| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/refractory hematological malignancies |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed/refractory hematological malignancies |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066481 |
| E.1.2 | Term | Hematological malignancy |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 1. Part 1: To determine the safety and tolerability of MK-7684A (Cohorts A to F) |
|
| E.2.2 | Secondary objectives of the trial |
1. Part 1: To evaluate ORR following administration of MK-7684A (Cohorts A to F) per disease-specific criteria as assessed by the investigator
2. Part 1: To evaluate the DOR following administration of MK-7684A (Cohorts A to F)
3. Part 1: To evaluate the DCR following administration of MK-7684A (Cohorts A to F)
4. Part 1: To characterize the PK profile of vibostolimab (Cohorts A to F)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Cohort A
cHL
a) Diagnosis of cHL
b) Relapsed or refractory cHL to at least 1 prior line of therapy
c) Not been previously treated with an anti-PD-1 or anti-PD-L1 therapy PMBCL
d) Diagnosis of PMBCL
e) Relapsed or refractory to PMBCL to at least 2 prior lines of therapies
f) Relapsed or refractory to CAR-T-cell Therapy or unable to receive it.
g) Mus have previously received rituximab as part of prior treatment
h) Not been previously treated with an anti-PD-1-L1 therapy
2. Cohort B
cHL
a) Diagnosis of cHL
b) Relapsed or refractory cHL to at least 2 prior lines of therapies
c) Have progressed on treatment with an anti-PD-1/L1 mAb administered as monotherapy or with other checkpoint inhibitors or other therapies PMBCL
d) Diagnosis of PMBCL, according to the WHO classification
e) Relapsed or refractory PMBCL to at least 3 prior lines of therapies
f) Must have previously received rituximab as part of prior treatment
g) Relapsed or refractory to CAR-T-cell therapy or unable to receive it
h) Have progressed on treatment with an anti-PD-1/L1 mAb administered as monotherapy or with other checkpoint inhibitors or other therapies
3. Cohort C
a) Diagnosis of FL
b) Relapsed or refractory to at least 2 prior lines of therapy
c) Relapsed or refractory to CAR-T-cell therapy or unable to receive it
4. Cohort D
a) Diagnosis of DLBCL. Cell of Origin is known for DLBCL, NOS, germinal center B-cell type or activated B-cell type.
b) Must have progressed after at least 2 lines of previous therapy, including progression after an auto-SCT, or are not a candidate for an auto-SCT
c)Relapsed or refractory to CAR-T-cell therapy or unable to receive it
d) Exhausted or be ineligible for or intolerant to all treatments.
5. Cohort E
a) Histologically or cytologically confirmed diagnosis of active MM as per IMWG criteria
b) Measurable disease defined as meeting at least 1 of the following criteria:
i. Serum monoclonal protein (M-protein) levels ≥0.5 g/dL (≥5 g/L), OR
ii. Urine monoclonal protein (M-protein) levels ≥200 mg/24 h, OR
iii. Abnormal FLC chain ratio (FLC k/l <0.26 or >1.65) with involved FLC level ≥100 mg/L (normal serum FLC k/l value: 0.26-1.65)
c) Must have undergone stem cell transplant and have relapsed after auto-SCT or have failed to achieve a CR or PR following auto-SCT, or is considered ineligible for auto-SCT
d) Participants must have received all regionally approved antimyeloma therapy including IMiD, proteasome inhibitor, steroids, anti-CD38 monoclonal antibody, selinexor, and anti BCMA therapies alone or in combination.
e) Participants must have failed their last line of therapy
f) Relapsed or refractory to CAR-T-cell therapy or unable to receive it
6. Cohort F
a) Have histologically confirmed diagnosis of B-cell lymphoma other than cHL, PMBCL, DLBCL, or FL, according to the WHO classification
b) Participants with MCL must have received prior Bruton's tyrosine kinase inhibitor therapy.
c) Participants must have progressed after at least 2 lines of previous therapy
d) Participants must have exhausted or be ineligible for or intolerant to all standard of care treatment options for their disease.
