This study has been transitioned to CTIS with ID 2024-514139-50-00 check the CTIS register for the current data. Part 1PrimaryTo assess dose limiting toxicities (DLTs) of EDR to select an RP3D for the combination to be used in Part 2 of this study.…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1
DLTs during the DLT observation period:
• For all Dose Level (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 daratumumab (D) and lenalidomide (R).
Part 2
• Sustained MRD negativity rate (central lab) for at least 12 months per IMWG
as assessed via next generation sequencing (NGS)
• PFS by blinded independent central review (BICR) per IMWG
Secondary outcome
Part 1
• Adverse events (AEs) as characterized by type, frequency, severity (as graded
by National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE v5.0), timing, seriousness, and relationship to study treatment.
Severity of cytokine release syndrome (CRS) and immune effector cell-associated
neurotoxicity syndrome (ICANS) will be graded according to American Society for
Transplantation and Cellular Therapy (ASTCT) criteria.
• Laboratory abnormalities as characterized by type, frequency, severity (as
graded by NCI CTCAE v5.0), and timing.
• Objective response rate (ORR) and complete response rate (CRR), per
International Myeloma Working Group (IMWG) response criteria as determined by
investigator.
• Time to event endpoints: time to response (TTR), duration of response (DOR),
duration of complete response (DOCR) and progression-free survival (PFS) per
IMWG response criteria as determined by investigator, and overall survival (OS);
• Minimal residual disease (MRD) negativity rate (central laboratory) per IMWG
sequencing criteria.
• Predose and post dose concentrations of elranatamab
• Anti-drug antibodies (ADAs) and neutralizing antibodies (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 progression-free survival on next line of therapy (PFS2) by
investigatorper 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
et al, 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
• MY20European Organisation for Research and Treatment of Cancer (EORTC) Core
Quality of Life Questionnaire (QLQ-C30) and Myeloma Module 20 (MY20
Background summary
This is an open-label, 2-arm, multicenter, randomized Phase 3 study to evaluate
the efficacy and safety of elranatamab (PF-06863135) + daratumumab +
lenalidomide (EDR) versus daratumumab + lenalidomide + dexamethasone (DRd) in
transplant-ineligible participants with newly-diagnosed multiple myeloma
(NDMM). The randomized Phase 3 part of the study (Part 2 in participants with
NDMM) will be preceded by Part 1 to select the optimal recommended Phase 3 dose
(RP3D) of EDR and to assess the safety, tolerability, pharmacokinetics (PK),
pharmacodynamics (PD), and preliminary efficacy of elranatamab in combination
with daratumumab and lenalidomide in participants with NDMM and
relapsed/refractory multiple myeloma (RRMM). Part 1 of the study will inform
the RP3D of elranatamab and lenalidomide to be used in combination with
daratumumab in Part 2 of the study. Participants with RRMM will have received 1
to 2 prior lines of therapy and will not be refractory to an anti-CD38
monoclonal antibody (mAb). Part 2 of the study will evaluate whether EDR can
provide superior clinical benefit compared to standard of care therapy (DRd) in
transplant-ineligible participants with NDMM. Participants with NDMM will 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.
Study objective
This study has been transitioned to CTIS with ID 2024-514139-50-00 check the CTIS register for the current data.
Part 1
Primary
To assess dose limiting toxicities (DLTs) of EDR to select an RP3D for the
combination to be used in Part 2 of this study.
Secondary
• 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
Primary
• To compare the efficacy of EDR (Arm A) vs DRd (Arm B) as measured by MRD
status and PFS
Key Secondary
• To compare the efficacy of EDR (Arm A) vs DRd (Arm B) as measured by OS
Secondary
• To evaluate the efficacy of Arm A and Arm B
• To determine the safety and tolerability of elranatamab when used in
combination with daratumumab + lenalidomide
• To evaluate the PK of elranatamab when used in combination with daratumumab +
lenalidomide
• To evaluate the immunogenicity of elranatamab when used in combination with
daratumumab and lenalidomide
• To evaluate the impact of treatment on participant health-related quality of
life (HRQoL)
Study design
Study C1071006 is a Phase 3, open-label, 2-arm, multicenter, randomized study
to evaluate the efficacy and safety of experimental therapy in Arm A (EDR)
versus control therapy in Arm B (DRd) in transplant-ineligible participants
with NDMM (See Figure 1 of the protocol). The randomized Phase 3 part of the
study (Part 2 in participants with NDMM) will be preceded by Part 1 to select
the optimal RP3D of EDR and to assess the safety, tolerability, PK, PD, and
preliminary efficacy of elranatamab in combination with daratumumab and
lenalidomide in participants with NDMM and RRMM.
