| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy of Tal-DP and Tal-D, respectively, with DPd |
|
| E.2.2 | Secondary objectives of the trial |
1. To further compare the efficacy of Tal-DP and Tal- D, respectively, with DPd
2. To assess the safety profile of Tal-DP and Tal-D
3. To characterize the PK of talquetamab and daratumumab
4. To assess the immunogenicity of talquetamab and daratumumab
5. To assess changes in patient-reported outcomes (PROs) with Tal-DP, DPd, and Tal-D |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥18 years of age.
2. 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 ≥0.5 g/dL (central laboratory); or
2) Urine M-protein level ≥200 mg/24 hours (central laboratory); or
3) Light chain multiple myeloma without measurable M-protein in the serum or the urine: serum immunoglobulin free light chain ≥10 mg/dL (central laboratory), and abnormal serum immunoglobulin kappa lambda free light chain ratio (central laboratory normal ranges).
3. Relapsed or refractory disease as defined below:
a. Relapsed disease is defined as an initial response to prior treatment, followed by confirmed progressive disease by IMWG criteria >60 days after cessation of treatment.
b. Refractory disease is defined as <25% reduction in M-protein or confirmed progressive disease by IMWG criteria during previous treatment or =60 days after cessation of treatment.
4. Received at least 1 prior line of antimyeloma therapy including a PI and lenalidomide. Participants who have received only 1 prior line of antimyeloma therapy must be considered lenalidomide-refractory (ie, have demonstrated progressive disease by IMWG criteria on or within 60 days of completion of lenalidomide-containing regimen). Participants who have received ≥2 prior lines of antimyeloma therapy must be considered lenalidomide exposed.
5. Documented evidence of progressive disease based on investigator’s determination of response by the IMWG criteria on or after their last regimen.
6. Have an ECOG performance status score of 0, 1, or 2 at screening and immediately prior to the start of administration of study treatment.
7. Have clinical laboratory values as defined in the protocol
8. Human immunodeficiency virus-positive participants are eligible if they meet all of the following:
- No detectable viral load (ie, <50 copies/mL) at screening
- CD4+ count >300 cells/mm3 at screening
- No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of screening
- Receiving highly active antiretroviral therapy (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.
9. A participant of childbearing potential must have a negative highly sensitive urine or serum (β human chorionic gonadotropin [β hCG]) pregnancy test at screening, within 24 hours prior to the start of study treatment, and must agree to further urine or serum pregnancy tests during the study and within 100 days after receiving the last dose of study treatment.
10. A participant must be:
a. Not of childbearing potential, or
b. Of childbearing potential and
1) Practicing true abstinence; or
2) Have a sole partner who is bilaterally vasectomized; or
3) Practicing 2 effective methods of contraception (at least 1 highlyeffective, method of contraception). For participants who are of childbearing potential, see protocol Section 6.12.3 for details regarding concomitant use of estrogen containing products and pomalidomide
11. 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 for at least 100 days after the last dose of study treatment. Participants should consider preservation of eggs prior to study treatment as anticancer treatments may impair fertility.
12. A participant 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 minimum of 100 days after receiving the last dose of study treatment. Participants should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility. If a partner is of childbearing potential, a highly effective method of contraception should be used.
13. 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.
14. Must be willing and able to adhere to the lifestyle restrictions specified in this protocol including to not donate blood or blood components during the study and for 100 days after the last dose of study drug), including adherence to the global PPP or local PPP/REMS program for pomalidomide.
15. 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.
For additional details, see protocol |
|
| E.4 | Principal exclusion criteria |
1. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to study drug excipients (refer to the talquetamab and daratumumab IB and appropriate prescribing information).
2. Disease is considered refractory to an anti-CD38 monoclonal antibody as defined per IMWG consensus guidelines (progression during treatment or within 60 days of completing therapy with an anti-CD38 monoclonal antibody).
3. Prior or concurrent exposure to any of the following, in the specified time frame prior to randomization:
a. GPRC5D-directed therapy
b. Received prior pomalidomide therapy
c. T cell redirection therapy (for example, antibody therapy or BiTE’s) within 3 months
d. Gene-modified adoptive cell therapy (eg, chimeric antigen receptor modified T cells, NK cells) within 3 months
e. Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an invasive investigational medical device within 21 days or ≥5 half-lives, whichever is less
f. Investigational vaccine other than SARS CoV-2 vaccine approved/ in use under emergency approval within 4 weeks
g. Live, attenuated vaccine within 4 weeks
h. Monoclonal antibody therapy within 21 days
i. Cytotoxic therapy within 21 days
j. PI therapy within 14 days
k. IMiD agent therapy within 14 days
l. Radiotherapy within 14 days or focal radiation within 7 days
4. Received either of the following:
a. An allogeneic SCT within 6 months before the first dose of study treatment. Participants who received an allogeneic transplant must be off all immunosuppressive medications during the 6 weeks before the start of study treatment administration without signs of graft versus host disease
b. An autologous SCT within 12 weeks before the start of study treatment administration.
5. A maximum cumulative dose of corticosteroids to ≥140 mg of prednisone or equivalent within 14-day period before the first dose of study drug
6. Known active CNS involvement or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required.
7. Plasma cell leukemia (per IMWG criteria) at the time of screening, Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or
primary amyloid light chain amyloidosis.
8. Myelodysplastic syndrome or active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than relapsed/refractory multiple myeloma. The only allowed exceptions are:
a. Any history of malignancy other than multiple myeloma, which is considered at high risk of recurrence requiring systemic therapy
b. Any ongoing B-cell malignancy or myelodysplastic syndrome
c. Any active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than relapsed/refractory 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-PUNLMP 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)Noninvasive cervical cancer
4) Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer (antiantihormonal 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
9. Stroke, transient ischemic attack or seizure within 6 months prior to randomization.
10. Participant is pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 100 days after the last dose of study treatment.
11. Participant plans to father a child while enrolled in this study or within 100 days after the last dose of study treatment.
12. Presence of the following cardiac conditions:
a. New York Heart Association stage III or IV congestive heart failure
b. Myocardial infarction or coronary artery bypass graft ≤6 months prior to randomization
c. History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
d. History of severe non-ischemic cardiomyopathy
13. Any of the following:
a. Hepatitis B infection (HBsAg or HBV-DNA positive): In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status.
b. Active hepatitis C infection as measured by positive HCV-RNA testing.
For additional details, see protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Subjects will have disease evaluation performed by the central laboratory Day 1 of every cycle until disease progression. This endpoint will be evaluated at interim analysis and primary analysis. The projected time frame is up to 4 years. |
|
| E.5.2 | Secondary end point(s) |
1.
-Overall response (PR or better)
- VGPR or better
- CR or better
- Overall MRD negative CR
- OS
- PFS2
- TTNT
2. Incidence and severity of AEs
3. Talquetamab and daratumumab serum concentrations
4. Presence of ADAs to talquetamab and daratumumab
5.
-Time to worsening in symptoms, functioning, and overall HRQoL
- Change from baseline in symptoms, functioning, and overall HRQoL |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| These endpoints will be evaluated at interim analysis and primary analysis. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Taiwan |
| Brazil |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Türkiye |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will end upon completion of the Final OS Analysis. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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