A phase II study to assess the efficacy of the antibody atezolizumab administered with stereotactic ablative radiotherapy in patients with metastatic cancer

Phase 1

• Conditions: Patients with one of following metastatic tumours:- Metastatic colorectal cancer- Metastatic non-small lung cancer- Metastatic renal cell carcinoma; MedDRA version: 20.0Level: PTClassification code 10050513Term: Metastatic renal cell carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10059515Term: Non-small cell lung cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 100000016864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-005464-42-ES
• Lead Sponsor: Gustave Roussy

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2017-07-04
• Last Update Posted: 11 December 2017

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 180

Inclusion Criteria

1. Patients must be 18 years of age or older.
2. Histologically or cytologically proven metastatic solid tumours including: colorectal (CRC, Microsatellite instability negative and positive) in treatment failure as per the current standard recommendation ; non-small cell lung cancer (NSCLC) pretreated by at least one line chemotherapy by platinum salt. Patients EGFR mutant can be included only if they have been treated with, or developed toxicity with or refused to be treated with anti-EGFR therapy ; renal cell carcinoma (RCC) pretreated by at least one line therapy by a tyrosin kinase inhibitor.
3. Patients with at least: one measurable metastasis by RECIST 1.1 eligible for SABR in terms of dose constraints at organ at risk 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.
4.Evaluation by a radiation oncologist within 45 days prior to study registration, including imaging workup to document metastases
5. The irradiated and unirradiated tumour sites must be accessible to tumour biopsy (additional written consent required)
6. Patients may not have used any systemic anticancer treatment (approved or investigational agent) within 4 weeks prior to cycle 1 day 1
7. Life expectancy of more than 3 months
8. Patients must have adequate organ function
9. Patients must be affiliated to a social security system
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 120
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 60

Exclusion Criteria

1. Metastases located to the brain and with clinical signs and/or leptomingeal carcinomatosis, or with indistinct borders making targeting not feasible
2. Metastasis localized to the central part of the chest and requiring irradiation
3. Irradiation by SABR should not include metastases located within 3 cm of the previously irradiated structures:
* Spinal cord previously irradiated to > 40 Gy
* Brachial plexus previously irradiated to > 50 Gy
* Small intestine, large intestine, or stomach previously irradiated to > 45 Gy
* Brainstem previously irradiated to > 50 Gy
* Lung previously irradiated with prior V20Gy > 30%
4. Irradiation required for cord compression and for superior veina cava syndrome.
5. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD1, or anti-PDL1 therapeutic antibodies
Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided at least 5 half-lives (approximately 75 days) have elapsed from the last dose of anti-CTLA-4 to the first dose of atezolizumab and there was no history of severe immune-mediated adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3 and 4)
6. Treatment with systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-a) and interleukin-2 (IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1
7. Active or History of autoimmune or inflammatory disease
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible
Patients with vitiligo or psoriasis or grave’s disease, not requiring systemic treatment within the last 2 years, are eligible
8. Any malignancy other than the disease under study in the past 5 years excepting skin cancers such as BCC or SCC
9. 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 enrollment.
10. 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.
11. 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.
12. Severe active co-morbidity as defined in the protocol

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Determine, in each cohort, the 1 year PFS rate (based on RECIST v1.1.) under combined SABR and anti-PDL1 atezolizumab therapy;Secondary Objective: 1. Determine the PFS rate under combined SABR and anti-PDL1 atezolizumab therapy<br><br>2. Further describe, the efficacy of combination (SABR and atezolizumab) both on the irradiated lesions and the non-irradiated lesions based on tumour response indicators and clinical endpoints <br><br>3. Determine the Treatment failure rate <br><br>4. Evaluate the toxicity of atezolizumab in combination with SABR;Primary end point(s): Proportion of patients alive and free of progression at 1 year. Progression is defined using RECIST 1.1. criteria, or death, whatever the cause of death, whichever occurs first.;Timepoint(s) of evaluation of this end point: Tumor evaluation performed at baseline, week 4, week 7, week 13 and then every 12 weeks up to 1 year from treatment initiation or to disease progression, whichever occurs first.