AGADIR : Atezolizumab combined with EIK10001 (BDB001) and Immunogenic Radiotherapy in Patients with Advanced Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Bergonie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Mar 2021 → ongoing

Decision date (initial)

2024-08-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509492-16-00

EudraCT number

2019-000850-78

ClinicalTrials.gov

NCT03915678

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Safety, Therapy

 To evaluate the antitumor activity of atezolizumab combined with the Toll-like receptor agonist 7/8 (EIK1001, also known as BDB001) and early radiation therapy (RT) of one or more metastatic sites independently for 6 populations of participants:
o [Population 1] Participants with pancreatic cancer,
o [Population 2] Participants with virus-associated tumors,
o [Population 3] Participants with anti-PD-1/L1 refractory non-small cell lung cancer,
o [Population 4] Participants with soft-tissue sarcomas,
o [Population 5] Participants with anti-PD-1/L1 refractory bladder cancer,
o [Population 6] Participants with triple negative breast cancer.
 Antitumor activity will be assessed in terms of:
o [Populations 1, 2, 3, 5, 6]: disease control rate within 24 weeks of treatment onset.
o [Population 4]: 6-month progression-free status.

Secondary objectives 4

1. To evaluate the efficacy of the combination in terms of additional endpoints: o [Populations 1, 2, 3, 5, 6]: Objective response within 24 weeks of treatment onset and at 6 months, 6-month progression-free status, best overall response under treatment, Overall survival (OS), Progression-free survival (PFS), Growth modulation index (GMI). o [Population 4]: Objective response within 24 weeks of treatment onset and at 6 months, Best overall response under treatment, Overall survival (OS), Progression-free survival (PFS), Growth modulation index (GMI).
2. To evaluate the efficacy of the combination according to immune response (iRECIST) [28].
3. To evaluate the safety profile of the combination treatment.
4. To perform integrative assessment of prognostic factors of objective response, progression-free status, PFS and OS. Investigated markers include genetic and immunological, profiling in blood/tissue.

Conditions and MedDRA coding

Adult participants with metastatic (advanced) solid tumors.

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Histology: histologically confirmed pancreatic cancer (population 1), virus-associated tumors [including papillomaviruses-related cancers (cervical, head and neck, and anal), Epstein-Barr virus (nasopharyngeal carcinoma) and Kaposi's sarcoma-associated herpes virus (Kaposi's sarcoma)] (population 2), non-small cell lung cancer (population 3), soft-tissue sarcomas (population 4), bladder cancer (population 5), triple negative breast cancer (population 6). For population 4, diagnosis must be confirmed by the RRePS Network as recommended by the French NCI. For population 2, papillomavirus-related cancers must be eligible whatever the genotype but in case of viral genotype is not available, IHC p16 positive must be provided ; hepatocellular carcinoma must be confirmed by Hepatite B or C infection, HHV-8 and Epstein-Barr virus related cancers must be confirmed by molecular analysis,
2. Metastatic disease,
3. Age ≥ 18 years,
4. ECOG, Performance status ≤ 1,
5. At least two lesions: one extra cerebral lesion that can be treated by radiotherapy and one site of disease that must be uni-dimensionally ≥ 10 mm considered as measurable according to RECIST v1.1 (outside any previously irradiated field, except if progressive as per RECIST v1.1 at inclusion). This lesion will not be treated by radiotherapy, however, note that lesion that will be treated by radiotherapy will also be considered as measurable. Note that the largest size of the metastase to be irradiated will be 3 cm and that previous irradiation of this lesions is not allowed,
6. Life expectancy > 6 months,
7. At least one tumor site that can be biopsied for research purpose. Tumor lesion in close proximity to vascular structures such as large vessels, aneurysm or pulmonary arteriovenous malformation will not be considered for biopsy,
8. Availability of archived paraffin-embedded tumor tissue for research purpose,
9. Participant must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement,
10. Participants who received prior anti-PD-1/L1 therapy must fulfill the following requirements – population 3 and population 5 only - Have achieved a complete response, partial response or stable disease and subsequently had disease progression while still on anti-PD-1/L1 therapy - Have received at least two doses of an approved anti-PD-1/L1 therapy (by any regulatory authority) - Have demonstrated disease progression as defined by RECIST v1.1 within 18 weeks from the last dose of the anti- PD-1/L1 therapy.
11. Adequate hematological, renal, metabolic and hepatic functions: a. Hemoglobin ≥ 9 g/dl (participants may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 G/l, platelet count ≥ 100 G/l, white blood cell count ≥ 2.5 G/l (or within local laboratory normal limits) and lymphocyte count ≥ 0.75 G/l b. Alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (ASP) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive skeletal involvement and/or liver metastasis for AP and ≤ 5 x ULN in case of liver metastasis for AST and ALT). c. Direct bilirubin ≤ 1.5 x ULN, d. Albumin ≥ 25 g/l. e. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockcroft and Gault formula). f. INR ≤ 1.5 x ULN g. aPTT ≤ 1.5 X ULN h. Serum calcium within normal laboratory ranges, i. Thyroid function within normal laboratory ranges (TSH, free T3, free T4)
12. No prior or concurrent malignant disease needing an active treatment,
13. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
14. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment, excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 5.0)),
15. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to inclusion. Note that serum pregnancy test must be repeated 72 hours prior to receiving the first dose of study medication,
16. Both women and men must agree to use an effective method of contraception throughout the treatment period and for five months after discontinuation of treatment. Acceptable methods for contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier. Participants of childbearing potential are those who have not been surgically sterilized (e.g., vasectomy for males and hysterectomy for females) or have not been free from menses for ≥ 1 year.
17. Voluntary signed and dated written informed consents prior to any specific study procedure,
18. Participants with a social security in compliance with the French law.

Exclusion criteria 29

1. Previous treatment with a TLR agonist
2. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases,
3. Women who are pregnant or breast feeding,
4. Participation in a study involving a medical or therapeutic intervention in the last 30 days,
5. Previous enrolment in the present study,
6. Participant unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons,
7. Known hypersensitivity to CHO cell products or to any involved study drug or of its formulation components,
8. History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins,
9. Treatment with systemic immunosuppressive medications including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within 2 weeks prior to inclusion. Participants who have received acute and/or low-dose systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea or chronic use of ≤10 mg/day of prednisone or dose-equivalent corticosteroid) may be enrolled in the study after discussion and approval by the Sponsor.
10. Major surgical procedure, open biopsy or significant traumatic injury within 28 days before inclusion,
11. Any of the following cardiac criteria: - Congestive heart failure ≥ New York Heart Association (NYHA) class 2, - Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), - Myocardial infarction less than 6 months before inclusion - Uncontrolled cardiac arrhythmias, - Known left ventricular ejection fraction (LVEF) <50% - Previously experience of pericardial disorder (following MSA6)
12. Individuals deprived of liberty or placed under legal guardianship,
13. Prior organ transplantation, including allogeneic stem cell transplantation,
14. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver and inherited liver disease,
15. History of intra-abdominal inflammatory process within the last 12 months such as, but not limited to, diverticulitis, peptic ulcer disease or colitis
16. History of autoimmune disease including, but not limited to systemic lupus erythematosus (SLE), Sjögren’s syndrome, glomerulonephritis, multiple sclerosis, rheumatoid arthritis, vasculitis, systemic immune activation, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Guillain-Barré syndrome, Bell’s palsy. - Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible, - Participants with controlled Type I diabetes mellitus on a stable insulin regimen are eligible, - Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with only dermatologic manifestations <10% of the skin (e.g., participants with psoriatic arthritis would be excluded) are eligible.
17. 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.
18. Poorly controlled Type II diabetes mellitus defined as a screening fasting plasma glucose ≥160 mg/dL (or 8.8 mmol/L).
19. Severe infections within 2 weeks prior to inclusion, including but not limited to SARS-Cov-2 infection, hospitalization for complications of infection, bacteremia, or severe pneumonia.
20. Received therapeutic oral or IV antibiotics within 2 weeks prior to inclusion. Participants receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.
21. Any contraindication to tumor biopsy,
22. Participant has spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease is clinically stable at least 14 days prior to inclusion.
23. Administration of a live, attenuated vaccine within 4 weeks before the start of study medication or anticipation that such a live attenuated vaccine will be required during the study. Influenza vaccination should be given during influenza season only (approximatively October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to the start of study medication or at any time during the study or within 5 months after the last dose of atezolizumab.
24. Has known active hepatitis B or hepatitis C,
25. Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS),
26. Has a known history of tuberculosis,
27. Concomitant use of prohibited concomitant therapy or anticipation that such concomitant medication/therapies will be required during the study – please refer to section 7.1.4.2.
28. Patients with current retinal disorder confirmed by retinal examination (external ocular examination, routine slit lamp biomicroscopy of anterior ocular structures and evaluation of the anterior and posterior chamber,
29. Patients who wear contact lenses unable to replace them with glasses.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Antitumor activity of the combination will be assessed, independently for the 6 distinct populations, as follows:
2. 1a)Participants with pancreatic cancer [Population 1]: in terms of disease control rate (DCR) within 24 weeks of treatment onset. DCR is defined as the proportion of participants with confirmed complete response (CR), unconfirmed complete response (CRu), confirmed partial response (PR) or unconfirmed partial response (PRu) or stable disease (SD), as per adapted RECIST v1.1, observed within 24 weeks of treatment onset (while treated with the investigational product).
3. 1b) Participants with virus-associated tumors [Population 2]: same primary endpoint as for population 1.
4. 1c)Participants with non-small cell lung cancer [Population 3]: same primary endpoint as for population 1.
5. 1d) Participants with soft-tissue sarcomas [Population 4]: in terms of 6-month progression-free rate (PFR). 6-month PFR is defined as the proportion of participants with confirmed complete response (CR), unconfirmed complete response (CRu), confirmed partial response (PR) or unconfirmed partial response (PRu) or stable disease (SD) more than 24 weeks as per adapted RECIST v1.1, observed at 6 months following treatment onset.
6. 1e) Participants with bladder cancer [Population 5]: Same primary endpoint as for population 1.
7. 1f) Participants with triple negative breast cancer [Population 6]: Same primary endpoint as for population 1.
8. For all populations: Primary efficacy analysis will be based on the centralized radiological review data. Note that confirmation of claimed responses at 4 weeks later is not required (adapted RECIST v1.1).

Secondary endpoints 10

1. Antitumor activity of the combination will be assessed, independently for each of the 6 distinct populations, as well in terms of:
2. 1a) [Populations 1, 2, 3, 5, 6]: 6-month progression-free rate (PFR). 6-month PFR defined as for primary endpoint of population 4.
3. 1b)ORR defined as the proportion of participants with confirmed complete response (CR), unconfirmed complete response (CRu), confirmed partial response (PR) or unconfirmed partial response (PRu), as per adapted RECIST v1.1 and will be assessed: within 24 weeks of treatment onset (while treated with the investigational product) and at 6 months (6-month ORR).
4. 1c)Best overall response (BoR) defined as the best response across all time points (RECIST v1.1). The best overall response is determined once all the data for the participant is known (RECIST v1.1).
5. 1d)Progression-free survival (PFS) defined as the time from first day of study intervention to the first documented disease progression (as per RECIST v1.1) or death (due to any cause), whichever occurs first. Median PFS, 1- and 2-year PFS rates will be reported for each population.
6. 1e)Overall survival (OS) defined as the time from first day of study intervention to death (due to any cause). Median OS, 1- and 2-year OS rate will be reported for each population
7. 1f)Growth modulation index: GMI is defined for each participant as the ratio of PFS on the combination of atezolizumab, EIK1001 and RT to PFS on the previous line of therapy. This method accounts for inter-participant variability, the participant serving as his/her own control and implies by the natural history of the disease that the PFS tends to become shorter in successive lines of therapy. It is thought that an anti-cancer agent should be considered effective if the GMI is greater than 1.3
8. 1g)ORR, PFR, BoR, PFS determined according to immune response (iRECIST) defined following Seymour et al. (Lancet Oncol 2017).
9. 1h)The safety profile of the combination treatment. Events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. Both AE and SAE will be coded according to the standardized medical terminology MedDRA.
10. 1i)Ancillary/translational study: To perform integrative assessment of prognostic factors of ORR, PFR, PFS and OS. Investigated markers include genetic and immunological parameters (see translational study section).

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Bergonie

Sponsor organisation

Institut Bergonie

Address

229 Cours De L Argonne

City

Bordeaux

Postcode

33000

Country

France

Scientific contact point

Organisation

Institut Bergonie

Contact name

Pr Antoine ITALIANO

Public contact point

Organisation

Institut Bergonie

Contact name

Aurore Barthod- Malat

Locations

1 EU/EEA country · 9 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

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