| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Multiple Myeloma |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10005330 |
| E.1.2 | Term | Blood and lymphatic system disorders congenital |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| 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 |
-Part 1 (Dose Escalation): To characterize the safety of talquetamab and recommend the Phase 2 dose(s) and schedule
-Part 2 (Dose Expansion): To further characterize the safety of talquetamab at the recommended Phase 2 dose(s) (RP2Ds)
-Part 3 (Phase 2): To evaluate the efficacy of talquetamab at the RP2Ds
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| E.2.2 | Secondary objectives of the trial |
Part 1
1. To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of talquetamab
2. To assess the immunogenicity of talquetamab
Part 2
3. To evaluate the preliminary antitumor activity of talquetamab at the RP2D(s)
Part 3
1. To further assess the efficacy of talquetamab at the RP2Ds
2. To evaluate MRD at the RP2Ds
3. To further assess the safety and tolerability of talquetamab at the RP2Ds
4. To characterize the PK of talquetamab at the RP2Ds
5. To assess the immunogenicity of talquetamab
6. To assess PROs after treatment with talquetamab
7. To evaluate the efficacy of talquetamab in high risk molecular subgroups |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥18 years of age.
2. Criterion modified per Amendment 11
2.1. Documented initial diagnosis of multiple myeloma according to IMWG diagnostic a criteria
3. Criterion modified per Amendment 1
3.1. Criterion modified per Amendment 13
3.2. Part 1:
Subjects with measurable multiple myeloma who have progressed on, or could not tolerate, all available established therapies.
Part 2:
Subjects with multiple myeloma measurable by central laboratory assessment who have progressed on, or could not tolerate, all available established therapies:
Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours;
or
Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio
If central laboratory assessments are not available, relevant local laboratory measurements must exceed the minimum required level by at least 25%.
Part 3
Measurable disease
Cohort A, B and Cohort C: Multiple myeloma must be measurable by central laboratory assessment:
. Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine Mprotein level ≥200 mg/24 hours; or
. Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
If central laboratory assessments are not available, relevant local laboratory measurements must exceed the minimum required level by at least 25%.
Prior treatment
. Cohort A and Cohort C: have previously received ≥3 prior lines of therapy that included at least one PI, one IMiD, and an anti-CD38 monoclonal antibody, and have not been exposed to T cell redirection therapies such as CAR-T or bispecific antibodies.
. Cohort B: have previously received ≥3 prior lines of therapy that included at least one PI, one IMiD, and an anti-CD38 monoclonal antibody, and have been exposed to T cell redirection therapies such as CAR-T or bispecific antibodies.
Cohorts A, B and C:
Undergone at least 1 complete cycle of treatment for each line of therapy, unless progressive disease was the best response to the line of therapy.
Subject must have documented evidence of progressive disease based on investigator’s determination of response by the IMWG 2016 criteria on or within 12 months of their last line of therapy. Also, subjects with documented evidence of progressive disease within the previous 6 months and who are refractory or non-responsive to their most recent line of therapy afterwards are eligible.
4. Criterion modified per Amendment 11
4.1. Criterion modified per Amendment 12
4.2. Eastern Cooperative Oncology Group (ECOG) performance status
score of 0 or 1 for Parts 1 and 2 and 0-2 for Part 3 of the study..
5. Criterion modified per Amendment 1, 9, 11
5.3 Criterion modified per Amendment 12
5.4. Pretreatment clinical laboratory values meeting the predefined
criteria during the Screening Phase
6. Criterion modified per Amendment 10
6.1. Criterion modified per Amendment 11
Women of childbearing potential (WOCBP) must have a negative pregnancy test at screening and prior to the first dose of study drug using a highly sensitive pregnancy test either serum (β human chorionic gonadotropin [β-hCG]) or urine.
. a woman is considered of childbearing potential (WOCBP) ie, fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
7. Criterion modified per Amendment 13
7.1. Before the first dose of study drug:
Women
Women must be (as defined in Attachment 16) either one of the following:
a) Not of childbearing potential
b) Of childbearing potential and
- Practicing true abstinence OR
- Have a sole partner who is vasectomized OR
- Practicing at least 1 highy effective user-independent method of contraception (see Attachment 16)
Subject must agree to continue to above from the time of signing the informed consent form (ICF), while receiving study drug, and until 100 days after the last dose of study drug. Women of childbearing potential must agree to pregnancy testing (serum or urine) within 100 days after the last study drug administration.
Please refer to protocol for all the inclusion criteria.
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| E.4 | Principal exclusion criteria |
1. Criterion modified per Amendment 11
1.1. Prior Grade 3 CRS or higher (Per Lee Criteria 2014) related to any T cell redirection (eg, CD-3 redirection technology or CAR-T cell therapy) or any prior GPRC5D targeting therapy
2. Criterion modified per Amendment 10.
2.1 Criterion modified per Amendment 11
2.2 Prior antitumor therapy as follows, prior to the first dose of study drug:
. Gene modified adoptive cell therapy (eg, chimeric antigen receptor modified T cells [CAR-T], natural killer [NK] cells) within 3 months.
. Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an invasive investigational medical device within 21 days or at least 5 half-lives, whichever is less.
. Monoclonal antibody treatment for multiple myeloma within 21 days.
. Cytotoxic therapy within 21 days.
. Proteasome inhibitor therapy within 14 days.
. Immunomodulatory agent therapy within 7 days.
. Radiotherapy within 14 days. However, if palliative focal radiation is used, the subject is eligible irrespective of the end date of radiotherapy.
Part 3 only:
. Cohort A and Cohort C only: exposed to a CAR-T or T cell redirection therapy at any time.
. Cohort B: T cell redirection therapy within 3 months
3. Criterion modified per Amendment 11
3.1. Vaccinated with live, attenuated vaccine within 4 weeks or as recommended by the product manufacturer prior to the first dose, during treatment, or within 100 days of the last dose of talquetamab.
4. Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy.
5. Criterion modified per Amendment 11.
5.1. Received a cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within the 14-day period before the first dose of study drug (does not include pretreatment medication).
6. Received either of the following:
. An allogenic stem cell transplant within 6 months before first dose of study drug. Subjects who received an allogeneic transplant must be off all immunosuppressive medications for 6 weeks without signs of graft versus host disease (GVHD).
. An autologous stem cell transplant ≤12 weeks before first dose of study drug
7. Central nervous system (CNS) involvement or clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain magnetic resonance imaging (MRI) and lumbar cytology are required.
8. Criterion modified per Amendment 6
8.1. Criterion modified per Amendment 11
8.2. Plasma cell leukemia (>2.0 x 10 to the 9th/L plasma cells by standard differential), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein], and skin changes), or primary amyloid light chain amyloidosis.
9. Known to be seropositive for human immunodeficiency virus or acquired immune deficiency syndrome.
10. Criterion modified per Amendment 11
10.1. Hepatitis B infection as defined according to the American Society of Clinical Oncology guidelines. In the event the infection status is unclear, quantitative levels are necessary to determine the infection status.
Active Hepatitis C infection as measured by positive HCV-RNA testing. Subjects with a history of Hepatitis C virus antibody positivity must undergo HCV-RNA testing.
11. Pulmonary compromise requiring supplemental oxygen use to maintain adequate oxygenation.
12. Criterion modified per Amendment 11
12.1. Known allergies, hypersensitivity, or intolerance to talquetamab or its excipients.
13. Criterion modified per Amendment 11
13.1. Any serious underlying medical condition, such as:
• Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection
• Active autoimmune disease or a documented history of autoimmune disease, with the exception of vitiligo, resolved childhood atopic dermatitis, and prior Grave’s disease that is currently euthyroid based on clinical symptoms and laboratory testing.
• Psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status
• Any other issue that would impair the ability of the subject 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 subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
14. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 100 days after the last dose of study drug.
15. Plans to father a child while enrolled in this study or within 100 days after the last dose of study drug.
Please refer to protocol for all the exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 (Dose Escalation):
1. Frequency and type of dose-limiting toxicity (DLT); frequency and severity of adverse events, serious adverse events, and laboratory abnormalities
Part 2 (Dose Expansion):
2. Frequency and severity of adverse events, serious adverse events, and laboratory abnormalities
Part 3 (Phase 2):
3. ORR (PR or better) as defined by the IMWG criteria based on review by the IRC. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to Day 28
2. Duration of follow-up (up to 16 weeks after last dose)
3. 6-months after the 120th subject in Cohort A receives initial dose of talquetamab and after response can be assessed for last subject in Cohort B. |
|
| E.5.2 | Secondary end point(s) |
Part 1 and Part 2:
1.Pharmacokinetic parameters and PD markers including, but not limited to, depletion of GPRC5D expressing cells, systemic cytokine concentrations, and markers of T cell
2. Presence and activity of anti-talquetamab antibodies
3. Assess the overall response rate (ORR) (at least a partial response [PR] or better), clinical benefit rate (CBR); as defined by the International Myeloma Working Group (IMWG) response criteria
4. DOR
5. TTR
6. VGPR or better/CR or better/sCR rate as defined by IMWG response criteria
7. PFS
Part 3:
1. DOR; VGPR or better/CR or better/sCR as defined by IMWG response criteria; TTR; PFS; OS
2. MRD-negative status
3. Occurrence and severity of adverse events, serious adverse events, and laboratory values
4. Pharmacokinetic parameters in a population PK analysis
5. Presence and activity of anti-talquetamab antibodies
6. Change from baseline in overall HRQoL, symptoms, and functioning
7. ORR in patients with high-risk molecular features |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to Cycle 7, Day 1
2. Up to Cycle 7, Day 1
3-7. Duration of the study
Part 3:
1-3, 5,7: Duration of the study
4. D1 of priming dose
6. D1 of Cycle 1, D1 of every odd cycle and EOT |
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| 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 | No |
| 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 |
-Immunogenecity
-Biomarker
-Immunoregulatory activity |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose Escalation/Expansion |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| Belgium |
| France |
| Germany |
| Israel |
| Korea, Republic of |
| Netherlands |
| Poland |
| Spain |
| United States |
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| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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