7. Cohorts A, B, C, D, and F:
a) Have measurable disease, defined as at least 1 lesion that can be accurately measured in at least 2 dimensions with spiral CT scan
b) Be able to provide newly obtained bone marrow biopsy material for tumor response assessment by local investigator sites
8. Cohort E (MM participants): Be able to provide newly obtained (within 3 months) bone marrow biopsy or aspirate material for disease assessment and submit biomarker analysis
9. Participants who have received CAR T-cell therapy before study entry and have experienced disease progression post therapy may be considered for the study.
10. Is male or female, ≥18 years of age
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least 120 days after the last dose of study intervention
- A WOCBP must have a negative highly sensitive pregnancy test within 72 h for serum sample and within 24 h for urine test before the first dose of study intervention
12. The participant provided documented informed consent for the study
13. Participants with endocrine-related conditions, are eligible if controlled with treatment.
14. Have a performance status of 0 or 1 on the ECOG PS
15. Have adequate organ function. Specimens must be collected within 7 days before the start of study intervention
|
E.3 Principal inclusion criteria cont. in english language:
16. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load before allocation
17. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening |
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| E.4 | Principal exclusion criteria |
1. For Cohort D and F (DLBCL and NHL): Has lymphoplasmacytic lymphomas, Waldenstrom’s macroglobulinemia, chronic lymphocytic leukemia (not associated with small lymphocytic lymphoma), Burkitt (-like) lymphoma, mature T cell and NK cell neoplasms, immunodeficiency associated lymphoproliferative neoplasms, or histiocytic and dendritic cell neoplasms.
2. For Cohort E (MM):
a) Has oligo-secretory myeloma, plasma cell leukemia, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance.
b) History of primary amyloidosis, hyperviscosity or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
3. For Cohort F (EBV+ DLBCL): For patients with EBV+ DLBCL should NOT be associated with a solid organ transplant.
4. Has known prior or current CNS involvement.
5. A WOCBP who has a positive urine pregnancy test within 72 hours before study intervention allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
6. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
7. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
8. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years.
9. Has received prior therapy with an mAb blocking TIGIT, an anti-TIGIT agent or an agent modulating the TIGIT axis, or an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (except where specified) or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
10. Any PMBCL participants in Cohort A and B that require the use of urgent cytoreductive therapy.
11. Has received prior systemic anticancer therapy, including investigational agents, within 2 weeks (small molecules like kinase inhibitors) or 4 weeks (chemotherapies and monoclonal antibodies) before cohort allocation.
12. If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery before starting study intervention.
13. Has received prior radiotherapy within 2 weeks of start of study intervention.
14. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
15. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
16. Known severe hypersensitivity to MK-7684A, vibostolimab or pembrolizumab and/or any of its excipients.
17. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
18. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
19. Has an active infection requiring systemic therapy.
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
21. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
22. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks before enrollment.
23. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
24. Participant, in the judgment of the investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study.
25. Has had an allogenic hematopoietic stem cell/solid organ transplantation within the last 5 years. Participants who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Part 1: Number of Participants with a Dose-Limiting Toxicity (DLT)
2. Part 1: Number of Participants Who Experienced an Adverse Event (AE)
3. Part 1: Number of Participants Who Discontinued Study Treatment Due to an AE
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 6 weeks
2. Up to approximately 27 months
3. Up to approximately 24 months
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|
| E.5.2 | Secondary end point(s) |
1. Part 1: Objective Response Rate (ORR)
2. Part 1: Duration of Response (DOR)
3. Part 1: Disease Control Rate (DCR)
4. Part 1: Lowest Plasma Concentration (Ctrough) of Vibostolimab
5. Maximum Concentration (Cmax) of Vibostolimab
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 24 months
2. Up to approximately 24 months
3. Up to approximately 24 months
4. Predose at Cycles 1, 2, 4, 8, and every 12 weeks afterwards (up to ~2 years). Cycle = 3 weeks
5. Postdose: after end of infusion (up to ~10 minutes) at Cycles 1 and 8. Cycle = 3 weeks
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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 | 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Brazil |
| Canada |
| Chile |
| Israel |
| Taiwan |
| United States |
| France |
| Poland |
| Spain |
| Germany |
| Italy |
| Denmark |
| Hungary |
| Russian Federation |
| Turkey |
| Ukraine |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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