A Phase 2 Study to Evaluate Safety and Efficacy of Teclistamab-,Talquetamab- and JNJ-79635322-based Combination Regimens in Participants with Newly Diagnosed Transplant Eligible Multiple Myeloma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Heidelberg AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

30 Nov 2022 → ongoing

Decision date (initial)

2024-09-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Janssen Research & Development, LLC United States

External identifiers

EU CT number

2024-517382-17-00

EudraCT number

2022-001186-12

ClinicalTrials.gov

NCT05695508

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Safety, Efficacy

The primary objective is to evaluate the safety and tolerability of teclistamab-, talquetamab-, and JNJ-79635322-based combination regimens over the entire treatment phase for each arm, in participants with ND-TEMM.

Secondary objectives 9

1. Rate of MRD negative CR, defined as the proportion of participants who achieve MRD negative status as determined by NGF (and NGS if evaluated) with a sensitivity of 10-5, and achieve CR or better response post-induction (Arms A, A1, B, D, E, and E1, and G, and [if applicable] F and F1), post-ASCT (Arms A, A1, B, E, and E1, and [if applicable] F and F1), post Tec-Tal (Arm D), post-JNJ-79635322-D (Arm G), post-maintenance (Arms C, C1, and C2), and overall (all arms).
2. Rate of sustained MRD negative CR is defined as the proportion of participants who achieve MRD negative CR, confirmed for a minimum of 12 months apart and without any examination in between showing MRD-positive status, occurrence of PD, or start of subsequent anti-myeloma therapy, during the entire study treatment phase of each arm (all arms).
3. Rate of MRD negative CR conversion and deepening during maintenance (all arms except Arm D and Arm G), Tec-Tal treatment (Arm D), or JNJ-79635322-D treatment (Arm G).
4. Response rates post-induction treatment (Arms A, A1, B, D, E, E1, G, and, if applicable, F and F1), post-ASCT (Arms A, A1, B, E, E1, and, if applicable, F and F1), post-maintenance (Arms A, A1, B, E, E1, and, if applicable, F and F1), post Tec-Tal (Arm D), post-JNJ-79635322-D (Arm G), and overall:  ORR defined as the proportion of participants who achieve PR or better, according to the IMWG criteria, by the respective time point.  CR or better rate, defined as the proportion of participants who achieve CR or better, according to the IMWG criteria, by the respective time point.  VGPR or better rate is defined as the proportion of participants achieving VGPR or better, according to the IMWG criteria, by the respective time point.
5. Response rates post-maintenance and overall (Arms C, C1, and C2)  CR or better rate.
6. Arms A, A1, B, D, E, E1, G, and, if applicable, F and F1: Duration of response, defined as the duration from the date of initial documentation of a response (PR or better) according to the IMWG criteria (Appendix 5) to the date of first documented evidence of progressive disease according to the IMWG criteria (Appendix 5) or death due to any cause, whichever occurs first. Participants who have not progressed and are alive will be censored at the last disease evaluation before the start of subsequent anti-myeloma therapy.
7. Arms C, C1, and C2: Duration of response defined as the date from the first maintenance dose to the date of first documented evidence of progressive disease according to the IMWG criteria (Appendix 5) or death due to any cause, whichever occurs first. Participants who have not progressed and are alive will be censored at the last disease evaluation before the start of subsequent anti-myeloma therapy.
8. PFS defined as the duration from the date of first dosing to the date of first documented evidence of progressive disease or death, whichever occurs first (all arms). Disease progression will be determined according to the IMWG criteria. For participants who have not progressed and are alive, data will be censored at the last disease assessment before the start of any subsequent anti-myeloma therapy. For participants who are lost to follow-up or who withdraw consent and who have not progressed before loss to follow-up or withdrawal of consent, data will be censored at the last disease assessment.
9. Stem Cell Harvest (Arms A, A1, B, D, E, E1, G and [if applicable] F and F1)  Number (%) of participants who undergo stem cell mobilization (all above cohorts) and who undergo ASCT (except Arms D and G) will be summarized. Stem cell yield, the number of CD34+ cells transplanted, days to engraftment for neutrophils, and days to engraftment for platelets will be summarized by mean, standard deviation, median, minimum, and maximum.

Conditions and MedDRA coding

Newly Diagnosed Multiple Myeloma in patients eligible for stem cell transplantation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. 18 to 70 years of age, inclusive
2. Have an ECOG performance status score of 0 to 2 at screening and immediately prior to the start of administration of study treatment
3. Have clinical laboratory values meeting the following criteria: Hematology Hemoglobin 7.5 g/dL (4.65 mmol/L; without prior RBC transfusion within 7 days before the laboratory test prior to enrollment; recombinant human erythropoietin use is permitted) Platelets 75×109/L in participants in whom <50% of bone marrow nucleated cells are plasma cells and 50×109/L in participants 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 prior to enrollment) Absolute neutrophil count 1.0×109/L (prior 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 eGFR ≥30 mL/min based on Cockcroft-Gault formula (Appendix 7) or a 24-hour urine collection Total bilirubin ≤2.0×ULN; (isolated total bilirubin ≥ 1.5 x ULN with conjugated [direct] bilirubin <1.5xULN is allowed for those participants with known congenital nonhemolytic hyperbilirubinemia such as Gilbert’s syndrome). Serum calcium corrected for albumin ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL
4. A participant of childbearing potential must have a negative highly sensitive serum pregnancy test at screening 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.
5. Not of childbearing potential
6. Of childbearing potential and practicing 2 effective methods of contraception from the time of signing the ICF until 6 months after the last dose of study treatment.
7. A participant must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and 6 months after receiving the last dose of study treatment. Participants should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility.
8. A participant must wear a condom (with or without 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 minimum of 100 days after receiving the last dose of study treatment.
9. If the participant’s partner is of childbearing potential, the participant must use condoms (with or without spermicide) and the partner of the participant must also be practicing a highly effective method of contraception
10. A participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 100 days after receiving the last dose of study treatment. Participants should consider preservation of sperm prior to study treatment as anticancer treatments may impair fertility.
11. Must be willing and able to adhere to the lifestyle restrictions specified in this protocol, including adherence to the global PPP or local PPP program for lenalidomide.
12. Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
13. Documented multiple myeloma as defined by the criteria below: a. Multiple myeloma diagnosis according to the IMWG diagnostic criteria b. Measurable disease at screening as defined by any of the following: 1. Serum M-protein level ≥1.0 g/dL (central laboratory); or 2. Urine M-protein level ≥200 mg/24 hours (central laboratory); or 3. Serum immunoglobulin free light chain level ≥10 mg/dL (central laboratory) and abnormal serum immunoglobulin kappa lambda free light chain ratio.
14. Newly diagnosed participants for whom HDT and ASCT is part of the intended treatment plan.
15. Participants in Arms C, C1, and C2 must also satisfy all of the following criteria to be enrolled in the study: Newly diagnosed multiple myeloma according to IMWG criteria
16. Must have received 4 to 6 28-day cycles or equivalent of 3 or 4 drug-induction therapy that includes a proteasome inhibitor and/or an IMiD with or without anti-CD38 monoclonal antibody and a single or tandem ASCT. Post-ASCT consolidation is permitted for up to 2 cycles as long as the total number of induction plus consolidation cycles does not exceed 6.
17. Must have received only one line of therapy and achieved at least a PR as per IMWG 2016 response criteria based on the investigator’s assessment. Participants with plasmacytomas at the time of diagnosis must meet IMWG 2016 response criteria for ≥PR based on repeat imaging utilizing the same modality
18. Must have received HDT and ASCT within 12 months of the start of induction therapy and be within 6 months of the last ASCT (7 months for participants who received consolidation at the time of enrollment).

Exclusion criteria 34

1. Any ongoing myelodysplastic syndrome or B-cell malignancy (other than multiple myeloma)
2. Any history of malignancy, other than multiple myeloma, which is considered at high risk of recurrence requiring systemic therapy.
3. Any active malignancy (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: 1) Non-muscle invasive bladder cancer (solitary Ta-PUN-LMP or low grade, <3 cm, no CIS) 2) Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone. 3) Non-invasive cervical cancer 4) Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ or history of localized breast cancer (antihormonal therapy is permitted) 5) Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (RP/RT/focal treatment) 6) Other malignancy that is considered cured with minimal risk of recurrence in consultation with the sponsor’s medical monitor.
4. CNS involvement or clinical signs of meningeal involvement of multiple myeloma. If either is suspected, brain MRI and lumbar cytology are required and results must exclude CNS involvement.
5. Stroke, transient ischemic attack or seizure within 6 months prior to start of treatment.
6. History of allogeneic stem cell transplant or prior organ transplant requiring immunosuppressive therapy.
7. Seropositive for human immunodeficiency virus.
8. 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 .
9. Active hepatitis C infection as measured by detectable HCV-RNA testing. Participants with a history of HCV antibody positivity must undergo HCV-RNA testing. If a participant 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 participant is eligible for the study.
10. COPD with a FEV1 <50% of predicted normal. Note that FEV1 testing is required for participants with known or suspected of having COPD or asthma and participants must be excluded if FEV1 <50% of predicted normal.
11. Moderate or severe persistent asthma within the past 2 years (see Appendix 11), or uncontrolled asthma of any classification. Note that FEV1 testing is required for participants with known or suspected asthma and participants must be excluded if FEV1 <50% of predicted normal.
12. 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 b. Evidence of active systemic viral, fungal or bacterial infection, requiring systemic antimicrobial therapy c. Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before start of study treatment. Exception: Participants with vitiligo, controlled type I diabetes, and prior autoimmune thyroid disease that is currently euthyroid based on clinical symptoms and laboratory testing are eligible regardless of when these conditions were diagnosed. d. Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status e. Any other issue that would impair the ability of the participant 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 participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. f. History of noncompliance with recommended medical treatments
13. Presence of the following cardiac conditions: a. New York Heart Association stage III or IV congestive heart failure b. Myocardial infarction, unstable angina, 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.
14. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients
15. Participant is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of any component of the study treatment regimen.
16. Participant plans to father a child while enrolled in this study or within 100 days after the last dose of any component of the study treatment regimen.
17. Participant had significant traumatic injury or major surgery 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 participant is expected to be treated in the study or within 2 weeks after administration of the last dose of study treatment.
18. Received an investigational drug (including investigational vaccines; COVID vaccine released for emergency use is permitted) or used an invasive investigational medical device within 4 weeks or 5 half-lives of the respective drug/IMP (whichever is longer) before enrollment or is currently enrolled in an interventional investigational study.
19. Have gastrointestinal disease that may significantly alter the absorption of oral drugs
20. Received a live, attenuated vaccine within 4 weeks before the first dose of study drug. Non-live or non-replicating vaccines authorized for emergency use (eg, COVID-19) by local health authorities are allowed.
21. Be unable or unwilling to undergo antithrombotic prophylactic treatment.
22. For Arms A, A1, B, D, E, E1, F, F1, and G, any potential participant will also be excluded from participating in the study if they meet any of the following criteria: 1. Prior or current systemic therapy or stem cell transplant 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. 2. Radiotherapy within 14 days or focal radiation within 7 days of enrollment. Radiotherapy on measurable soft-tissue plasmacytoma(s) is not permitted even in the setting of palliation for symptomatic management. 3. Plasmapheresis within 28 days of enrollment. 4. Criterion modified as per Amendment 3. 4.1. Plasma cell leukemia at the time of screening, as defined by the presence of 5% or more circulating plasma cells in peripheral blood (Fernández de Larrea 2021), smoldering multiple myeloma, Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or primary light chain amyloidosis. 5. Criterion modified as per Amendment 4. 5.1. Arms B, F, and F1 only: Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI-CTCAE Version 5. 6. Criterion modified as per Amendment 4. 6.1. Arms B, F, and F1 only: Due to a potential interaction with bortezomib, received a strong CYP3A4 inducer within 5 half-lives prior to enrollment
23. For Arms C, C1, and C2, any potential participant will also be excluded from participating in the study if they meet any of the following criteria: 1. Received any prior BCMA-directed therapy (Arms C and C1 only) or GPRC5Ddirected therapy (Arm C2 only).
24. 2. Any previous therapy with an immune cell redirecting agent or gene modified adoptive cell therapy (eg, chimeric antigen receptor modified T cells, NK cells). 3. Discontinued treatment due to any AE related to lenalidomide as determined by the investigator. 4. Radiotherapy within 14 days or focal radiation within 7 days of enrollment. 5. Progressed on multiple myeloma therapy at any time prior to screening.
25. 6. Received a cumulative dose of corticosteroids equivalent ≥40 mg dexamethasone within the 14-day period before the start of study treatment administration
26. 7. Plasma cell leukemia, smoldering multiple myeloma, Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or primary light chain amyloidosis.
27. 8. Intolerant to the starting dose of lenalidomide (10 mg).
28. Potential participants must be willing and able to adhere to the following lifestyle restrictions during the course of the study to be eligible for participation: 1. Refer to Section 6.12.3, and subsections therein for details regarding prohibited and restricted therapy during the study. 2. Agree to follow all requirements that must be met during the study as noted in the Inclusion and Exclusion Criteria (eg, contraceptive requirements) and the relevant Schedule of Activities.
29. 3. Agree not to donate blood during therapy, during dose interruptions, and for at least 6 months after the last dose of study treatment.
30. 4. Be willing to be hospitalized or remain in close proximity (within 60 minutes) to the hospital:  starting after step-up dose 1 until 48 hours after the first 3 doses of teclistamab or talquetamab as described in Section 6.4.1.1; or  for 2 days after the step-up dose and after the first treatment dose of JNJ-79635322 as described in Section 6.4.2.1.
31. 5. Be willing to be hospitalized for administration of teclistamab or talquetamab following specified AEs as described in Section 6.4.1.1.2 or for administration of JNJ-79635322 following specified AEs as described in Section 6.4.2.2.
32. 6. Due to the embryo-fetal risk associated with IMiDs, all participants must adhere to the local PPP program for lenalidomide. A participant using oral contraceptives must use an additional barrier contraceptive method (see Inclusion Criteria in Section 5.1).
33. 7. Agree to self-monitor for signs and symptoms of CRS or infection, including fever or feeling tired, and to seek immediate medical intervention.
34. 8. Be willing to avoid driving or operating heavy or potentially dangerous machinery starting after step-up dose 1 until 48 hours after administration of the third dose of teclistamab or talquetamab.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoints are incidence and severity of AEs and SAEs during treatment with teclistamab-, talquetamab-, and JNJ-79635322-based combination regimens for each arm.

Secondary endpoints 11

1. Rate of MRD negative CR, defined as the proportion of participants who achieve MRD negative status as determined by NGF (and NGS if evaluated) with a sensitivity of 10-5, and achieve CR or better response post-induction (Arms A, A1, B, D, E, and E1, and G, and [if applicable] F and F1), post-ASCT (Arms A, A1, B, E, and E1, and [if applicable] F and F1), post Tec-Tal (Arm D), post-JNJ-79635322-D (Arm G), post-maintenance (Arms C, C1, and C2), and overall (all arms).
2. Rate of sustained MRD negative CR is defined as the proportion of participants who achieve MRD negative CR, confirmed for a minimum of 12 months apart and without any examination in between showing MRD-positive status, occurrence of PD, or start of subsequent anti-myeloma therapy, during the entire study treatment phase of each arm (all arms).
3. Rate of MRD negative CR conversion and deepening during maintenance (all arms except Arm D and Arm G), Tec-Tal treatment (Arm D), or JNJ-79635322-D treatment (Arm G).
4. Response rates post-induction treatment (Arms A, A1, B, D, E, E1, G, and, if applicable, F and F1), post-ASCT (Arms A, A1, B, E, E1, and, if applicable, F and F1), post-maintenance (Arms A, A1, B, E, E1, and, if applicable, F and F1), post Tec-Tal (Arm D), post-JNJ-79635322-D (Arm G), and overall:  ORR defined as the proportion of participants who achieve PR or better, according to the IMWG criteria, by the respective time point.
5.  CR or better rate, defined as the proportion of participants who achieve CR or better, according to the IMWG criteria, by the respective time point.
6.  VGPR or better rate is defined as the proportion of participants achieving VGPR or better, according to the IMWG criteria, by the respective time point.
7. Response rates post-maintenance and overall (Arms C, C1, and C2)  CR or better rate.
8. Arms A, A1, B, D, E, E1, G, and, if applicable, F and F1: Duration of response, defined as the duration from the date of initial documentation of a response (PR or better) according to the IMWG criteria (Appendix 5) to the date of first documented evidence of progressive disease according to the IMWG criteria (Appendix 5) or death due to any cause, whichever occurs first. Participants who have not progressed and are alive will be censored at the last disease evaluation before the start of subseq
9. Arms C, C1, and C2: Duration of response defined as the date from the first maintenance dose to the date of first documented evidence of progressive disease according to the IMWG criteria (Appendix 5) or death due to any cause, whichever occurs first. Participants who have not progressed and are alive will be censored at the last disease evaluation before the start of subsequent anti-myeloma therapy.
10. PFS defined as the duration from the date of first dosing to the date of first documented evidence of progressive disease or death, whichever occurs first (all arms). Disease progression will be determined according to the IMWG criteria. For participants who have not progressed and are alive, data will be censored at the last disease assessment before the start of any subsequent anti-myeloma therapy. For participants who are lost to follow-up or who withdraw consent and who have not progressed b
11. Stem Cell Harvest (Arms A, A1, B, D, E, E1, G and [if applicable] F and F1)  Number (%) of participants who undergo stem cell mobilization (all above cohorts) and who undergo ASCT (except Arms D and G) will be summarized. Stem cell yield, the number of CD34+ cells transplanted, days to engraftment for neutrophils, and days to engraftment for platelets will be summarized by mean, standard deviation, median, minimum, and maximum.

Investigational products

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

Test 7

Auxiliary 14

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Heidelberg AöR

Sponsor organisation

Universitaetsklinikum Heidelberg AöR

Address

Im Neuenheimer Feld 672, Neuenheim Neuenheim

City

Heidelberg

Postcode

69120

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

GMMG Studiensekretariat

Public contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

GMMG Studiensekretariat

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 21 files

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

Application history

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