Phase II Evaluation of Atezolizumab Combined with Stereotactic Ablative Radiotherapy in Metastatic Colorectal, Non-Small Cell Lung, Renal Cell Carcinoma, and Sarcoma

Trial ID: 2024-515678-29-00
Protocol: 2015/2335
Sponsor: Institut Gustave Roussy

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Diseases & Conditions

Renal cancer Renal cancer metastatic Non-small cell lung cancer Non-small cell lung cancer metastatic

Objectives

The primary objective of this phase II study is to determine the 1-year **progression-free survival** (PFS) rate under combined stereotactic ablative radiotherapy (SABR) and anti-PD-L1 atezolizumab therapy using RECIST v1.1 criteria. This is evaluated in patients with metastatic colorectal cancer, non-small cell lung cancer, renal cell carcinoma, and sarcoma, although these cohorts are currently closed to new inclusions. The clinical relevance of this objective lies in assessing the potential of this combination therapy to extend the period during which the disease does not worsen, which is crucial for improving patient outcomes in metastatic cancers.

Secondary objectives include:

Determining the PFS rate under combined SABR and atezolizumab therapy using both RECIST v1.1 and modified RECIST (mRECIST).
Describing the efficacy of the combination on both irradiated and non-irradiated lesions based on tumor response indicators and clinical endpoints.
Determining the treatment failure rate, defined as the proportion of patients unable to receive the planned irradiation dose or a relative atezolizumab dose intensity below 75% of the initially targeted dose.
Evaluating the toxicity of atezolizumab in combination with SABR according to the NCI-CTCAE scale (version 4.03).
Investigating the safety profile following the second SABR course in combination with atezolizumab in patients with lung cancer and sarcoma.
Assessing the time to progression ratio after a second SABR course in patients with lung cancer and sarcoma.
Assessing the objective response rate at 6 weeks after the second SABR course in cases of oligoprogression and continuation of atezolizumab.
Comparing the modification of the size of lesions that received the second SABR session versus those that did not (abscopal effect).
Evaluating functional imaging changes using FDG PET/CT and tumor growth rates.
Evaluating the systemic immunologic anti-tumor response based on sequential tumor biopsies and immunomonitoring on peripheral blood samples.

These secondary objectives aim to provide a comprehensive understanding of the treatment's efficacy, safety, and biological effects, which are essential for optimizing therapeutic strategies in metastatic cancer management.

Participants

The clinical trial involves **patients with metastatic tumours**, specifically those with colorectal, non-small cell lung, renal, and sarcoma cancers. The study population includes both male and female participants aged 18 years and older. Participants are required to be in generally good health, free from significant comorbid conditions that could interfere with the safe administration or completion of the protocol therapy. The trial population was selected based on specific inclusion criteria, including the requirement for histologically or cytologically proven metastatic solid tumours and a WHO performance status of 0-1. Participants must have adequate organ function and a life expectancy of more than three months. The trial does not provide information on the total number of participants, as this data was not disclosed by the sponsor. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use effective contraception methods if they are sexually active. The trial includes a vulnerable population, and all participants must provide written informed consent, acknowledging the investigational nature of the therapy.

Plans and Procedures

The clinical trial is designed as a **phase II** study to evaluate the efficacy of the anti-PD-L1 antibody **atezolizumab** in combination with stereotactic ablative radiotherapy (SABR) in patients with metastatic tumors, specifically colorectal, non-small cell lung, renal, and sarcoma. The trial employs a **randomized, double-blind, controlled** methodology to ensure the reliability and validity of the results. The overall duration of the trial is estimated to conclude by July 14, 2026, with recruitment having commenced on November 15, 2016.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, comorbid conditions, and tumor accessibility for biopsy. Follow-up visits will be scheduled to monitor progression-free survival and assess tumor response using RECIST v1.1 criteria. The end-of-study visit will evaluate the primary endpoint, which is the one-year progression-free survival rate, and secondary endpoints, including efficacy and toxicity, measured by the NCI-CTCAE V4.03 scale.

The expected length of participant involvement is up to 96 weeks, corresponding to the maximum treatment period with atezolizumab. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants must meet inclusion criteria, such as being 18 years or older, having a WHO performance status of 0-1, and providing informed consent. Exclusion criteria are not specified in the provided data.

Treatment

The clinical trial involves the administration of **atezolizumab**, an anti-PD-L1 antibody, as the experimental medication. Atezolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF05. It is administered in the form of an intravenous infusion, with a maximum daily dose of 1200 mg. The total maximum dose over the course of the treatment is 115,200 mg, and the treatment period extends up to 96 weeks. The pharmaceutical form of atezolizumab is designated as PHF00231MIG. The administration schedule and participant compliance are closely monitored to ensure adherence to the dosing regimen.

