| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The main objective of this study is :
To show that subcutaneous (SC) administration of daratumumab co-formulated with recombinant human hyaluronidase PH20 (Dara-SC) is non-inferior to intravenous (IV) administration of daratumumab (Dara-IV) in terms of the overall response rate (ORR)
To show that Dara-SC is non-inferior to Dara-IV in terms of the maximum trough concentration (Ctrough) |
|
| E.2.2 | Secondary objectives of the trial |
To assess the pharmacokinetics and immunogenicity of Dara-SC and Dara-IV
To evaluate the safety of Dara-SC and Dara-IV
To evaluate the clinical benefit of Dara-SC and Dara-IV
To evaluate the immunogenicity of recombinant human hyaluronidase (rHuPH20) following Dara- SC administration
To evaluate patient-reported satisfaction with Dara-SC and Dara-IV |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.At least 18 years of age
2.documented with multiple myeloma as defined by the criteria below:
a)Multiple myeloma diagnosis according to the IMWG diagnostic criteria
b)Measurable disease at Screening as defined by any of the following:
i) Serum M-protein level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
ii) Light chain multiple myeloma without measurable disease in the serum or the urine:
Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
3. Evidence of a response (partial response [PR] or better based on investigator’s determination of response by IMWG criteria) to at least 1 prior treatment regimen.
4. Relapsed or refractory disease as defined below:
a) Relapsed disease is defined as an initial response to previous treatment, followed by confirmed PD by IMWG criteria greater than (>) 60 days after cessation of treatment.
b) Refractory disease is defined as less than (<) 25 percent (%) reduction in M-protein or confirmed PD by IMWG criteria during previous treatment or > 60 days after cessation of treatment.
5. Received at least 3 prior lines of therapy including a PI (≥2 cycles or 2 months of treatment) and an IMiD (≥ 2 cycles or 2 months of treatment) in any order during the course of treatment (except for subjects who discontinued either of these treatments due to a severe allergic reaction within the first 2 cycles/months). A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy
OR
Refractory to both a PI and an IMiD. For subjects who have received more than 1 type of PI, their disease must be refractory to the most recent one. Similarly, for those who have received more than 1 type of IMiD, their disease must be refractory to the most recent one.
6. Eastern cooperative oncology group (ECOG) performance Status score of 0, 1, or 2
7. Subjects who has pretreatment clinical laboratory values meeting the following criteria during the screening phase:
a) Hemoglobin ≥7.5 gram per decilitre (g/dL) (≥ 5 millimoles per litre [mmol/L])(without prior red blood cells [RBC] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted)
b) Absolute neutrophil count >= 1.0 × 10^9/Litre (L)
c) Platelet count >= 50 × 10^9/L (transfusions are not permitted within 7 days of testing to achieve this minimum platelet count)
d) Aspartate aminotransferase (AST) <= 2.5 × upper limit of normal (ULN)
e) Alanine aminotransferase (ALT) <= 2.5 × ULN
f) Total bilirubin <= 2.0 × ULN; except in subjects with congenital bilirubinemia, such as Gilbert syndrome
g) Estimated creatinine clearance > 20 milliletre per minute (mL/min) per 1.73m^2
h) Albumin-corrected serum calcium <=14 mg/dL (<= 3.5 mmol/L) or free ionized calcium <= 6.5 mg/dL (<=1.6 mmol/L).
8. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse 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. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
9. Women of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization.
10. Each subject (or their 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. |
|
| E.4 | Principal exclusion criteria |
1.Subjects who received daratumumab or other anti-CD38 therapies previously
2.Subjects who received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer,before the date of randomization.The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days)before treatment
3.Subjects who received autologous stem cell transplant within 12weeks before the date of randomization,or the subject has previously received allogeneic stem cell transplant (regardless of timing)
4.Subjects who has plans to undergo a stem cell transplant prior to progression of disease on this study
5.History of malignancy (other than multiple myeloma) unless all treatment of that malignancy was completed at least 2 years before consent and the patient has no evidence of disease. Further exceptions are squamous and basal cell carcinomas of the skin and 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.
6.Subjects with clinical signs of meningeal involvement of multiple myeloma
7.Subjects with either of the following:
a)Known chronic obstructive pulmonary disease(COPD)with a forced expiratory volume in 1 second (FEV1) is <50% of predicted normal
b)Known moderate or severe persistent asthma,or a history of asthma within the last 2 years,or currently has uncontrolled asthma of any classification (Subjects who currently have controlled intermittent
asthma or controlled mild persistent asthma are allowed to participate in the study)
8.Subjects with any of the following:
a)Known to be seropositive for human immunodeficiency virus(HIV)
b)Known to be hepatitis B (hepatitis B surface antigen [HBsAg]positive,or antibodies to hepatitis B surface or core antigens [antiHBs or antiHBc]with hepatitis B virus [HBV]-DNA quantitation positive).Subjects who are positive for antiHBs or antiHBc must have a negative polymerase chain reaction (PCR) for HBV-DNA quantitation result at screening. Those who are PCR positive will be excluded
c)Known to be seropositive for hepatitisC
9.Subjects with concurrent medical or psychiatric condition or disease (example,active systemic infection,uncontrolled diabetes,acute diffuse infiltrative pulmonary 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
10.Subjects with clinically significant cardiac disease,including:
a)Myocardial infarction within 6 months before date of randomization,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)or clinically significant electrocardiogram (ECG) abnormalities.
c)Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula >470 msec.
11.Subjects with known allergies,hypersensitivity,or intolerance to any of the study drugs,hyaluronidase,mAbs,human proteins, or their excipients, or known sensitivity to mammalian-derived products.
12.Subjects with plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström's macroglobulinemia or POEMS syndrome or amyloidosis.
13.Subjects with 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 interestof the subject (eg,compromise their well-being)or that could
prevent,limit,or confound the protocol-specified assessments
14.Subjects who are pregnant,breast-feeding,or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug
15.Subjects who has plans to father a child while enrolled in this study or within 3 months after the last dose of study drug
16.Subjects who received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the planned first dose of study drug(except for investigational anti-myeloma treatments,which cannot be taken within 2 weeks before Cycle 1 Day 1)
17.Subjects with major surgery within 2 weeks before randomization,or has not fully recovered from an earlier surgery, or has major surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration. Kyphoplasty or vertebroplasty are not considered major surgery
18.Subjects with plasmapheresis within 28 days before randomization |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The co-primary endpoints of this study are:
ORR, defined as the proportion of subjects with a PR or better according to the International Myeloma Working Group (IMWG) response criteria
Maximum Ctrough, defined as the serum predose concentration of daratumumab on Cycle 3 Day 1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. 6 months after 480 subjects have been randomized.
2. Cycle 3 Day 1 |
|
| E.5.2 | Secondary end point(s) |
1. Rate of infusion-related reaction (IRRs)
2. PFS, defined as the time from randomization to the date of disease progression or death dueto any cause, whichever occurs first
3. Rate of VGPR or better, according to the IMWG response criteria
4. Rate of CR or better, according to the IMWG response criteria
5. Time to next therapy (TNT), defined as the time from randomization to the start of the first subsequent anti-cancer therapy
6. Overall survival (OS), defined as the time from randomization to the date of death
7. Patient-reported satisfaction with therapy, defined as the mean of responses to 7 of 9 questions in the modified Cancer Therapy Satisfaction Questionnaire (modified-CTSQ)
8. Duration of response, defined as date of onset of first response until date of disease progression or death
9. Time to response, defined as the time from randomization until onset of first response |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| There is no interim analysis planned for the primary or secondary endpoints. Both sets of endpoints will be analyzed 6 months after the last subject has been randomized. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 71 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| China |
| Czech Republic |
| France |
| Greece |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will be considered complete when all subjects still receiving study drug have commercial or alternative access to the appropriate formulation of daratumumab, have stopped receiving daratumumab treatment, or at approximately 5 years after the last subject was randomized, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
