Anti-PD-1 re-challenge after immune priming by ipilimumab and immune boosting by radiotherapy in advanced NSCLC.
- Trial ID
- 2022-500713-79-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **clinical benefit rate (CBR)** in patients with advanced non-small cell lung cancer (NSCLC) who have previously progressed after anti-PD-(L)1 treatment. The CBR is defined as the proportion of patients achieving a complete or partial response, or stable disease lasting six months or more following the re-introduction of PD-1 inhibition. This objective is clinically relevant as it aims to assess the potential for re-challenging patients with PD-1 inhibitors to achieve sustained disease control, which could provide a therapeutic option for patients with limited treatment alternatives.
Secondary objectives include: - Overall response rate (ORR) at 12 weeks after re-introduction of PD-1 inhibition. - Disease control rate (DCR) at 12 weeks after re-introduction of PD-1 inhibition. - Best overall response at any time point after re-introduction of PD-1 inhibition. - Progression-free survival (PFS). - Overall survival (OS). - Comparison of CBR, ORR, DCR, PFS, and OS in patients with acquired resistance versus primary immunotherapy-resistant patients. - Evaluation of toxicity.
Participants
The clinical trial involves participants diagnosed with **advanced non-small cell lung cancer (NSCLC)** who have progressed following at least one prior anti-PD-(L)1 treatment. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants must have measurable disease based on RECIST 1.1 criteria and demonstrate adequate organ function. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria require participants to have at least two separate metastatic lesions, one eligible for irradiation and another for biopsy and RECIST evaluation. Lifestyle factors such as diet and physical activity are not specified. Participants with a targetable driver mutation are eligible only if all targeted therapy options have been exhausted. The trial does not impose a maximum number of previous systemic treatments, and both primary and acquired resistance to PD-(L)1 inhibition are considered for eligibility. The sponsor has not disclosed specific lifestyle considerations or habits for the trial population.
Plans and Procedures
The clinical trial is designed to evaluate the **clinical benefit rate** (CBR) of re-introducing PD-1 inhibition in patients with advanced non-small cell lung cancer (NSCLC) who have previously progressed after anti-PD-(L)1 treatment. The trial employs a **randomized, double-blind, controlled** methodology to ensure the reliability and validity of the results. The trial is expected to span approximately three years, with an estimated end date in September 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a proven diagnosis of recurrent advanced NSCLC and adequate organ function. Following the screening, participants will receive treatment with **cemiplimab** and **ipilimumab** via intravenous infusion. The primary endpoint will be assessed at Week 27, with secondary endpoints evaluated at Week 15. Follow-up visits will occur at regular intervals to monitor the participants' response to treatment and any adverse effects.
The expected length of participant involvement is up to 24 months, depending on individual response and disease progression. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or disease progression that necessitates alternative treatment. The end-of-study visit will involve a comprehensive assessment of the participant's health status and the collection of final data for analysis.
Treatment
The clinical trial involves the administration of **LIBTAYO** (cemiplimab), a **concentrate for solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for intravenous (IV) infusion. The dosage is set at 350 mg per administration, with a maximum total dose of 12,250 mg over the course of the treatment. The treatment period for LIBTAYO is up to 24 weeks. The active substance, cemiplimab, is a protein-based therapeutic agent, specifically classified under the ATC code L01XC33. The administration of LIBTAYO is conducted under controlled conditions to ensure participant compliance and safety.
In addition to LIBTAYO, the trial also includes the administration of **YERVOY** (ipilimumab), another **concentrate for solution for infusion**. YERVOY is also administered via IV infusion, with a dosage of 1 mg/kg. The maximum treatment period for YERVOY is limited to 1 week. Ipilimumab, the active substance in YERVOY, is similarly a protein-based therapeutic agent, classified under the ATC code L01FX04. The administration of YERVOY is carefully monitored to ensure adherence to the dosing schedule and to assess any potential adverse effects.
Both LIBTAYO and YERVOY are utilized in this trial to evaluate their combined efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). The trial aims to assess the clinical benefit rate, defined as complete or partial response, or stable disease lasting six months after the re-introduction of PD-1 inhibition. The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. Participant compliance is monitored through regular assessments and follow-ups to ensure the integrity of the trial data.
Efficacy
Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint is the **Clinical Benefit Rate (CBR)**, which is defined as the occurrence of a complete response (CR) or partial response (PR) at any time point, and stable disease (SD) lasting at least 6 months after the re-introduction of PD-1 inhibition by cemiplimab, starting on Day 1 of Week 27. This assessment will be conducted according to the RECIST 1.1 criteria, which exclude lesions irradiated as part of the study treatment from being considered measurable disease.
