Atezolizumab With Stereotactic Ablative Radiotherapy in Patients With Metastatic Tumours

NCT02992912 | Active Not Recruiting Phase 2

• 2 other identifiers: 2015-005464-422335/2015
• Study Type: interventional
• Target: 138
• Locations: 1 country
• Sites: 1

Brief Summary

Although it is usually described as an immunosuppressive modality and not thought of as immunotherapy, there are new preclinical evidences suggesting that high-dose ionizing irradiation (IR) results in direct tumour cell death and augments tumour-specific immunity, which enhances tumour control both locally and distantly. Importantly, IR effects exceed the classical cytocidal properties by also causing phenotypic changes in the fraction of surviving cells, markedly enhancing their susceptibility to T cell-mediated elimination. However, not all IR-induced modifications of the tumour and its microenvironment favor immune rejection. The tumour microenvironment is populated by various types of inhibitory immune cells including Tregs, alternatively activated macrophages, and myeloid-derived suppression cells (MDSCs), which suppress T cell activation and promote tumour outgrowth. Chiang et al. showed the accumulation of pro-tumourigenic M2 macrophages in areas of hypoxia present in irradiated tumours. IR then may also induced responses that are inadequate to maintain antitumour immunity. Close interaction between IR, T cells, and the PD-L1/PD-1 axis exsit and provide a basis for the rational design of combination therapy with immune modulators and radiotherapy. Deng et al. demonstrate that PD-L1 was upregulated in the tumour microenvironment after IR. Moreover, administration of anti-PD-L1 enhanced the efficacy of IR through a cytotoxic T cell-dependent mechanism. Concomitant with IR-mediated tumour regression, IR and anti-PD-L1 synergistically reduced the local accumulation of tumour-infiltrating MDSCs, which suppress T cells and alter the tumour immune microenvironment. Finally, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumours through the cytotoxic actions of TNF. Sagiv-Barfi et al, also demonstrated in 5 patients receiving atezolizumab and radiation therapy, at least stabilization of systemic progression in all patients and a RECIST partial response at systemic sites in 1 patient. Transient, grade 1-2 inflammatory adverse events (fevers, flu-like symptoms) occurred with no serious immune-related toxicities. Abscopal out-field effects of irradiation has also been described in addition to a reduction in circulating MDSCs in a melanoma patient treated with the anti CTLA-4 ipilimumab and radiotherapy. Lastly, recent evidence demonstrates that loco-regional curative treatment with stereotactic ablative radiotherapy (SABR) is a good alternative as compared with conventional 3D RT for patients with solid tumour, with durable remissions and a low toxicity profile. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. For colorectal, non-small cell, and renal cell cancers, 1-year metastasis control rates ranged from 67 to 91%. Moreover, abscopal responses in the setting of immune checkpoints inhibitors and radiotherapy combinations have been made in the setting of metastatic disease event in patients with extensive tumor burden. The goal of SABR is to deliver appropriate metastasis directed radiotherapy while minimizing exposure of surrounding normal tissues. Interestingly, the dose and fractionation employed modulate RT ability to synergize with immunotherapy. Vanpouille-Box et al, showed that immune response genes were differentially expressed in irradiated tumours by 8Gyx3 but not 20Gyx1. This highlight the interest of hypofractionated SABR acting as a "in situ tumour vaccine". As hypofractionated SABR may, in addition to its good local control, increase the effectiveness of anti PD-L1, investigators aimed to investigate the efficacy and the tolerability of the combination of anti-PD-L1 antibody with SABR.

Conditions

Patients With Metastatic Tumours (Colorectal Cancer, Non-small Lung Cancer, Renal Cell Carcinoma or Sarcoma )

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival

  Using RECIST 1.1

  1 year after inclusion

Study Arms (4)

Cohort 1: metastatic colorectal cancer

EXPERIMENTAL

Drug: Anti-PD-L1 antibody atezolizumab; Procedure: SABR

Cohort 2: metastatic non-small lung cancer

EXPERIMENTAL

Drug: Anti-PD-L1 antibody atezolizumab; Procedure: SABR

Cohort 3: metastatic renal cell carcinoma

EXPERIMENTAL

Drug: Anti-PD-L1 antibody atezolizumab; Procedure: SABR

Cohort 4: metastatic sarcoma

EXPERIMENTAL

Drug: Anti-PD-L1 antibody atezolizumab; Procedure: SABR

Interventions

Anti-PD-L1 antibody atezolizumab DRUG

1200 mg every 3 weeks

Cohort 1: metastatic colorectal cancer; Cohort 2: metastatic non-small lung cancer; Cohort 3: metastatic renal cell carcinoma; Cohort 4: metastatic sarcoma

