Classical Hodgkin Lymphoma
Conditions
Keywords
Programmed Cell Death 1 (PD-1, PD1), Programmed Cell Death-Ligand 1 (PD-L1, PDL1), Programmed Cell Death-Ligand 2 (PD-L2, PDL2)
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.
Interventions
BIOLOGICALPembrolizumab
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.
DRUGDoxorubicin
25 mg/m\^2 IV administered as part of AVD chemotherapy on Days 1 and 15 of each 4-week cycle for 2 cycles in all participants after PET scan 2 and up to 4 additional cycles after PET scan 3 (participants who are PET scan 3 negative, or positive and ≥60 years of age). 35 mg/m\^2 IV administered as part of escBEACOPP chemotherapy on Day 1 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive, \<60 years of age).
DRUGVinblastine
6 mg/m\^2 IV administered as part of AVD chemotherapy on Days 1 and 15 of each 4-week cycle for 2 cycles after PET scan 2 (all participants) and up to 4 additional cycles after PET scan 3 (participants who are PET scan 3 negative, or positive and ≥60 years of age).
DRUGDacarbazine
375 mg/m\^2 IV administered as part of AVD chemotherapy on Days 1 and 15 of each 4-week cycle for 2 cycles after PET scan 2 (all participants) and up to 4 additional cycles after PET scan 3 (participants who are PET scan 3 negative, or positive and ≥60 years of age).
DRUGBleomycin
10 units/m\^2 IV administered as part of escBEACOPP chemotherapy on Day 8 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age).
DRUGEtoposide
200 mg/m\^2 IV administered as part of escBEACOPP chemotherapy on Days 1-3 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age).
DRUGCyclophosphamide
1250 mg/m\^2 IV administered as part of escBEACOPP chemotherapy on Day 1 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age).
DRUGVincristine
1.4 mg/m\^2 IV administered as part of escBEACOPP chemotherapy on Day 8 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age).
DRUGProcarbazine
100 mg/m\^2 orally (PO) administered as part of escBEACOPP chemotherapy on Days 1-7 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age).
DRUGPrednisone
40 mg/m\^2 PO administered as part of escBEACOPP chemotherapy on Days 1-14 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age).
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Australia, Canada, Chile, France, Israel, Italy, Poland, Russia, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
Male or female participants with newly diagnosed early unfavorable or advanced-stage classical Hodgkin Lymphoma (cHL), who were at least 18 years old, were enrolled in this study.
Pre-assignment details
146 participants were allocated to the treatment arm and received sequential treatments beginning with pembrolizumab monotherapy, followed by chemotherapy (phases 1 and 2), and finishing with pembrolizumab consolidation. Per protocol, efficacy analysis was planned and conducted on the treatment arm of participants that received these sequential treatments. Safety outcome measures were analyzed based on the individual study treatment received by the participant at the time of the event.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation After completing PET scan 1 during eligibility screening, participants received pembrolizumab monotherapy 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 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 escBEACOPP IV.
All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan. | 146 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | Did Not Continue on Extension Study | 39 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Transferred to Extension Study | 100 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation |
|---|---|
| Age, Continuous | 38.9 Years STANDARD_DEVIATION 16.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) White | 126 Participants |
| Sex: Female, Male Female | 66 Participants |
| Sex: Female, Male Male | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 146 | 3 / 136 | 0 / 17 |
| other Total, other adverse events | 122 / 146 | 131 / 136 | 17 / 17 |
| serious Total, serious adverse events | 26 / 146 | 26 / 136 | 6 / 17 |
Outcome results
Primary
Complete Response (CR) Rate at the End of Study Intervention as Assessed by Blinded Independent Central Review (BICR) Per Lugano 2014 Response Criteria
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.
Time frame: Up to approximately 24 months
Population: The analysis population consisted of all participants who received at least 1 dose of pembrolizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation | Complete Response (CR) Rate at the End of Study Intervention as Assessed by Blinded Independent Central Review (BICR) Per Lugano 2014 Response Criteria | 67.0 Percentage of Participants |
Secondary
CR Rate at the End of Study Intervention as Assessed by Investigator Per Lugano 2014 Response Criteria
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.
Time frame: Up to approximately 31 months
Population: The analysis population consisted of all participants who received at least 1 dose of pembrolizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation | CR Rate at the End of Study Intervention as Assessed by Investigator Per Lugano 2014 Response Criteria | 71.9 Percentage of Participants |
Secondary
Duration of Complete Response (DurCR) as Assessed by BICR Per Lugano 2014 Response Criteria
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.
Time frame: Up to approximately 31 months
Population: The analysis population consisted of all participants who received at least 1 dose of pembrolizumab and who had achieved CR.~DurCR data was censored on the date of the last disease assessment documenting absence of PD for participants who do not have progression and are still on study at the time of an analysis, are given antitumor treatment other than the study treatment, or are removed from study prior to documentation of tumor progression.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation | Duration of Complete Response (DurCR) as Assessed by BICR Per Lugano 2014 Response Criteria | NA Months |
Secondary
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. 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.
Time frame: Up to approximately 17 months
Population: The analysis population consisted of all participants who received at least 1 dose of study intervention. Per protocol, analysis was based on the study treatment received by the participant (pembrolizumab, AVD chemotherapy, or escBEACOPP chemotherapy) at the time of the event.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation | Number of Participants Who Discontinued Study Treatment Due to an AE | 15 Participants |
| AVD Chemotherapy | Number of Participants Who Discontinued Study Treatment Due to an AE | 1 Participants |
| escBEACOPP Chemotherapy | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
Secondary
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. 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.
Time frame: Up to approximately 31 months
Population: The analysis population consisted of all participants who received at least 1 dose of study intervention. Per protocol, analysis was based on the study treatment received by the participant (pembrolizumab, AVD chemotherapy, or escBEACOPP chemotherapy) at the time of the event.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation | Number of Participants Who Experienced an Adverse Event (AE) | 135 Participants |
| AVD Chemotherapy | Number of Participants Who Experienced an Adverse Event (AE) | 132 Participants |
| escBEACOPP Chemotherapy | Number of Participants Who Experienced an Adverse Event (AE) | 17 Participants |
Secondary
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)
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.
Time frame: Up to approximately 5 months
Population: The analysis population consisted of all participants who had completed 3 cycles of pembrolizumab monotherapy and phase 1 AVD chemotherapy (2 AVD cycles).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation | 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) | 70.5 Percentage of Participants |
Secondary
Rate of PET Negativity Assessed by BICR According to the FDG-PET 5-point Scale After Administration of Pembrolizumab Monotherapy (PET Scan 2)
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.
Time frame: Up to approximately 10 weeks
Population: The analysis population consisted of all participants who had completed 3 cycles of pembrolizumab monotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Monotherapy + AVD Chemotherapy/escBEACOPP Chemotherapy + Pembrolizumab Consolidation | Rate of PET Negativity Assessed by BICR According to the FDG-PET 5-point Scale After Administration of Pembrolizumab Monotherapy (PET Scan 2) | 19.9 Percentage of Participants |