NCT05000710

Concomitant Radiotherapy, Tremelimumab & Durvalumab for Advanced NSCLC Patients Progressing on First-line Immunotherapy

Single Arm Phase II, Multicenter Study of Concomitant Radiotherapy, Tremelimumab and Durvalumab (MEDI4736) for Metastatic or Locally Advanced NSCLC Patients Progressing on First-line Immunotherapy

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 29 (estimated)
• Sponsor: Sheba Medical Center · Other Government
• Sex: All
• Age: —
• Healthy volunteers: Not accepted

Summary

This is an open-label, single-arm, phase 2a trial with a safety run-in cohort followed by a Simon two-step design expansion cohort, of two checkpoint blockage treatments and radiotherapy in the treatment of locally advanced or metastatic NSCLC who have failed first-line immunotherapy (alone or as a combination regimen with chemotherapy). Study objectives: Objective of the safety run-in phase: • To evaluate safety of the triple combination of irradiation -Durvalumab - Tremelimumab Co-Primary objectives of the entire study: * To evaluate safety of the triple combination (as for the run-in phase). * To evaluate response rate on study drug compared to historical data of response to first-line platinum-doublet chemotherapy and 2nd-line docetaxel. Secondary objective: • To evaluate PFS and OS compared to historical data . Exploratory objectives: * Examine the mechanism of resistance to first-line immunotherapy . * Examine the immune response in irradiation -Durvalumab - Tremelimumab treated patients and identify potential predictors of clinical benefit.

Detailed description

A cycle is defined as 28 days. Eligible patients who have a radiologically confirmed progressive disease on first line Immunotherapy treatment will receive an intravenous injection of 300 mg Tremelimumab at D1 and 12 weeks later a second dose of 300 mg tremelimumab, and an intravenous injections of 1500 mg Durvalumab q4w (starting from D1) . Treatment duration is until objective radiological disease progression as per RECIST 1.1 assessed by the local radiologist, and as long as the patients are benefiting from treatment according to the investigator's opinion and they do not meet any other discontinuation criteria. 21 days after the first immunotherapy treatment, a radiotherapy course of 11 fractions of 3 Gy (total of 33 Gy) will be administrated to metastatic or primary lesion/s over two weeks and one day. The second durvalumab treatment will be administered at the beginning of the 2nd week of radiotherapy, one week after radiotherapy start day. Following patients consent, a fresh biopsy specimen will be obtained (if not previously obtained after PD) for correlative studies, preferably from site of disease progression on first line immunotherapy. In addition, tissue samples will be obtained from both existing archived biopsy (diagnostic specimen), if available. An optional newly biopsied tissue sample will be taken 20 weeks after initiation of study treatment and at the time of progression on study treatment. Biopsy at PD is mandatory if can be performed with no significant risk. Blood and microbiome samples for correlative studies will be taken at predefined intervals, to explore predictive biomarkers for clinical efficacy, determine pharmacodynamic effects on immune cells, determine immune response signatures. Tumor imaging should be acquired by CT and include the chest, abdomen, and pelvis with and without IV contrast and with oral contrast. CT should be performed at baseline and every 8 weeks until objective radiological disease progression assessed as per RECIST 1.1. Patients who have discontinued treatment should be seen at end of treatment and 28 days post discontinuation for the evaluations outlined in the study schedule. Patients will be contacted every 90 days following discontinuation visit to capture survival status. Any patient who discontinues study treatment for reasons other than objective radiological progression should continue to undergo scheduled objective tumor assessments according to the study schedule in order to assess objective radiological progression of disease.

Conditions

• Metastatic or Locally Advanced NSCLC

Interventions

Type	Name	Description
DRUG	Durvalumab	Durvalumab administered IV over 60 minutes at a dose of 1500 mg every 4 weeks
DRUG	Tremelimumab	Tremelimumab administered IV over 60 minutes at a dose of 300 mg , twice: at C1D1 and C4D1
RADIATION	Low dose irradiation	21 days after the first immunotherapy treatment 11 fractions of 3 Gy will be administrated to metastatic or primary lesion/s over 2 weeks and one day

Timeline

• Start date: 2021-12-09
• Primary completion: 2026-12-01
• Completion: 2026-12-01
• First posted: 2021-08-11
• Last updated: 2024-12-05

Locations

1 site across 1 country: Israel