Study of Safety and Efficacy of Pembrolizumab and Chemotherapy in Participants With Newly Diagnosed Classical Hodgkin Lymphoma (cHL) (MK-3475-C11/KEYNOTE-C11)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of pembrolizumab (MK-3475) monotherapy, followed by chemotherapy, followed by pembrolizumab consolidation. The primary hypothesis of the study is that the complete response (CR) rate at the end of study intervention according to Lugano 2014 response criteria is higher than conventional chemotherapy.

Official Title
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Phase 2 Study of Pembrolizumab and Chemotherapy in Patients With Newly Diagnosed Classical Hodgkin Lymphoma (KEYNOTE-C11)

Conditions
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Classical Hodgkin Lymphoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Doxorubicin
* Drug: Vinblastine
* Drug: Dacarbazine
* Drug: Bleomycin
* Drug: Etoposide
* Drug: Cyclophosphamide
* Drug: Vincristine
* Drug: Procarbazine
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The main inclusion criteria include, but are not limited to the following: Has a histologically confirmed diagnosis of Ann Arbor Stage III or IV classical Hodgkin Lymphoma (cHL). Stage I and II participants may be enrolled, but must have at least one National Comprehensive Cancer Network (NCCN) unfavorable risk factor per protocol Has measurable 2-fluorodeoxyglucose (FDG)-avid disease based on investigator assessment according to Lugano 2014 response criteria Has not received prior radiation therapy, chemotherapy, immunotherapy, or other systemic therapy for the treatment of cHL before the first dose of study intervention Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 assessed within 7 days before the start of study intervention Exclusion Criteria: The main exclusion criteria include, but are not limited to the following: Has confirmed nodular lymphocyte-predominant Hodgkin Lymphoma (HL) Has an uncontrolled intercurrent cardiovascular illness Has received prior therapy with an anti-programmed cell death 1 protein (PD-1), anti-programmed cell death ligand 1 protein (PD-L1), or anti- programmed cell death ligand 2 protein (PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor Has received or is expected to receive a live or live-attenuated vaccine within 30 days before the first dose of study intervention Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication Has a known additional malignancy that is progressing or has required active treatment within the past 5 years Has radiographically detectable central nervous system metastases and/or carcinomatous meningitis Has an active autoimmune disease that has required systemic treatment in past 2 years Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Has a history or current evidence of pulmonary fibrosis Has had an allogenic tissue/solid organ transplant

