Treatment of participants with Relapsed or Refractory Diffuse Large B-Cell Lymphoma MedDRA version: 21.1 Level: LLT Classification code 10012857 Term: Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) refractory System Organ Class: 100000004864
Conditions
Sponsors
Merck Sharp & Dohme LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Type of Participant and Disease Characteristics 1.Has a histologically confirmed diagnosis of DLBCL, according to the WHO classification of neoplasms of the hematopoietic and lymphoid tissues 2.Has radiographically measurable DLBCL per the Lugano response criteria with at least 1 nodal lesion (nonirradiated) that is =1.5 cm in the long axis, regardless of length of the short axis, AND/OR extranodal lesion of =1.0 cm in the long and short axis. Cohort A 3.Has relapsed or refractory DLBCL and is ineligible for or have failed ASCT and have failed at least 1 line of prior therapy. Participants with DLBCL who have failed at least 2 lines of prior therapy will be capped at 50% 4.Has post-CAR-T cell therapy failure or is ineligible for CAR-T cell therapy Cohort B 5.Has relapsed or refractory DLBCL and is ineligible for or have failed ASCT and have failed at least 2 lines of prior therapy 6.Has post-CAR-T therapy failure or is ineligible for CAR-T cell therapy Demographics 7.Is male or female, from 18 years of age inclusive, at the time of signing the informed consent. 8.Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: -Zilovertamab vedotin 110 days -Chemotherapy 90 days Refrain from donating sperm, PLUS either: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR Must agree to use contraception unless confirmed to be azoospermic as detailed below: -Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. -Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Female Participants 9.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: - Uses a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: ?Zilovertamab vedotin: 50 days ?Chemotherapy: 180 days The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed. -Has a negative highly sensitive pregnancy test within 24 hours for urine and 72 hours for serum before the first dose of study intervention. -Abstains from breastfeeding during the study intervention period and for at lea
Exclusion criteria
Exclusion criteria: Medical Conditions 1. Has history of transformation of indolent disease to DLBCL 2. Has received solid organ transplant at any time 3. Has received a diagnosis of PMBCL 4. Has clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (1 peripheral neuropathy 8. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years 9. Has a demyelinating form of Charcot-Marie-Tooth disease Prior/Concomitant Therapy 10. Has received prior therapy with a ROR1-directed therapy. Prior exposure to MMAEcontaining drugs (eg, polatuzumab vedotin) is allowed 11. Has contraindication to any of the study intervention components 12. Has received prior systemic anticancer therapy, including investigational agents within 4 weeks prior to the first dose of study intervention 13. Has received prior radiotherapy within 4 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis 14. Has ongoing corticosteroid therapy (exceeding 30 mg daily of prednisone equivalent). Prednisone equivalent dosing must have been stable for at least 4 weeks prior to C1D1 15. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed 16. Has received a strong inhibitor or inducer of CYP3A4 (including itraconazole, ketoconazole, posaconazole, or voriconazole) within 7 days prior to C1D1 or expected requirement for chronic use of a strong CYP3A4 inhibitor or inducer during Cycle 1 of study therapy Prior/Concurrent Clinical Study Experience 17. 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 Diagnostic Assessments 18. Has known active CNS lymphoma involvement or active CNS involvement by lymphoma. Participants with prior CNS involvement are eligible if their CNS disease is in radiographic, cytological (for cerebrospinal fluid disease), and clinical remission 19. Has an active infection requiring systemic therapy 20. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority 21. Has a known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection 22. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator 23. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To evaluate the safety and tolerability and to establish a RP2D of zilovertamab vedotin when used in combination with R-GemOx and BR. 2. To compare zilovertamab vedotin in combination with R-GemOx to R-GemOx with respect to PFS per Lugano response criteria by BICR in part 2 of the study. 3. To compare zilovertamab vedotin in combination with BR to BR with respect to PFS per Lugano response criteria by BICR in part 2 of the study.;Secondary Objective: 1. To compare zilovertamab vedotin in combination with R-GemOx to R-GemOx with respect to OS in part 2 of the study. 2. To compare zilovertamab vedotin in combination with BR to BR with respect to OS in part 2 of the study. 3. To compare zilovertamab vedotin in combination with R-GemOx to R-GemOx with respect to ORR per Lugano response criteria as assessed by BICR in part 2 of the study. 4. To compare zilovertamab vedotin in combination with BR to BR with respect to ORR per Lugano response criteria by BICR in part 2 of the study. 5. To evaluate zilovertamab vedotin in combination with R-GemOx and R-GemOx with respect to DOR per Lugano response criteria as assessed by BICR in part 2 of the study. 6. To evaluate zilovertamab vedotin in combination with BR and BR with respect to DOR per Lugano response criteria as assessed by BICR in part 2 of the study.;Primary end point(s): 1. Percentage of Participants with Dose-limiting Toxicities (DLTs) 2. Percentage of Participants with Adverse Events (AEs) 3. Percentage of Participants who Discontinue Study Treatment due to AE 4. Progression-Free Survival (PFS).;Timepoint(s) of evaluation of this end point: 1. Up to ~6 weeks 2. Up to ~6 months 3. Up to ~6 months 4. Up to ~36 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall Survival (OS) 2. Objective Response Rate (OR) 3. Duration of Response (DOR);Timepoint(s) of evaluation of this end point: 1. Up to ~36 months 2. Up to ~36 months 3. Up to ~36 months | — |
Countries
Argentina, Brazil, Canada, Chile, China, Colombia, Costa Rica, Czechia, Estonia, France, Germany, Greece, Guatemala, Ireland, Israel, Italy, Korea, Republic of, Mexico, Peru, Poland, Puerto Rico, Russian Federation, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, Ukraine, United Kingdom, United States
Outcome results
None listed