| 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 |
| Relapsed or Refractory Lymphoma |
|
| 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 | 10025315 |
| E.1.2 | Term | Lymphoma malignant |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
To determine the safety and tolerability and to establish a preliminary recommended Phase 2 dose (RPTD) RP2D) of MK-4280 when used in combination with pembrolizumab.
To determine the safety and tolerability of MK-4280 monotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the objective response rate (ORR) of MK-4280 as assessed by the investigator when used in combination with pembrolizumab, Assessment will be based on the Lymphoma Disease Response criteria
- To evaluate the ORR of MK-4280 monotherapy as assessed by the investigator. Assessment will be based on the Lymphoma Disease Response criteria
- To evaluate the pharmacokinetics (PK) of MK-4280 administered by IV infusion alone and in combination with pembrolizumab.
- To evaluate the PK of pembrolizumab administered by IV infusion in combination with MK-4280 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (Blood, plasma, serum and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
|
| E.3 | Principal inclusion criteria |
1. Have measureable disease, defined as at least 1 lesion that can be accurately measured in 2 dimensions with diagnostic quality cross sectional anatomic imaging (CT or MRI). Minimum measurement must be >15 mm in the longest diameter or >10 mm in the short axis
2. Be able to provide a core or excisional tumor biopsy for biomarker analysis from an archival (within 3 months) or newly obtained biopsy (within 3 months) at Screening
PD-1/L1-Naive R/R cHL (Cohort 1)
3. Have histologically confirmed classical Hodgkin lymphoma
4. Have relapse (defined as disease progression after most recent therapy) or refractory (defined as failure to achieve CR or PR to most recent therapy) cHL and meet at least 1 of the following inclusions:
a.Have failed to achieve a response or progressed after autologous stem cell transplant.
b.Were unable to achieve a CR or PR to salvage chemotherapy and therefore did not proceed to auto- SCT, or were ineligible for auto-SCT due to age/co-morbidities as judged by treating physician.
5. Have not previously been treated with an anti-PD-1 or anti-PD-L1 therapy
PD-1/L1-Refractory R/R cHL (Cohort 2 and Cohort 5)
6. Have histologically confirmed classical Hodgkin lymphoma
7. Have relapsed (defined as disease progression after most recent therapy) or refractory (defined as failure to achieve CR or PR to most recent therapy) cHL and meet 1 of the following inclusions:
a.Have failed to achieve a response or progressed after auto-SCT.
b.Were unable to achieve a CR or PR to salvage chemotherapy and therefore did not proceed to auto -SCT, or were ineligible for auto-SCT due to age/co-morbidities as judged by treating physician.
8. Have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
a.Have received at least 2 doses of an anti-PD-1 mAb that has been approved in Hodgkin's lymphoma, with the agent administered at the approved dose and schedule
b.Have demonstrated disease progression after anti-PD-1/L1 as defined by Lymphoma Disease Response criteria. This determination is made by the investigator
c.Progressive disease has been documented within 12 weeks from the last dose of anti-PD- 1/L1 mAb
9. Have submitted pretrial imaging
R/R DLBCL (Cohort 3)
10. Have a histologically confirmed diagnosis of DLBCL. Transformed DLBCL, Gray zone lymphoma, Double hit lymphoma, PMBCL , T-cell histiocyte rich, EBV+ DLBCL, Alk positive, primary testicular DLBCL are permitted.
11. Must have progressed following at least 2 lines of previous therapy, including progression after an auto-SCT, have declined SCT, or are not a candidate (per institutional criteria) for an auto-SCT. Participants who are ineligible for standard treatment or who have withdrawn from standard treatment before disease progression due to unacceptable toxicity warranting discontinuation of that treatment and precluding retreatment with the same agent will also be eligible. R/R-iNHL (Cohort 4)
12. Have histologically confirmed diagnosis of indolent (low-grade) Bcell lymphoma, defined as FL, marginal zone lymphoma, mucosaassociated lymphoid tissue lymphoma, or small lymphocytic lymphoma (not associated with CLL). ymphoplasmacytic lymphomas, Waldenstrom's macroglobulinema, CLL, and T-cell lymphomas are not eligible.
13. Participants must have progressed following at least 2 lines of previous therapy. Participants must have received and failed, been intolerant to, or determined by their treating physician to be a poor candidate or ineligible for a phosphatidylinositol 3-kinase (PI3K) inhibitor. Participants who are ineligible for standard treatment or who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of that treatment and precluding retreatment with the same agent before progression of disease will also be eligible. Participants who have received prior CAR T-cell therapy will also be eligible.
14. Participant is Male or Female
15. Participant is ≥18 years of age at the time of providing informed consent
16. Have a performance status of 0 or 1 on the ECOG Scale
17. Have adequate organ function
18. Male participant must agree to use a contraception during the study and for at least 120 days after the last dose and refrain from donating sperm during this period
19. Female is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
a. Not a woman of childbearing potential
b. A WOCBP who agrees to use contraception during the study and for at
least 120 days after last dose
20. Provide written informed consent |
|
| E.4 | Principal exclusion criteria |
1. Has known clinically active central nervous system involvement
2. A WOCBP who has a positive urine pregnancy test within 72 hours
prior to study intervention allocation. If the urine test is positive or
cannot be confirmed as negative, a serum pregnancy test will be
required
3. Has known clinically significant heart disease
4. Has received prior therapy with an anti-LAG-3 antibody
5. Cohorts 1, 2, 3, 5: Has received CAR-T cell therapy
6. Cohort 1: Has received prior therapy with an anti-PD-1 or anti-PD-L1 antibody
7. Cohorts 2, 3, 4, 5: Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
8. Has received prior anticancer therapy or thoracic radiation therapy within 14 days before the first dose of study intervention
9. Grade 2 or higher nonhematological residual toxicities from prior therapy. Residual toxicity of Grade 1 from prior therapy or persistent
treatment-related Grade 1 neurotoxicity will be allowed
10. Has had a prior anticancer monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (ie, ≤Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier
11. Has received a live vaccine within 30 days prior to first dose. Administration of killed vaccines are allowed.
12. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 28 days before study Day 1
Diagnostic Assessment
13. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
14. Has a known additional malignancy that is progressing or requires active treatment within the past 3 years.
15. Has active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
16. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
17. Has an active infection requiring intravenous systemic therapy
18. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
19. Has known, active hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is detected). No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority
20. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
21. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention
22. Has had an allogeneic hematopoetic 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) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety:
Number of Participants with:
- Dose-limiting toxicity (DLT)
- Adverse event (AE)
- Discontinuing study treatment due to an AE |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After the last subject’s last visit |
|
| E.5.2 | Secondary end point(s) |
- Objective response: individuals who have complete remission (CR) or partial remission (PR)
- Pharmacokinetic parameters including area under the curve (AUC), minimum concentration (Cmin), and maximum concentration (Cmax) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After the last subject’s last visit |
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | 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 | No |
| 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 | 10 |
| 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 |
| Australia |
| Canada |
| Israel |
| United States |
| France |
| Germany |
| Italy |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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