CTRI/2024/01/062127 [Registered on: 31/01/2024] Trial Registered Prospectively
Last Modified On:
30/01/2024
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Active Controlled Trial
Public Title of Study
A Study Comparing Iberdomide, Daratumumab And Dexamethasone Versus
Daratumumab, Bortezomib, And Dexamethasone In Subjects With Relapsed Or
Refractory Multiple Myeloma
Scientific Title of Study
A Phase 3, Two-Stage, Randomized, Multicenter, Open-Label Study Comparing Iberdomide, Daratumumab And Dexamethasone (IBERDD) Versus Daratumumab, Bortezomib, And Dexamethasone (DVD) In Subjects With Relapsed Or Refractory Multiple Myeloma (RRMM) (EXCALIBER-RRMM)
Trial Acronym
EXCALIBER-RRMM
Secondary IDs if Any
Secondary ID
Identifier
2020-000431-49
EudraCT
CC-220-MM-002_Protocol Amendment 3.0 _20Sep2022
Protocol Number
IND NUMBER: 129254
Other
NCT04975997
ClinicalTrials.gov
U1111-1260-2872
UTN
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Rashmi Chitgupi
Designation
Country Head - Clinical Management
Affiliation
PPD Pharmaceutical development Pvt Ltd.
Address
PPD Pharmaceutical development Pvt Ltd., 101, A Wing, Fulcrum
Hiranandani Business Park, Andheri, Mumbai
Mumbai MAHARASHTRA 400099 India
Phone
912266022900
Fax
Email
rashmi.chitgupi@ppd.com
Details of Contact Person Public Query
Name
Rashmi Chitgupi
Designation
Country Head - Clinical Management
Affiliation
PPD Pharmaceutical development Pvt Ltd.
Address
PPD Pharmaceutical development Pvt Ltd., 101, A Wing, Fulcrum
Hiranandani Business Park, Andheri, Mumbai
PPD Pharmaceutical Development India Private Limited
101-A Wing Fulcrum, Hiranandani Business Park, Sahar Road, Andheri East, Mumbai – 400 099
Countries of Recruitment
Argentina Australia Austria Belgium Brazil Canada China Czech Republic Denmark Finland France Germany Greece India Ireland Israel Italy Japan Mexico Netherlands Norway Poland Portugal Spain Sweden Switzerland Taiwan Turkey United Kingdom United States of America Republic of Korea
Sites of Study
No of Sites = 6
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr Neeraj Sidharthan
Amrita Institute of Medical Sciences and Research Centre
Dept. of Clinical Haematology and Stem Cell Transplant Unit,
AIMS Ponekkara P O, Kochi – 682041, Kerala, India
Ernakulam KERALA
Jawaharlal Institute of Postgraduate Medical Education and Research
Department of Medical oncology, 3rd Floor, Dhanvantari Nagar, JIPMER, Puducherry, 605006, India Perambalur TAMIL NADU
8056338405
dr.biswajitdm@gmail.com
Dr Santhosh Kumar Devadas
M.S. Ramaiah Medical College and Hospital
Room No-10, Ground Floor, M S Ramaiah Nagar, Msrit Post, New Bel Rd Bengalore, Karnataka 560054, India Bangalore KARNATAKA
9036939296
drsanthoshkumar28@gmail.com
Dr Udip Dilip Maheshwari
Mumbai Oncocare Centre (Unit of Cellcure Cancer Centre Pvt Ltd)
1 to 4, Floor-1st, Shreepati Arcade, August Kranti Marg,
Nana Chowk, Mumbai, Maharashtra, India- 400036 Mumbai MAHARASHTRA
7677434237
drudipdm@mocindia.co.in
Dr Rajib De
Nil Ratan Sircar Medical College and Hospital
Department of Haematology, 138, A.J.C Bose Road, Kolkata, West Bengal - 700014
Kolkata WEST BENGAL
9433196143
rajibdrde@gmail.com
Dr Ganesh S Jaishetwar
Yashoda Hospitals
Room no-156, Floor-1st,
Department-OPD 5
Hitech City, Cyber Towers to JNTU Road,
Hyderabad-500084, India Hyderabad TELANGANA
9849388806
ganeshjaishetwar@gmail.com
Details of Ethics Committee
No of Ethics Committees= 6
Name of Committee
Approval Status
Ethics Committee, M.S. Ramaiah Medical College and Hospital
Approved
Institutional Ethics Committee, Amrita Institute of Medical Sciences
Submittted/Under Review
Institutional Ethics Committee, NRSMC
Submittted/Under Review
Institutional Ethics Committee- Human Studies
Submittted/Under Review
Mumbai Oncocare Centre Institutional Ethics Committee
Approved
Yashoda Academy of Medical Education and Research
Submittted/Under Review
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: C900||Multiple myeloma,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Treatment Arm A: IBERDOMIDE, DARATUMUMAB AND DEXAMETHASONE (IBERDD)
Oral iberdomide at 1, 1.3 or 1.6 mg once daily from Days 1 to 21 of a 28-day cycle
Daratumumab administered as 1800 mg subcutaneously co-formulated with 30,000 units of
recombinant human hyaluronidase (rHuPH20) for:
- Cycles 1 and 2 on Days 1, 8, 15 and 22 of a 28-day cycle
- Cycles 3 to 6 on Days 1 and 15 of a 28-day cycle
- Cycles 7+ on Day 1 of a 28-day cycle
Oral dexamethasone will be administered at a total dose of 40 mg weekly on Days 1, 8, 15 and
22. For subjects older than 75 years, underweight (body mass index [BMI] 18.5), have poorly
controlled diabetes, or prior intolerance/adverse event to steroid therapy, dexamethasone may
be administered at a dose of 20 mg weekly on Days 1, 8, 15 and 22.
- On daratumumab administration days, dexamethasone will be utilized as the treatment dose
of steroid for that particular day, as well as the required premedication prior to the
daratumumab administration.
Total duration - Treatment will continue until confirmed PD, unacceptable toxicity, or withdrawal of consent
Comparator Agent
Treatment Arm B:
DARATUMUMAB, BORTEZOMIB, AND DEXAMETHASONE (DVD)
Daratumumab administered as 1800 mg subcutaneously co-formulated with 30,000 units
recombinant human hyaluronidase (rHuPH20) for:
- Cycles 1 to 3 on Days 1, 8 and 15 of a 21-day cycle
- Cycles 4 to 8 on Day 1 of a 21-day cycle
- Cycles 9+ on Day 1 of a 28-day cycle
Bortezomib administered subcutaneously at a starting dose of 1.3 mg/m2 for:
- Cycles 1 to 8 on Days 1, 4, 8 and 11 of a 21-day cycle
Oral dexamethasone will be administered at a starting dose of 20 mg for:
- Cycles 1 to 8 on Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle. For subjects older than
75 years, underweight (BMI 18.5), have poorly controlled diabetes, or prior
intolerance/adverse event to steroid therapy, dexamethasone may be administered at a dose
of 10 mg on Days 1, 2, 4, 5, 8, 9, 11 and 12.
- On daratumumab administration days, dexamethasone will be utilized as the treatment dose
of steroid for that particular day, as well as the required premedication prior to the
daratumumab administration.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is more than or equal to 18 years (there is no upper age limit) of age at the time of signing the informed consent form (ICF)
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements
4. Subject has documented diagnosis of MM and measurable disease, defined as any of the following:
a. M-protein quantities more than or equal to 1 g/dL by serum protein electrophoresis (sPEP) or more than or equal to 200 mg/24-hour urine collection by urine protein electrophoresis (uPEP); or
b. Light chain MM without measurable disease in serum or urine: serum-free light chain (FLC) levels > 100 mg/L (10 mg/dL) involved light chain and an abnormal kappa/lambda FLC ratio
5. Subject has received one to 2 prior lines of anti-myeloma therapy
6. Subject achieved a response (partial response [PR] or better) to at least 1 prior antimyeloma regimen.
7. Subject must have documented disease progression during or after their last anti-myeloma regimen.
8. Prior treatment with CD38-directed therapy:
In Stage 1, subjects with prior CD38-directed therapy are not eligible.
In Stage 2, prior treatment with CD38-directed therapy is permitted only if all the following are fulfilled:
a. Best response achieved during CD38-directed-containing therapy was > PR.
b. Subject did not progress while receiving CD38-directed therapy or within 60 days of last dose of therapy.
c. Subject did not discontinue CD38-directed therapy due to a related AE.
d. Last dose of daratumumab was more than or equal to 3 months prior to randomization.
9. Prior treatment with bortezomib therapy is permitted, if all the following are fulfilled:
a. Best response achieved during bortezomib-containing therapy was at least a minimal response (MR).
b. Subject did not progress while receiving bortezomib therapy or within 60 days of last dose of therapy.
10. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
11. Females of childbearing potential (FCBP) must:
ExclusionCriteria
Details
The presence of any of the following will exclude a subject from enrollment:
1. Subject has any significant medical condition, including active or uncontrolled infection, presence of laboratory abnormality, or psychiatric illness that places the subject at an unacceptable risk for treatment-related complications, if he/she were to participate in the study.
2. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 14 days for mild or asymptomatic infections or within 28 days for severe/critical illness prior to randomization.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject has any of the following laboratory abnormalities:
a. Absolute neutrophil count (ANC) < 1,000 cells/µL. It is not permissible to administer granulocyte colony-stimulating factor (GCSF) to achieve minimum ANC levels.
b. Platelet count: < 75,000 cells/µL for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; or a platelet count < 50,000 cells/µL for subjects in whom ≥ 50% of bone marrow nucleated cells are plasma cells. It is not permissible to transfuse subjects to achieve minimum platelet counts.
c. Hemoglobin < 8 g/dL (< 4.9 mmol/L).
d. Estimated glomerular filtration rate (eGFR) < 30 mL/min or requiring dialysis. The eGFR should be calculated using the Modification of Diet in Renal Disease (MDRD) formula adjusted for actual BSA
e. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L).
f. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN).
g. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome.
5. Subject has plasma cell leukemia, Waldenstrom’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis.
6. Subject has peripheral neuropathy Grade 3, Grade 4 or Grade 2 with pain.
7. Subject has gastrointestinal disease that may significantly alter the absorption of iberdomide and/or other oral study treatment.
8. Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for more than or equal to 5 years with the exception of the following noninvasive malignancies:
- Basal cell carcinoma of the skin
- Squamous cell carcinoma of the skin in situ (stage 0)
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
- Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative
9. Subject with known central nervous system involvement with MM.
10. Subject has received immunosuppressive medication within the last 14 days of initiating study treatment. The following are exceptions to this criterion:
- Intranasal, inhaled, topical or local corticosteroid injections (eg, intra-articular injection)
- Systemic corticosteroids at doses that do not exceed 10 mg/day of prednisone
- Steroids as premedication for hypersensitivity reactions
11. Subject has impaired cardiac function or clinically significant cardiac disease, including:
a. Myocardial infarction within 1 year before randomization, or an 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 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 5.0 Grade 2 or higher) or clinically significant electrocardiogram (ECG) abnormalities.
12. Subject received prior therapy with iberdomide.
13. Subject received any of the following:
a. Plasmapheresis within the last 28 days of initiating study treatment
b. Major surgery (as defined by the Investigator) within 28 days of initiating study treatment.
c. Radiation therapy, other than local palliative therapy, for myeloma associated bone lesions within 14 days of initiating study treatment.
d. Use of any systemic anti-myeloma drug therapy within 14 days of initiating study treatment
14. Subject received any investigational agent within 28 days.
- Subjects who are participating in other interventional trials may not participate in BMS clinical trials, except for those who have completed treatment with the prior investigational agent(s) and are currently in Long-term Follow up.
- Trial participation for subjects who have received an investigational vaccine (such as an investigational SARS-CoV-2 vaccine) will be determined by discussion between the Investigator and Sponsor Medical Monitor.
15. Subject has previously received a live vaccine within 3 months of initiating study
treatment.
16. Concurrent administration of a strong inhibitor or inducer of cytochrome P450 (CYP3A4/5) (including within 14 days of initiating study treatment).
17. Subject is unable or unwilling to undergo protocol required thromboembolism or herpes zoster prophylaxis.
18. Subject has previously received allogeneic stem cell transplantation at any time during prior therapy or received autologous stem cell transplantation within 12 weeks of initiating study treatment.
19. Subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that forced expiratory testing (FEV1) is required for subjects suspected of having COPD.
20. Subject has known moderate or severe persistent asthma within the last 2 years, or currently has uncontrolled asthma of any classification.
21. Subject is a female who is pregnant, nursing or breastfeeding, or who intends to become pregnant during participation in the study.
22. Subject is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B, active hepatitis A, or active hepatitis C:
a. Known to be seropositive for HIV.
b. 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 real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (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.
c. Known to be seropositive for hepatitis C virus (HCV); anti-HCV antibody positive or HCV- ribonucleic acid (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.
23. Subject has known allergies, hypersensitivity, or intolerance to boron or mannitol, hyaluronidase, sorbitol, corticosteroids, monoclonal antibodies or human proteins, cereblon modulating agents or their excipients
24. Subject has any contraindications to daratumumab, bortezomib or dexamethasone, per local PI.
25. Vulnerable, under judicial protection, people without freedom by administrative or judicial decision, people with psychiatric conditions without their consent, people accepted in a health or social institution for other purposes than the research, adults under legal guardianship, curatorship, and people incapable of giving consent personally.
Method of Generating Random Sequence
Stratified randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
Progression-free survival
(PFS)
Time from randomization to the first documentation of progressive disease according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma 2016 or death due to any cause, whichever occurs first.
Secondary Outcome
Outcome
TimePoints
Overall Survival
Time from randomization to death from any cause.
Minimal Residual Disease Negativity Rate
Sensitivity of a minimum of 1 in 10 raise to power of 5 nucleated cells by next generation flow cytometry in bone marrow aspirate for subjects who are CR or better per IMWG Uniform Response Criteria for Multiple Myeloma.
Overall response rate (ORR)
Proportion of subjects who achieve PR or better response according to the IMWG criteria
Time to response (TTR)
Time from randomization to the first documentation of response (PR or better).
Duration of response (DoR)
Time from initial documented response (PR or better) until the first date the response criteria are met for PD or death due to any cause, whichever occurs
first.
Time to progression (TTP)
Time from randomization to the first documented disease progression.
Time to next treatment (TTNT)
Time from randomization to the start of the subject receiving any anti-myeloma treatment other than study treatment. Subjects who do not start new
anti-myeloma therapy are censored at the last assessment date or follow-up visit known to have
not received new anti-myeloma treatment, whichever is later.
Progression-free survival 2 (PFS2)
Time from randomization to documented disease progression on next-line therapy, or death from any cause, whichever occurs first.
Target Sample Size
Total Sample Size="664" Sample Size from India="41" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Phase of Trial
Phase 3
Date of First Enrollment (India)
09/02/2024
Date of Study Completion (India)
Applicable only for Completed/Terminated trials
Date of First Enrollment (Global)
14/07/2022
Date of Study Completion (Global)
Applicable only for Completed/Terminated trials
Estimated Duration of Trial
Years="5" Months="0" Days="0"
Recruitment Status of Trial (Global)
Open to Recruitment
Recruitment Status of Trial (India)
Not Yet Recruiting
Publication Details
N/A
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This is a two-stage, multicenter, randomized, controlled, open-label, Phase 3 study comparing the efficacy and safety of IberDd versus DVd in subjects with Relapsed or Refractory Multiple Myeloma (RRMM).
India will participate in Stage 2 of the study.
Primary Objective
·To
compare the efficacy of iberdomide, daratumumab and dexamethasone (IberDd) to
that of daratumumab, bortezomib and dexamethasone (DVd) in terms of
progression-free survival (PFS) in subjects with relapsed or refractory
multiple myeloma (RRMM)
Secondary Objective(s):
·To
evaluate overall survival (OS) in subjects with RRMM treated with IberDd
compared to DVd
·To
evaluate achievement of minimal residual disease (MRD) negative status in
subjects with RRMM (who achieve complete response [CR] or better) when treated
with IberDd compared to DVd
·To
evaluate additional efficacy parameters in subjects with RRMM treated with
IberDd compared to DVd
·To
evaluate safety of IberDd compared to DVd in subjects with RRMM
·To
evaluate cancer-related symptoms and health-related quality of life (HRQoL)
using the European Organization for Research and Treatment of Cancer – Quality
of Life C30 questionnaire (EORTC QLQ-C30) and the European Quality of Life
Multiple Myeloma Module (EORTC QLQMY20) in subjects with RRMM treated with
IberDd compared to DVd
Stage 2:
In Stage 2 of the study, approximately 664 additional
subjects will be randomized 1:1 between 2 treatment arms:
- Approximately 332 subjects will be randomized to
receive Treatment Arm A (IberDd)
- Approximately 332 subjects will be randomized to
receive Treatment Arm B (DVd)
The total number of subjects enrolled in Stage 2 will
be adjusted according to the number of subjects enrolled in the selected
iberdomide dose level arm and in the DVd arm during Stage 1.
Overall, approximately 764 subjects are planned to be
enrolled in these 2 arms considering Stage 1 and Stage 2 combined.
Length of Study:
The study will consist of the following consecutive
periods: Screening, Treatment and Follow-up.
- The Screening period may not exceed a 28-day window
prior to randomization (Day -28 to Day -1).
- The Treatment period will extend from randomization
to discontinuation of all study treatment.
- The Follow-up period consists of the 28-day
Follow-up Visit, the PFS Follow-up Phase, and the Long-term Follow-up Phase.