| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 |
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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 |
Part 1
• To assess DLTs of EDR to select an RP3D for the combination to be used in Part 2 of this study.
Part 2
To compare the efficacy of EDR (Arm A) vs DRd (Arm B) as measured by MRD status and PFS
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| E.2.2 | Secondary objectives of the trial |
Part 1
•To evaluate the overall safety profile of EDR to select an RP3D for the combination to be used in Part 2 of this study.
•To evaluate the efficacy of EDR to select an RP3D for the combination to be used in Part 2 of this study.
•To evaluate the PK of elranatamab when used in combination with daratumumab and lenalidomide
•To evaluate the immunogenicity of elranatamab when used in combination with daratumumab and lenalidomide
•To evaluate the PK of daratumumab and lenalidomide when used in combination with elranatamab
Part 2
Key Secondary: To compare the efficacy of EDR (Arm A) vs DRd (Arm B) as measured by OS.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants must meet the following inclusion criteria to be eligible for enrollment into the study. Criteria are for both Part 1 and Part 2 unless otherwise specified:
Age and Sex:
1. Participant’s age ≥18 years (or the minimum country specific age of consent if >18) at Visit 1 (Screening).
• Male participants and female participants of childbearing potential must agree to use methods of contraception as described in Section 5.3.1.
• A female participant is eligible to participate if she is not pregnant or breastfeeding.
• Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Diagnosis of MM as defined according to IMWG criteria (Rajkumar et al, 2014), including measurable disease based on IMWG criteria as defined by at least 1 of the following (as assessed by the central laboratory for Part 2):
o Serum M-protein ≥0.5 g/dL;
o Urinary M-protein excretion ≥200 mg/24 hours;
o Involved FLC ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65).
3. Part 1 only: Participant with NDMM or RRMM. NDMM participant must be transplant-ineligible as defined by age ≥65 years or transplant-ineligible as defined by age <65 years with comorbidities impacting the possibility of transplant. Participants with RRMM must have received 1-2 prior lines of MM therapy including at least one IMiD and one PI (See Appendix 17 of the protocol).
Part 2 only: Participant has NDMM and is transplant-ineligible as defined by age ≥65 years or is transplant-ineligible as defined by age <65 years with comorbidities impacting the possibility of transplant.
4. ECOG performance status ≤2.
5. BM function characterized by the following:
a. ANC ≥1.0 × 109/L (use of G-CSFs is permitted if completed at least 7 days prior to planned start of dosing);
b. Platelet count ≥75,000/µL if <50% of BM nucleated cells are plasma cells, or ≥50,000/µL if ≥50% of BM nucleated cells are plasma cells (transfusion support is permitted if completed at least 7 days prior to planned start of dosing); and
c. Hemoglobin ≥8 g/dL (transfusion support is permitted if completed at least 14 days prior to planned start of dosing).
NOTE: Hematologic parameters are also to be met on Day 1 prior to proceeding with
study treatment administration.
6. Corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L).
7. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1.
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| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Smoldering MM or MGUS or Waldenströms Macroglobulinemia or Plasma cell leukemia defined as ≥20 % circulating plasma cells in the peripheral blood with an absolute plasma cell count of more than 2x10 9/L or Systemic light chain amyloidosis, or POEMS Syndrome.
2. Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as any of the following within 6 months prior to enrollment:
a. Acute myocardial infarction or acute coronary syndromes (eg, unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, symptomatic pericardial effusion);
b. Clinically significant cardiac arrhythmias (eg, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
c. Thromboembolic or cerebrovascular events (eg, transient ischemic attack, cerebrovascular accident, deep vein thrombosis [unless associated with a central venous access complication] or pulmonary embolism);
d. Prolonged QT syndrome (or QTcF >470 msec at screening).
e. LVEF <40% as determined by a MUGA scan or ECHO.
3. Ongoing Grade 3 or higher peripheral sensory or motor neuropathy, history of GBS or GBS variants, or history of any Grade >3 peripheral motor polyneuropathy.
4. Participants with active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) COVID-19/SARS-CoV-2, HBV, HCV, and known HIV or AIDS-related illness. Active infections must be resolved at least 21 days prior to enrolment.
Participants treated with systemic anti-infective agents within 28 days prior to enrolment are not eligible. Prophylactic use of systemic agents is permitted.
Comments regarding specific circumstances follow:
4.1 COVID-19/SAR-CoV-2: SARS-CoV-2 PCR testing is mandated within 5 days prior to randomization. If a participant has a positive PCR test result for SARS-CoV-2 infection within 5 days prior to randomization, is known to have asymptomatic infection or is suspected of having SARS-CoV-2, they are excluded.
4.2 HIV: In equivocal cases, participants whose viral load is negative may be eligible. HIV seropositive participants who are otherwise healthy and at low risk for AIDS-related outcomes could be considered eligible. Potential eligibility for a specific HIV positive protocol candidate should be evaluated and discussed with the Sponsor prior to any screening, based on current and past CD4 and T-cell counts, history (if any) of AIDS defining conditions (eg, opportunistic infections), and status of HIV treatment. Also, the potential for drug-drug interactions will be taken into consideration.
4.3 HBV/HCV: Relevant laboratory tests should be performed at screening. Refer to CDC website (https://www.cdc.gov/hepatitis/index.htm) for further details.
4.4 HBV:
• This criterion excludes participants with a positive HbsAg (ie, either acute or chronic active hepatitis).
• However, participants with HBV antibody positivity indicating immunity, either due to vaccination or prior natural infection, are eligible.
• Participants with positive anti-HbcAb but negative HbsAg and anti-HbsAb profile are eligible if HBV DNA is not detected.
4.5 HCV: Positive HCV antibody is indicative of infection but may not necessarily render a potential participant ineligible, depending on clinical circumstances. If exposure to HCV is recent, HCV antibody may not have yet turned positive. In this circumstance it is recommended to test HCV RNA. Refer to CDC website for further details (https://www.cdc.gov/hepatitis/hcv/pdfs/hcv_graph.pdf).
4.6 Lung imaging is required within 7 days prior to randomization (See SoA). Participants with radiologic signs consistent with active respiratory infection are excluded.
5. Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ, or Stage 0/1 with minimal risk of recurrence per investigator.
6. Participants with known or suspected hypersensitivity to the study interventions or any of their excipients.
7. Participants with known or suspected CNS or clinical signs of myelomatous meningeal involvement.
8. Other surgical (including major surgery within 14 days prior to enrollment), medical or psychiatric conditions including recent (within the past year) or active suicidal ideation/behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
• Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed (assuming no drug interaction potential).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
DLTs during the DLT observation period:
•For all DLs except DL F: From the first priming dose of elranatamab in the 2 Step-up Priming Dose Period until 28 days (± visit windows) from the first administration of the EDR combination.
•For DL F: 28 days (± visit windows) from the day of the first full dose of elranatamab (76 mg) in combination with D and R.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assessments are to be conducted at the time points specified in the Schedule of Activity (SoA) in Section 1 of the protocol |
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| E.5.2 | Secondary end point(s) |
Part 1
• AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), timing, seriousness, and relationship to study treatment. Severity of CRS and ICANS will be graded according to ASTCT criteria.
• Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), and timing.
• ORR and CRR, per IMWG response criteria as determined by investigator.
• Time to event endpoints: TTR, DOR, DOCR and PFS per IMWG response criteria as determined by investigator, and OS;
• MRD negativity rate (central laboratory) per IMWG sequencing criteria.
• Predose and post dose concentrations of elranatamab
• ADAs and NAbs against elranatamab
• Predose concentrations of daratumumab and lenalidomide
Part 2
Key Secondary: OS
Secondary:
•Overall MRD negativity rate per IMWG
•Duration of MRD negativity per IMWG
•PFS and PFS2 by investigator per IMWG
•ORR, CRR, TTR, DOR, and DOCR by BICR per IMWG
•AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), timing, seriousness, and relationship to study treatment. The severity of CRS and ICANS will be graded according to ASTCT criteria (Lee, 2019).
• Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), and timing.
• Predose and post dose concentrations of elranatamab.
• ADAs and NAbs against elranatamab.
• EORTC QLQ-C30 and MY20
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assessments are to be conducted at the time points specified in the Schedule of Activity (SoA) in Section 1 of the protocol |
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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 | Yes |
| E.6.13 | Others | No |
| 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 | 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) | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
| New Zealand |
| Switzerland |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Korea, Republic of |
| Mexico |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Sweden |
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| 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
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| The end of the study is defined as the date of the last study visit which is triggered by 345 OS events or 73 months of study duration, whichever is earlier. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| 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 | 19 |
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