Secondary endpoints include the Overall Response Rate (ORR), defined as CR or PR at 12 weeks after re-introduction of PD-1 inhibition by cemiplimab, starting on Day 1 of Week 15. Additionally, the Disease Control Rate (DCR) will be evaluated, defined as CR, PR, or SD at 12 weeks post re-introduction of PD-1 inhibition. Other secondary endpoints include the best overall response at any time point, progression-free survival (PFS) defined as the time between the start of treatment and progression of disease or death, and overall survival (OS) defined as the time between the start of treatment and death.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Have proven diagnosis of recurrent advanced NSCLC, irrespective of histological subtype.
- Be willing and able to provide written informed consent/assent for the trial.
- Be 18 years of age on day of signing informed consent.
- Must still have measurable disease based on RECIST 1.1 after application of study SBRT. Lesions that were irradiated prior to the study, but have progressed since irradiation but prior to study inclusion will be allowed as measurable disease.
- Must provide newly obtained tissue from a core or excisional biopsy of a tumor lesion and are willing to have a second biopsy performed from any non-irradiated lesion after the radiation and immune-modulating treatment. This lesion may be used for RECIST measurements.
- Have a performance status of 0 or 1 on the ECOG Performance Scale.
- Stage IV NSCLC treated with at least PD-(L)1 blockade. There is no maximum number of previous lines of systemic treatment. Patients with both primary or acquired resistance to PD-(L)1 inhibition may be considered eligible. However, in the 1st stage ≥4 of 12 patients, in the 2nd stage a total of ≥8 of 25 patients and in the 3rd stage a total of ≥27 of 54 patients need to fulfill the definition of acquired resistance. Also, a maximum of 27 patients with a PD-L1 negative tumor will be included.
- Have at least 2 separate (metastatic) lesions of which one is eligible for irradiation and another for biopsy and RECIST tumor evaluation.
- Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 14 days of treatment initiation.
- Female subject of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the 1st dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
- Male subjects should agree to use an adequate method of contraception starting with the 1st dose of study therapy through 6 months after the last dose of study therapy.
Exclusion Criteria
- Has a non-smoking-related targetable driver mutation, e.g. EGFR, ALK, RET or ROS1. Patients with advanced NSCLC with a smoking-related targetable driver mutation, e.g. KRAS or BRAF, may be found eligible if they have a history of ≥10 PY, but only when all options for targeted therapy have been exhausted and when progression on previous PD-(L)1 blockade has occurred.
- Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the 1st dose of treatment.
- Has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. o Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. o Note: Patients who experienced significant autoimmune side effects related to previous PD-(L)1 checkpoint inhibition, i.e. requiring use of steroids or other anti-inflammatory drugs and/or the need to (temporarily) withhold PD-(L)1 checkpoint inhibition, may be considered eligible after discussion with the coordinating investigator if adverse events have recovered, i.e. ≤ Grade 1 or at baseline. o Note: If subjects received major surgery (defined as surgical intervention requiring general or spinal anesthesia and hospital admission), they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Major surgery within 14 days prior to start of study treatment is not allowed.
- Has had previous radical radiation to any tumor site within 3 months prior to study Day 1. Previous palliative radiation to any tumor site is not considered an exclusion criterion; however, this site will not be eligible for SBRT, biopsy location or RECIST tumor evaluation within this study.
- Has received prior therapy with any antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways other than PD-(L)1 blockade, e.g. anti-CD137 or a CTLA-4 antibody.
- Patients who have uncontrolled central nervous system (CNS) metastases. Patients who have untreated asymptomatic CNS metastases no greater than 2cm before start of treatment may be eligible. Patients who have any CNS lesion that is symptomatic, greater than 2cm, show significant surrounding edema on MRI scan or have leptomeningeal disease will not be eligible. Patients who have previously been treated for CNS metastases are eligible when they comply with the hereby mentioned criteria. NB. A brain lesion is not amendable for study SBRT.
- Has a known additional malignancy that is progressing or requires active treatment.
- Has an active autoimmune disease or a documented history of clinically severe autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Subjects who require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with an active or history of autoimmune disease or syndrome who underwent previous PD-(L)1 checkpoint inhibition without significant side effects, i.e. not requiring use of steroids or other anti-inflammatory drugs and/or the need to (temporarily) withhold PD-(L)1 checkpoint inhibition, may be considered eligible for this trial after discussion with the coordinating investigator. Requirement for immunosuppressive doses of systemic corticosteroids ≤10 mg/day prednisone or equivalent may be considered eligible after discussion as well.
- Has evidence of symptomatic interstitial lung disease or an active, non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Recruiting | 31 Oct 2022 | — |
| Netherlands | — | — | 54 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
LIBTAYO 350 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 350 | 24 | PRD7478447 |
YERVOY 5 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 1 | 1 | PRD363755 |