SABR PROCEDURE

Hypofractionated SABR will be delivered at a dose of 45 Gy in 3 fractions of 15 Gy

Also known as: Stereotactic ablative radiotherapy

Cohort 1: metastatic colorectal cancer; Cohort 2: metastatic non-small lung cancer; Cohort 3: metastatic renal cell carcinoma; Cohort 4: metastatic sarcoma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be 18 years of age or older.
• Patients with at least :
• one measurable metastasis by RECIST 1.1 eligible for SABR in terms of dose constraints at organ at risk (refer to Appendix 1: Rules for SABR administration according to tumour location ; distinct criteria apply regarding lung and liver metastases) and ≤ 4 cm, and
• one not treated measurable metastasis by RECIST 1.1. If all tumour sites are accessible to SABR, one of them will not be treated.
• Metastase located within the proximal bronchial tree as defined in RTOG 0236 (refer to Appendix 1: Rules for SABR administration according to tumour location) or within the brain are not eligible for SABR treatment in the present study. However, it can be considered as a not treated evaluable metastase.
• WHO performance status of 0-1
• Evaluation by a radiation oncologist within 45 days prior to study registration, including imaging workup to document metastases (cf. description in assessment section)
• Patients must have adequate organ function defined by the following laboratory results obtained within 28 days prior to the first study treatment:
• Absolute neutrophil count of ≥ 1500/mm3;
• Lymphocyte count ≥ 500 mm3;
• Platelets ≥ 100,000/mm3;
• Hemoglobin \> 9 gr/dL;
• Clearance Creatinine ≥ 50 mL/min;
• Total bilirubin ≤ 1.5X ULN (unless Gilbert where 3X ULN is permitted);
• Serum ALT and AST ≤ 2.5X ULN (unless documented liver metastases where ≤ 5X ULN is permitted),

You may not qualify if:

• Known allergy to anti-PD-L1 including :
• History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins.
• Known hypersensitivity to CHO cell products or any component of the atezolizumab formulation.
• Pregnant or breastfeeding women
• Any malignancy other than the disease under study in the past 5 years excepting skin cancers such as BCC or SCC.
• Uncontrolled tumour-related pain Patients requiring pain medication must be on a stable regimen at study entry. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrolment.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
• Patients with indwelling catheters (e.g., PleurX) are allowed.
• Uncontrolled hypercalcemia (\> 1.5 mmol/L ionized calcium or Ca \> 12 mg/dL or corrected serum calcium \> ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
• Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. However, patients who are receiving denosumab prior to enrollment must be eligible to receive bisphosphonate instead and willing to switch to bisphosphonate therapy while on the study.
• Severe, active co-morbidity, defined as follows:
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to registration;
• Transmural myocardial infarction within the last 6 months prior to registration;
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
• Uncontrolled Chronic Obstructive Pulmonary Disease or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to registration

Sponsors & Collaborators

• Gustave Roussy, Cancer Campus, Grand Paris: lead

Study Sites (1)

Gustave Roussy

Villejuif, Val De Marne, 94805, France

Location

Related Publications (2)

• Levy A, Morel D, Texier M, Rodriguez-Ruiz ME, Bouarroudj L, Bouquet F, Bustillos A, Quevrin C, Clemenson C, Mondini M, Meziani L, Sun R, Zaghdoud N, Tselikas L, Assi T, Faron M, Honore C, Ngo C, Verret B, Le Pechoux C, Le Cesne A, Ginhoux F, Massard C, Bahleda R, Deutsch E. Monocyte-lineage tumor infiltration predicts immunoradiotherapy response in advanced pretreated soft-tissue sarcoma: phase 2 trial results. Signal Transduct Target Ther. 2025 Mar 17;10(1):103. doi: 10.1038/s41392-025-02173-3.

  PMID: 40097400 DERIVED

• Levy A, Morel D, Texier M, Sun R, Durand-Labrunie J, Rodriguez-Ruiz ME, Racadot S, Supiot S, Magne N, Cyrille S, Louvel G, Massard C, Verlingue L, Bouquet F, Bustillos A, Bouarroudj L, Quevrin C, Clemenson C, Mondini M, Meziani L, Tselikas L, Bahleda R, Hollebecque A, Deutsch E. An international phase II trial and immune profiling of SBRT and atezolizumab in advanced pretreated colorectal cancer. Mol Cancer. 2024 Mar 23;23(1):61. doi: 10.1186/s12943-024-01970-8.

  PMID: 38519913 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Carcinoma, Renal Cell; Sarcoma

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Neoplasms, Connective and Soft Tissue

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2016
• First Posted: December 14, 2016
• Study Start: November 15, 2016
• Primary Completion: May 20, 2022
• Study Completion: October 1, 2024
• Last Updated: May 16, 2024

Record last verified: 2024-05

Locations

FR (1)