Long-term Safety Evaluation of Nivolumab Monotherapy or in Combination with Other Cancer Therapies in Patients with Pan Tumor Conditions

The primary objective of this study is to evaluate the long-term **safety** of nivolumab, either as a monotherapy or in combination with other cancer therapies. This is clinically relevant as it aims to ensure the sustained safety profile of nivolumab, which is crucial for its continued use in treating various cancer types.

Secondary objectives include:

• To follow participants who have completed therapy and are in or have completed follow-up on a Parent Study investigating nivolumab or nivolumab combination therapy for long-term efficacy, including overall survival.
• To assess the safety of cancer therapies used as comparators in Parent Studies.

The clinical trial involves a total of **281 participants** diagnosed with **cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their eligibility to continue study treatment as per the Parent Study, including those on treatment hold following a long-lasting response or eligible for treatment rechallenge. The trial does not include a vulnerable population. Participants are required to have signed a written informed consent and must be willing and able to comply with the study's scheduled visits, treatment schedule, and laboratory testing. The study aims to evaluate the long-term safety of **nivolumab** alone or in combination with other cancer therapies. No specific lifestyle considerations such as diet or physical activity are highlighted in the trial data provided.

The clinical trial is designed to evaluate the long-term safety of **nivolumab** alone or in combination with other cancer therapies. This study is a phase IV, randomized, double-blind, controlled trial, with an estimated end date of August 22, 2030. The trial aims to assess the incidence of adverse events, including related adverse events, those leading to discontinuation, serious adverse events, select adverse events, immune-mediated adverse events, and deaths. Secondary endpoints include overall survival and the incidence of adverse events. The trial is authorized in Greece and recruitment began on May 5, 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as signed informed consent and compliance with the study requirements. Participants must be eligible to continue study treatment as per the Parent Study, including treatment beyond progression if assessed by the investigator. Follow-up visits will be scheduled to monitor safety and efficacy, with the end-of-study visit marking the conclusion of the participant's involvement. The expected length of participant involvement is until the estimated end date, unless early termination is warranted due to adverse events or other protocol-defined criteria.

Key elements of the research methodology include the use of **nivolumab** and other investigational products such as **trametinib**, **sunitinib**, **temozolomide**, **pembrolizumab**, **cabozantinib**, **capecitabine**, **rucaparib**, **ipilimumab**, **bevacizumab**, **fluorouracil**, **oxaliplatin**, **daratumumab**, **pemetrexed**, **enzalutamide**, and **disodium folinate**. These products are administered via oral or intravenous routes, depending on the specific formulation. The trial's design ensures rigorous monitoring and data collection to evaluate the safety profile of the treatments under investigation.

The clinical trial involves the administration of several experimental and non-experimental medications. **Trametinib** is provided in the form of a film-coated tablet for oral use. The dosage is measured in milligrams, with a maximum daily dose and total dose amount set at 9999 mg. The treatment period is not specified, allowing for flexibility in administration based on the trial's requirements.

**Sunitinib** is administered as a hard capsule, also for oral use. The dosage is similarly measured in milligrams, with the same maximum daily and total dose limits as trametinib. The treatment period is likewise unspecified, providing adaptability in dosing schedules.

**Temozolomide** is available in hard capsule form for oral administration. The dosing parameters mirror those of trametinib and sunitinib, with a maximum daily and total dose of 9999 mg. The treatment duration is flexible, accommodating the trial's needs.

**Pembrolizumab** is administered as a concentrate for solution for infusion, delivered intravenously. The dosage is measured in milligrams, with the same maximum daily and total dose limits as the oral medications. The treatment period remains open-ended to suit the trial's design.

**Capecitabine** is provided as a film-coated tablet for oral use. The dosing follows the same guidelines as the other oral medications, with a maximum daily and total dose of 9999 mg. The treatment duration is not fixed, allowing for adjustments as necessary.

**Rucaparib** is administered in tablet form for oral use. The dosage and treatment period are consistent with the other oral medications, with a maximum daily and total dose of 9999 mg.

**Nivolumab** and **Relatlimab** are administered as a solution for infusion, with the route of administration currently unspecified. The dosage is measured in milligrams, with the same maximum daily and total dose limits as the other medications. The treatment period is flexible, allowing for adjustments based on trial requirements.

**Cabozantinib** is provided as a film-coated tablet for oral use. The dosing parameters are consistent with the other oral medications, with a maximum daily and total dose of 9999 mg. The treatment duration is not specified, allowing for flexibility in administration.

**Oxaliplatin** is administered as a concentrate for solution for infusion, delivered intravenously. The dosage is measured in milligrams per square meter, with the same maximum daily and total dose limits as the other medications. The treatment period remains open-ended to suit the trial's design.

**Ipilimumab** is provided as a concentrate for solution for infusion, with the route of administration currently unspecified. The dosage is measured in milligrams per kilogram, with the same maximum daily and total dose limits as the other medications. The treatment period is flexible, allowing for adjustments based on trial requirements.

**Bevacizumab** is administered as a solution for infusion, delivered intravenously. The dosage is measured in milligrams per kilogram, with the same maximum daily and total dose limits as the other medications. The treatment period remains open-ended to suit the trial's design.

**Fluorouracil** is provided as a solution for injection or infusion, delivered intravenously. The dosage is measured in milligrams per square meter, with the same maximum daily and total dose limits as the other medications. The treatment period is flexible, allowing for adjustments based on trial requirements.

**Pemetrexed** is administered as a powder for concentrate for solution for infusion, delivered intravenously. The dosage is measured in milligrams per square meter, with the same maximum daily and total dose limits as the other medications. The treatment period remains open-ended to suit the trial's design.

**Disodium Folinate** is provided as a solution for injection or infusion, delivered intravenously. The dosage is measured in milligrams per square meter, with the same maximum daily and total dose limits as the other medications. The treatment period is flexible, allowing for adjustments based on trial requirements.

**Enzalutamide** is administered as a soft capsule for oral use. The dosing parameters are consistent with the other oral medications, with a maximum daily and total dose of 9999 mg. The treatment duration is not specified, allowing for flexibility in administration.

**Daratumumab** is provided as a solution for infusion, delivered intravenously. The dosage is measured in milligrams per kilogram, with the same maximum daily and total dose limits as the other medications. The treatment period remains open-ended to suit the trial's design.

**Regorafenib** is administered as a film-coated tablet for oral use. The dosing parameters are consistent with the other oral medications, with a maximum daily and total dose of 9999 mg. The treatment duration is not specified, allowing for flexibility in administration.

Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules and to assess the safety and efficacy of the treatments. The trial design allows for adjustments in dosing and treatment duration based on individual participant responses and overall trial objectives.

The efficacy of the clinical trial will be assessed through the evaluation of primary and secondary endpoints. The primary endpoint focuses on the incidence of adverse events, including related adverse events, adverse events leading to discontinuation, serious adverse events, select adverse events, immune-mediated adverse events, and deaths. Secondary endpoints include overall survival (OS), defined as the time from randomization, first dose, or as specified in the Parent Study until the date of death from any cause or censored on the last known alive date in the rollover study, and the incidence of adverse events.