| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 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 | 100000004864 |
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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 |
| The primary objective is to compare the efficacy of talquetamab versus belantamab mafodotin in terms of ORR or PFS. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
●To further compare the efficacy of talquetamab versus belantamab mafodotin.
●To assess the safety and tolerability of talquetamab and belantamab mafodotin.
●To characterize the PK of talquetamab.
●To assess the immunogenicity of talquetamab.
●To assess participant’s reported symptoms and general well-being with talquetamab and belantamab mafodotin. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. Be ≥18 years of age at the time of informed consent.
Disease Characteristics
2. Documented multiple myeloma as defined by the criteria below:
a. Multiple myeloma according to IMWG diagnostic criteria.
b. Measurable disease at screening, as assessed by central laboratory, 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) Light chain multiple myeloma without measurable M-protein in the serum or the urine: sFLC ≥10 mg/dL (central laboratory) and abnormal serum immunoglobulin kappa lambda FLC ratio.
Prior Therapy Restrictions or Requirements
3. Received at least 4 prior antimyeloma therapies including an anti-CD38 mAb (alone or in combination) and is refractory per IMWG criteria to at least one PI, and one IMiD.
4. Documented evidence of progressive disease based on investigator’s determination of response by IMWG criteria on or after their last regimen.
Performance Status
5. Have an ECOG performance status of 0 to 2 at screening.
Clinical Laboratory Values
6. Have clinical laboratory values meeting the criteria during the Screening Phase.
7. 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/mm^3 at screening
● No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of screening
● 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. Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to enrollment).
Sex and Contraceptive/Barrier Requirements
8. A female participant of childbearing potential must have a negative serum pregnancy testat screening, and must agree to further serum or urine pregnancy tests during the study and within 6 months after receiving the last dose of study treatment.
9. A female participant must agree not to be pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or for 6 months after the last dose of study treatment.
10. A female participant must be either of the following:
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 at least 1 highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and
agrees to remain on a highly effective method while receiving study treatment and until 6 months after the last dose of study treatment. The investigator must evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention.
11. A female participant using oral contraceptives must use an additional barrier contraceptive method.
12. A female 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 a period of 6 months after receiving the last dose of study treatment. Female participants should consider preservation of eggs prior to study treatment as anticancer treatments may impair fertility.
13. A male participant must agree not to plan to father a child while enrolled in this study or within 6 months after the last dose of study treatment.
14. A male participant must wear a condom (with or without spermicide) when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after receiving the last dose of study treatment.
If partner is a female of childbearing potential, the male participant must use condom(with or without spermicide) and the partner must also be practicing a highly effective method of contraception.
15. A male participant must agree not to donate sperm for the purposes of reproduction during the study and for 6 months after receiving the last dose of study treatment.
Informed Consent
16. Must sign an ICF (or their legally acceptable representative must sign) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
17. Be willing and able to adhere to the lifestyle restrictions specified in this protocol.
Refer the protocol for full inclusion criteria
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| E.4 | Principal exclusion criteria |
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
Medical Conditions
1. Contraindications or life-threatening known allergies, hypersensitivity, or intolerance to any study drug or its excipients.
2. Stroke or seizure within 6 months prior to signing ICF.
3. 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.
4. Any of the following:
a. Hepatitis B infection (hepatitis B surface antigen 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.
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 for at least 12 weeks following the completion of therapy, the participant is eligible for the study.
5. Major surgery or had significant traumatic injury 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.
6. Current corneal epithelial disease except mild punctate keratopathy.
7. 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. Uncontrolled diabetes
b. Acute diffuse infiltrative pulmonary disease.
c. Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy.
d. 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 thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing are eligible regardless of when these conditions were diagnosed.
e. Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status.
f. 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.
g. History of noncompliance with recommended medical treatments.
Disease Characteristics
8. 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.
9. Plasma cell leukemia (>2.0×10^9/L) at the time of screening, Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or primary amyloid light chain amyloidosis.
10. 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. Non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured.
b. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.
c. Noninvasive cervical cancer treated within the last 24 months that is considered completely cured.
d. Localized prostate cancer (N0M0):
1) With a Gleason score of ≤6, treated within the last 24 months, or untreated and under surveillance.
2) With a Gleason score of 3+4 that has been treated >6 months prior to full study screening and considered to have a very low-risk of recurrence, or
e. History of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low-risk of recurrence.
f. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low-risk of recurrence.
Refer the protocol for full exclusion criteria
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Overall response: defined as confirmed best overall response of PR or better according to IMWG criteria.
2. PFS: defined as the duration from the date of randomization to either progressive disease or death, whichever comes first.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Subjects will have disease evaluation performed by the central laboratory every 6 weeks until disease progression. These endpoints will be evaluated at interim analysis and primary analysis. |
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| E.5.2 | Secondary end point(s) |
1. Depth of response characteristic:
- VGPR or better: defined as confirmed best overall response of VGPR or better according to IMWG criteria.
- CR or better: defined as confirmed best overall response of CR or better according to IMWG criteria.
2. OS: defined as the time from randomization to date of death due to any cause.
3. PFS2: defined as time from randomization to progression on the first subsequent line of therapy or death due to any cause, whichever comes first.
4. Incidence and severity of AEs, laboratory results, and other safety parameters
5. Serum concentration of talquetamab.
6. Incidence and titers of ADAs to talquetamab.
7. Change from baseline in symptoms, functioning, and general well-being.
8. Time to sustained worsening in symptoms and general well-being. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| These endpoints will be evaluated at interim analysis and primary analysis. |
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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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Immunogenicity and Biomarker Evaluations |
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| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Canada |
| Israel |
| United States |
| Poland |
| Spain |
| Czechia |
| Germany |
| Greece |
| Italy |
| Portugal |
| United Kingdom |
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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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| The study will end upon completion of the Final OS Analysis. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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