MK-4280 and Pembrolizumab in Hematologic Malignancies

Phase 1

Conditions: Hematologic malignancies
MedDRA version: 21.1Level: LLTClassification code 10025315Term: Lymphoma malignantSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2018-001461-16-IT

Lead Sponsor: MERCK SHARP & DOHME CORP. UNA SUSSIDIARIA DI MERCK & CO. INC.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 84

Inclusion Criteria

1Have meas disease,def as at least1lesion can be accurat measured in2dimens with diagn quality cross sectional anat imaging(CTorMRI).Min meas must be>15mm in the longest diameter or>10mm in the short axis
2Be able to provide a core or excisional tum biopsy fr biomarker analysis from an arch or newly obtained biopsy(within3months)at Screening
PD1/L1Naive R/RcHL(C.1)
3Have histol conf clas Hodgkin lymph
4Have relapse (def as disease progr after most recent ther)or refractory (def as failure to achieveCRorPRto most recent ther)cHL and meet at least1of the incl:
aHave failed to achieve a resp or progres after autoSCT.Must have relapsed after treatm with or failed to resp to brentuximab ved post autoSCT
bWere unable to achieve aCRorPR to salvage chemot and did not receive autoSCT.Must have relapsed after treatm with or failed to resp to brentuximab ved
cPts who are ineleg fr brentuximab ved, who discontinued brentit ved due to tox, or who reside in a region where brentuximab is not appr or available are eligib fr the stud
5Havenot prev been treated with antiPD1or antiPDL1ther
PD1/L1Refractory R/R cHL(C.2)
6Have histol confirmed clas Hodgkin lymph
7Have relapsed(def as disease progr after most recent ther)or refractory(def as failure to achieveCR orPR to most recent ther)cHL and meet1of the following incl:
aHave failed to achieve a resp or progr after autoSCT.Must have relapsed after treatm with or failed to resp to brentuximab ved post autoSCT
bWere unable to achieve a CRorPR to salvage chemot and did not receive autoSCT.Must have relapsed after treatm with or failed to resp to brentuximab ved
cPts who are ineleg fr brentuximab ved, who discontinued brentit ved due to tox, or who reside in a region where brentuximab is not approved or available are eligible fr the stud
8Have progr on treatm with an antiPD1/L1mAb administered either as monother or in comb with other checkpoint inhibitors or other therap.PD1 treatm progr is def by meeting all of the following criteria:
aHave received at least2doses of antiPD1 mAb that has been approved in Hodgkin’s lymph,with the agent administered at the approv dose and schedule
bHave demonstrated disease progr after PD1/L1 as def by Lymph Disease Resp criteria.Determination is made by the invest
cProgres disease has been doc within12w from the last dose of antiPD1/L1mAb
R/R DLBCL(C.3)
9Have a hist confirmed diagn ofDLBCL.TransfrmedDLBCL,Gray zone lymph,Double hit lymph,and Primary mediastinalBcell lymph are permitted
10Have progr fol at least2lines of previous ther, including progr after an autologous SCT,have declined SCT,or are not a candidate(per institutional criteria)fr an autol SCT.Pts ineleg fr standard treatm or who have withdrawn from standard treatm befre disease progr due to unaccept tox warranting discont of that treatm and precluding retreatm with the same agent will be eligible
R/R-iNHL(C.4)
11Have hist confirm diagn of indolent(low-grade)Bcell lymph,def as FL,marginal zone lymph,mucosa-associated lymphoid tissue lymph,or small lymphocytic lymph. Lymphoplasmacytic lymphs,Waldenstrom’s macroglobulinema,chronic lymphocytic leukemia(not associated with small lymphocytic lymph)and Tcell lymphs are not eligible.At least10pts must haveFL
12Have progr follow at least2lines of previous ther,which may include an autologous SCT.Pts ineleg fr standard treatm or who have withdrawn from standard treatm due to unaccept tox warrant discont of that treatm and precluding retreatm with the same agent befre prog

Exclusion Criteria

1Has known clinically active central nervous system involvement
2A WOCBP who has a positive urine pregnancy test within 72hours prior to study intervention allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
3Has known clinically significant heart disease
4Has received prior therapy with an antiLAG3 antibody
5Has received CAR-T cells therapy
6Cohort 1: Has received prior therapy with an antiPD1 or antiPDL1 antibody
7Cohorts 2, 3, 4: Has severe hypersensitivity (=Grade3) to pembrolizumab and/or any of its excipients
8Has received prior anticancer therapy or thoracic radiation therapy within14days before the first dose of study intervention
9Grade2or higher nonhematological toxicities from prior therapy.Residual toxicity of Grade 1from prior therapy or persistent treatment-related Grade 1 neurotoxicity will be allowed
10Has 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
11Has received a live vaccine within 30 days prior to first dose
12Is 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
13Has a known history of a primary immune disorder or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study intervention
14Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
15Has 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
16Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
17Has an active infection requiring intravenous systemic therapy
18Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
19Has 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
20Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
21Is 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
22Has 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)

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To determine the safety and tolerability and to establish a preliminary recommended Phase 2 dose (RPTD) ;Secondary Objective: - To evaluate the objective response rate (ORR) as assessed by the investigator using the Lymphoma Disease Response criteria<br>- To evaluate the pharmacokinetics (PK) of MK-4280<br>- To evaluate the PK of pembrolizumab;Primary end point(s): Safety:<br>Number of Participants with:<br>- Dose-limiting toxicity (DLT)<br>- Adverse event (AE)<br>- Discontinuing study treatment due to an AE;Timepoint(s) of evaluation of this end point: After the last subject’s last visit

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Objective Response Rate (ORR) according to investigator assessment using the Lymphoma Disease Response criteria<br>- Pharmacokinetic endpoints include serum concentrations of MK-4280 and pembrolizumab, and derived PK parameters;Timepoint(s) of evaluation of this end point: After the last subject’s last visit

Related Trials