| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or unresectable locally advanced squamous anal carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| squamous cell carcinoma of the anal canal |
|
| 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 | LLT |
| E.1.2 | Classification code | 10002141 |
| E.1.2 | Term | Anal carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the Progression-Free-Survival rate at 12 months |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate OS,
• To evaluate PFS,
• To assess health-related QoL (HRQoL),
• To assess ORR,
• To evaluate the tolerance of mDCF in association with anti-PDL1,
• To evaluate the predictive value of HPV-specific and telomerase-specific T cell responses monitored before and after treatment,
• To analyze HPV, p53, neoantigens genotypes and their correlation with the treatment efficacy,
• To investigate the impact of peripheral immune system status (Treg, CD4 polarization, MDSC, T cell exhaustion) on clinical outcomes and HPV/telomerase specific immunity,
• To investigate the prognostic value of tumor-infiltrating lymphocytes and PD-L1 expression,
• To explore the correlation of both peripheral CD4 anti-telomerase immunity and PDL1 immunohistochemistry with PFS,
• To characterize the predictive value of soluble biomarkers (soluble PDL1…) and plasmatic HPV DNA monitoring.
• To evaluate the correlation between neoantigen burden and survival at 12 months.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, aged ≥18 years,
2. Performance status Eastern Cooperative Oncology Group World Health Organization (ECOG-WHO) ≤1,
3. Histologically proven and unresectable locally advanced recurrent or metastatic squamous cell anal carcinoma,
4. Presence of a target lesion on CT-scan assessed by RECIST v1.1 criteria,
5. Patient eligible to the mDCF regimen,
6. CT scan performed within 28 days prior inclusion,
7. PET scan performed within 28 days prior inclusion,
8. Signed and dated informed consent,
9. Patient affiliated to or beneficiary of French social security system,
10. Ability to comply with the study protocol, in the Investigator’s judgment,
11. Life expectancy >=6 months,
12. Adequate hematologic and end-organ function.
NB: Previous concomitant chemoradiotherapy is allowed.
|
|
| E.4 | Principal exclusion criteria |
1. Previously received chemotherapy for metastatic disease,
2. Previously received cisplatin except for concomitant chemoradiotherapy,
3. Previously received taxanes (paclitaxel or docetaxel) or another spindle poison (navelbine) in the treatment of SCCA,
4. Previously received anti-tumor immunotherapy (HPV vaccination is allowed),
5. Diagnosis of additional malignancy within 3 years prior to the randomization with the exception for curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer,
6. Any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study,
7. Current participation in a study of an investigational agent or in the period of exclusion,
8. Pregnancy, breast-feeding or absence/refusal of adequate contraception for fertile patients during the period of treatment and for 6 months from the last treatment administration,
9. Patient under guardianship, curatorship or under the protection of justice.
10. Inadequate organ functions: uncontrolled cardiac condition, known cardiac failure, unstable coronaropathy, respiratory failure, and Chronic Obstructive Pulmonary Disease (COPD),
11. Diabetes with vascular or neurovascular complications,
12. Preexistent peripheral neuropathy or impaired audition,
13. HIV positive with CD4 count under 400 cells/mm3 (VIH test is mandatory before inclusion),
14. Active hepatitis B or C virus (HBV or HCV) infection (chronic or acute), (Defined as having a positive HBV surface antigen (HBsAg) test at screening. Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total HBV core antibody (HBcAb) test at screening, are eligible for the study.
15. Active tuberculosis,
16. Concomitant treatment with CYP3A4 inhibitor like ritonavir, indinavir, or ketoconazole, etc. Replacement by another drug before randomization, whenever is possible, is allowed,
17. Known hypersensitivity or contraindication to any of the study chemotherapy drugs (taxanes, cisplatin, 5FU),
18. Uncontrolled infection or another life-risk condition,
19. Known hearing impairment that contraindicates cisplatin administration,
20. Administration of a live (attenuated) vaccine within 28 days of planned start of study therapy of known need for this vaccine during treatment,
21. Administration of prophylactic phenytoin,
22. Inadequate laboratory values: creatinine clearance <60 ml/min, neutrophil count <1500 /mm3, platelets <100000/mm3, bilirubin 2.5 x upper limit of normal (ULN), aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 x ULN or 5 x ULN with liver metastasis.
Non-eligible to immunotherapy:
23. Any immunosuppressive therapy (i.e. corticosteroids >10mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy,
24. Active autoimmune disease that has required a systemic treatment in past 2 years (i.e. corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin) is allowed.
Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, (see Annex 7 for a more comprehensive list of autoimmune diseases and immune deficiencies)
25. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
26. Known active central nervous system metastases and/or carcinomatous meningitis. Subject with previously treated brain metastases and with radiological and clinical stability are allowed,
27. Previously received an anti-PD1, anti-PDL1, or anti-CTLA4 agent,
28. Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of atezolizumab formulation,
29. History of colorectal inflammatory disease,
30. History of idiopathic or secondary pulmonary fibrosis (history of radiation pneumonitis in the radiation field fibrosis is permitted), or evidence of active pneumonitis requiring a systemic treatment with 28 days before the planned start of study therapy,
31. Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study,
32. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia,
33. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Overall survival,
- Progression-free survival,
- Health-related QoL (HRQoL) analyzed with EORTC-QLQ-C30 questionnaire,
- Objective response rate evaluated by RECIST criteria v1.1,
- Toxicities,
- HPV and telomerase-specific T cell responses
- Peripheral immunological status characterization (immune checkpoint analyses on CD4 and CD8 T cells, Treg, MDSC subsets, CXCR5+ CD8+ lymphocytes and CD4 T cell polarization),
- Characterization of tumor genotyping for HPV, p53, and neoantigens using the next-generation sequencing,
- Level of circulating HPV DNA assessed by PCR on cell free tumor DNA,
- Tumor-infiltrating lymphocytes (TIL isolation or immunohistochemical analysis of Tbet, CD8, Foxp3, RoR-yt) and PD-L1 expression (immunohistochemistry) analysis,
- A whole exome sequencing for determination of mutation-driven neoantigen burden. The predictive value of the number/heterogeneity of neoantigens in SCCA will be assessed and the role of neoantigen-specific T cell immunity in comparison to HPV and telomerase immunity will be defined |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- OS is defined as the time interval from randomization to the date of death from any cause. Follow-up until death or 36 months from enrolment
- PFS is defined as the time interval from randomization to the date of first documented disease progression or death from any cause
Quality of life: every month during phase 1 then every 2 months during phase 2 until end-point visit
- Objective response rate will be assessed using RECIST version 1.1. at baseline and every 2 months during treatment.
- Toxicities : graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] criteria v4.03
- HPV and telomerase-specific T cell responses before and after treatment measured by ELISPOT assay.
|
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 17 |
| 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
|
| 36 months from randomization |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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