In Part 2, approximately 870 participants will be enrolled using a 1:1
randomization ratio to the experimental Arm A (EDR) or the control Arm B (DRd),
stratified by Revised International Staging System (R-ISS) (I/II vs III),
region (North America (NA) vs Europe (EU) vs Rest of World (ROW)) and age (< 75
vs >=75 years old).
Intervention
The design of Part 1 allows evaluation of the safety and tolerability of 3 dose
schedules (76 mg QW, 76 mg Q2W, 76 mg Q4W) of elranatamab when used in
combination with daratumumab and with up to 2 doses of lenalidomide (15 mg, 25
mg) to allow selection of an appropriate RP3D for Part 2 of the study.
Part 1 of the study is composed of a dose-finding phase and an expansion phase.
The Sponsor, together with participating investigators, will evaluate the
available safety data after at least 3 evaluable participants have been
enrolled in a dose level and each participant has been followed during the DLT
period. The RP3D of EDR to be further evaluated in Part 2 will be determined by
the Sponsor based on an assessment of the totality of the available data
including safety, tolerability, PK, PD and preliminary anti-myeloma activity
Study interventions are outlined in Table 9 of the protocol.
Once the RP3D is identified in Part 1, participants will be randomized into
experimental Arm A (EDR) and control Arm B (DRd) for Part 2
Study burden and risks
The study is expected to last up to 6 years in total. Patients will continue to
receive the study drug until tests show that the multiple myeloma has worsened,
the study doctor thinks patients are no longer benefiting from the study drug,
patients have unacceptable side effects, the study ends, or patients choose to
stop taking part in the study.
The study consists of a screening period, a treatment period and a follow-up
period.
Study treatment is broken up into 28-day cycles. During the treatment period,
patients assigned to Treatment Arm A will be hospitalized 2 days for the first
elranatamab administration (Day 1 and Day 2). A third day of hospitalization is
required on Day 4 of C0. This study will require patients to visit the study
doctor every week for the first 6 months of therapy, and then possibly every 2
weeks thereafter, to undergo study procedures. Study visits will last about 30
minutes to 3 hours.
The following procedures will be done no matter which arm patients will be
assigned to:
• Patients will have an electrocardiogram (ECG).
• Patients will provide blood samples for laboratory and safety testing.
• Patients will give urine samples to measure how your cancer is responding to
the study drug.
• For women of childbearing potential, urine pregnancy tests will be taken.
• Scans of patients' body will be made to measure how their cancer is
responding to the study drug.
• Gene testing: Samples of patients' saliva, blood and bone marrow aspirates
will be collected for testing genes that may be related to their cancer.
The study doctor may ask patients to come in for additional tests, procedures
and assessments, if necessary.
During the follow-up period, patients will have an end of treatment visit
within 14 days from last dose and then a follow-up visit approximately 1 month
after the last dose of study drug. Thereafter, depending on their response to
the study drug, they will have visits approximately every month to continue to
monitor their disease, or the study team will contact them by telephone about
every 3 months to ask them about their health and medications until the sponsor
determines the study is complete, which may take many years, or until they
withdraw their consent to be contacted. The study team may ask patients to come
back for a visit to check on their well-being. If they decide they do not want
to participate in the study procedures, information about their survival status
will be collected.
Patients' participation may help future patients by increasing our
understanding of elranatamab in treating multiple myeloma. It is possible that
patients' condition or health may improve, worsen, or stay the same.
Taking part in the study can have these cons:
o Patients may experience the side effects or adverse effects of the study
drug, as described in Section 6.
o There may be some discomfort from the measurements during the study. For
example: taking a blood sample can be a little painful. Or patients could get a
bruise as a result.
o Taking part in the study will cost patients extra time.
o Patients need to be hospitalized for longer than usual.
o Patients have to comply with the study agreements.
Risks of study drugs are outlined in the Risk Section of the Informed Consent
Document
Risks of study procedures outlined in the Informed Consent Document are
summarized below:
• Bone marrow aspirate/biopsy: The risks of a bone marrow aspirate/biopsy can
include bleeding, bruising, pain, nerve damage, and infection. To reduce these
risks, the site of the sample collection will be numbed, and sterile techniques
will be used. The numbing drug used may cause a burning feeling, rash, allergic
reaction, redness or soreness where patients receive the shot.
• Blood draw: A blood draw may cause faintness, inflammation of the vein, pain,
bruising, or bleeding at the site of puncture. You may feel dizzy, or you may
faint. There is also a slight chance of infection.
• Blood Pressure: The test is usually painless, however as the blood pressure
cuff squeezes patients arm while it inflates it may be uncomfortable. This
feeling lasts only a few seconds.
