An open label, multicenter, Phase 2, pilot study, evaluating early treatment with bispecific T-cell redirectors (teclistamab and talquetamab) in the therapy of newly diagnosed high -risk multiple myeloma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Pethema

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

22 Jun 2023 → ongoing

Decision date (initial)

2024-08-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Jassen Cilag

External identifiers

EU CT number

2024-514016-26-00

EudraCT number

2022-000598-15

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To evaluate efficacy in terms of MRD negative CR rate after Teclistamab - Daratumumab intensification

Secondary objectives 9

1. To evaluate MRD negative CR rate after D-VRD induction.
2. To evaluate MRD negativity after Tec-Dara intensification using alternative methods.
3. To evaluate MRD conversion after early rescue intervention with Tal- Dara.
4. To evaluate MRD conversion after Tec-Dara intensification.
5. To evaluate sustained MRD negativity during maintenance treatment in both Tec-Dara and Tal-Dara treatment arms
6. To assess reappearance of MRD positivity or relapse from CR in patients during the Tec-Dara treatment
7. To assess Time to event data
8. To assess the safety of the treatment described in the protocol
9. Immune profiling and genetic characterization

Conditions and MedDRA coding

Multiple Myeloma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements
2. A female of childbearing potential must have a negative highly sensitive urine or serum (β human chorionic gonadotropin [β-hCG]) pregnancy test at screening and 24h prior to the start of study treatment and must agree to further urine or serum pregnancy tests during the study and within 6 months after receiving the last dose of study treatment
3. A woman must be: a. Not of childbearing potential, or b. Of childbearing potential and i. Practicing true abstinence; or ii. Have a sole partner who is vasectomized; or iii. Practicing 2 methods of contraception (at least 1 highly‑effective)
4. 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 6 months after receiving the last dose of study treatment
5. A male patient must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 3 months after receiving the last dose of study treatment. Male participants must also be advised of the benefit for a female partner to use a highly effective method of contraception as condoms may break or leak.
6. A male patients must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 3 months after receiving the last dose of study treatment.
7. Patient must be willing and able to adhere to the lifestyle restrictions specified in the protocol (Section 4.3)
8. All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events [NCI-CTCAE], Version 5.0 must be ≤ Grade 1 at the time of enrolment except for alopecia.
9. Patient has given voluntary written informed consent before performance of any study-related procedure nor part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
10. Age between 18 – 80 years regardless of transplant eligibility at the time of inclusion.
11. Patient has documented diagnosis of multiple myeloma according to IMWG diagnostic criteria, with at least one of the following high-risk features: a)High-risk FISH: del(1p), del(17p), t(4;14), t(14;16) and 1q amplifications. b)R-ISS 3. c)Presence of extramedullary disease, defined as presence of paramedullary lesions or extramedullary plasmacytoma.
12. Patient has measurable secretory disease defined as either serum monoclonal protein of ≥ 0.5 g/dL or urine monoclonal (light chain) protein ≥ 200 mg/24 h. For patients whose disease is only measurable by serum FLC, the involved FLC should be ≥ 10mg/dL (100 mg/L), with an abnormal serum FLC ratio.
13. Human inmunodeficiency virus-positive patients are elegible if they meet all of the following: a. No detectable viral load (ie, < 50 copies/mL) at screening b. CD4+ count > 300 cells/mm3 at screening c. No AIDS defining opportunistic infection within 6 months of screening d. Receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.
14. Patient has an ECOG performance status of 0, 1 or 2.
15. Patient must have adequate organ function, defined in: Hemoglobin ≥ 8 g/dL, Platelets ≥ 75 x 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), ANC ≥ 1.0 x 109 /L, ALT and AST ≤ 2.5 x upper limit normal, eGFR ≥30 mL/min based on Modified Diet in Renal Disease Formula calculation or creatine clearance measured by a 24-hour urine collection, Total bilirubin ≤ 1.5 x ULN (isolated total bilirubin ≥ 1.5 x ULN with conjugated [direct] bilirubin < 1.5 x ULN is allowed for those patients Corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L)

Exclusion criteria 22

1. Prior or current systemic therapy or SCT for any plasma cell dyscrasia, with the exception of 1 cycle of antimyeloma treatment or the emergency use of a short course of corticosteroids before treatment while waiting for results of genetic analysis
2. Plasmapheresis within 28 days of starting study treatment defined as C1D1 of D-VRD.
3. 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
4. Moderate or severe persistent asthma within the past 24 months, or uncontrolled asthma of any classification
5. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to other molecular antibodies.
6. Major surgery or significant traumatic injury within 2 weeks prior to the start of administration of study treatment, or will not have fully recovered from surgery, or 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
7. Peripheral neuropathy or neuropathic pain Grade ≥ 2
8. Patient has a diagnosis of primary light chain amyloidosis, MGUS, SMM, plasma cell leukemia or active POEMS syndrome at the time of screening.
9. Myelodysplastic syndrome or active malignancies (progressing or requiring treatment change in the last 24 months) other than relapsed/refractory MM. Exceptions: malignancies treated within the last 24 months that are considered completely cured: -Non-muscle invasive bladder cancer -Skin cancer: non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone -Noninvasive cervical cancer -Localized prostate cancer, Gleason score of ≤ 7a, treated locally only -Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving antihormonal agents -Other malignancy that is considered cured with minimal risk of recurrence
10. Patient has CNS or exhibits clinical signs of meningeal involvement of MM
11. Patient is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study treatment
12. Patient plans to father a child while enrolled in this study or within 3 months after the last dose of study treatment
13. Patient is simultaneously enrolled in other interventional CT
14. Patient has received prior radiotherapy within 2 weeks of start of study therapy. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy ) to non CNS disease
15. Prior or concurrent exposure to any of the following: -Investigational vaccine other than SARS CoV-2 vaccine approved/ in use under emergency approval within 4 weeks -Live, attenuated vaccine within 4 weeks, before enrollment.Non-life vaccines authorized for emergency use (eg. COVID-19) and allowed (APPENDIX 22). - Monoclonal antibody therapy within 21 days (not use for the treatment of MM)
16. Received a strong CYP3A4 inducer within 5 half-lives prior to starting study treatment
17. A maximum cumulative dose of corticosteroids of ≥ 140 mg of prednisone or equivalent within 14 day period before the first dose of Tec-Dara or Tal-Dara
18. Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients, or sensitivity to mammalian-derived products or lenalidomide
19. Presence of the following cardiac conditions: a) New York Heart Association stage III or IV congestive heart failure (APPENDIX 19) b) Myocardial infarction or coronary artery bypass graft ≤ 6 months prior to starting study treatment 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.
20. Stroke, transient ischemic attack or seizure within 6 months prior to signing ICF
21. Any of the following: -Hepatitis B infection (ie, HBsAg or HBV-DNA +). In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status -Active hepatitis C infection as measured by + HCV-RNA testing. Patients with a history of HCV antibody + must undergo HCV-RNA testing. If a patient with history of chronic hepatitis C infection (HCV antibody and HCV-RNA positive) completed antiviral therapy and has undetectable HCV-RNA for at least 12 weeks following the completion of therapy, the patient is eligible for the study
22. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MRD measured by NGF (sensitivity level of 10-6) and FDG PET-CT scan using the Deauville score and CR evaluated per IMWG 2016 response criteria after 6 cycles of Tec-Dara therapy

Secondary endpoints 9

1. MRD measured by NGF (sensitivity level of 10-6) and FDG PET-CT scan using the Deauville score and CR evaluated per IMWG 2016 response criteria after 4 cycles of D-VRD induction
2. MRD negative rates measured by NGS, and QIP-MS-FLC after 6 cycles of Tec-Dara therapy
3. Percentage of patients converting from positive MRD to negative MRD evaluated by NGF, NGS, QIP-MS-FLC and FDG-PET-CT scan.
4. Percentage of patients converting from positive MRD after D-VRD induction to negative MRD evaluated by NGF, NGS, QIP-MS-FLC and FDG-PET-CT scan after Tec-Dara intensification.
5. Proportion of patients with persistent MRD negative disease at month 6, 12, 18 and 24 of maintenance treatment in both Tec-Dara and Tal-Dara treatment, by NGF, NGS, QIP-MS-FLC and FDG-PET-CT scan and annually thereafter
6. Proportion of patients relapsing from MRD negative CR to MRD positive or who relapse from CR (not fulfilling criteria for disease progression) during any phase of Tec-Dara treatment (intensification or maintenance)
7. PFS, EFS, TNT, DoR and OS
8. Incidence of treatment-emergent adverse events
9. Analysis of immune subpopulation and genetic markers.

Investigational products

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

Test 12

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Pethema

Sponsor organisation

Fundacion Pethema

Address

Calle De Santa Balbina 2 Oficinas 3 4 5

City

Madrid

Postcode

28023

Country

Spain

Scientific contact point

Organisation

Fundacion Pethema

Contact name

Juan José Lahuerta Palacios

Public contact point

Organisation

Fundacion Pethema

Contact name

Juan José Lahuerta Palacios

Third parties 2

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 11 files

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

Application history

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