Phase II Evaluation of Pembrolizumab with Chemotherapy in Pediatric and Young Adult Classical Hodgkin Lymphoma with Slow Early Response

The primary objective of this study is to evaluate the **objective response rate (ORR)** by International Working Group (IWG) criteria, as assessed by blinded independent central review (BICR), of pembrolizumab in combination with chemotherapy in slow early responders (SERs) by risk group (low, high). This is clinically relevant as it aims to determine the efficacy of pembrolizumab, a checkpoint inhibitor, in improving treatment outcomes for children and young adults with newly diagnosed classical Hodgkin lymphoma who exhibit an inadequate response to frontline chemotherapy.

Secondary objectives include:

• Evaluating the rate of Positron Emission Tomography (PET) negativity, 2-year event-free survival (EFS) from study enrollment by IWG criteria as assessed by BICR, and overall survival (OS) of pembrolizumab in combination with chemotherapy in SERs by risk group.
• Assessing the exposure to radiation therapy (RT) and its associated toxicity in SERs by risk group.
• Determining the rate of PET negativity per investigator assessment in Group 1 participants after completing 2 cycles of ABVD induction.
• Evaluating the 3-year EFS per investigator assessment and OS in rapid early responders (RERs) by risk group.
• Investigating serum thymus and activation-regulated chemokine (TARC) as a potential biomarker in SERs by risk group.
• Assessing the safety of pembrolizumab in combination with chemotherapy in SERs by risk group.

The clinical trial involves a total of **145 participants** diagnosed with **Classical Hodgkin lymphoma** in children and young adults. The study population includes both male and female subjects, with an age range that encompasses children and young adults. Participants were selected based on their diagnosis of newly confirmed classical Hodgkin Lymphoma at various stages, as well as their measurable disease status. The trial includes individuals with a performance status of at least 50 on the Lansky Play-Performance Scale for children up to 16 years of age or a Karnofsky score of at least 50 for participants aged 16 and older. Both genders are represented, and the trial includes a vulnerable population. Participants are required to have adequate organ function and adhere to specific lifestyle considerations, such as the use of contraception and restrictions on sperm and egg donation during the intervention period. The trial does not specify any particular dietary or physical activity requirements.

The clinical trial is designed to evaluate the **objective response rate** (ORR) of **pembrolizumab** in combination with chemotherapy in children and young adults with newly diagnosed classical Hodgkin lymphoma who exhibit a slow early response to frontline chemotherapy. This is a Phase II, open-label, uncontrolled, multicenter trial. The study employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial is expected to run from November 6, 2019, to November 6, 2028, with recruitment having started on November 6, 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as having measurable disease and adequate organ function. The trial includes several follow-up visits to monitor the participants' response to the treatment and to assess any adverse events. The end-of-study visit will conclude the participants' involvement, during which final assessments will be conducted to evaluate the primary and secondary endpoints, including ORR, event-free survival, and overall survival.

The expected length of participant involvement varies depending on the treatment regimen, with a maximum treatment period of up to 51 weeks for some participants. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial aims to provide valuable insights into the efficacy and safety of pembrolizumab in combination with chemotherapy for this patient population.

The clinical trial involves the administration of **vinblastine sulfate**, a chemical compound used as an experimental medication. It is provided in the pharmaceutical form PHF00231MIG and administered via **intravenous infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 6 mg/m² and a total maximum dose of 24 mg/m² over a treatment period of up to 8 weeks.

**Bleomycin** is another experimental medication used in this trial. It is a mixture administered through intravenous infusion, with a maximum daily dose of 10 units and a total maximum dose of 40 units over 8 weeks. The pharmaceutical form is PHF00231MIG.

**Prednisone** is included as a non-experimental treatment in the study. It is administered orally in tablet form, with a maximum daily dose of 60 mg/m² and a total maximum dose of 800 mg/m² over a 16-week period.

Similarly, **prednisolone** is administered orally in tablet form, with the same dosing schedule as prednisone: a maximum daily dose of 60 mg/m² and a total maximum dose of 800 mg/m² over 16 weeks.

**Dacarbazine** is administered via intravenous infusion in the pharmaceutical form PHF00231MIG. The maximum daily dose is 375 mg/m², with a total maximum dose of 3000 mg/m² over a 16-week period.

**Vincristine**, also known as vinblastine sulfate, is administered via intravenous infusion in the pharmaceutical form PHF675. The maximum daily dose is 2 mg, with a total maximum dose of 16 mg over a 16-week period.

**Doxorubicin** is administered via intravenous infusion in the pharmaceutical form PHF00231MIG. The maximum daily dose is 40 mg/m², with a total maximum dose of 1500 mg/m² over an 8-week period.

**Etoposide** is administered via intravenous infusion in the pharmaceutical form PHF675. The maximum daily dose is 125 mg/m², with a total maximum dose of 1250 mg/m² over an 8-week period.

**Pembrolizumab**, marketed as Keytruda, is a biological agent administered via intravenous infusion. It is provided as a concentrate for solution for infusion, with a maximum daily dose of 200 mg and a total maximum dose of 3400 mg over a 51-week period.

**Anhydrous cyclophosphamide** is administered via intravenous infusion in the pharmaceutical form PHF00231MIG. The maximum daily dose is 500 mg/m², with a total maximum dose of 4000 mg/m² over a 16-week period.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **Objective Response Rate (ORR)** in Slow Early Responder (SER) participants by risk group (low, high), as evaluated by Blinded Independent Central Review (BICR). Secondary endpoints include the rate of Positron Emission Tomography (PET) scan negativity in SER participants by risk group after AVD (doxorubicin, vinblastine, and dacarbazine) or COPDAC-28 (cyclophosphamide, vincristine, prednisone, and dacarbazine) chemotherapy, Event-Free Survival (EFS), Overall Survival (OS), exposure to radiotherapy, and serum Thymus and Activation-Regulated Chemokine (TARC) levels in SER participants by risk group. Additionally, the number of SER participants experiencing adverse events and those discontinuing study treatment due to adverse events will be recorded.

The efficacy parameters will be measured and analyzed at various timepoints throughout the trial. The ORR will be assessed according to the International Working Group (IWG) criteria, and PET scan results will be evaluated to determine negativity rates. EFS and OS will be monitored to provide insights into the long-term benefits of the treatment. The trial will also track the exposure to radiotherapy and changes in serum TARC levels, which may serve as biomarkers for treatment response. The collection and analysis of these data points will be conducted in accordance with the trial's protocol to ensure the reliability and validity of the results.