Safety and Efficacy of Pembrolizumab (MK-3475) in Children and Young Adults With Classical Hodgkin Lymphoma (MK-3475-667/KEYNOTE-667)

Hodgkin Lymphoma Clinical Trial

Official title:

An Open-label, Uncontrolled, Multicenter Phase II Trial of MK-3475 (Pembrolizumab) in Children and Young Adults With Newly Diagnosed Classical Hodgkin Lymphoma With Inadequate (Slow Early) Response to Frontline Chemotherapy (KEYNOTE 667)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03407144
• Other study ID #: 3475-667
• Secondary ID: MK-3475-6672023-
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 9, 2018
• Est. completion date: February 13, 2027

Study information

• Verified date: April 2024
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will examine the safety and efficacy of pembrolizumab (MK-3475) in combination with chemotherapy in children and young adults with newly diagnosed classical Hodgkin Lymphoma (cHL) who are slow early responders (SERs) to frontline chemotherapy.

Description:

Group 1 will consist of low-risk participants with cHL Stages IA, IB and IIA without bulky disease. Group 2 will consist of high-risk participants with cHL Stages IIEB, IIIEA, IIIEB, IIIB, IVA and IVB.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 340
• Est. completion date: February 13, 2027
• Est. primary completion date: February 13, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 25 Years

Eligibility

Inclusion Criteria:

• Group 1: Must have newly diagnosed, pathologically confirmed classical Hodgkin Lymphoma (cHL) at Stages IA, IB and IIA without bulky disease. Group 2: Must have newly diagnosed, pathologically confirmed cHL at Stages IIEB, IIIEA,IIIEB, IIIB, IVA and IVB

• Has measurable disease per investigator assessment.

• Male participants are eligible to participate if they agree to the following during the intervention period: 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 per protocol unless confirmed to be azoospermic.

• Female participants who are not pregnant or breastfeeding, and who are either not a woman of childbearing potential (WOCBP), or are a WOCBP who agrees to use approved contraception during the intervention period and for at least 120 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period.

• Performance status: Lansky Play-Performance Scale =50 for children up to 16 years of age OR Karnofsky score =50 for participants = 16 years of age

• Has adequate organ function

Exclusion Criteria:

• Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic stem cell transplantation within the last 5 years

• WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment

• Baseline left ventricular ejection fraction value <50% or shortening fraction of <27%

• Has received prior therapy with an anti-Programmed Death (PD)-1, anti-Programmed Death-Ligand 1 (PD-L1), or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor or has previously participated in a MSD pembrolizumab (MK-3475) clinical study

• Has received any prior systemic anti-cancer therapy,including investigational agents for current diagnosis before randomization

• Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed

• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration

• Has a diagnosis of lymphocyte-predominant Hodgkin Lymphoma (HL)

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab

• Has a known additional malignancy that is progressing or requires active treatment within the past 3 years

• Has radiographically detectable central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator at the time of diagnosis

• Has severe hypersensitivity (=Grade 3) to any study therapies including any excipients

• An active autoimmune disease that has required systemic treatment in past 2 years

• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

• Has an active infection requiring systemic therapy

• Has a known history of human immunodeficiency virus (HIV) infection

• Has a known history of Hepatitis B or known active Hepatitis C virus infection

• 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

• Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study

• Participants who have not adequately recovered from major surgery or have ongoing surgical complications

Related Conditions & MeSH terms

• Hodgkin Disease
• Hodgkin Lymphoma
• Lymphoma

Intervention

Biological:
• pembrolizumab
2 mg/kg intravenous (IV) up to a max of 200 mg (3 to 17 years of age) or 200 mg IV (18 to 25 years of age); cycle frequency Q3W

Drug:
• doxorubicin
25 mg/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1) 40 mg/m^2 IV on Days 1 and 15 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2) 25 mg/m^2 IV on Days 1 and 15 as part of AVD chemotherapy (cycle frequency: Q4W, Group 1)
• vinblastine
6 mg/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1) 6 mg/m^2 IV on Days 1 and 15 as part of AVD chemotherapy (cycle frequency: Q4W, Group 1)
• dacarbazine
375 mg/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1) 375 mg/m^2 IV on Days 1 and 15 as part of AVD chemotherapy (cycle frequency: Q4W, Group 1) 250 mg/m^2 IV on Days 1 to 3 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)
• cyclophosphamide
500 mg/m^2 IV on days 1 and 8 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)
• vincristine
1.5 mg/m^2 IV with maximum single dose 2 mg on Days 1, 8, and 15 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2) 1.5 mg/m^2 IV with maximum single dose 2 mg on Days 1 and 8 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)
• prednisone/prednisolone
60 mg/m^2/day orally divided in 3 doses on Days 1 to 15 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2) 40 mg/m^2/day orally divided in 3 doses on Days 1 to 15 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)
• bleomycin
10 units/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1)
• etoposide
125 mg/m^2 IV on Days 1 to 5 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2)

Radiation:
• Radiotherapy (RT)
RT administered daily, dose dependent on randomization group and disease response.

Locations

Country	Name	City	State
Brazil	Hospital Erasto Gaertner-CEPEP - Pesquisa Clínica ( Site 0507)	Curitiba	Parana
Brazil	Liga Norte Riograndense Contra o Câncer-Centro de Pesquisa Clínica ( Site 0510)	Natal	Rio Grande Do Norte
Brazil	Instituto de Oncologia Pediatrica - GRAACC - Unifesp ( Site 0500)	Sao Paulo
Colombia	Organizacion Clinica Bonnadona-Prevenir S.A.S. ( Site 0529)	Barranquilla	Atlantico
Colombia	Instituto Nacional De Cancerologia ( Site 0566)	Bogotá	Distrito Capital De Bogota
Colombia	Hospital Pablo Tobon Uribe-Hematology ( Site 0565)	Medellin	Antioquia
Colombia	Oncomédica S.A.S ( Site 0527)	Monteria	Cordoba
Czechia	Fakultni nemocnice v Motole ( Site 0356)	Praha 5
France	CHU de Bordeaux. Hopital Pellegrin ( Site 0447)	Bordeaux	Gironde
France	Hôpital Jeanne de Flandre ( Site 0450)	Lille	Nord
France	Institut d'Hematologie-Oncologie Pediatrique (IHOP) ( Site 0448)	Lyon	Rhone-Alpes
France	CHU de Marseille Hopital de la Timone Enfants ( Site 0449)	Marseille	Bouches-du-Rhone
France	Hopital d'Enfants Armand Trousseau ( Site 0443)	Paris
France	Hopital Universitaire Robert Debre ( Site 0446)	Paris
France	Institut Gustave Roussy ( Site 0445)	Villejuif	Val-de-Marne
Germany	Charite-Universitaetsmedizin Berlin Campus Virchow-Klinikum ( Site 0413)	Berlin
Germany	Universitaetsklinikum Essen ( Site 0415)	Essen	Nordrhein-Westfalen
Germany	Universitaetsklinikum Giessen und Marburg GmbH ( Site 0411)	Giessen	Hessen
Germany	Klinikum der Universitaet Muenchen-Campus Innenstadt ( Site 0414)	Muenchen	Bayern
Germany	Universitätsklinikum Münster - Albert Schweitzer Campus-Pädiatrische Hämatologie und Onkologie ( Sit	Münster	Nordrhein-Westfalen
Greece	Athens Childrens Hospital Aglaia Kyriakou ( Site 0361)	Athens	Attiki
Greece	University of Athens - Aghia Sophia Childrens Hospital ( Site 0362)	Athens	Attiki
Greece	University General Hospital of Thessaloniki "AHEPA" ( Site 0363)	Thessaloniki	Kentriki Makedonia
Guatemala	Medi-K Cayala ( Site 0544)	Guatemala
Guatemala	Oncomedica ( Site 0545)	Guatemala
Guatemala	Unidad Nacional de Oncologia Pediatrica ( Site 0542)	Guatemala
Italy	Centro di Riferimento Oncologico CRO ( Site 0404)	Aviano	Pordenone
Italy	Azienda Ospedaliera Santobono - Pausilipon ( Site 0402)	Napoli
Italy	IRCCS Ospedale Pediatrico Bambino Gesu ( Site 0400)	Roma
Italy	Universita degli Studi di Roma La Sapienza ( Site 0403)	Roma	Abruzzo
Italy	Ospedale Infantile Regina Margherita ( Site 0401)	Torino
Korea, Republic of	Samsung Medical Center ( Site 0222)	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System ( Site 0221)	Seoul
Mexico	UMAE Hospital de Especialidades - CMN La Raza ( Site 0536)	Azcapotzalco
Mexico	Hematologica Alta Especialidad ( Site 0532)	Huixquilucan
Mexico	Hospital Infantil de Mexico Federico Gomez ( Site 0535)	Mexico D.F.	Distrito Federal
Mexico	Hospital Universitario "Dr. Jose Eleuterio Gonzalez" ( Site 0531)	Monterrey	Nuevo Leon
Netherlands	Prinses Maxima Centrum ( Site 0461)	Utrecht
Slovakia	Narodny ustav detskych chorob ( Site 0372)	Bratislava	Bratislavsky Kraj
South Africa	Wits Clinical Research ( Site 0323)	Johannesburg	Gauteng
South Africa	Albert Alberts Stem Cell Transplant Centre ( Site 0324)	Pretoria	Gauteng
South Africa	Wits Clinical Research ( Site 0321)	Soweto	Gauteng
Spain	Hospital Universitari Vall d Hebron ( Site 0432)	Barcelona
Spain	Hospital Infantil Universitario Nino Jesus ( Site 0433)	Madrid
Spain	Hospital Universitario La Paz ( Site 0434)	Madrid
United Kingdom	University College London Hospitals NHS Foundation Trust ( Site 0454)	London	London, City Of
United States	Kaiser - Orange County ( Site 0084)	Anaheim	California
United States	Children's Healthcare of Atlanta at Egleston ( Site 0033)	Atlanta	Georgia
United States	Children's Hospital - Colorado ( Site 0028)	Aurora	Colorado
United States	Dell Children's Medical Center Of Central Texas ( Site 0058)	Austin	Texas
United States	Johns Hopkins University ( Site 0025)	Baltimore	Maryland
United States	Children's Hospital of Alabama ( Site 0023)	Birmingham	Alabama
United States	Roswell Park Cancer Institute ( Site 0040)	Buffalo	New York
United States	UNC Lineberger Comprehensive Cancer ( Site 0044)	Chapel Hill	North Carolina
United States	University of Chicago ( Site 0066)	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center ( Site 0035)	Cincinnati	Ohio
United States	Nationwide Children's Hospital ( Site 0037)	Columbus	Ohio
United States	Children's Medical Center ( Site 0030)	Dallas	Texas
United States	Children's Hospital of Michigan ( Site 0056)	Detroit	Michigan
United States	Karmanos Cancer Institute ( Site 0002)	Detroit	Michigan
United States	Kaiser Permanente ( Site 0082)	Downey	California
United States	Inova Fairfax Hospital ( Site 0031)	Falls Church	Virginia
United States	Kaiser - Fontana ( Site 0083)	Fontana	California
United States	University of Florida ( Site 0051)	Gainesville	Florida
United States	St. Francis Hospital Cancer Center ( Site 0001)	Greenville	South Carolina
United States	Hackensack University Medical Center ( Site 0026)	Hackensack	New Jersey
United States	Connecticut Children's Medical Center ( Site 0045)	Hartford	Connecticut
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital ( Site 0048)	Hollywood	Florida
United States	Texas Children's Hospital ( Site 0042)	Houston	Texas
United States	Riley Hospital for Children ( Site 0091)	Indianapolis	Indiana
United States	Alliance for Childhood Diseases ( Site 0064)	Las Vegas	Nevada
United States	University of Kentucky Markey Cancer Center ( Site 0057)	Lexington	Kentucky
United States	Arkansas Children's Hospital ( Site 0046)	Little Rock	Arkansas
United States	MemorialCare Health System - Long Beach Medical Center-Cherese Mari Laulhere Children's Village ( Si	Long Beach	California
United States	Kaiser Permanente Downey Medical Center ( Site 0024)	Los Angeles	California
United States	University of Louisville-Norton Children's Hospital ( Site 0059)	Louisville	Kentucky
United States	Children's Hospitals and Clinics of Minnesota ( Site 0036)	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center-Ingram Cancer Center ( Site 0054)	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey ( Site 0027)	New Brunswick	New Jersey
United States	Yale Cancer Center ( Site 0061)	New Haven	Connecticut
United States	Cohen Children's Medical Center of New York ( Site 0052)	New Hyde Park	New York
United States	Columbia University/Herbert Irving Cancer Center ( Site 0063)	New York	New York
United States	Memorial Sloan Kettering Cancer Center ( Site 0060)	New York	New York
United States	Weill Cornell Medicine ( Site 0032)	New York	New York
United States	Kaiser Permanente - Oakland ( Site 0047)	Oakland	California
United States	Arnold Palmer Hospital ( Site 0065)	Orlando	Florida
United States	Phoenix Childrens Hospital ( Site 0034)	Phoenix	Arizona
United States	Kaiser Permanente - Roseville ( Site 0080)	Roseville	California
United States	St. Louis Children's Hospital ( Site 0038)	Saint Louis	Missouri
United States	Methodist HealthCare System of San Antonio Clinical Trials Office, Texas Transplant Institute ( Site	San Antonio	Texas
United States	Kaiser Permanente - Santa Clara ( Site 0079)	Santa Clara	California
United States	Seattle Childrens Hospital ( Site 0022)	Seattle	Washington
United States	Children's National Medical Center ( Site 0090)	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Brazil,  Colombia,  Czechia,  France,  Germany,  Greece,  Guatemala,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Slovakia,  South Africa,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) in SER Participants By Risk Group (Low, High) as Assessed by Blinded Independent Central Review (BICR)	ORR is defined as the percentage of SER participants who have a Complete Response ([CR], disappearance of all evidence of disease) or Partial Response ([PR], regression of measurable disease and no new sites) using IWG revised response criteria and determined by BICR. The ORR will be estimated by risk group in SER participants.	Up to approximately 8 years
Secondary	Rate of Positron Emission Tomography (PET) Scan Negativity in SER Participants By Risk Group (Low, High) After AVD or COPDAC-28 Chemotherapy	The rate of PET negativity for SER participants is the percentage of participants with PET negativity (defined as Deauville score 1, 2 or 3) after two cycles of AVD (Group 1) or four cycles of COPDAC-28 (Group 2), in combination with pembrolizumab. The Deauville 5-point scoring system is an internationally accepted and utilized five-point scoring system for the Fluorodeoxyglucose (FDG) avidity of a Hodgkin's lymphoma or Non-Hodgkin's lymphoma tumor mass as seen on FDG PET scan: Score 1= No uptake above the background, Score 2= Uptake = mediastinum, Score 3= Uptake > mediastinum but = liver, Score 4= Uptake moderately increased compared to the liver at any site, Score 5= Uptake markedly increased compared to the liver at any site or new lesions, Score X= New areas of uptake unlikely to be related to lymphoma. In the present study, scores of 1, 2 and 3 are considered to be negative and scores of 4 and 5 are considered to be positive.	Up to approximately 8 years
Secondary	Event-Free Survival (EFS) in SER Participants By Risk Group (Low, High) as Assessed by BICR	EFS is defined as the time from study enrollment to the first documented disease progression or recurrence, or death due to any cause, whichever occurs first. Progression/disease recurrence will be determined by BICR using IWG criteria.	Up to approximately 8 years
Secondary	Overall Survival (OS) in SER Participants By Risk Group (Low, High)	OS is defined as the time from study enrollment to death due to any cause. Participants without documented death will be censored at the date of the last follow-up.	Up to approximately 8 years
Secondary	Exposure to Radiotherapy (RT) in SER Participants By Risk Group (Low, High)	The frequency of RT received by eligible participants (positive PET response, i.e. Deauville score of 4 or 5) will be reported.	Up to approximately 8 years
Secondary	Rate of PET Scan Negativity In Group 1 Participants After ABVD Induction Therapy	The rate of PET negativity for Group 1 participants is the percentage of participants with PET negativity (defined as Deauville score 1, 2 or 3) after two cycles of ABVD induction as per investigator assessment. The Deauville 5-point scoring system is an internationally accepted and utilized five-point scoring system for the FDG avidity of a Hodgkin's lymphoma or Non-Hodgkin's lymphoma tumor mass as seen on FDG PET scan: Score 1= No uptake above the background, Score 2= Uptake = mediastinum, Score 3= Uptake > mediastinum but = liver, Score 4= Uptake moderately increased compared to the liver at any site, Score 5= Uptake markedly increased compared to the liver at any site or new lesions, Score X= New areas of uptake unlikely to be related to lymphoma. In the present study, scores of 1, 2 and 3 are considered to be negative and scores of 4 and 5 are considered to be positive.	Up to approximately 8 years
Secondary	EFS in Rapid Early Responder (RER) Participants By Risk Group (Low, High) as Assessed by Investigator	EFS is defined as the time from study enrollment to the first documented disease progression or recurrence, or death due to any cause, whichever occurs first. Progression/disease recurrence will be determined by the investigator.	Up to approximately 8 years
Secondary	OS in RER Participants By Risk Group (Low, High)	OS is defined as the time from study enrollment to death due to any cause. Participants without documented death will be censored at the date of the last follow-up.	Up to approximately 8 years
Secondary	Serum Thymus and Activation-Regulated Chemokine (TARC) Levels in SER Participants By Risk Group (Low, High)	Serum TARC levels will be measured and evaluated as a potential biomarker in SER participants by risk group at screening, early, and late response assessments.	Up to approximately 8 years
Secondary	Number of SER Participants Experiencing an Adverse Event (AE) By Risk Group (Low, High)	An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of SER participants who experience an AE will be reported for each arm.	Up to approximately 8 years
Secondary	Number of SER Participants Discontinuing Study Treatment Due to AEs By Risk Group (Low, High)	An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of SER participants who discontinue study treatment due to an AE will be reported for each arm.	Up to approximately 8 years

External Links

•   Merck Clinical Trials Information
•   Plain Language Summary