Phase 2 Evaluation of Pembrolizumab in Relapsed/Refractory Classical Hodgkin's Lymphoma and Primary Mediastinal Large B-cell Lymphoma

Trial ID: 2024-510979-38-00
Protocol: MK-3475-B68
Sponsor: Merck Sharp & Dohme LLC

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Diseases & Conditions

Hodgkin's disease refractory Primary mediastinal large B-cell lymphoma refractory

Objectives

The primary objective of this Phase 2 study is to evaluate the **objective response rate (ORR)** in participants with relapsed or refractory Classical Hodgkin's Lymphoma (rrcHL) and relapsed or refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL). This assessment is conducted by the investigator according to the Lugano classification criteria in individuals treated with pembrolizumab every six weeks (Q6W). The clinical relevance of this objective lies in determining the efficacy of pembrolizumab in inducing a measurable response in these specific lymphoma subtypes, which are often challenging to treat.

Secondary objectives include:

Evaluating the ORR by cohort, rrcHL and rrPMBCL, as assessed by blinded independent central review (BICR) according to the Lugano classification criteria.
Assessing the duration of response (DOR) by cohort, rrcHL and rrPMBCL, both by investigator assessment and BICR, according to the Lugano classification criteria.
Evaluating the pharmacokinetic (PK) profile and immunogenicity of pembrolizumab 400 mg Q6W.
Assessing the safety and tolerability of pembrolizumab Q6W.

Participants

The clinical trial involves a total of **32 participants** diagnosed with **relapsed or refractory Classical Hodgkin's Lymphoma** (cHL) and **relapsed or refractory Primary Mediastinal Large B-cell Lymphoma** (PMBCL). The study population includes both male and female subjects, with an age range that spans from young adults to older adults. Participants were selected based on a histologically confirmed diagnosis of cHL or PMBCL, with radiographically measurable disease as per the Lugano classification. The trial does not include vulnerable populations. Lifestyle factors such as diet, physical activity, or habits were not specified as part of the selection criteria. Key inclusion criteria required participants to have relapsed or refractory disease characteristics specific to cHL or PMBCL, including relapse after auto-stem cell transplant for PMBCL or relapse during or after previous cHL treatment regimens. The sponsor did not provide additional information regarding the general health status of the participants.

Plans and Procedures

The clinical trial is designed to evaluate the **objective response rate** (ORR) of **pembrolizumab** administered every six weeks in participants with **relapsed or refractory Classical Hodgkin's Lymphoma** (cHL) and **relapsed or refractory Primary Mediastinal Large B-cell Lymphoma** (PMBCL). This is a Phase 2, randomized, double-blind, controlled study. The trial aims to assess the efficacy and safety of pembrolizumab, with the primary endpoint being the ORR as assessed by the investigator according to the Lugano classification criteria. Secondary endpoints include ORR as assessed by Blinded Independent Central Review (BICR), duration of response, pharmacokinetic parameters such as area under the curve (AUC), maximum serum concentration (Cmax), minimum serum concentration (Cmin), antidrug antibody levels, and the incidence of adverse events.

The trial is expected to last until December 31, 2025, with participant recruitment having commenced on June 7, 2021. Participants will be involved in the study for a maximum treatment period of 24 months. The study includes several key visits: an initial screening visit to confirm eligibility based on histological diagnosis and measurable disease criteria, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study is conducted under strict adherence to ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants.

Treatment

The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is intended for intravenous infusion. The dosing regimen for pembrolizumab in this study is set at a maximum daily dose of 400 mg, with a total maximum dose of 7200 mg over the course of the treatment period. The treatment is administered every six weeks (Q6W) for a maximum duration of 24 months. Pembrolizumab is classified as a biological medicinal product and is not a pediatric formulation. The active substance, pembrolizumab, is a protein of other origin, and it is also known by several synonyms, including Lambrolizumab, MK-3475, and SCH-900475.

In this clinical trial, pembrolizumab is the primary investigational treatment, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The study focuses on evaluating the objective response rate in participants with relapsed or refractory classical Hodgkin's lymphoma (rrcHL) or relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) as assessed by the investigator according to the Lugano classification criteria. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, evaluated according to the Lugano classification criteria. The ORR will be determined by the investigator for each cohort, specifically for participants with relapsed or refractory classical Hodgkin's lymphoma (rrcHL) and relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL). Secondary efficacy endpoints include the ORR as assessed by a Blinded Independent Central Review (BICR), the Duration of Response (DOR) per Lugano classification as assessed by both the investigator and BICR, and pharmacokinetic parameters such as the Area Under the Curve (AUC), Maximum Serum Concentration (Cmax), and Minimum Serum Concentration (Cmin) of **pembrolizumab**. Additionally, antidrug antibody levels (ADA) for pembrolizumab will be measured, along with the number of participants experiencing adverse events (AEs) and those who discontinued treatment due to AEs.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Have a histologically confirmed diagnosis of cHL or PMBCL, according to the World Health Organization (WHO) classification
Has radiographically measurable cHL or PMBCL disease as per Lugano classification with at least 1 nodal lesion (which has not been previously radiated) that is >15 mm in long axis, regardless of the length of the short axis, and/or extranodal lesion of >10 mm in long and short axis
PMBCL-Specific Disease Characteristics: • Have relapsed or refractory PMBCL and: • Have relapsed after auto-stem cell transplant (SCT)
cHL-Specific Disease Characteristics: • Have relapsed or refractory cHL • Have relapsed during their last cHL regimen after receiving at least 2 cycles of therapy or within 12 months after completing the last regimen for cHL

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Exclusion Criteria

Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic SCT within the last 5 years
Has clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), or serious cardiac arrhythmia requiring medication
Has pericardial effusion or clinically significant pleural effusion
Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers
Is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) <3 days prior to the first dose of study intervention. Note: Participants who receive daily steroid replacement therapy are an exception
Has received prior monoclonal antibody within 4 weeks prior to first dose of study intervention or has not recovered (i.e., ≤Grade 1 or at baseline) from adverse event (AEs) due to agents administered more than 4 weeks earlier
Has received prior therapy with an anti-programmed cell death 1 protein (PD-1), anti-programmed cell death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
Has received prior chimeric antigen receptor T-cell (CAR-T) therapy
Has received prior systemic anticancer therapy, or radiotherapy, including investigational agents within 4 weeks prior to the first dose of study intervention. Note: If the participant had a major operation, the participant must have recovered adequately from the procedure and/or any complications from the operation before starting study intervention
Has received prior radiotherapy within 2 weeks of start of study intervention or have had a history of radiation pneumonitis. Participants must have recovered from all radiation-related toxicities, and not require corticosteroids
Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug
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 (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
Has known active central nervous system (CNS) lymphoma involvement or active CNS involvement by lymphoma
Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
Has a history of (noninfectious) 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. No HIV testing is required unless mandated by local health authority
Has a known history of Hepatitis B (defined as hepatitis B surface antigen (HBsAg) reactive) or known active Hepatitis C virus infection