• COVID-19 testing: Since the nasal swab will be going from your nostril to
just about where your ear is, it can be uncomfortable. It may make patients gag
or cough briefly. In some cases, people can get a nosebleed after the test.
• CT, PET-CT Scan: A CT scan exposes patients to a small dose of radiation,
between 3.5 and 20.1 mSV. Although all radiation patients receive builds up
over their lifetime, this amount of radiation should not create a significant
risk to their health. Contrast dye is usually injected when patients get a CT
scan. The contrast dye may cause pain or burning when it is injected and may
worsen kidney function if patients already have kidney disease or who are
dehydrated. The contrast dye may also cause an allergic reaction, which could
be severe and life-threatening.
• Demographic Questions: While collection of demographic information does not
expose patients to physical risk, collection of such information may result in
a loss of their privacy if the information is lost or stolen.
• ECG: The risks from an ECG can include skin irritation and a rash from the
gel that is used or from wearing or removing the sticky patches.
• Echocardiogram: Patients may feel some discomfort from the transducer being
held very firmly against their chest.
• Health and Medication Questions: These questions may be sensitive in nature.
Patients may refuse to answer any question that makes them feel uncomfortable.
If patients have concerns after responding to these questions,they should tell
the study doctor.
• MRI or magnetic resonance imaging: There are risks from an MRI if patients
are pregnant or have one of the following, for example: an artificial heart
valve, pacemaker, metal plate, pin, or other metallic objects in their body
(including from a gunshot or shrapnel). Patients may also become anxious from
the loud noise or lying in a tight space without moving. The MRI scan does not
cause any pain and does not expose patients to x-ray radiation.
• MUGA or multi-gated radionuclide angiography (scan using a radiotracer): The
level of radioactivity produced by the tracer material and camera is extremely
low and isn*t known to cause any short-term or long-term damage to patients
body. It is possible to have an allergic reaction to the radioactive tracer
material.
• Questionnaires: A questionnaire may contain questions that are sensitive in
nature. Patients may refuse to answer any question that makes them feel
uncomfortable.
• Study Diary: While collection of study diary information does not expose
patients to physical risk, collection of such information may result in a loss
of their privacy if the information contained in the study diary is lost or
stolen.
• Testing of DNA and/or RNA: This may include analyzing all of patients genetic
information (called *whole genome sequencing*). While collection of genetic
information does not expose patients to physical risk, collection of such
information may result in a loss of their privacy if their genetic information
is lost or stolen.
• There is a very small chance that patients' genetic information could be
misused by people not involved with the research, including to discriminate
against them. However, steps are in place to prevent a particular result from
being linked to patients and to prevent unauthorized people from even knowing
genetic research was done.
• X-ray: Patients may be concerned about radiation exposure from chest X-rays,
especially if they have them regularly, but the amount of radiation from an
X-ray is low - even lower than what patients exposed to through natur
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Listed location countries
Age
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). Type of
Participant and Disease Characteristics: 2. Diagnosis of multiple myeloma (MM)
as defined according to IMWG criteria, 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 Free Light Chain (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 immunomodulatory drug (IMiD) and one proteasome
inhibitor (PI). 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.Eastern Cooperative Oncology Group (ECOG) performance status <=2.
5. Adequate hepatic, renal, and bone marrow (BM) function
absolute neutrophil count and [ANC], platelet count, hemoglobin).
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.
Exclusion criteria
Medical Conditions:
1. Smoldering MM
2. Monoclonal gammopathy of undetermined significance (MGUS)
3. Plasma cell leukemia
4. Waldenstro*ms Macroglobulinemia 5. Systemic light chain amyloidosis
6. Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and
Skin abnormalities (POEMS) Syndrome.
7. Impaired cardiovascular function or clinically significant cardiovascular
diseases within 6 months prior to enrollment
8. Ongoing Grade 3 or higher peripheral sensory or motor neuropathy, history of
Guillain-Barré syndrome (GBS) or GBS variants, or history of any Grade >3
peripheral motor polyneuropathy.
9. Active, uncontrolled bacterial, fungal, or viral infection, including (but
not limited to) coronavirus disease 2019 (COVID-19) / severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), hepatitis B virus (HBV), hepatitis C
virus(HCV), and known human immunodeficiency virus (HIV) or acquired
immunodeficiency syndrome (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.
10. 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.
11. Participants with known or suspected hypersensitivity to the study
interventions or any of their excipients.
12. Participants with known or suspected central nervous system (CNS) or
clinical signs of myelomatous meningeal involvement.
13 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).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-514139-50-00 |
| EudraCT | EUCTR2021-000803-20-NL |
| ClinicalTrials.gov | NCT05623020 |
| CCMO | NL83523.056.23 |