A Phase 2, Multicohort Study of Daratumumab-Based Therapies in Participants with Amyloid Light Chain (AL) Amyloidosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Janssen - Cilag International

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

29 Apr 2022 → ongoing

Decision date (initial)

2023-11-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Janssen Research & Development, LLC

External identifiers

EU CT number

2023-507069-25-00

EudraCT number

2021-002639-48

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

1. To characterize cardiac safety of different D-VCd treatment regimens in newly diagnosed systemic AL amyloidosis with cardiac involvement
2. To identify potential mitigation strategies for cardiac toxicity
3. To characterize the PK of SC daratumumab, among racial and ethnic minorities with newly diagnosed systemic AL amyloidosis treated with D-VCd

Secondary objectives 5

1. to evaluate efficacy measures
2. to assess the safety profile, including cardiac events
3. to characterize the PK of SC daratumumab
4. to assess the immunogenicity of SC daratumumab
5. to monitor the clinical signs and symptoms of cardiac AL amyloidosis to identify possible predictive factors for cardiac events

Conditions and MedDRA coding

Amyloid Light Chain Amyloidosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. ≥18 years of age
2. A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for a period of least 1 year after the last dose of cyclophosphamide or 100 days after discontinuation of daratumumab, whichever is longer.
3. 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.
4. Signed an informed consent form (ICF).
5. Cohort 2 only: self-identified racial and ethnic minorities, including Black or African American.
6. New diagnosis of systemic AL amyloidosis based on both: (a) tissue deposition of amyloid in any organ other than bone marrow and (b) an underlying clonal plasma cell disorder as demonstrated by any one of the following: • Clonal plasma cells in the bone marrow • Monoclonal gammopathy in the serum or urine • Abnormal free light chain ratio. Measurable disease at screening defined by one of the following: • difference between iFLC and uninvolved FLC (dFLC) ≥40mg/L per central laboratory • serum involved free light chain (iFLC) ≥40 mg/L with an abnormal kappa:lambda ratio • serum M-protein ≥0.5 g/dL.
7. Cohort 1: Cardiac involvement (AL amyloidosis Mayo Cardiac Stage II and Stage IIIa; see Appendix 6) with or without other organ(s) involved Cohort 2: One or more organs impacted by systemic AL amyloidosis according to consensus guidelines
8. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2
9. Pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase: • Hemoglobin ≥8.0 g/dL (≥5 mmol/L); red blood cell transfusion allowed until 7 days before randomization/enrollment • Platelets ≥50×10^9/L; platelet transfusions are allowed until 7 days before randomization/enrollment • Absolute Neutrophil count ≥1.0×10^9/L • Aspartate aminotransferase and alanine aminotransferase ≤2.5× ULN • Total bilirubin ≤1.5 × ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤2×ULN is required) • Estimated glomerular filtration rate ≥20 mL/min/1.73 m^2
10. 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
11. A female participant must be either of the following: a. Not of childbearing potential b. Of childbearing potential and practicing true abstinence or have a sole partner who is vasectomized or practicing at least 1 highly effective user independent method of contraception. Contraception must begin 4 weeks prior to dosing and continue for 1 year after discontinuation of cyclophosphamide or 100 days after discontinuation of daratumumab, whichever is longer.
12. A male participant must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after discontinuation of cyclophosphamide or 100 days after discontinuation of daratumumab, whichever is longer. His female partner, if of childbearing potential, must also be practicing a highly effective method of contraception. If the male participant is vasectomized, he still must wear a condom (with or without spermicidal foam/gel/film/cream/suppository), but his female partner is not required to use contraception.

Exclusion criteria 20

1. Prior therapy for systemic 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/enrollment.
2. Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, ≥60% plasma cells in the bone marrow, or hypercalcemia related to myeloma.
3. Participant received any of the following therapies: a. treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less. b. vaccinated with an investigational vaccine (except for COVID-19, live attenuated, or replicating viral vector vaccines < 4 weeks prior to randomization/enrollment.
4. 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.
5. Grade 2 sensory or Grade 1 painful peripheral neuropathy.
6. Evidence of significant cardiovascular conditions (as specified in protocol)
7. Participant has an active malignancy (ie, progressing or requiring treatment change in the last 12 months) other than the disease being treated under study.
8. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any component of study treatment or its excipients, including bortezomib, boron, mannitol, or cyclophosphamide or any of its metabolites
9. Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, hyaluronidase, human proteins, or their excipients, or known sensitivity to mammalian-derived products
10. Pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 1 year after discontinuation of cyclophosphamide or 100 days after the last dose of daratumumab, whichever is longer
11. Plans to father a child while enrolled in this study or within 6 months after discontinuation of cyclophosphamide or 100 days after the last dose of daratumumab, whichever is longer.
12. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal
13. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification
14. Participant is known to be positive for human immunodeficiency virus (HIV), with 1 or more of the following: • Not receiving highly active antiretroviral therapy (ART) • Had a change in ART within 6 months of the start of screening • Receiving ART that may interfere with study treatment (consult Sponsor for review of medication prior to enrollment) • CD4 count <350 at screening • Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of start of screening • Not agreeing to start ART and be on ART >4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled)
15. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HbsAg]). (Conditions for resolved infection are specified in protocol)
16. 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).
17. Any serious underlying medical or psychiatric condition or disease, that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study, such as: • Evidence of serious active viral or bacterial infection, requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection. • Active autoimmune disease or a history of autoimmune disease within 2 years. EXCEPTION: Participants with vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing are eligible regardless of when these conditions were diagnosed. • Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status
18. Any other issue that would impair the ability of the participant to receive or tolerate the planned treatment at the study site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments
19. Major surgical procedure within 2 weeks before randomization/enrollment or has not fully recovered from an earlier surgical procedure, or has major surgical procedure planned during the time the participant is expected to participate in the study.
20. Any form of non-AL amyloidosis, including ATTR amyloidosis.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. incidence of any toxicity grade of cardiac events
2. - C[trough]

Secondary endpoints 11

1. Overall HemCR and HemCR rate at 6 months
2. Rate of VGPR or better
3. Time to HemCR (or VGPR or better)
4. Duration of response (HemCR and VGPR or better)
5. Organ response rate (OrRR) at 6 months and 12 months for kidney, heart, liver
6. Overall survival (OS)
7. Time to next treatment (TNT)
8. Incidence and severity of AEs
9. Pharmacokinetic profile of daratumumab
10. Immunogenicity of daratumumab and rHuPH20
11. Clinical signs and symptoms of cardiac AL amyloidosis

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Janssen - Cilag International

Sponsor organisation

Janssen - Cilag International

Address

Turnhoutseweg 30

City

Beerse

Postcode

2340

Country

Belgium

Scientific contact point

Organisation

Janssen - Cilag International

Contact name

CTIS Point of Contact

Public contact point

Organisation

Janssen - Cilag International

Contact name

CTIS Point of Contact

Third parties 13

Locations

6 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 68 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications