Clinical trial NCT05695508: GMMG-HD10 / DSMM-XX / 64007957MMY2003, MajesTEC-5
Official title: A Phase 2 Study to Evaluate Safety and Efficacy of Teclistamab- and Talquetamab-based Combination Regimens in Participants with Newly Diagnosed Transplant Eligible Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Multiple Myeloma
Lead sponsor: University of Heidelberg Medical Center
Sponsor class: OTHER
Collaborators: name: Janssen Research & Development, LLC
name: Deutsche Studiengruppe Multiples Myelom (DSMM)
First posted: 2023-01-25
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Induction Treatment of Arms A, A1, B, D, E, E1, F, F1 contain 6 cycles of Tec-DRd \[Arm A, A1, D\] , Tec-DVRd \[Arm B\], Tal-DRd \[Arm E, E1\] or Tal-DVRd \[Arm F, F1\]. Enrollment will be staggered with Arm A opening first.

Induction therapy (except Arm D) is followed by HDT and a single ASCT according to local SoC. After ASCT, participants will receive maintenance treatment with Tec-D \[Arm A, A1, B, E. F\] or Tal-D \[E1, F1\] Arm C and C1 participants will enter the study at Maintenance Treatment with Tec-D or Tal-DR after induction, HDT, and ASCT according to local SoC (outside of the study).

All Arms will receive maintenance treatment for a max. of 18 cycles or until confirmed progressive disease, death, intolerable toxicity, loss to follow-up, or consent withdrawal, whichever comes first. An optional end of treatment is possible for those patients who have sustained MRD negativity of 12 months.

Periodic safety evaluations will be conducted to ensure that treatment is safe and tolerable.
Primary purpose: TREATMENT

Brief summary: Phase 2 Study to Evaluate Safety and Efficacy of Teclistamab- and Talquetamab-based Combination Regimens in Participants with Newly Diagnosed Transplant Eligible Multiple Myeloma

OBJECTIVES:

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

The key secondary objective is to evaluate the efficacy of teclistamab- and talquetamab-based combination regimens as induction and post-transplant maintenance treatments, and teclistamab in combination with talquetamab as replacement for HDT+ASCT following induction

Detailed description: OVERALL DESIGN:

130 participants will be enrolled with 10 participants in Arm A, 20 participants in Arm A1, 20 participants in Arm B, 10 participants in Arms C and 10 in C2, 20 participants in Arm D, 10 participants in each Arm E, E1 and optionally F and F1. Cohorts may be further expanded.

Arms A, A1, B, D, E, E1, F, F1 will receive Induction Therapy of 6 cycles (28-days each):

Treatment: Tec-DRd (Arm A, A1), Tec-DVRd (Arm B), Tal-DRd (Arms E, E1), Tal-DVRd (Arms F, F1) followed by HDT and a single ASCT according to local SoC treatment. Thereafter a Maintenance Therapy of maximum 18 cycles with either Tec-D (Arms A, A1, B, E, F) or Tal-D (E1, F1) is performed.

Arm D will receive Tec-DVRd induction followed by 18 cycles Tec-Tal. No HDT ASCT will be performed in Arm D.

In Arm C and C2 participants will enter the study for maintenance treatment of 18 cycles with Tec-D (Arm C) or Tal-DR (Arm C2) , after induction, HDT and ASCT according to local SoC (outside of the study).

Participants will receive maintenance treatment or following induction treatment (Arm D) for a maximum of 18 cycles or until confirmed progressive disease, death, intolerable toxicity, loss to follow-up, or consent withdrawal, whichever comes first. An optional end of treatment is possible for patients who have 12 months sustained MRD negativity.

Periodic safety evaluations will be conducted to ensure that treatment is safe and tolerable. Upon treatment discontinuation, an EOT Visit will be conducted. Thereafter, the participant will continue in the Follow-up Phase until death, withdrawal of consent, loss to follow-up, or end of the study, whichever occurs first.

Eligibility criteria: Inclusion Criteria:

- 18 years of age to 70 years of age, inclusive

* Have an ECOG performance status score of 0 to 2 at screening
* Have clinical laboratory values meeting prespecified criteria during the Screening Phase.

Participants in Arms A, A1, B, D, E, E1, F and F1 must also satisfy all of the following criteria to be enrolled in the study:

1. Documented multiple myeloma requiring treatment as defined by the criteria below:

1. Multiple myeloma diagnosis according to the IMWG diagnostic criteria
2. Measurable disease at screening as defined by any of the following:

   1. Serum M-protein level ≥1.0 g/dL or
   2. Urine M-protein level ≥200 mg/24 hours or
   3. Serum immunoglobulin free light chain level ≥10 mg/dL and abnormal serum free light chain ratio

   2. Newly diagnosed participants for whom HDT and ASCT is part of the intended treatment plan (except Arm D participants).

   Participants Arm C and C2 must also satisfy all of the following criteria:
   1. Newly diagnosed multiple myeloma according to IMWG criteria.
   2. Must have received 4 to 6 cycles 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.

   3 Must have received only one line of therapy and achieved at least a PR as per IMWG 2016 without evidence of progression at the time of enrollment.

   4. 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:

   - CNS involvement or clinical signs of meningeal involvement of multiple myeloma.
   * Stroke or seizure within 6 months prior study start Cycle1 Day1.
   * History of transplantations requiring immunosuppressive therapy.
   * Seropositive for HIV, HEP B, Active Hep C infection (details see protocol).
   * COPD with a FEV1 \<50% of predicted normal.
   * Moderate /severe persistent asthma within the past 2 years or any uncontrolled asthma. Exclude if FEV1 \<50% of predicted normal.
   * Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures, or that in the investigators opinion would constitute a hazard for participants.
   * Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug/excipients.
   * Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of any study treatment regimen.
   * 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.

   Arm A, A1, B, D, E, E1, F, F1

   - 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.

   - Arm B only: Peripheral neuropathy or neuropathic pain Grade 2 or higher as defined by the NCI-CTCAE Version 5.

   Due to a potential interaction with bortezomib, received a strong CYP3A4 inducer within 5 half-lives prior to enrollment

   Arm C and C2

   - Discontinued treatment due to any AE related to lenalidomide as determined by the investigator.

   - Progressed on multiple myeloma therapy at any time prior to screening.
   * Received a cumulative dose of corticosteroids equivalent to ≥40 mg of dexamethasone within the 14 day period before the start of study treatment administration.
   * Intolerant to the starting dose of lenalidomide (10 mg).

   For further details on inclusion/exclusion criteria please refer to the study protocol.

Primary outcomes:
measure: number of incidence and severity of adverse events [safety and tolerability]
timeFrame: through study completion, up to 28 months
Secondary outcomes:
measure: MRD negativity rate
timeFrame: after 6 cycles (each cycle is 28 days) induction therapy (app.month 6), after High Dose Therapy (app. month 10), after 18 cycles (each cycle is 28 days) of maintenance therapy (app. month 28)
measure: Response on therapy [efficacy]
timeFrame: after each cycle (each cycle is 28 days) induction ( app. at month 1,2,...,6), after High Dose therapy (app. month 10), after each cycle (each cycle is 28 days) of maintenance (app. at month 11,12, ...28), during FU every 3 months (app. up to 3-4 years)
measure: Progression Free Survival [efficacy]
timeFrame: From randomization to the date of disease progression to death (app. up to 3-4 years)
measure: Serum concentration of teclistamab, talquetamab and daratumumab [pharmacokinetics]
timeFrame: through study completion, up to 28 months
measure: Presence of ADAs to teclistamab, talquetamab and daratumumab [immunogenicity]
timeFrame: through study completion, up to 28 months
measure: Stem cell yield
timeFrame: after High Dose Therapy (after app. 10 months)
measure: days to engraftment
timeFrame: after High Dose Therapy (after app. 10 months)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité University Medicin Berlin
city: Chemnitz
country: Germany
facility: Clinic Chemnitz gGmbH
city: Dresden
country: Germany
facility: University Clinic Technical University Dresden
city: Düsseldorf
country: Germany
facility: University Clinic Düsseldorf
city: Freiburg
country: Germany
facility: University Clinic Freiburg
city: Hamburg
country: Germany
facility: Hamburg University Clinic Eppendorf
city: Hamburg
country: Germany
facility: Asklepios Clinic Hamburg Altona
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg
city: Kiel
country: Germany
facility: University Clinic Schleswig-Holstein Campus Kiel
city: Munich
country: Germany
facility: Technical University Munich
city: Würzburg
country: Germany
facility: University Würzburg
Study officials:
References: