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

Phase 2

Completed

Conditions: Classical Hodgkin Lymphoma

Interventions: Biological: Pembrolizumab
Drug: Doxorubicin
Drug: Vinblastine
Drug: Dacarbazine
Drug: Bleomycin
Drug: Etoposide
Drug: Cyclophosphamide
Drug: Vincristine
Drug: Procarbazine
Drug: Prednisone

Registration Number: NCT05008224

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 146

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Pembrolizumab	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Doxorubicin	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Vinblastine	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Dacarbazine	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Bleomycin	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Etoposide	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Cyclophosphamide	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Vincristine	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Procarbazine	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.
Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation	Prednisone	After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2. Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV. All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.

Primary Outcome Measures

Name	Time	Method
Complete Response (CR) Rate at the End of Study Intervention as Assessed by Blinded Independent Central Review (BICR) Per Lugano 2014 Response Criteria	Up to approximately 24 months	CR rate was assessed by BICR using Computed Tomography (CT) and PET scan according to Lugano 2014 response criteria (Cheson, B.D. et al, Journal of Clinical Oncology, 2014). At each timepoint, CR was determined by combining the anatomic response, metabolic response, and clinical data. The criteria for CR included complete metabolic (no/minimal 2-fluorodeoxyglucose \[FDG\] uptake) and radiologic response (target lesions regress to ≤1.5 cm in longest transverse diameter of a lesion) and no new lesions. Per protocol, participants who discontinued study intervention during pembrolizumab monotherapy, chemotherapy, or pembrolizumab consolidation, or are lost to follow-up, or receive any new non-study anticancer therapy prior to end of treatment were classified as non-responders. The percentage of participants who had CR after the completion of pembrolizumab consolidation is presented.

Secondary Outcome Measures

Name	Time	Method
CR Rate at the End of Study Intervention as Assessed by Investigator Per Lugano 2014 Response Criteria	Up to approximately 31 months	CR rate was assessed by the investigator using CT and PET scan according to Lugano 2014 response criteria (Cheson, B.D. et al, Journal of Clinical Oncology, 2014). At each timepoint, CR was determined by combining the anatomic response, metabolic response, and clinical data. The criteria for CR included complete metabolic (no/minimal FDG uptake) and radiologic response (target lesions regress to ≤1.5 cm in longest transverse diameter of a lesion) and no new lesions. Per protocol, participants who discontinued study intervention during pembrolizumab monotherapy, chemotherapy, or pembrolizumab consolidation, or are lost to follow-up, or receive any new non-study anticancer therapy prior to end of treatment were classified as non-responders. The percentage of participants who had CR after the completion of pembrolizumab consolidation is presented.
Duration of Complete Response (DurCR) as Assessed by BICR Per Lugano 2014 Response Criteria	Up to approximately 31 months	DurCR was defined as the time from CR to progressive disease (PD) or death due to any cause, whichever came first. CR was assessed by BICR using CT and PET scan according to Lugano 2014 response criteria (Cheson, B.D. et al, Journal of Clinical Oncology, 2014). At each timepoint, CR was determined by combining the anatomic response, metabolic response, and clinical data. The criteria for CR included complete metabolic (no/minimal FDG uptake) and radiologic response (target lesions regress to ≤1.5 cm in longest transverse diameter of a lesion) and no new lesions. PD was defined as uptake moderately or markedly higher than the liver and/or new lesions. DurCR was analyzed by the Kaplan-Meier method for censored data and is presented for participants who demonstrated CR.
Rate of PET Negativity Assessed by BICR According to the FDG-PET 5-point Scale After Administration of Pembrolizumab Monotherapy (PET Scan 2)	Up to approximately 10 weeks	The rate of PET negativity was defined as the percentage of participants considered negative on the FDG-PET 5-point scale, as assessed by BICR according to Lugano 2014 response criteria (Cheson, B.D. et al, Journal of Clinical Oncology, 2014). Participants were assigned a single score on the FDG-PET 5-point scale measuring FDG uptake (1 = no uptake above background, 2 = uptake above background but ≤ mediastinum, 3 = uptake \> mediastinum but ≤ liver, 4 = uptake moderately \> liver, 5 = uptake markedly \> liver or new FDG-positive lesions). Higher scores corresponded to greater uptake (greater disease). FDG-PET 5-point scale scores of 1, 2, and 3 were considered negative and scores of 4 and 5 were considered positive. The percentage of participants who were assessed as negative at PET scan 2, after completion of 3 cycles of pembrolizumab monotherapy, is presented.
Rate of PET Negativity Assessed by BICR According to the FDG-PET 5-point Scale After Administration of Pembrolizumab Monotherapy and AVD Chemotherapy (PET Scan 3)	Up to approximately 5 months	The rate of PET negativity was defined as the percentage of participants considered negative on the FDG-PET 5-point scale, as assessed by BICR according to Lugano 2014 response criteria (Cheson, B.D. et al, Journal of Clinical Oncology, 2014). Participants were assigned a single score on the FDG-PET 5-point scale measuring FDG uptake (1 = no uptake above background, 2 = uptake above background but ≤ mediastinum, 3 = uptake \> mediastinum but ≤ liver, 4 = uptake moderately \> liver, 5 = uptake markedly \> liver or new FDG-positive lesions). Higher scores corresponded to greater uptake (greater disease). FDG-PET 5-point scale scores of 1, 2, and 3 were considered negative and scores of 4 and 5 were considered positive. The percentage of participants who were assessed as negative at PET scan 3, after completion of 3 cycles of pembrolizumab monotherapy and phase 1 AVD chemotherapy (2 AVD cycles), is presented.
Number of Participants Who Experienced an Adverse Event (AE)	Up to approximately 31 months	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. Per protocol, collection and reporting of AEs was based on the study treatment received by the participant (pembrolizumab, AVD chemotherapy, or escBEACOPP chemotherapy) at the time of the event. The number of participants who experienced an AE is reported.
Number of Participants Who Discontinued Study Treatment Due to an AE	Up to approximately 17 months	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. Per protocol, collection and reporting of AEs was based on the study treatment received by the participant (pembrolizumab, AVD chemotherapy, or escBEACOPP chemotherapy) at the time of the event. The number of participants who discontinued study intervention due to an AE is reported.

Trial Locations

Locations (48): St Joseph Heritage Healthcare-Oncology ( Site 0004)
🇺🇸
Fullerton, California, United States
Stanford Cancer Center ( Site 0023)
🇺🇸
Palo Alto, California, United States
Northwestern Memorial Hospital ( Site 0002)
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Chicago, Illinois, United States
OptumCare Cancer Care-Research Department ( Site 0005)
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Las Vegas, Nevada, United States
University of Tennessee Medical Center-Cancer Institute ( Site 0006)
🇺🇸
Knoxville, Tennessee, United States
Texas Oncology-Plano East ( Site 0020)
🇺🇸
Plano, Texas, United States
Liverpool Hospital-Haematology ( Site 0906)
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Liverpool, New South Wales, Australia
Mater Misericordiae Limited ( Site 0904)
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Brisbane, Queensland, Australia
Princess Alexandra Hospital-Division of Cancer Services Trials Unit ( Site 0907)
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Woolloongabba, Queensland, Australia
Monash Health-Haematology Research ( Site 0908)
🇦🇺
Clayton, Victoria, Australia
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St Joseph Heritage Healthcare-Oncology ( Site 0004)
🇺🇸Fullerton, California, United States