Ezabenlimab (BI 754091) and DCFm (docetaxel, cisplatin and 5-fluorouracil) followed by chemoradiotherapy for the treatment of stage III anal canal cancer. Phase II study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Regional Universitaire

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

26 Jul 2024 → ongoing

Decision date (initial)

2024-07-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-514083-31-00

EudraCT number

2020-006046-40

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

The primary objective of this clinical trial is to evaluate the clinical complete response (cCR) rate at week 40 from first DCF cycle, defined as no clinical and radiological sign of residual disease.

Conditions and MedDRA coding

squamous cell anal carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Signed and dated informed consent,
2. 10. PET scan performed within 30 days prior inclusion,
3. 11. Adequate hematologic and end-organ function: defined by the following laboratory test results obtained within 7 days prior to initiation of study treatment:
4. 12. Serum albumin  25 g/L (2.5 g/dL),
5. 13. For patients not receiving therapeutic anticoagulation: International normalized ratio (INR) or activated partial thromboplastin time (PTT)  1.5  ULN,
6. 14. Patient affiliated to or beneficiary of French social security health insurance system (PUMA; La protection Universelle Maladie).
7. 2. Age ≥18 years,
8. 4. Performance status ECOG-WHO ≤ 1,
9. 5. Histologically proved squamous cell anal carcinoma,
10. 6. Locally advanced disease defined as: • Stage III (TxN1 or T4N0) Lymph node can be considered positive if one of the following criteria is satisfied: • Enlargement (largest short-axis diameter > 1 cm for mesorectal nodes, and > 1.5 cm for other nodes) OR, • Heterogeneity or necrosis OR, • Irregular contours OR, • Strong enhancement at magnetic resonance imaging (MRI) OR, • Positivity on positron emission tomography (PET) scan,
11. 7. Patient eligible to the mDCF regimen,
12. 8. Computed tomography (CT) scan performed within 30 days prior inclusion,
13. 9. MRI of pelvis performed within 30 days prior inclusion,
14. 3. Ability to comply with the study protocol in the Investigator’s judgment,

Exclusion criteria 35

1. 1. Previously received chemotherapy or pelvic radiotherapy,
2. 2. Previously received anti-tumor immunotherapy (HPV vaccination is allowed),
3. 3. Metastatic disease,
4. 4. Diagnosis of additional malignancy within 3 years prior to the inclusion date with the exception of curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer,
5. 5. Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study,
6. 6. Current participation in a study of an investigational agent or in the period of exclusion,
7. 7. 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; men must refrain from donating sperm during this same period. In addition, men who are sexually active with woman of childbearing potential will be instructed to adhere to contraception for a period of 7 months after the last last treatment administration,
8. 8. Female participants of childbearing potential and male participants with partners of childbearing potential must agree to use a highly effective method of birth control (i.e., pregnancy rate of less than 1% per year) during the study,
9. 9. Patient under guardianship, curatorship, or under the protection of justice.
10. 10. Inadequate organ functions: uncontrolled cardiac condition, known cardiac failure, unstable coronaropathy, respiratory failure, and chronic obstructive pulmonary disease,
11. 11. Diabetes with vascular or neurovascular complications,
12. 12. Preexistent peripheral neuropathy or impaired audition,
13. 13. HIV positive patient with CD4 count under 400/mm3 (HIV test is mandatory before inclusion),
14. 14. Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (chronic or acute), defined as having a positive hepatitis B 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. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test,
15. 15. Active tuberculosis,
16. 16. Concomitant treatment with CYP3A4 inhibitor like ritonavir, indinavir, ketoconazole, etc.,
17. 17. Known hypersensitivity or contraindication to any of the study chemotherapy drugs (taxanes, cisplatin, 5-FU, mitomycin, capecitabine) and dihydro pyrimidine dehydrogenase (DPD) complete deficit,
18. 18. Uncontrolled infection or another life-risk condition,
19. 19. Known hearing impairment that contraindicates cisplatin administration,
20. 20. Administration of a (attenuated) live vaccine within 28 days of planned start of study therapy of known need for this vaccine during treatment,
21. 21. Administration of prophylactic phenytoin,
22. 22. Inadequate laboratory values: MDRD CrCl < 60 ml/min, neutrophil count < 1500/mm3, platelets < 100.000/mm3, bilirubin 2.5 x ULN, AST/ALT 2.5 x ULN,
23. 23. Previous major surgery (requiring general anesthesia) within 28 days of enrollment.
24. 24. Any immunosuppressive therapy (i.e. corticosteroids > 10 mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy,
25. 25. 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,
26. 26. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
27. 27. Known active central nervous system metastases and/or carcinomatous meningitis. Subject with previously treated brain metastases and with radiological and clinical stability are allowed,
28. 28. Previously received an anti-PD-1, anti-PD-L1, or anti-CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) agent,
29. 29. Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of Ezabenlimab (BI 754091) formulation,
30. 30. History of colorectal inflammatory disease,
31. 31. 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.
32. 32. History of severe hypersensitivity reactions to other mAbs
33. 33. History of Chronic colorectal inflammatory disease (Ulcerative colitis, Crohn's disease),
34. 34. History of connective disease,
35. 35. History of autoimmune diseases.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. the Clinical complete response (cCR) 40 weeks from the treatment initiation (the best time to evaluate the local response is 26 weeks from the commencement of standard CRT

Secondary endpoints 10

1. 1. Major pathological response: complete response (pCR)/ near-complete response (pnCR) after induction treatment
2. 2. Biological complete response (bCR) after radiotherapy measured by E6/E7 ctDNA monitoring as previously reported by our team
3. 1. Objective response rate (ORR) evaluated by RECIST criteria v1.1 (Appendix 1). ORR is defined as the addition of complete response (CR) and partial response (PR) rates. Disease control rate is defined as the addition of ORR and SD (stable disease).
4. 2. Overall survival (OS). OS is defined as the time between the date of the treatment initiation and death from any cause. Alive patients will be censored at the last date known to be alive, either during study treatment period or during follow-up period.
5. 3. Biological complete response (bCR). bCR is defined as non-detectable HPV ctDNA.
6. 4. Progression-Free Survival (PFS). PFS is defined as the length of time from the date of treatment inititation to the disease progression or death from any cause, whichever occurs first. Alive patients without progression will be censored at the last tumor assessment, either during study treatment period or during follow-up period.
7. 5. Recurrence-free survival (RFS) or disease-free survival (DFS). RFS/DFS is defined as the lengh of time from the date of the end of the radiotherapy to local recurrence and/or metastases or death irrespective of cause and censored at the date of last tumor assessment.
8. 6. Health-related Quality of Life (HRQoL) assessment. HRQoL will be assessed by the EORTC QLQ-C30 at baseline, at evaluation visits, at the end of treatment visit, at the end-point visit, and at follow-up visit.
9. 7. Safety. Safety will be assessed during the study by evaluation of adverse events (AEs) and serious AEs (SAEs), clinical safety laboratory tests, vital signs, and physical examinations according to NCI-CTCAE criteria version 5.0.
10. 8. PET-CT complete response (PET-CR). PET-CR is defined as the absence of pathological hypercaptation. PET-CR will be correlated to cCR, DFS and PFS end-points.

Investigational products

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

Test 4

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Regional Universitaire

Sponsor organisation

Centre Hospitalier Regional Universitaire

Address

2 Place Saint Jacques, Cs 51804 Cs 51804

City

Besancon Cedex

Postcode

25030

Country

France

Scientific contact point

Organisation

Centre Hospitalier Regional Universitaire

Contact name

Investigateur

Public contact point

Organisation

Centre Hospitalier Regional Universitaire

Contact name

CEC

Locations

1 EU/EEA country · 13 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 7 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