In this study, atezolizumab is combined with stereotactic ablative radiotherapy (SABR) as part of the treatment protocol. SABR is a non-experimental treatment that serves as a standard-of-care therapy in this trial. The combination aims to assess the efficacy of atezolizumab in conjunction with SABR in patients with metastatic tumors. The trial does not include a placebo or comparator treatment, as the focus is on the combined therapeutic effect of the experimental medication and SABR. Participant compliance with the treatment regimen is monitored through regular assessments and adherence checks to ensure the integrity of the trial data.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the measurement of the one-year **progression-free survival** (PFS) rate. This is defined as the proportion of patients who are alive and free of disease progression at one year, with progression determined using RECIST v1.1 criteria or death, whichever occurs first. Secondary efficacy endpoints include the overall PFS, measured from the date of treatment initiation to the date of progression or death, whichever comes first. Patients who are alive and free of progression at the cut-off date will be censored at the last assessment date. Tumor response indicators and clinical endpoints will also be evaluated according to RECIST v1.1 and modified RECIST criteria.

The efficacy assessments will be conducted using validated scales and criteria, ensuring the reliability and accuracy of the data collected. The schedule for measuring and collecting these efficacy parameters will be aligned with the trial's protocol, with specific timepoints for assessments not explicitly detailed in the provided data. The trial will utilize the NCI-CTCAE v4.03 scale to evaluate toxicity, which is considered an adverse event possibly related to the treatment. This comprehensive approach to efficacy assessment will provide a robust evaluation of the treatment's impact on patients with metastatic tumors.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients must be 18 years of age or older.
Histologically or cytologically proven metastatic solid tumours including: - colorectal (CRC, Microsatellite instability negative and positive) in treatment failure as per the current standard recommendation (cohort closed to inclusions). - non-small cell lung cancer (NSCLC) pretreated by at least one line of treatment. 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; Patients pretreated by anti−PD1, or anti−PDL1 therapeutic antibodies can be included only if they have received at least 4 months of treatment (cohort closed to inclusions). - renal cell carcinoma (RCC) pretreated by at least one line therapy by a tyrosin kinase inhibitor (cohort closed to inclusions). - metastatic sarcomas of any type (soft tissue, bone, GISTs) pretreated by at least one line of standard therapy ; at least three lines of standard TKi must be given in patients with GISTs. No enrolment restriction to certain sarcoma subtypes/groups was decided given the relative rarity of this disease type and that immunotherapy efficacy in certain histological subtypes is only preliminary (cohort closed to inclusions).
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), - ALK ≤ 2.5 ULN (unless documented bone or liver metastases where ≤ 5X ULN is permitted).
Life expectancy of more than 3 months
Patients must be aware of the investigational nature of the therapy and provide written informed consent.
Sexually active women of childbearing potential must agree to use a highly effective method of contraception supplemented with a barrier method, or to abstain from sexual activity during the study and for at least 5 months after the last dose of atezolizumab Sexually active males patients must agree to use condom while on SABR treatment and for at least 90 days after SABR treatment. Taking into account the irradiated area, use of condom after SABR treatment can be shortened at investigator discretion. Also, their women of childbearing potential partner should use a highly effective method of contraception. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum β-HCG pregnancy test result within 7 days prior to initiation of study drug. A list of highly effective birth control methods and the definition of a woman of childbearing potential are provided in the core protocol (section 4.1).
Patients must be free of significant comorbid conditions that would preclude safe administration or completion of protocol therapy.
The irradiated and unirradiated tumour sites must be accessible to tumour biopsy (additional written consent required).
Patients must be affiliated to a social security system

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Exclusion Criteria

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 - History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan History of radiation pneumonitis in the radiation field (fibrosis) is permitted. - Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or C hepatic disease. - Known HIV positive status. - End-stage renal disease (i.e., on dialysis or dialysis has been recommended). - Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
Active or History of autoimmune or inflammatory disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 3 for a more comprehensive list of autoimmune diseases) 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
Metastases located to the brain and with clinical signs and/or leptomingeal carcinomatosis, or with indistinct borders making targeting not feasible Metastases located to the brain and without clinical signs can be included.
Irradiation required for cord compression and for superior veina cava syndrome.
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%
Metastasis localized to the central part of the chest and requiring irradiation (see “no fly zone” in Appendix 1: Rules for SABR administration according to tumour location).
Any approved anticancer therapy, including chemotherapy, hormonal therapy or radiotherapy, under the following guidelines: - investigational or cytotoxic treatments within 4 weeks prior to the study treatment initiation and while on study treatment - localized palliative radiotherapy within 2 weeks prior to the study treatment initiation and while on study treatment - any approved TKIs within 3 weeks prior to the study treatment initiation and while on study treatment however Hormone-replacement therapy or oral contraceptives are allowed
Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study.
Influenza vaccination should be given during influenza season only (example: approximately October to March in the Northern Hemisphere). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study
Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumour necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
Patient already enrolled in another therapeutic trial involving an investigational substance, and when such a substance has been taken during the previous 4 weeks.
Persons deprived of their freedom or under guardianship, or for whom it would be impossible to undergo the medical follow-up required by the trial, for geographic, social or psychological reasons
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD1, or anti−PDL1 therapeutic antibodies Only patients with non-small cell lung cancer are allowed to have received anti−PD1, or anti−PDL1 therapeutic antibodies. Subjects who have received prior anti-PD-1/L1 therapies must have received at least 4 months of treatment. 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)
Treatment with systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-α) and interleukin-2 (IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1