| 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 |
hematological B-cell malignancy characterized by dysregulated
proliferation of BM plasma cells. |
|
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
PART 1:
To assess DLTs, safety and tolerability of elranatamab + daratumumab in order to select a RP3D for the combination to be used in Part 2 of this study
PART 2:
•To compare the efficacy of elranatamab (Arm A) vs daratumumab + pomalidomide + dexamethasone (Arm C) as measured by PFS
•To compare the efficacy of elranatamab + daratumumab (Arm B) vs. Arm C as measured by PFS
|
|
| E.2.2 | Secondary objectives of the trial |
PART 1
•To assess the rate of Grade ≥2 CRS when elranatamab is administered with a 2 step-up priming regimen along with premedications.
•To evaluate the overall safety profile of elranatamab using a 2 step-up priming doses and in combination with daratumumab.
•To evaluate the efficacy of elranatamab + daratumumab as measured by PFS,ORR,DOR,CRR,DOCR, TTR,OS, and % MRD negative
•To evaluate the PK of elranatamab
•To evaluate the immunogenicity of elranatamab
•To evaluate the PK of daratumumab
PART 2
•To compare the efficacy of Arm A vs Arm C as measured by OS
•To compare the efficacy of Arm B vs Arm C as measured by OS
•To compare the efficacy of Arm A vs Arm C as measured by PFS,PFS2,ORR,DOR,CRR,DOCR,TTR, and % MRD negative and % Sustained MRD negative
•To compare the efficacy of Arm B vs Arm C as measured by PFS,PFS2,ORR,DOR,CRR,DOCR, TTR, and % MRD negative and % Sustained MRD negative
Please refer to section 3 of the protocol for full list. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age and Sex:
1. Participant's age ≥18 years (or the minimum country specific age of consent if >18).
a.Male participants and female participants of childbearing potential must agree to use methods of contraception as described in Section 5.3.1.
•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.Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
3.Prior diagnosis of MM as defined according to IMWG criteria.
4.Measurable disease based on IMWG criteria as defined by at least 1 of the following:
a.Serum M-protein ≥0.5 g/dL by SPEP;
b.Urinary M-protein excretion ≥200 mg/24 hours by UPEP;
c.Serum immunoglobulin FLC ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65).
5.Prior anti-MM therapy: (refer to Appendix 15 for quantitating number of prior lines of therapy):
a.Part 1: At least 3 prior lines of anti-MM therapy including treatment with lenalidomide and a PI.
b.Part 2: At least 1 prior line of anti-MM therapy including treatment with lenalidomide and a PI. A response of MR or better must have been achieved with any prior anti-MM therapy based on investigator assessment using IMWG criteria.
6.ECOG performance status <1.
7.LVEF ≥40% as determined by a MUGA scan or ECHO.
8.Adequate hepatic function characterised by the following:
a.Total bilirubin ≤1.5 x ULN;
b.AST ≤2.5 x ULN and ALT ≤2.5 x ULN.
9.Estimated creatinine clearance ≥30 mL/min (according to the Cockcroft Gault formula, by 24-hour urine collection for creatinine clearance, or per the local institutional standard method).
10.Adequate BM function characterised by the following:
a.ANC ≥1.0 × 109/L (use of GCSFs 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).
11.Corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L).
12.Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1.
Informed Consent:
13.Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol. |
|
| E.4 | Principal exclusion criteria |
Medical Conditions:
1.Smoldering MM.
2.Plasma cell leukemia.
3.Systemic amyloid light chain amyloidosis.
4.POEMS Syndrome
5.Stem cell transplant within 12 weeks prior to enrolment, or active GVHD.
6.Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as any of the following within 6 months prior to enrolment:
a.Acute myocardial infarction or acute coronary syndromes (eg, unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, symptomatic pericardial effusion);
a.Clinically significant cardiac arrhythmias (eg, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
b.Thromboembolic or cerebrovascular events (eg, transient ischemic attack, cerebrovascular accident, deep vein thrombosis or pulmonary embolism);
c.Prolonged QT syndrome (or QTcF >470 msec at screening).