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab Monotherapy + Chemotherapy + Pembrolizumab Consolidation<br>Participants receive pembrolizumab monotherapy followed by chemotherapy with doxorubicin in combination with vinblastine & dacarbazine (AVD) or chemotherapy with escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, & prednisone (escBEACOPP) followed by pembrolizumab consolidation. All participants receive pembrolizumab monotherapy intravenous (IV) for 3 cycles (cycle length = 3 weeks (wks); up to 9 wks). All participants receive AVD IV for 2 cycles (cycle length = 4 wks; up to 8 wks) after Positron Emission Tomography (PET) 2. Participants who are PET 3 -ve, or +ve & age ≥ 60 years, receive up to 4 additional cycles of AVD IV (cycle length = 4 wks, up to 16 wks), or up to 4 cycles of escBEACOPP IV if PET 3 +ve, age <60 years; cycle length = 3 wks; up to 12 wks. All participants receive pembrolizumab consolidation IV for 4 cycles (cycle length = 6 wks; up to 24 wks). Total treatment duration is up to 57 wks. | Biological: Pembrolizumab<br>* 200 mg IV administered on Day 1 of each 3-week cycle for 3 cycles during pembrolizumab monotherapy. 400 mg IV administered on Day 1 of each 6-week cycle for 4 cycles as pembrolizumab consolidation.<br>* Other names: KEYTRUDA®;Drug: Doxorubicin<br>* 25 mg/m^2 IV administered on Days 1 and 15 of each 4-week cycle for 2 cycles in all participants after PET2 and up to 4 additional cycles after PET3 (participants who are PET3 -ve, or +ve & ≥60 years of age). 35 mg/m^2 IV administered on Day 1 of each 3-week cycle for up to 4 cycles after PET3 (participants who are PET3 +ve, <60 years of age).<br>* Other names: Rubex®;Drug: Vinblastine<br>* 6 mg/m^2 IV administered on Days 1 and 15 of each 4-week cycle for 2 cycles after PET2 (all participants) and up to 4 additional cycles after PET3 (participants who are PET3 -ve, or +ve & ≥60 years of age).<br>* Other names: Velban®;Drug: Dacarbazine<br>* 375 mg/m^2 IV on Days 1 and 15 of each 4-week cycle for 2 cycles after PET2 (all participants) and up to 4 additional cycles after PET3 (participants who are PET3 -ve, or +ve & ≥60 years of age).<br>* Other names: Dtic-Dome®;Drug: Bleomycin<br>* 10 units/m^2 IV administered on Day 8 of each 3-week cycle for up to 4 cycles after PET3 (participants who are PET3 +ve & <60 years of age).<br>* Other names: Blenoxane®;Drug: Etoposide<br>* 200 mg/m^2 IV administered on Days 1-3 of each 3-week cycle for up to 4 cycles after PET3 (participants who are PET3 +ve & <60 years of age).<br>* Other names: Etoposide phosphate;Drug: Cyclophosphamide<br>* 1250 mg/m^2 IV administered on Day 1 of each 3-week cycle for up to 4 cycles after PET3 (participants who are PET3 +ve & <60 years of age).<br>* Other names: Cytoxan®;Drug: Vincristine<br>* 1.4 mg/m^2 IV on Day 8 of each 3-week cycle for up to 4 cycles after PET3 (participants who are PET3 +ve &<60 years of age).<br>* Other names: Vincasar PFS®;Drug: Procarbazine<br>* 100 mg/m^2 orally (PO) administered on Days 1-7 of each 3-week cycle for up to 4 cycles after PET3 (participants who are PET3 +ve & <60 years of age).<br>* Other names: Matulane®;Drug: Prednisone<br>* 40 mg/m^2 PO administered on Days 1-14 of each 3-week cycle for up to 4 cycles after PET3 (participants who are PET3 +ve & <60 years of age).<br>* Other names: Deltasone®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) at the End of Study Intervention as Assessed by Independent Central Review (ICR) Per Lugano 2014 Response Criteria | The percentage of participants who have CR at the end of study intervention, after the completion of pembrolizumab consolidation, as assessed by ICR per Lugano 2014 response criteria will be presented. | Up to approximately 57 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR at the End of Study Intervention as Assessed by Investigator Per Lugano 2014 Response Criteria | The percentage of participants who have CR at the end of study intervention, after the completion of pembrolizumab consolidation, as assessed by the investigator per Lugano 2014 response criteria will be presented. | Up to approximately 57 weeks | 
| Duration of Complete Response (DurCR) as Assessed by Independent Central Review Per Lugano 2014 Response Criteria | DurCR is defined, only for the subgroup of participants who achieve CR, as the time from the first documentation of CR to disease progression or to death due to any cause, whichever comes first as assessed by the independent central review per Lugano 2014 response criteria. | Up to approximately 72 months | 
| Positron Emission Tomography (PET) Negativity by Independent Central Review Per 3-Fluorodeoxyglucose (FDG)-PET 5-point Scale After Administration of Pembrolizumab Monotherapy | The rate of PET negativity is defined as the percentage of participants with a score of 1, 2, or 3, assessed by independent central review according to the FDG-PET 5-point scale, after administration of pembrolizumab monotherapy. Per FDG-PET 5-point scale: Score 1= No uptake above the background, Score 2= Uptake ≤ mediastinum, Score 3= Uptake > mediastinum but ≤ liver, Score 4= Uptake moderately higher than liver, Score 5= Uptake markedly higher than liver or new lesions. 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 9 weeks | 
| PET Negativity by Independent Central Review Per FDG-PET 5-point Scale After Administration of Pembrolizumab Monotherapy and Chemotherapy | The rate of PET negativity is defined as the percentage of participants with a score of 1, 2, or 3, assessed by independent central review according to the FDG-PET 5-point scale, after administration of pembrolizumab monotherapy and chemotherapy. Per FDG-PET 5-point scale: Score 1= No uptake above the background, Score 2= Uptake ≤ mediastinum, Score 3= Uptake > mediastinum but ≤ liver, Score 4= Uptake moderately higher than liver, Score 5= Uptake markedly higher than liver or new lesions. 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 17 weeks | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. 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 intervention. The number of participants who experienced an AE will be reported. | Up to approximately 64 weeks | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. 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 intervention. The number of participants who discontinue study treatment due to an AE will be reported. | Up to approximately 57 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death 1 (PD-1, PD1), Programmed Cell Death-Ligand 1 (PD-L1, PDL1), Programmed Cell Death-Ligand 2 (PD-L2, PDL2)