ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03407144
Recruitment Status : Recruiting
First Posted : January 23, 2018
Last Update Posted : June 25, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief 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.

Condition or disease Intervention/treatment Phase
Hodgkin Lymphoma Biological: pembrolizumab Drug: doxorubicin Drug: vinblastine Drug: dacarbazine Drug: cyclophosphamide Drug: vincristine Drug: prednisone/prednisolone Drug: bleomycin Drug: etoposide Radiation: radiotherapy Phase 2

Detailed 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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : April 9, 2018
Estimated Primary Completion Date : November 24, 2023
Estimated Study Completion Date : November 24, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab + AVD (Group 1)
After receiving 2 4-week cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) induction therapy, SER participants in Group 1 will receive pembrolizumab 2 mg/kg up to a maximum of 200 mg (3 to 17 years of age) or 200 mg (18 to 25 years of age) on Day 1 of each 3-week cycle (Q3W) in combination with 2 cycles of AVD chemotherapy (doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2 and dacarbazine 375 mg/m^2 on Days 1 and 15; cycle frequency every 4 weeks [Q4W]). All SERs in Group 1 will receive radiotherapy (RT) after completing AVD chemotherapy.
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
Other Name: MK-3475

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)


Drug: 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)


Drug: 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)


Drug: bleomycin
10 units/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1)

Radiation: radiotherapy
21 Grays (Gy) with boosts to 30 Gy for PET-avid sites

Experimental: Pembrolizumab + COPDAC-28 (Group 2)
After receiving 2 4-week cycles of OEPA (vincristine, etoposide/etopophos, prednisone/prednisolone and doxorubicin) induction therapy, SER participants in Group 2 will receive pembrolizumab 2 mg/kg up to a maximum of 200 mg (3 to 17 years of age) or 200 mg (18 to 25 years of age) Q3W, in combination with 4 cycles of COPDAC-28 chemotherapy (cyclophosphamide 500 mg/m^2 on Days 1 and 8, vincristine 1.5 mg/m^2 with maximum single dose 2 mg on Days 1 and 8, prednisone/prednisolone 40 mg/m^2/day divided in 3 doses on Days 1 to 15, dacarbazine 250 mg/m^2 on Days 1 to 3; cycle frequency Q4W). SERs in Group 2 will receive RT if they have a positive Positron Emission Tomography (PET) response after completing COPDAC-28 chemotherapy.
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
Other Name: MK-3475

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)


Drug: cyclophosphamide
500 mg/m^2 IV on days 1 and 8 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)

Drug: 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)

Drug: 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)


Drug: etoposide
125 mg/m^2 IV on Days 1 to 5 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2)
Other Name: Etoposide Phosphate

Radiation: radiotherapy
21 Grays (Gy) with boosts to 30 Gy for PET-avid sites




Primary Outcome Measures :
  1. Objective Response Rate (ORR) According to International Working Group (IWG) Criteria as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to 5 years ]
    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.


Secondary Outcome Measures :
  1. Rate of Positron Emission Tomography (PET) Scan Negativity [ Time Frame: Up to 5 years ]
    The rate of PET negativity is the percentage of participants with PET negativity, which is defined as Deauville score 1, 2 or 3, after 2 cycles of AVD or 2 or 4 cycles of COPDAC-28, 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, Score X= New areas of uptake unlikely to be related to lymphoma. In the present study, scores of 1 and 2 are considered to be negative and scores of 3, 4, and 5 are considered to be positive.

  2. Event-Free Survival (EFS) According to IWG Criteria as Assessed by BICR in SER Participants [ Time Frame: Up to 5 years ]
    EFS is defined as the time from study enrollment to the first documented progressive disease (PD) according to IWG or death due to any cause, whichever occurs first. Progression/disease recurrence will be determined by BICR using IWG criteria. EFS rate will be estimated from time of initial diagnosis in SER participants.

  3. Overall Survival (OS) in SER Participants [ Time Frame: Up to 5 years ]
    OS is defined as the time from study enrollment to death due to any cause. The OS rate will be estimated from the start of initial diagnosis in SER participants. Participants without documented death will be censored at the date of the last follow-up.

  4. Frequency of Radiotherapy (RT) [ Time Frame: Up to 5 years ]
    The frequency of RT received by eligible participants (positive PET response, i.e. Deauville score of 4 or 5) will be reported.

  5. Adverse Events (AE) [ Time Frame: Up to 5 years ]
    The number of participants who experience an AE will be reported for each arm. 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.

  6. Treatment Discontinuations Due to AEs [ Time Frame: Up to 5 years ]
    The number of participants who discontinue study treatment due to an AE will be reported for each arm. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   3 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Group 1: Must have newly diagnosed, pathologically confirmed 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 must agree to use approved contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
  • 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 treatment period and for at least 120 days after the last dose of study treatment
  • Performance status: Lansky Play-Performance Scale ≥50 for children up to and including 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 72 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 Merck pembrolizumab (MK-3475) clinical study
  • Has received any prior anti-cancer therapy, monoclonal antibody, chemotherapy, or an investigational agent or device before the first dose of study treatment, or has not recovered from AEs due to previously administered agents
  • Has received prior RT within 2 weeks of start of study treatment
  • Has received a live vaccine within 30 days prior to the first dose of study drug
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
  • Has a diagnosis of lymphocyte-predominant Hodgkin Lymphoma (HL)
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
  • Has a known additional malignancy that is progressing or requires active treatment
  • 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
  • Has an active autoimmune disease that has required systemic treatment in past 2 years
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  • 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 known history of active tuberculosis
  • 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
  • Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03407144


Contacts
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
United States, Michigan
Karmanos Cancer Institute ( Site 0002) Recruiting
Detroit, Michigan, United States, 48201
Contact: Study Coordinator    313-576-8673      
United States, South Carolina
St. Francis Hospital Cancer Center ( Site 0001) Recruiting
Greenville, South Carolina, United States, 29607
Contact: Study Coordinator    864-603-6213      
Korea, Republic of
Severance Hospital Yonsei University Health System ( Site 0221) Recruiting
Seoul, Korea, Republic of, 03722
Contact: Study Coordinator    +82222274726      
Samsung Medical Center ( Site 0222) Recruiting
Seoul, Korea, Republic of, 06351
Contact: Study Coordinator    +82234103524      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03407144     History of Changes
Other Study ID Numbers: 3475-667
2017-001123-53 ( EudraCT Number )
MK-3475-667 ( Other Identifier: Merck Protocol Number )
First Posted: January 23, 2018    Key Record Dates
Last Update Posted: June 25, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:
Programmed Death-1 (PD-1)
PD1
Programmed Death-Ligand 1 (PD-L1)
PDL1

Additional relevant MeSH terms:
Lymphoma
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Liposomal doxorubicin
Pembrolizumab
Etoposide phosphate
Doxorubicin
Prednisone
Etoposide
Vincristine
Prednisolone
Methylprednisolone Hemisuccinate
Bleomycin
Vinblastine
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating