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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Hodgkin Lymphoma

Intervention / Treatment
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* Biological: pembrolizumab
* Drug: doxorubicin
* Drug: vinblastine
* Drug: dacarbazine
* Drug: cyclophosphamide
* Drug: vincristine
* Drug: prednisone/prednisolone
* Drug: bleomycin
* Drug: etoposide
* Radiation: Radiotherapy (RT)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + AVD (Group 1)<br>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<br>* 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<br>* Other names: MK-3475;Drug: doxorubicin<br>* 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)<br>Drug: vinblastine<br>* 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)<br>Drug: dacarbazine<br>* 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)<br>Drug: bleomycin<br>* 10 units/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1)<br>Radiation: Radiotherapy (RT)<br>* RT administered daily, dose dependent on randomization group and disease response.<br>|
| Experimental: Pembrolizumab + COPDAC-28 (Group 2)<br>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<br>* 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<br>* Other names: MK-3475;Drug: doxorubicin<br>* 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)<br>Drug: dacarbazine<br>* 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)<br>Drug: cyclophosphamide<br>* 500 mg/m^2 IV on days 1 and 8 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)<br>Drug: vincristine<br>* 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)<br>Drug: prednisone/prednisolone<br>* 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)<br>Drug: etoposide<br>* 125 mg/m^2 IV on Days 1 to 5 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2)<br>* Other names: Etoposide Phosphate;Radiation: Radiotherapy (RT)<br>* RT administered daily, dose dependent on randomization group and disease response.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Death-1 (PD-1), PD1, Programmed Death-Ligand 1 (PD-L1), PDL1