Minimal Residual Disease-based Strategy with T-Cell Redirector After Treatment with Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone (D-VRd) in Newly Diagnosed Multiple Myeloma: A Phase 2 (IFM 2022-01).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nantes

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Not possible to specify

Trial duration

26 Jun 2024 → ongoing

Decision date (initial)

2024-04-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Janssen Pharmaceutica NV

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

• Cohort A only (Patients MRD [-] after induction): to determine the rate of sustained MRD negativity (NGS, 10^-5).
• Cohort B only (Patients MRD [+] after induction): to determine the rate of conversion from positive MRD to negative MRD (NGS, 10^-5).

Secondary objectives 7

1. • Cohort A and Cohort B: determine safety and tolerability of Tec-Len and Tec-Tal respectively (after induction). NOTE: overall safety will be assessed.
2. • Cohort A only (Patients MRD [-] after induction): to determine the rate of sustained MRD negativity (NGS, 10-6). • Cohort B only (patients MRD [+] after induction): to determine the rate of conversion from positive MRD to negative MRD (NGS, 10 6).
3. • Cohort B only (patients MRD [+] after induction): to determine the rate of conversion from positive MRD to negative MRD (NGS, 10 5).
4. • To determine OS, PFS, DOR, TTR per IMWG criteria (2016).
5. • To determine CR or better, VGPR or better, ORR.
6. • To determine biological prognostic factors influencing outcome and response
7. • To assess QoL

Conditions and MedDRA coding

Multiple myeloma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Male or female patients must be at least 18 years of age at the time of consent younger than 66 years.
2. A male patient must agree not to donate sperm for the purpose of reproduction during the study and for a period of 6 months after receiving the last dose of study. Male patients should consider preservation of sperm prior to study treatment as anti cancer treatments may impair fertility.
3. Documented multiple myeloma satisfying the CRAB criteria and measurable disease as defined by: a. Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma AND any one or more of the following myeloma defining events: i. Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than ULN or >2.75 mmol/L (>11 mg/dL) ii. Renal insufficiency: creatinine clearance <40 mL/min (as calculated by the Cockcroft-Gault, see Appendix 6) or serum creatinine >177 μmol/L (>2 mg/dL) iii. Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL (Hemoglobin measurement performed as part of standard of care within 42 days before enrollment is acceptable for screening for CRAB criteria; but must be performed within 28 days before enrollment for other eligibility requirements) iv. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT (PET-CT=18F-fluorodeoxyglucose positron emission tomography with computed tomography. If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement). v. Clonal bone marrow plasma cell percentage ≥60% (Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used). vi. Involved: uninvolved serum free light chain ratio ≥100 (These values are based on the serum Freelite assay [The Binding Site Group, Birmingham, UK]. The involved free light chain must be ≥100 mg/L.) vii. >1 focal lesion on MRI studies (Each focal lesion must be 5 mm or more in size.) b. Measurable disease at Screening as defined by any of the following: i. Serum M-protein level ≥0.5 g/dL; or ii. Urine M-protein level ≥200 mg/24 hours; or iii. Serum Ig FLC ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio. Source: Rajkumar 2014
4. Newly diagnosed patients eligible for high dose therapy and autologous SCT.
5. Have a Karnofsky performance status score ≥50% (ECOG performance status ECOG score ≤2; Appendix 5
6. Have clinical laboratory values meeting the following criteria. Hematology : Hemoglobin ≥8 g/dL (≥5 mmol/L; without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted). Platelets : ≥75×109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and ≥50×109/L in patients in whom ≥50% of bone marrow nucleated cells are plasma cells (without transfusion support or thrombopoietin receptor agonist within 7 days before the laboratory test). ANC : ≥1.0×109/L (before the first dose of treatment, growth factor support is permitted but must be without support for 7 days for G-CSF or GM CSF and for 14 days for pegylated G CSF). Chemistry : AST and ALT ≤2.5×ULN . Total bilirubin ≤2.0×ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5×ULN is required). eGFR ≥30 mL/min based on Cockroft-Gault Formula calculation (Appendix 6) or creatinine clearance measured by a 24-hour urine collection. Serum calcium corrected for albumin ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L; see Appendix 7)
7. A female patient of childbearing potential must have a negative serum pregnancy test within 10 to 14 days prior to the start of study treatment and again either a serum or urine pregnancy test within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study and for a period of 6 months after the last dose of study treatments.
8. A female patient must be (as defined in Appendix 1): a. Not of childbearing potential, or b. Of childbearing potential and 1) Practicing 2 reliable methods of contraception simultaneously including one highly effective method of contraception and one other effective method of contraception (see Appendix 1) starting 4 weeks prior to dosing, throughout the study including during dose interruptions and for period of 6 months after the last dose of study treatments. For patients who are of childbearing potential, see Section 6.8.3.3 for details regarding concomitant use of estrogen containing products and lenalidomide.
9. A female patient must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for a period of 6 months after the last dose of other study treatments. Female patients should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility.
10. A male patient must wear a condom (with spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for a period of 6 months after the last dose of study treatments. If the male patient’s partner is a female of childbearing potential, she must also be practicing a highly effective method of contraception (see Appendix 1). NOTE: If the male patient is vasectomized, he still must wear a condom (with or without spermicidal foam/gel/film/cream/suppository), but his female partner is not required to use contraception.
11. Voluntary written informed consent must be given before performance of any study related procedure not part of normal medical care, with the understanding that the patient may withdraw consent at any time without prejudice to future medical care.
12. Willing and able to adhere to the lifestyle restrictions specified in this protocol.
13. Affiliation with French social security system or beneficiary from such system.

Exclusion criteria 27

1. Medical Conditions 1. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI CTCAE Version 5.0.
2. 2. COPD with a FEV1 <50% of predicted normal. Note that FEV1 testing is required for patients with known or suspected of having COPD or asthma and patients must be excluded if FEV1 <50% of predicted normal.
3. 3. Moderate or severe persistent asthma within the past 2 years (see Appendix 8 [for severity of Asthma]), uncontrolled asthma of any classification. Note that FEV1 testing is required for patients known or suspected asthma and patients must be excluded if FEV1 <50% of predicted normal.
4. 4. CNS involvement or clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required.
5. 5. Plasma cell leukemia, Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or primary light chain amyloidosis.
6. 6. Any ongoing myelodysplastic syndrome or B cell malignancy (other than multiple myeloma).
7. 7. Any history of malignancy, other than multiple myeloma, which is considered at high risk of recurrence requiring systemic therapy.
8. 8. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than multiple myeloma. The only allowed exceptions are malignancies treated within the last 24 months that are considered cured: a. Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade, <3 cm, no CIS). b. Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone c. Noninvasive cervical cancer d. Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (radical prostatectomy/radiation therapy/focal treatment) e. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer (antihormonal therapy is permitted) f. Other malignancy that is considered cured with minimal risk of recurrence in consultation with the Sponsor NOTE: In the event of any questions, consult the Sponsor prior to enrolling a patient.
9. 9. Stroke, transient ischemic attack, or seizure within 6 months prior to signing ICF.
10. 10. Presence of the following cardiac conditions: a. New York Heart Association stage III or IV congestive heart failure (Appendix 10) b. Myocardial infarction or coronary artery bypass graft ≤6 months prior to enrollment c. History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration d. Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities e. History of severe non-ischemic cardiomyopathy
11. 11. Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study, such as: a. Acute diffuse infiltrative pulmonary disease a. Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy b. History of autoimmune disease with the exception of vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing. c. Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status. d. Any other issue that would impair the ability of the patient to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. e. History of noncompliance with recommended medical treatments
12. 12. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug (daratumumab, bortezomib, lenalidomide, dexamethasone, teclistamab or talquetamab) or its excipients (refer to the appropriate IBs and SmPCs) or analogues and study–required co-medication.
13. 13. Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
14. Prior/Concomitant Therapy 14. Prior or current systemic therapy or SCT for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
15. 15. Received a strong CYP3A4 inducer within 5 half-lives prior to the first dose of study treatment (Flockhart 2016: http://medicine.iupui.edu/flockhart/).
16. 16. Plasmapheresis within 28 days prior to the first dose of study treatment.
17. 17. Patient had major surgery or had significant traumatic injury within 2 weeks prior to the start of administration of study treatment, or will not have fully recovered from surgery, or has major surgery planned during the time the patient is expected to be treated in the study or within 2 weeks after administration of the last dose of study treatment. NOTE: Patients with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery. If there is a question whether a procedure is considered a major surgery, the investigator must consult with the appropriate Sponsor representative and resolve any issues before enrolling a patient in the study.
18. 18. Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy before the planned first dose of study intervention.
19. 19. Received a live, attenuated vaccine within 4 weeks before the first dose of study drug. Non-live or replicating vaccines authorized for emergency use (eg, COVID-19) are allowed.
20. Diagnostic Assessments 20. HIV infection (positive, history, treatment for HIV).
21. 21. Hepatitis B infection (ie, HBsAg or HBV-DNA positive). In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status see Section 8.4.4.1 for further required assessments.
22. 22. Active hepatitis C infection as measured by positive HCV-RNA testing. Patients with a history of HCV antibody positivity must undergo HCV RNA testing. If a patient with history of chronic hepatitis C infection (defined as both HCV antibody and HCV RNA positive) completed antiviral therapy and has undetectable HCV-RNA 12 weeks following the completion of therapy, the patient is eligible for the study.
23. Other non-inclusions 23. Patients unable to complete baseline NGS evaluation at Screening.
24. 24. Patient is pregnant, a nursing mother, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study treatment.
25. 25. Patient plans to father a child while enrolled in this study or within 6 months after the last dose of study treatment, whichever is later.
26. 26. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
27. 27. Person under guardianship, trusteeship or deprived of freedom by a judicial or administrative decision.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • Cohort A only: sustained MRD [-] status at one year (ie, Cycle 13 Day 1). • Cohort B only: conversion to MRD [-] status by one year (ie, Cycle 13 Day 1) Note: MRD assessment at 1 year done after completion of 12 cycles of maintenance therapy, ie, on Cycle 13 Day 1. MRD [-] status is defined by a value of NGS MRD <10-5 and MRD [+] status is defined by a value of NGS MRD ≥10-5.

Secondary endpoints 7

1. • Presence and severity of TEAEs defined by NCI CTCAE Version 5.0 (Number of TEAEs), except for CRS and ICANS, which will be assessed based on ASTCT guidelines.
2. • Cohort A only: sustained MRD [-] status at one year (ie, Cycle 13 Day 1). • Cohort B only: conversion to MRD [-] status by one year (ie, Cycle 13 Day 1) Note: MRD assessment at 1 year done after completion of 12 cycles of maintenance therapy, ie, on Cycle 13 Day 1. MRD [-] status is defined by a value of NGS MRD <10-6 and MRD [+] status is defined by a value of NGS MRD ≥10-6
3. • Cohort B only: conversion to MRD [-] status by three months (ie, Cycle 4 Day 1) Note: MRD assessment at 3 months done after completion of 3 cycles of maintenance therapy, ie, on Cycle 4 Day 1. MRD [-] status is defined by a value of NGS MRD <10-5 and MRD [+] status is defined by a value of NGS MRD ≥10-5
4. • OS: time from the first dose of study drug to the date of death due to any cause • PFS: time from the date of first dose of study drug either PD, or death, whichever occurs first • DOR: time from the first response (PR or better) to the date of disease progression or death due to any cause. • TTR: time from the first dose of study drug to the date of the first response (PR or better)
5. • ORR, (PR or better) as defined by the IMWG response criteria (2016) • VGPR or better, CR or better will be evaluated according to IMWG response criteria
6. • Value of biological prognostic factors (at Screening), such as: - ISS stage - Cytogenetics as del(17p), t(4;14), t(14;16), t(14;20), amp(1q) and del(1p)
7. • Change in EQ-5D-5L and EORTC QC30 score over time (Screening, C1D1, C3D1, Maintenance C1D1, D1 every 3rd cycle, EOT, FU before PD)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nantes

Sponsor organisation

Centre Hospitalier Universitaire De Nantes

Address

5 Allee De L Ile Gloriette, Cs 69301 Cs 69301

City

Nantes Cedex 1

Postcode

44093

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Pr Touzeau

Public contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Pr Touzeau

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications