A phase II study to assess the efficacy of the anti-PD-L1 antibody atezolizumab (MPDL3280A) administered with stereotactic ablative radiotherapy (SABR) in patients with metastatic tumours (SABR-PDL1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Nov 2016 → ongoing

Decision date (initial)

2024-10-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-515678-29-00

EudraCT number

2015-005464-42

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To determine the 1 year progression-free survival rate under combined SABR and anti-PDL1 atezolizumab therapy using RECIST v 1.1. :
• in patients with metastatic colorectal cancer (closed to inclusions)
• in patients with metastatic non-small lung cancer (closed to inclusions);
• in patients with metastatic renal cell carcinoma (closed to inclusions);
• in patients with metastatic sarcoma (closed to inclusions)

Secondary objectives 10

1. To determine, the Progression-Free Survival (PFS) rate under combined SABR and anti-PDL1 atezolizumab therapy using RECIST v 1.1 and modified RECIST (mRECIST).
2. To further describe, the efficacy of combination both on the irradiated lesions and the non-irradiated lesions based on tumour response indicators and clinical endpoints using RECIST v 1.1 and mRECIST
3. To determine the Treatment failure rate defined as the proportion of patients who cannot receive the planned irradiation dose or relative atezolizumab dose intensity below 75% of the initially targeted dose (i.e. below 900 mg).
4. To evaluate the toxicity of atezolizumab in combination with SABR according to the NCI-CTCAE scale (version 4.03).
5. To investigate the safety profile using NCI CTC-AE 4.03 scale following the second SABR course in combination with atezolizumab of tumor lesions after progression in patients with lung cancer and sarcoma.
6. To assess the time to progression ratio after a second SABR course, i.e. the ratio of the TTP2 measured from the time of first progression to the time of progression after the second SABR course, over the TTP1 measured from the time of inclusion in the trial to the time of first progression, in patients with lung cancer and sarcoma who received a second SABR course.
7. To assess the objective response rate at 6 weeks after the second SABR course, using RECIST v1.1, in the case of an oligoprogression and continuation of Atezolizumab at the time of progression in patients with lung cancer and sarcoma.
8. To compare the modification of the size of the lesion which received the second SABR session versus the lesion that is not (abscopal effect) in patients with lung cancer and sarcoma.
9. Exploratory Objectives: To evaluate the functional imaging changes using FDG PET/CT and tumour growth rates
10. Exploratory Objectives: To evaluate the systemic immunologic anti-tumour response based on the sequential tumour biopsies and immunomonitoring on peripheral blood samples.

Conditions and MedDRA coding

Patients with metastatic tumours (colorectal, non-small cell lung, renal and sarcoma)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

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 (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).
3. 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.
4. WHO performance status of 0-1
5. Evaluation by a radiation oncologist within 45 days prior to study registration, including imaging workup to document metastases (cf. description in assessment section)
6. 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).
7. Life expectancy of more than 3 months
8. Patients must be aware of the investigational nature of the therapy and provide written informed consent.
9. 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).
10. Patients must be free of significant comorbid conditions that would preclude safe administration or completion of protocol therapy.
11. The irradiated and unirradiated tumour sites must be accessible to tumour biopsy (additional written consent required).
12. Patients must be affiliated to a social security system

Exclusion criteria 20

1. 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.
2. Pregnant or breastfeeding women
3. Any malignancy other than the disease under study in the past 5 years excepting skin cancers such as BCC or SCC.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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
9. 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.
10. Irradiation required for cord compression and for superior veina cava syndrome.
11. 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%
12. 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).
13. 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
14. 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.
15. 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
16. 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.
17. Patient already enrolled in another therapeutic trial involving an investigational substance, and when such a substance has been taken during the previous 4 weeks.
18. 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
19. 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)
20. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. One year-Progression-free survival rate is defined as the rate of patients alive and free of progression at one year. Progression is defined using RECIST 1.1. criteria, or death, whatever the cause of death, whichever occurs first

Secondary endpoints 3

1. Efficacy: Progression-free survival (PFS) measured from the date of treatment initiation to date of progression or death whichever comes first. Patients alive and free of progression at the cut-off date will be censored at the last assessment date Tumour response indicators and clinical endpoints, assessed according to RECIST v 1.1 and modified RECIST (see synopsis)
2. Toxicity : NCI- CTCAE V4.03 scale Toxicity is adverse events graded with the NCI-CTC-AE v4.03 scale, at least possibly related to the treatment.
3. For patients with lung cancer and sarcoma receiving a second SABR course for oligoprogression(see synopsis)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications