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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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03407144
Recruitment Status : Active, not recruiting
First Posted : January 23, 2018
Last Update Posted : April 18, 2024
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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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 (RT) 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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 340 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 : February 13, 2027
Estimated Study Completion Date : February 13, 2027

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Pembrolizumab + AVD (Group 1)
After receiving two 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 two 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 (RT)
RT administered daily, dose dependent on randomization group and disease response.
Experimental: Pembrolizumab + COPDAC-28 (Group 2)
After receiving two 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: 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: 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)

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)


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 (RT)
RT administered daily, dose dependent on randomization group and disease response.


Outcome Measures
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Primary Outcome Measures :
  1. Objective Response Rate (ORR) in SER Participants By Risk Group (Low, High) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to approximately 8 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 in SER Participants By Risk Group (Low, High) After AVD or COPDAC-28 Chemotherapy [ Time Frame: Up to approximately 8 years ]
    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.

  2. Event-Free Survival (EFS) in SER Participants By Risk Group (Low, High) as Assessed by BICR [ Time Frame: Up to approximately 8 years ]
    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.

  3. Overall Survival (OS) in SER Participants By Risk Group (Low, High) [ Time Frame: Up to approximately 8 years ]
    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.

  4. Exposure to Radiotherapy (RT) in SER Participants By Risk Group (Low, High) [ Time Frame: Up to approximately 8 years ]
    The frequency of RT received by eligible participants (positive PET response, i.e. Deauville score of 4 or 5) will be reported.

  5. Rate of PET Scan Negativity In Group 1 Participants After ABVD Induction Therapy [ Time Frame: Up to approximately 8 years ]
    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.

  6. EFS in Rapid Early Responder (RER) Participants By Risk Group (Low, High) as Assessed by Investigator [ Time Frame: Up to approximately 8 years ]
    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.

  7. OS in RER Participants By Risk Group (Low, High) [ Time Frame: Up to approximately 8 years ]
    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.

  8. Serum Thymus and Activation-Regulated Chemokine (TARC) Levels in SER Participants By Risk Group (Low, High) [ Time Frame: Up to approximately 8 years ]
    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.

  9. Number of SER Participants Experiencing an Adverse Event (AE) By Risk Group (Low, High) [ Time Frame: Up to approximately 8 years ]
    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.

  10. Number of SER Participants Discontinuing Study Treatment Due to AEs By Risk Group (Low, High) [ Time Frame: Up to approximately 8 years ]
    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.


Eligibility Criteria
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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 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
Contacts and Locations
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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


Locations
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Sponsors and Collaborators
Merck Sharp & Dohme LLC
Investigators
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Study Director: Medical Director Merck Sharp & Dohme LLC
More Information
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Additional Information:

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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT03407144    
Other Study ID Numbers: 3475-667
MK-3475-667 ( Other Identifier: Merck Protocol Number )
2023-504821-38 ( Registry Identifier: EU CT )
2017-001123-53 ( EudraCT Number )
First Posted: January 23, 2018    Key Record Dates
Last Update Posted: April 18, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme LLC:
Programmed Death-1 (PD-1)
PD1
Programmed Death-Ligand 1 (PD-L1)
PDL1
Additional relevant MeSH terms:
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Lymphoma
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Prednisone
Prednisolone
Cyclophosphamide
Dacarbazine
Pembrolizumab
Doxorubicin
Etoposide
 Etoposide phosphate
Vincristine
Bleomycin
Vinblastine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors