| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
- pancreatic cancer
- virus-associated tumors
- non-small cell lung cancer
- soft-tissue sarcoma
- bladder cancer
- Triple negative breast cancer |
- cancer du pancréas
- tumeurs viro-induites
- cancer bronchique non à petites cellules
- sarcomes des tissus mous
- cancer de la vessie
- cancer du sein triple négatif |
|
| E.1.1.1 | Medical condition in easily understood language |
- pancreatic cancer
- virus-associated tumors
- non-small cell lung cancer
- soft-tissue sarcoma
- bladder cancer
- Triple negative breast cancer |
- cancer du pancréas
- tumeurs viro-induites
- cancer bronchique non à petites cellules
- sarcomes des tissus mous
- cancer de la vessie
- cancer du sein triple négatif |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033605 |
| E.1.2 | Term | Pancreatic cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039494 |
| E.1.2 | Term | Sarcoma NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10005012 |
| E.1.2 | Term | Bladder cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the antitumor activity of atezolizumab combined with the Toll-like receptor agonist 7/8 (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 anti-PD-1/L1 refractory 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.
|
|
| E.2.2 | Secondary objectives of the trial |
• 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).
• To evaluate the efficacy of the combination according to Immune-related response (iRECIST) [28].
• To evaluate the safety profile of the combination treatment.
• 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.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histology: histologically confirmed pancreatic cancer (population 1), virus-associated tumors (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,
2. Metastatic disease,
3. Age ≥ 18 years,
4. ECOG, Performance status ≤ 1,
5. At least two lesions: one 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(s) that will be treated by radiotherapy will also be considered as measurable,
6. Life expectancy > 6 months,
7. At least one tumor site that can be biopsied for research purpose,
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
- 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:
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. |
|
| E.4 | Principal exclusion criteria |
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.
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%
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.
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 daysprior 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.
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 refed to section 7.1.4.2.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Antitumor activity of the combination will be assessed, independently for the 6 distinct populations, as follows:
• 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 complete response (CR), partial response (PR) or stable disease (SD), as per adapted RECIST v1.1, observed within 24 weeks of treatment onset (while treated with the investigational product).
• Participants with virus-associated tumors [Population 2]: same primary endpoint as for population 1.
• Participants with non-small cell lung cancer [Population 3]: same primary endpoint as for population 1.
• 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 complete response (CR), partial response (PR) or stable disease (SD) more than 24 weeks as per adapted RECIST v1.1, observed at 6 months following treatment onset.
• Participants with bladder cancer [Population 5]: Same primary endpoint as for population 1.
• Participants with triple negative breast cancer [Population 6]: Same primary endpoint as for population 1.
For all populations: Primary efficacy analysis will be based on the centralized radiological review data. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The DCR within 24 weeks of treatment onset will be reported for population 1, 2, 3, 5 and 6.
The PFR at 6 months will be reported for population 4.
Note that confirmation of claimed responses at 4 weeks later is not required (adapted RECIST v1.1). |
|
| E.5.2 | Secondary end point(s) |
Antitumor activity of the combination will be assessed, independently for each of the 6 distinct populations, as well in terms of:
1. [Populations 1, 2, 3, 5, 6]: 6-month progression-free rate (PFR). 6-month PFR defined as for primary endpoint of population 4.
2. ORR defined as the proportion of participants with complete response (CR), partial response (PR), 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).
3. 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).
4. 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.
5. 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.
6. Growth modulation index (GMI): GMI is defined for each participant as the ratio of PFS on the combination of atezolizumab, BDB001 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.
7. ORR, PFR, BoR, PFS determined according to Immune response (iRECIST) defined following Seymour et al. (Lancet Oncol 2017).
8. The safety profile of the combination treatment will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. Toxicity will be graded using the common toxicity criteria from the NCI CTCAE v5.0. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The PFR at 6 months will be reported independently for population 1, 2, 3, 5 and 6.
2. The ORR will be reported independently for each population at 6 months and within 24 weeks of treatment onset. Note that confirmation of claimed responses at 4 weeks later is not required (adapted RECIST v1.1).
3. The best overall response is determined once all the data for the patient is known (RECIST 1.1). Note that confirmation of claimed responses at 4 weeks later is not required (adapted RECIST v1.1).
4. Median PFS, 1- and 2-year PFS rates will be reported independently for each population.
5. Median OS, 1- and 2-year PFS rates will be reported independently for each population. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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