Clinical Trials /

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

NCT03407144

Description:

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.

Related Conditions:
  • Classical Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

  • ORG STUDY ID: 3475-667
  • SECONDARY ID: 2017-001123-53
  • SECONDARY ID: MK-3475-667
  • NCT ID: NCT03407144

Conditions

  • Hodgkin Lymphoma

Interventions

DrugSynonymsArms
pembrolizumabMK-3475Pembrolizumab + AVD (Group 1)
doxorubicinPembrolizumab + AVD (Group 1)
vinblastinePembrolizumab + AVD (Group 1)
dacarbazinePembrolizumab + AVD (Group 1)
cyclophosphamidePembrolizumab + COPDAC-28 (Group 2)
vincristinePembrolizumab + COPDAC-28 (Group 2)
prednisone/prednisolonePembrolizumab + COPDAC-28 (Group 2)
bleomycinPembrolizumab + AVD (Group 1)
etoposideEtoposide PhosphatePembrolizumab + COPDAC-28 (Group 2)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + AVD (Group 1)ExperimentalAfter 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.
  • pembrolizumab
  • doxorubicin
  • vinblastine
  • dacarbazine
  • bleomycin
Pembrolizumab + COPDAC-28 (Group 2)ExperimentalAfter 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.
  • pembrolizumab
  • doxorubicin
  • dacarbazine
  • cyclophosphamide
  • vincristine
  • prednisone/prednisolone
  • etoposide

Eligibility 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 (or longer, if required by the drug label of chemotherapy
             received by the participant on study) 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 (or longer, if
             required by the drug label of chemotherapy received by the participant on study) 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 a live vaccine within 30 days prior to the first dose of pembrolizumab

          -  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
             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

          -  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
             (or longer, if required by the drug label of chemotherapy received by the participant
             on study) after the last dose of trial treatment
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR) in SER Participants By Risk Group (Low, High) as Assessed by Blinded Independent Central Review (BICR)
Time Frame:Up to 5 years
Safety Issue:
Description: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

Measure: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 5 years
Safety Issue:
Description: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.
Measure:Event-Free Survival (EFS) in SER Participants By Risk Group (Low, High) as Assessed by BICR
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Overall Survival (OS) in SER Participants By Risk Group (Low, High)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Exposure to Radiotherapy (RT) in SER Participants By Risk Group (Low, High)
Time Frame:Up to 5 years
Safety Issue:
Description:The frequency of RT received by eligible participants (positive PET response, i.e. Deauville score of 4 or 5) will be reported.
Measure:Rate of PET Scan Negativity In Group 1 Participants After ABVD Induction Therapy
Time Frame:Up to 5 years
Safety Issue:
Description: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. 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.
Measure:EFS in Rapid Early Responder (RER) Participants By Risk Group (Low, High) as Assessed by Investigator
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:OS in RER Participants By Risk Group (Low, High)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Serum Thymus and Activation-Regulated Chemokine (TARC) Levels in SER Participants By Risk Group (Low, High)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Number of SER Participants Experiencing an Adverse Event (AE) By Risk Group (Low, High)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Number of SER Participants Discontinuing Study Treatment Due to AEs By Risk Group (Low, High)
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Death-1 (PD-1)
  • PD1
  • Programmed Death-Ligand 1 (PD-L1)
  • PDL1

Last Updated

January 30, 2020