 3 Day 1 predose (each cycle is of 28 days)]

   Ctrough is defined as the observed concentration immediately prior to the next study treatment administration.

Secondary Outcome Measures

1. Overall Complete Hematologic Response (HemCR) Rate [Up to 3 years]

   Overall HemCR rate is defined as percentage of participants who achieve HemCR during or after the study treatment.

2. HemCR Rate [At 6 months]

   HemCR rate at 6 month is defined as percentage of participants who achieve HemCR at 6 month during or after the study treatment.

3. Very Good Partial Response (VGPR) or Better Rate [Up to 3 Years]

   Hematologic greater than or equal to (>=) VGPR rate is defined as percentage of participants who achieve hematologic response of VGPR or better.

4. Time to HemCR or (VGPR or Better) [Up to 3 years]

   For participants who achieve HemCR (or >=VGPR), time to HemCR (or >=VGPR) is defined as the time between the date of randomization (Cohort1)/first treatment (Cohort 2) and the first efficacy evaluation at which the participant has met all criteria for hematologic complete response (CR) (or >=VGPR).

5. Duration of Response (HemCR and VGPR or Better) [Up to 3 years]

   For participants who achieve HemCR (or >=VGPR), duration of HemCR (or >=VGPR) is defined as the time between the date of initial documentation of HemCR (or >=VGPR) to the date of first documented evidence of hematologic progressive disease or death, whichever comes first.

6. Organ Response Rate (OrRR) [Up to 3 years]

   Organ response rate is defined as the percentage of participants who achieve organ response in each corresponding organ (kidney, heart, liver).

7. Overall Survival (OS) [Up to 3 years]

   OS is measured from the date of randomization (Cohort 1)/first treatment (Cohort 2) to the date of the participant's death.

8. Time to Next Treatment (TNT) [Up to 3 Years]

   TNT for amyloid light chain (AL) amyloidosis is defined as the time from the date of randomization (Cohort1)/first treatment (Cohort 2) to the start date of subsequent AL amyloidosis (non-protocol) treatment.

9. Number of Participants with Adverse Events (AEs) by Severity [Up to 3 Years]

   Number of participants with AEs by severity will be reported. An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study.

10. Serum Concentration of Daratumumab [Up to 3 Years]

    Serum samples will be analyzed to determine concentrations of daratumumab.

11. Number of Participants with Antibodies to Daratumumab [Up to 3 years]

    Number of participants with antibodies to daratumumab will be reported.

12. Number of Participants with Antibodies to Recombinant Human Hyaluronidase PH20 Enzyme (rHuPH20) [Up to 3 years]

    Number of participants with antibodies to rHuPH20 will be reported.

13. Change from Baseline in Clinical Signs and Symptoms Score of Cardiac AL Amyloidosis [Baseline up to 3 Years]

    Change from baseline in clinical signs and symptoms score of cardiac AL amyloidosis will be reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Cohort 1: Cardiac involvement (amyloid light chain [AL] amyloidosis Mayo Cardiac Stage II and Stage IIIa) with or without other organ(s) involved; Cohort 2: One or more organs impacted by systemic AL amyloidosis according to consensus guidelines

• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2

• A female participant of childbearing potential must have a negative serum or urine test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study

• A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 6 months after receiving the last dose of cyclophosphamide or 100 days after discontinuation of daratumumab, whichever is longer

• Cohort 2 only: self-identified racial and ethnic minorities, including Black or African American

Exclusion Criteria:

• Prior therapy for systemic AL amyloidosis or multiple myeloma including medications that target cluster of differentiation 38 (CD38), with the exception of 160 milligrams(mg) dexamethasone or equivalent corticosteroid maximum exposure prior to randomization/enrollment

• Previous or current diagnosis of symptomatic multiple myeloma per International Myeloma Working Group (IMWG) Criteria

• Participant received any of the following therapies:

1. treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less;

2. vaccinated with an investigational vaccine (except for COVID-19) live, attenuated or replicating viral vector vaccines less than (<) 4 weeks prior to randomization/enrollment. Participants who are taking strong Cytochrome P450 3A4(CYP3A4) inducers must discontinue their use at least 5 half-lives prior to the first dose of bortezomib