7.Ongoing Grade 2 or higher peripheral sensory or motor neuropathy.
8.History of GBS or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.
9.Active HBV, HCV, SARS-CoV2, HIV, or any active, uncontrolled bacterial, fungal, or viral infection. Active infections must be resolved at least 14 days prior to enrolment.
a.COVID-19/SARS-CoV2: While SARS-CoV2 testing is not mandated for entry into this study, testing should follow local clinical practice standards. If a participant has a positive test result for SARS-CoV2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV2, he/she is excluded.
10.Any other active malignancy within 3 years prior to enrolment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
11.Participants with known or suspected hypersensitivity to the study interventions or any of their excipients.
12.Other surgical (including major surgery within 14 days prior to enrolment), 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.
Prior/Concomitant Therapy:
13.Previous treatment with a BCMA-directed therapy.
14.Anti-CD38-directed therapy within 6 months preceding the first dose of treatment in this study.
15.Part 2 only: Refractory to prior anti-CD38-directed therapy (disease progression while on or within 60 days of the last dose of any anti-CD38-directed therapy, regardless of response).
16.Part 2 only: Previous pomalidomide therapy.
17.Part 2 only: Concurrent or anticipated use of a non-topical medication known to be a strong CYP1A2 inhibitor within 14 days or 5 half-lives (whichever is longer) prior to first dose of pomalidomide. Refer to Section 6.8 Concomitant Therapy.
18.Live attenuated vaccine must not be administered within 4 weeks of the first dose of study intervention.
Prior/Concurrent Clinical Study Experience:
19.Administration with an investigational product (eg. drug or vaccine) concurrent with study intervention or within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). A participant may be eligible if they are in the follow-up phase of an investigational study if they meet the criterion for time elapsed from previous administration of investigational product. Cases must be discussed with sponsor’s medical monitor to judge eligibility.
Diagnostic Assessments:
20.For females of childbearing potential: Serum pregnancy test positive at screening.
21.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).
Other Exclusions:
22.Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PART 1:
•DLTs during the DLT observation period (14 days from first elranatamab dose + first 28 days following first dose of elranatamab + daratumumab).
PART 2:
•PFS by BICR per IMWG
•OS |
|
| 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 |
|
| E.5.2 | Secondary end point(s) |
PART 1:
•Grade ≥2 CRS rate during the 28 days following the first dose of elranatamab.
•AEs as characterized by type, frequency, severity (as graded by NCI CTCAE V5.0), timing, seriousness, and relationship to elranatamab in combination with daratumumab. Severity of CRS and ICANS will be assessed according to ASTCT criteria;
•Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE V5.0), and timing.
•ORR and CCR, 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 lab) per IMWG sequencing criteria.
•Predose and postdose concentrations of elranatamab
•ADAs and NAbs against elranatamab
•Predose concentrations of daratumumab
PART 2:
•PFS and PFS2 by Investigator per IMWG
•ORR by BICR and investigator per IMWG
•DOR by BICR and investigator per IMWG
•CRR by BICR and investigator per IMWG
•DOCR by BICR and investigator per IMWG
•TTR by BICR and investigator per IMWG
•MRD negativity rate (central lab) per IMWG
•Sustained MRD negativity rate (central lab) 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 assessed according to ASTCT criteria.
•Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE V5.0), and timing.
•Predose and postdose concentrations of elranatamab
•ADAs and NAbs against elranatamab
•Predose concentrations of daratumumab
•EORTC QLQ-C30 and MY20 |
|
| 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 |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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 | 3 |
| 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 | 86 |
| 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 |
| Turkey |
| Argentina |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Germany |
| India |
| Italy |
| Netherlands |
| New Zealand |
| Norway |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| United States |
| France |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 8 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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