Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Intervention: One dose pembrolizumab 200 mg (week 1) followed by lung Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#) in week 3. Treatment with pembrolizumab 200 mg will be continued given every 3 weeks.

Intervention: One dose of pembrolizumab 200 mg (week 1) followed by lung Stereotactic Body Radiotherapy (SBRT) 54 Gy 3 fractions (#) in week 3. Treatment with pembrolizumab 200 mg will be continued given every 3 weeks.

Intervention: One dose of pembrolizumab 200 mg (week 1) followed in by lung Stereotactic Body Radiotherapy (SBRT) dosed at the maximum tolerated dose determined in Part A in week 3, dosed at the maximum tolerated dose determined in Part A. Treatment with pembrolizumab 200 mg will be continued given every 3 weeks.

Stereotactic Body Radiotherapy (SBRT) dosed at 30 Gy in 3 fractions (#) in week 3

Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Stereotactic Body Radiotherapy (SBRT) dosed at 54 Gy in 3 fractions (#) in week 3

Stereotactic Body Radiotherapy (SBRT) 54 Gy 3 fractions (#)

Stereotactic Body Radiotherapy (SBRT) dosed at the maximum tolerated dose (MTD) determined in Part A in week 3

Stereotactic Body Radiotherapy (SBRT) dosed at the maximum tolerated dose

Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks.

Fiona McDonald, MD

This is a single centre non-randomised open label phase 1 trial of lung SBRT to part of a lung lesion in patients with advanced NSCLC in combination with pembrolizumab. This study will recruit up to 24 patients whose lung cancer has progressed beyond one line of palliative chemotherapy, and an EGFR or ALK inhibitor if an EGFR driver mutation or ALK gene rearrangement is present, respectively, and now requires further palliative systemic treatment.

The study will be conducted in two parts; an initial lung SBRT dose escalation phase (Part A), followed by a lung SBRT dose expansion cohort (Part B). The dose escalation phase is based on a 3+3 design such that patients will be treated in cohorts of 3-6 patients. A maximum of 12 patients will be allocated to one of two doses of lung SBRT in combination with pembrolizumab to determine the MTD, DLTs and RP2D. If there is more than one DLT in cohort 1, this treatment combination will be deemed as being unacceptable, and it would lead to termination of the study. Note, there is no de-escalation in cohort 1. During the dose expansion cohort, 12 patients will have lung SBRT dosed at the RP2D determined during the dose escalation phase in combination with pembrolizumab to obtain additional safety and response data. Maintenance pembrolizumab will continue until disease progression, unacceptable toxicities, the patient withdraws consent to the trial, or the patient has completed 24 months of treatment. A maximum of 24 patients will be treated in the study.

All patients will receive pembrolizumab on cycle (C) 1 day (D) 1, in Part A and B of the study. All patients will receive lung SBRT on C1D15, C1D17, and C1D19 as per lung SBRT protocol (See Appendix 3). Although C1D1 can occur +/- 3 days, C1D15, C1D17, and C1D19, must be scheduled for a Monday, Wednesday and Friday, respectively. Patients in part A will receive lung SBRT dosed at 30 Gy in 3# in cohort 1, or 54 Gy in 3# in cohort 2. Patients in Part B will receive the RP2D of lung SBRT, determined in Part A. All patients in Part A and Part B will receive pembrolizumab dosed at 200 mg every 3 weeks, until disease progression, unacceptable toxicities, the patient withdraws consent from the trial, or the patient has completed 24 months of treatment.

In the dose escalation phase, a minimum of 3 patients will be required per dose level being assessed. A minimum gap of 1 week will be left between the treatment of the first and the second, and between the second and the third patients with the combination of pembrolizumab and lung SBRT to mitigate against multiple patients suffering from acute toxicity. The DLT period for this study is 12 weeks from the last dose of lung SBRT (i.e. at C6D1). The dose escalation will be considered by the Safety Review Committee (SRC) once the 3rd or 6th patient in the cohort has completed the DLT period. If no DLT is observed at a dose level, then lung SBRT will be dose escalated to the next dosing level (see Table 1). If 1 out of 3 patients experience a DLT, then the cohort will be expanded to 6 patients. If 1 in 6 patients experience a DLT, then the dose will be escalated to the next dosing level. However, if ≥ 2 in 6 patients experience a DLT then the maximum administered dose (MAD) will have been reached, and the RP2D will be the previous dosing level that will be used for the dose expansion cohorts. If the MAD is seen at dose level 1 then the study will be terminated. While waiting for 3 or 6 patients to complete the DLT period, no additional patients will be recruited. Further patients can only be recruited after the SRC has reviewed the toxicity data for the cohort and taken a decision to dose escalate to the next cohort or expand the current cohort to 6 patients.

Once the MTD has been determined the trial enters the dose expansion phase (unless the MTD is dose level 1). Here, 12 patients will be treated with the RP2D of SBRT combined with pembrolizumab.

If there is ongoing clinical benefit at 24 months, the CI/PI will need to discuss with the sponsor and MSD, on a case by case basis for the continuation of pembrolizumab.

Dose Escalation phase with 2 dose levels followed by an Expansion phase

PembRolIzuMab and Stereotactic Body Radiotherapy In Metastatic Non-small-cell lunG Cancer Patients

To characterise TILs and tumour antigens in the tumour biopsies. These immunohistochemistry analyses will include, but not necessarily be limited to, the following markers: CD4, CD8, FOXp3, PD-1, PD-L1, and PD-L2. To identify biomarkers that correlate with immunological response to therapy.

To correlate the number of patients that responded to the treatment with their tumour PD-1/PD-L1 expression.

Spots Global Cancer Trial Database for stereotactic body radiotherapy (sbrt) dosed at the maximum tolerated dose