• Stem cell transplantation -Planned stem cell transplant during the first 9 cycles of protocol therapy are excluded. Stem cell collection during the first 9 cycles of protocol therapy is permitted

• Grade 2 sensory or Grade 1 painful peripheral neuropathy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Moffitt Cancer Center	Tampa	Florida	United States	33612
3	Johns Hopkins University School of Medicine (JHUSOM)	Baltimore	Maryland	United States	21231
4	Tufts Medical Center	Boston	Massachusetts	United States	02111
5	Boston University Medical Center	Boston	Massachusetts	United States	02118
6	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
7	Washington Univ School of Meds - Div of Oncology	Saint Louis	Missouri	United States	63110
8	Roswell Park Comprehensive Cancer Center	Buffalo	New York	United States	14203
9	University Hospital of Cleveland	Cleveland	Ohio	United States	44106
10	The Ohio State University	Columbus	Ohio	United States	43210
11	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107-4215
12	West Penn Hospital	Pittsburgh	Pennsylvania	United States	15224
13	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
14	University of Washington	Seattle	Washington	United States	90805
15	Medical College Of Wisconsin	Milwaukee	Wisconsin	United States	53226
16	Tom Baker Cancer Center	Calgary	Alberta	Canada	T2N 4N2
17	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
18	London Health Sciences Center	London	Ontario	Canada	N6A 5W9
19	University Health Network (UHN) Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
20	Peking University First Hospital	Beijing		China	100034
21	Peking University People's Hospital	Beijing		China	100044
22	West China Hospital, Si Chuan University	Chengdu		China	610041
23	First affiliated Hospital of Zhejiang University	Hangzhou		China	310020
24	Ruijin Hospital, Shanghai Jiao Tong University	Shanghai		China	200025
25	CHU de Limoges	Limoges Cedex		France	87042
26	Centre hospitalier Lyon-Sud	Pierre Benite cedex		France	69495
27	CHU De Poitiers	Poitiers		France	86000
28	CHU Rangueil	Toulouse		France	31400
29	Charite Campus Benjamin Franklin	Berlin		Germany	12203
30	Universitatsklinikum Essen	Essen		Germany	45122
31	Universitaetsklinikum Heidelberg Medizinische Klinik V	Heidelberg		Germany	69120
32	Alexandra General Hospital of Athens	Athens		Greece	11528
33	Università Degli Studi Di Napoli Federico Ii	Napoli		Italy	80131
34	Fondazione IRCCS Policlinico San Matteo	Pavia		Italy	27100
35	DIPARTIMENTO DI BIOTECNOLOGIE CELLULARI ED EMATOLOGIA - UNIVERSITà ''LA SAPIENZA''	Roma		Italy	00161
36	A.O.Citta della Salute e della Scienza di Torino	Torino		Italy	10126
37	University Medical Center Groningen	Groningen		Netherlands	9713 GZ
38	Hospital Maastricht University Medical Center	Maastricht		Netherlands	6229 HX
39	UMC Utrecht	Utrecht		Netherlands	3584 CX
40	Hosp. Univ. Germans Trias I Pujol	Badalona		Spain	08916
41	Hosp. Univ. Vall D Hebron	Barcelona		Spain	08035
42	Hosp. Clinic I Provincial de Barcelona	Barcelona		Spain	08036
43	Clinica Univ. de Navarra	Madrid		Spain	28027
44	Clinica Univ. de Navarra	Pamplona		Spain	31008
45	Hosp. Clinico Univ. de Salamanca	Salamanca		Spain	37007
46	Leicester Royal Infirmary - Haematology	Leicester		United Kingdom	LE1 5WW
47	University College Hospital	London		United Kingdom	NW1 2PG

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT05250973
• Other Study ID Numbers: CR109160; 2021-002639-48; 54767414AMY2009
• First Posted: Feb 22, 2022
• Last Update Posted: Aug 9, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Amyloidosis; Dexamethasone; Cyclophosphamide; Bortezomib; Daratumumab

Study Results

No Results Posted as of Aug 9, 2022