| 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 | 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 |
|
| 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 |
| To evaluate the clinical benefit of subcutaneous (SC) daratumumab administered in combination with standard multiple myeloma (MM) regimens in subjects with MM as measured by overall response rate (ORR) or very good partial response (VGPR) or better rate. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate safety and pharmacokinetics (PK) of SC administration of daratumumab in combination with standard MM regimens
- To evaluate additional clinical benefit of SC daratumumab administered in combination with standard MM regimens in subjects with MM
- To characterize the immunogenicity of daratumumab and rHuPH20 following SC administration
- To evaluate minimal residual disease (MRD) negativity rate in the D-VMP (daratumumab SC in combination with bortezomib, melphalan, and prednisone), D-Kd (daratumumab SC in combination with carfilzomib and dexamethasone), and D-Rd (daratumumab SC in combination with lenalidomide and dexamethasone) cohorts. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.>18 years of age (or the legal age of consent if it is higher than 18 years of age in the jurisdiction in which the study is taking place)
2.MM diagnosed according to the IMWG diagnostic criteria
3.Measurable,secretory disease as defined by any of the following:
-Serum M-protein level ≥1.0 g/dL;or
-Urine M-protein level ≥200 mg/24 hours; or
-Light chain MM, for subjects without measurable disease in the serum or urine: serum Ig free light chain (FLC) ≥10 mg/dL and abnormal FLC ratio
4.a.For inclusion into the D-VRd cohort for newly diagnosed disease: - Newly diagnosed MM by IMWG criteria and eligible/planned for high dose therapy and ASCT
4.b.For inclusion into the D-VMP cohort: - Newly diagnosed and previously untreated MM by IMWG criteria and not considered a candidate for high-dose chemotherapy with ASCT due to:Being age ≥65years, or in subjects <65 years: presence of important comorbid condition(s) will make stem cell transplant intolerable for the subject
4.c.For inclusion into the D-Rd cohort for relapsed or refractory disease: •Subject must have received at least 1 prior line of therapy for MM•Subjects must have progressed from or be refractory to their last line of treatment•Subject must have achieved a response (PR or better based on investigator’s evaluation of response by the IMWG criteria) to at least 1 prior treatment regimen
4.d. For inclusion in the D-Kd cohort for relapsed or refractory disease:
-Subject must have received only 1 prior line of therapy for MM which included at least 2 consecutive cycles of lenalidomide therapy
-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 4days)would not be considered prior lines of therapy.
-Subject must have achieved a response (PR or better based on investigator’s evaluation of response by the IMWG criteria) to the first treatment regimen
-Subject must have progressed from or be refractory to the first line of treatment. •Relapsed disease is defined as progression of disease after an initial response to previous treatment, more than 60 days after cessation of treatment •Refractory disease is defined as confirmed PD by IMWG criteria during previous treatment or ≤60 days after cessation of treatment
5.ECOG Performance Status grade of 0,1,or2
6.Pre-treatment clinical laboratory values during the Screening Phase(all cohorts):
a.hemoglobin ≥7.5g/dL (≥4.65mmol/L); D-Kd cohort 8.0 g/dL (without prior RBC transfusion within 7days before the laboratory test;recombinant human erythropoietin use is permitted)
b.absolute neutrophil count ≥1.0×109/L (prior growth factor support is permitted)
c. platelet count for D-Rd,D-Kd and D-VRd cohorts: >75×109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells;otherwise platelet count >50×109/L (transfusions are not permitted within 7days of testing to achieve this minimum platelet count);for the D-VMP cohort:platelet count ≥70x109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells;otherwise platelet count >50×109/L (transfusions are not permitted within 7 days of testing to achieve this minimum platelet count
d.aspartate aminotransferase ≤2.5×ULN
e.alanine aminotransferase ≤2.5×ULN
f.For the D-Rd cohort: total bilirubin ≤2.0×ULN; except in subjects with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤2.0×ULN is required); for the, D-Kd, D-VMP, and D-VRd cohorts: total bilirubin ≤1.5×ULN; except in subjects with congenital bilirubinemia,such as Gilbert syndrome (in which case direct bilirubin ≤1.5 × ULN is required);
g. estimated creatinine clearance ≥40 mL/min(D-VMP cohort) or ≥30 mL/min (for D-VRd and D-Rd cohorts);or ≥20mL/min (D-Kd cohort)
h.corrected serum calcium ≤13.5 mg/dL(≤3.4 mmol/L)or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L)
7.1 D-VRd and D-Rd cohorts: A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at screening, the first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing
D-VMP and D-Kd cohorts: A woman of childbearing potential must have a negative serum or urine pregnancy test at screening within 14 days prior to dosing
8.Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse, or to use one highly effective form of contraception and one additional effective contraceptive.Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment
For an overview of all inclusion criteria please see Protocol |
|
| E.4 | Principal exclusion criteria |
1.Prior or concurrent exposure to any of the following:
-Daratumumab or other anti-CD38 therapies
-Approved or investigational treatments for MM within 2 weeks of Cycle 1 Day 1
-Maximum of 40 mg dexamethasone daily for a maximum of 4 days up to 21 days prior to the 1st dose
-Investigational drug or an invasive investigational medical device within 4 weeks or 5 half-lives before Cycle 1 Day 1, or is currently enrolled in another investigational study
-ASCT within 12 weeks before the date of administration of study treatment, or allogeneic stem cell transplant (regardless of timing) for the D-Rd and D-Kd cohorts
-For D-Rd cohort, only: Refractory to lenalidomide, or who are intolerant to lenalidomide while on lenalidomide treatment are not eligible for the lenalidomide-containing cohorts
-For D-Kd cohort, only: Subject has previously received carfilzomib
2.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.
3.Exhibits clinical signs of meningeal involvement of MM.
4.Either of the following:
-Chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) is <50% of predicted normal.
-Moderate or severe persistent asthma, or a history of asthma within the last 2 years, or currently has uncontrolled asthma of any classification
For D-Kd cohort: Known infiltrative pulmonary disease or known pulmonary hypertension.
5.Any of the following:
-Known to be seropositive for human immunodeficiency virus;
-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
6.Known to be seropositive for hepatitis C (anti-HCV antibody positive or HCV-RNA quantitation positive), except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
7.Concurrent medical or psychiatric condition or disease 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:
-myocardial infarction within 6 months before Cycle 1 Day 1, or an unstable or uncontrolled disease/condition related to or affecting cardiac;
-uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities; or screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTc) >470 msec.
For D-Kd cohort only:
-Transthoracic echocardiogram showing left ventricular ejection fraction (LVEF) <40%
-Uncontrolled hypertension, defined as an average systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment
9. Allergies,hypersensitivity, or intolerance to any of the study drugs,hylauronidase, monoclonal antibodies,human proteins, or their excipients or known sensitivity to mammalian-derived products.
For D-Kd cohort only: allergy, hypersensitivity, or intolerance to Captisol
10.Plasma cell leukemia, Waldenström’s macroglobulinemia, POEMS syndrome, or amyloidosis
11.Unable to comply with the study 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 or that could prevent, limit, or confound the protocol specified assessments
12.Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug
13.Plans to father a child while enrolled in this study or within 3 months after the last dose of study drug
14.Major surgery within 2 weeks before administration of study treatment, or has 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 study drug administration
15.Plasmapheresis within 28 days before Cycle 1 Day 1
16.For D-VRd and D-VMP cohorts: Received a strong CYP3A4 inducer within 5 half-lives prior to randomization.For D-VMP arm: neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI CTCAE Version 4.03.
17.For D-VMP cohort: Neuropathy or neuropathic pain Grade 2 or higher, as defined by NCI CTCAE Version 4.03.
For D-Kd cohort: Neuropathy or neuropathic pain Grade 3 or higher, as defined by NCI CTCAE Version 4.03
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Overall Response Rate (ORR), defined as the proportion of subjects with a partial response or better as defined by the International Myeloma Working Group (IMWG) response criteria (for D-VMP, D-Kd and D-Rd cohorts)
2. Very Good Partial Response (VGPR) or better rate, defined as the proportion of subjects with a VGPR or better rate as defined by the IMWG response criteria (for D-VRd cohort) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. At the end of each treatment cycle in D-VMP, D-Kd and D-Rd cohorts
2. At the end of each treatment cycle in D-VRd cohort |
|
| E.5.2 | Secondary end point(s) |
1. Serum concentrations of daratumumab
2. Rate of Infusion-related Reaction (IRRs)
3. VGPR or better rate as defined by the IMWG response criteria (for D-Kd, D-VMP and D-Rd cohort), and ORR as defined by the IMWG response criteria (for D-VRd cohort)
4. Complete Response (CR) or better rate, as defined by the IMWG response criteria
5. Duration of response (DOR), defined as the time from the date of initial documented response (PR or better for D-Kd, D-VMP and D-Rd cohorts, or VGPR or better for D-VRd cohort) to the date of first documented evidence of progressive disease or death due to progressive disease (PD)
6. Incidence of anti-drug antibodies against daratumumab or rHuPH20
7. Minimal residual disease (MRD) negativity rate in the D-Kd, D-VMP and D-Rd cohorts |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Predose on Day(D)1 of Cycle(C)1,C3,C4,postdose on D4 ofC1,C4(D-VRd cohort)Predose on D1 ofC1,C2,C3,C6,C9,postdose on D4 ofC1,C2(D-VMP)Predose on D1 ofC1,C3,C6,C9,C12,postdose on D4 ofC1,C3(D-Rd) &post-treatment visit at 30 Days (EOT)&at 8wks (FUP)after last dose of study drug in all cohorts
2.Throughout study at the time of daratumumab administration in all cohorts
3&4.At screening &when CR is suspected or maintained throughout treatment phase&30-days post-treatment
5.At the date of first documented evidence of progressive disease(PD) or death due to PD
6.Predose on D1 ofC1,C4(D-VRd)Predose on D1 ofC1,C3,C6,C9(D-VMP)Predose on D1 ofC1,C3,C6,C9,C12(D-Rd)&EOT&FUP
7.At screening, at the time of suspected CR,&in patients who maintain CR, at 12,18,24months(M)&every 12M thereafter |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| Brazil |
| Czech Republic |
| France |
| Germany |
| Israel |
| Japan |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 18 months after the last subject is enrolled or when the sponsor decides to stop the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
Print
