A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared with CyBorD Alone in Newly Diagnosed Systemic 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] - Neoplasms [C04]

Trial duration

21 Nov 2016 → 19 Nov 2024

Decision date (initial)

2024-06-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-511967-26-00

EudraCT number

2016-001737-27

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Pharmacokinetic, Efficacy, Safety, Therapy, Pharmacodynamic

The primary objective is to evaluate the efficacy of daratumumab plus CyBorD compared with CyBorD alone in the treatment of newly diagnosed AL amyloidosis patients.

Conditions and MedDRA coding

AL Amyloidosis (Newly Diagnosed Systemic AL Amyloidosis)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparecy. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1) 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) or older.
2. 2) Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry (IHC) and polarizing light microscopy of green birefringent material in congo red-stained tissue specimens (in an organ other than bone marrow) or characteristic electron microscopy appearance. Considerations for specific populations where other types of amyloidosis may be encountered: - For male subjects 70 years of age or older who have cardiac involvement only, and subjects of African descent (black subjects), mass spectrometry typing of AL amyloid in a tissue biopsy is recommended to rule out other types of amyloidosis such as age-related amyloidosis or hereditary amyloidosis (ATTR mutation)
3. 3) Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following: -serum M-protein ≥0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation (IFE) performed at a central laboratory), -serum free light chain ≥50 mg/L with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥50 mg/L.
4. 4) One or more organs impacted by AL amyloidosis according to consensus guidelines
5. 5) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2
6. 6) Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase: a. Absolute neutrophil count ≥1.0 ×1000000000 /L; b. Hemoglobin level ≥8.0 g/dL (≥5 mmol/L); red blood cell transfusion allowed until 7 days before randomization c. Platelet count ≥50 × 1000000000/L; Platelet transfusions are acceptable without restriction during the Screening period d. Alanine aminotransferase level (ALT) ≤2.5 times the ULN e. Aspartate aminotransferase (AST) ≤2.5 times the ULN f. Total bilirubin level ≤1.5 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin ≤2 × ULN g. Estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73m2. Please note the eGFR is measured by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
7. 7) Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing and continue for 1 year after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
8. 8)During the study and for 1 year after stopping cyclophosphamide or 3 months after receiving the last dose of daratumumab, whichever is longer, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
9. 9) A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control; eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. All men must also not donate sperm during the study and for 6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.
10. 10) A woman of childbearing potential must have a negative serum or urine pregnancy test (serum preferred) result within 14 days prior to randomization.
11. 11) Each subject, or legally acceptable representative, must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.

Exclusion criteria 19

1. 1.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
2. 7. Moderate or severe persistent asthma within the past 2 years,or currently has uncontrolled asthma of any classification.(Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
3. 8.Know to be seropositive for human immunodeficiency virus (HIV)
4. 9. Any of the following: a. seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using realtime polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. b. 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).
5. 13.Any form of non-AL amyloidosis,including wild type or mutated (ATTR)amyloidosis.
6. 14.Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, hyaluronidase, human proteins, or their excipients (refer to IB), or known sensitivity to mammalian-derived products.
7. 10.Grade 2 sensory or Grade 1 painful peripheral neuropathy.
8. 11.Known hypersensitivity or contraindication to any of the study drugs including bortezomib, boron, mannitol, or cyclophosphamide or any of its metabolites.
9. 12. Concurrent medical condition or disease (eg, active systemic infection) 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.
10. 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
11. 3.Evidence of significant cardiovascular conditions as specified below: a.NT-ProBNP >8500 ng/L b.New York Heart Association (NYHA) classification IIIB or IV heart failure c.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 ECG changes)or uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy d.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 e.For subjects with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to randomization f.Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/ICD is indicated but not placed (Subjects who do have a pacemaker/ICD are allowed on study) g.Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >500 msec.Subjects who have a pacemaker may be included regardless of calculated QTc interval h.Supine systolic blood pressure <90 mm Hg, 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
12. 4. 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
13. 5.History of malignancy (other than AL amyloidosis)within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin,carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years)
14. 6.Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal.Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal
15. 15. Known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
16. 16. Woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 1 year after discontinuation of cyclophosphamide or 3 months following discontinuation of daratumumab, whichever is longer.
17. 17. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before Cycle 1 Day 1.
18. 18. Major surgery within 2 weeks before Cycle 1 Day 1, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study treatment administration. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate.
19. 19. Subjects who are taking strong CYP3A4 inducers must discontinue their use at least 5 half-lives prior to the first dose of study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is overall complete hematologic response (CHR) rate.

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 6

Locations

11 EU/EEA countries · 36 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 12 files

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

Application history

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