A clinical study to compare the safety, effectiveness and pharmacokinetics (the way the body absorbs, distributes, and gets rid of a drug) of Daratumumab given through the subcutaneous route versus the active monitoring in patients with high risk smoldering multiple myeloma (precancerous form of blood cancer in the bone marrow)

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

8 Nov 2017 → 5 May 2026

Decision date (initial)

2023-11-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-507143-11-00

EudraCT number

2016-001205-16

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

To determine whether treatment with daratumumab administered subcutaneously (SC) prolongs progression free survival (PFS) compared with active monitoring in subjects with high-risk smoldering multiple myeloma (SMM).

Conditions and MedDRA coding

Precancerous form of blood cancer in the bone marrow

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. At least 18 years of age or at least the legal age of consent in the jurisdiction in which the study is taking place, whichever is the older age.
2. 2. Diagnosis of SMM for ≤5 years with measurable disease, defined as serum M protein ≥10 grams per litre (g/L) or urine M protein ≥200 milligrams (mg)/24 hours or involved serum free light chain (FLC) ≥100 milligrams per litre (mg/L) and abnormal serum FLC ratio.
3. 3. Bone marrow plasma cells (BMPCs) ≥10%; and At least 1 of the following; a. Serum M protein ≥30 g/L, b. Immunoglobulin A (IgA) SMM, c. Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes, d. Serum involved: uninvolved FLC ratio ≥8 and < 100, or e. Clonal BMPCs >50% to <60% with measurable disease.
4. 4. Eastern cooperative oncology group (ECOG) performance status score of 0 or 1.
5. 5. Pretreatment clinical laboratory values: refer to protocol
6. 6. Must sign an informed consent form (ICF) or their legally designated representative must sign indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
7. 7. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 1 method highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants], or partner's vasectomy). Contraception must begin 4 weeks prior to dosing. Highly effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
8. 8. A woman of childbearing potential must have a negative serum or urine pregnancy test at screening within 14 days prior to randomization.
9. 9. During the study and for 3 months after receiving the last dose of daratumumab, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
10. 10. Willing and able to adhere to the prohibitions and restrictions specified in the protocol.

Exclusion criteria 14

1. 1. Multiple myeloma, requiring treatment, defined by any of the following: a. Bone lesions (one or more osteolytic lesions on low-dose whole body computed tomography [LDCT], positron-emission tomography with computed tomography [PET-CT] or computed tomography [CT]) b. Hypercalcemia (serum calcium >0.25 mmol/L [>1 mg/dL] higher than ULN or >2.75 mmol/L [>11 mg/dL]) c. Renal insufficiency, preferably determined by creatinine clearance <40 mL/min measured or estimated using the modification of diet in renal disease (MDRD), or serum creatinine >177 micro mole per litre (μmol/L) d. Anemia, defined as hemoglobin <10 gram per deci litre (g/dL) or >2 g/dL below lower limit of normal or both; transfusion support or concurrent treatment with erythropoietin stimulating agents is not permitted e. Clonal BMPC percentage ≥60% f. Serum FLC ratio (involved:uninvolved) ≥100 (The involved FLC must be ≥100 mg/L) g. More than 1 focal lesion ≥5 mm in diameter by magnetic resonance imaging (MRI)
2. 2. Primary systemic (immunoglobulin light chain) amyloidosis (AL)
3. 3. Exposure to any of the following a. Prior exposure to daratumumab or prior exposure to other anti-CD38 therapies b. Prior exposure to approved or investigational treatments for SMM or MM (including but not limited to conventional chemotherapies, immunomodulatory agent [IMiDs], or proteasome inhibitor [PIs]). Stable standard dosing of bisphosphonate as indicated for osteoporosis is acceptable. c. Exposure to investigational drug (including investigational vaccines) or invasive investigational medical device for any indication within 4 weeks or 5 half-lives, whichever is longer, before Cycle 1, Day 1 d. Ongoing treatment with corticosteroids with a dose >10 mg prednisone or equivalent per day at the time of randomization; or >280 mg cumulative prednisone dose or equivalent for any 4-week period in the year prior to randomization
4. 4. Received treatment for a malignancy (other than SMM) 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, which is considered cured with minimal risk of recurrence within 3 years.
5. 5. Either of the following: a. Known or suspected chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal b. 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)
6. 6. Any of the following: a. Known to be seropositive for human immunodeficiency virus (HIV) b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Local testing and results of hepatitis B serology (Includes HBsAg, anti-HBs, and anti-HBc) is required for all patients prior to randomization when this amendment 3 is implemented. 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 real-time 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 c. 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)
7. 7. Medical or psychiatric condition or disease (eg, active systemic disease, uncontrolled diabetes) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study
8. 8. Clinically significant cardiac disease, including: a. Myocardial infarction within 6 months with left ventricular dysfunction or uncontrolled ischemic cardiac disease before Cycle 1 Day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV) b. Uncontrolled cardiac arrhythmia (Grade 2 or higher by National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version 4.03) or clinically significant electrocardiogram (ECG) abnormalities c. Screening 12-lead ECG showing a baseline QT interval as corrected QT interval corrected for heart rate >470 msec The LDCT/PET-CT/CT performed for screening should be taken into consideration to determine if additional cardiac workup is required
9. 9. Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies, hyaluronidase, or other human proteins, or their excipients (refer to Daratumumab Investigator Brochure11), or known sensitivity to mammalian-derived products (including dairy allergy).
10. 10. Vaccination with live attenuated vaccines within 4 weeks of first study agent administration
11. 11. Pregnant, breast-feeding, or planning to become pregnant while receiving study treatment or within 3 months after the last dose of daratumumab
12. 12. Plans to father a child while receiving study treatment or within 3 months after the last dose of daratumumab
13. 13. Major surgery (requiring general anesthesia or presence of other factors that determines surgery to be considered major) within 2 weeks before randomization or who have not 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 daratumumab. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate. If there is a question whether a procedure is considered a major surgery, then the investigator must consult with the appropriate sponsor representative and resolve any issues before enrolling a subject in the study.
14. 14. Known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). 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 the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Subject is taking any prohibited medications

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS), defined as the time from the date of randomization to the date of initial documented progression to MM according to the international myeloma working group (IMWG) diagnostic criteria for MM or the date of death, whichever occurs first

Investigational products

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

Test 1

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 8

Locations

13 EU/EEA countries · 44 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 100 files

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

Application history

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