E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Smoldering multiple myeloma |
|
E.1.1.1 | Medical condition in easily understood language |
Precancerous form of blood cancer in the bone marrow |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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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 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). |
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E.2.2 | Secondary objectives of the trial |
-To demonstrate additional clinical benefit (ORR, duration of response, OS, etc) for subjects
with high-risk SMM treated with daratumumab compared with active monitoring
- To assess the safety profile of daratumumab in subjects with high-risk SMM
- To assess the clinical characteristics of symptomatic MM following progression of disease
after therapy with daratumumab
- To evaluate the PK and immunogenicity of daratumumab administered SC in subjects with
high-risk SMM
- To evaluate the immunogenicity of rHuPH20 when administered in combination with
daratumumab SC in subjects with high-risk SMM
- To evaluate the effect of treatment with daratumumab on health-related quality of life
(HRQoL) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Refer to protocol
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
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. 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. 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. Eastern cooperative oncology group (ECOG) performance status score of 0 or 1.
5. Pretreatment clinical laboratory values: refer to protocol
6. Must sign an informed consent form (ICF) or their legally acceptable 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. 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. A woman of childbearing potential must have a negative serum or urine pregnancy test at screening within 14 days prior to randomization.
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. Willing and able to adhere to the prohibitions and restrictions specified in the protocol. |
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E.4 | Principal exclusion criteria |
Refer to protocol
Any potential subject who meets any of the following criteria will be excluded from participating in the study:
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. Primary systemic (immunoglobulin light chain) amyloidosis (AL)
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. 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. 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. Any of the following:
a. Known to be seropositive for human immunodeficiency virus (HIV)
b. Known to be seropositive for hepatitis B (defined by a positive test for hepatitis B surface and antigen [HBsAg]) or with known prior hepatitis B infection without evidence of immunity (ie, subjects who are positive for antibodies to hepatitis B core antigen [anti-HBc] but negative for antibodies to hepatitis B surface antigen [anti-Hbs])
c. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at lease 12 weeks after completion of antiviral therapy)
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. 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. Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products
10. Vaccination with live attenuated vaccines within 4 weeks of first study agent administration
11. Pregnant, breast-feeding, or planning to become pregnant while receiving study treatment or within 3 months after the last dose of daratumumab |
|
E.5 End points |
E.5.1 | Primary end point(s) |
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 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 12 weeks until progressive disease |
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E.5.2 | Secondary end point(s) |
1. Time to biochemical or diagnostic (SLiM-CRAB) progression defined as the earlier of time to the earlier of biochemical progression or diagnostic (SLiM-CRAB) progression
2. Overall response rate (ORR), defined as, the proportion of subjects with a PR or better as defined by the IMWG response criteria
3. Complete response (CR) rate, defined as, the proportion of subjects with a CR (or better) as defined by the IMWG response criteria
4. Time to first-line treatment for MM, defined as, the time from the date of randomization to the date of the first-line treatment for MM
5. Progression-free survival on first-line treatment for MM (PFS2), defined as, the time from the date of randomization to the date of documented progressive disease (PD) on the first-line treatment for MM or death, whichever comes first
6. Overall survival (OS), defined as, the time from the date of randomization to the date of death
7. Incidence of MM with adverse prognostic features, which include International Staging System Stage III (based on β2-microglobulin and albumin) and adverse cytogenetic characteristics
8. Serum daratumumab PK concentrations and parameters including minimum observed concentration (Cmin) and maximum observed concentration (Cmax)
9. Incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies
10. Change from baseline in global health status and emotional functioning scales of the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30, future perspective scale of the EORTC QLQ-MY20, and utility and visual analog scale of the European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L)
11. Duration of response, defined as date of onset of first response until date of disease progression or death
12. Time to response, defined as the time from randomization until onset of first response
Exploratory end point:
13. Identification of novel biomarkers in relation to PFS/OS |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,2,3, 11 and 12. Every 12 weeks until progressive disease
4&5. Every 6 months after PD duration until end of study
6. Throughout study, and at least every 12 weeks until PD
7. During screening and at the time of PD
8. Pre dose on Cycle 1 Day 1, C3D1, C5D1, C7D1, C12D1, C24D1, and post dose C1D4, C3D4, and 28 (±3) days and 8 weeks after the last Daratumumab dose
9. Pre dose on C1D1, C3D1, C5D1, C7D1, C12D1, C24D1, and 28 (±3) days and 8 weeks after the last Daratumumab dose
10. C1D1, Week 12, 24, 60, then every year until the end of the the study or PD and then at Months 3, 6, 12, and 18 during post-PD follow-up
13. At screening, 24, 48, and 96 weeks post randomization, end of treatment and during progressive disease |
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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 | Yes |
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 |
Immunogenicity and Biomarker analyses |
|
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
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 | 68 |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Canada |
China |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Japan |
Mexico |
Netherlands |
Norway |
Poland |
Russian Federation |
Spain |
Sweden |
Turkey |
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 is considered completed approximately 8 years after the first subject is randomized. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |