Perioperative/Adjuvant atezolizumab in patients with MSI-high or MMRdeficient stage II high risk or stage III colorectal cancer ineligible for oxaliplatin-based chemotherapy– a Phase II study (ANTONIO)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AIO-Studien gGmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Aug 2023 → ongoing

Decision date (initial)

2024-08-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-515224-37-00

EudraCT number

2020-002715-21

ClinicalTrials.gov

NCT05118724

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To determine whether atezolizumab alone can significantly improve disease-free survival rate at 3 years compared to historical control when used as adjuvant treatment in patients with MSIhigh/
dMMR stage II high risk or stage III colorectal cancer for whom oxaliplatin regimens are not a viable treatment option

Secondary objectives 1

1. determine whether atezolizumab (ATEZO) monotherapy (or ATEZO combined with IMM 101 show promising efficacy (DFS and OS) compared to historical control when used as adjuvant treatment in pats. with MSI-Hhigh/dMMR stage II high risk or stage III colon or rectal cancer for whom oxaliplatin regimens are not a viable treatment option. assess safety and tolerability profile of ATEZO (with/without IMM 101) in pats. with MSI-high stage II high risk or stage III colorectal cancer for whom oxaliplatin regimens are not a viable treatment option determine impact of ATEZO (with/without IMM 101) on PRO and healthrelated QoL, and functional domains of health-related QoL

Conditions and MedDRA coding

Patients with MSI-high or MMR-deficient stage III colorectal cancer who are ineligible for or who refuse oxaliplatin-based chemotherapy after R0 tumor resection (main study) or planned resection (sub-study)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Written informed consent including participation in translational research and any locally-required authorization
2. Male or female ≥ 18 years of age
3. Histologically confirmed adenocarcinoma of the colon or rectum
4. Pathological stage II high risk or Stage III disease
5. R0 or R1-resected primary tumor For the perioperative sub-study: Resectable primary tumor; R0 resection anticipated (R1-resected patients can remain on study.)
6. Tumor is MSI-high (MSI-H) or MMR-deficient (dMMR)
7. ECOG status 0 – 2
8. Ineligible for oxaliplatin-based adjuvant chemotherapy or patient's refusal of oxaliplatin-based adjuvant chemotherapy
9. Adequate blood count, liver enzymes, and renal function – re-testing can be undergone once in case of initial results near cutoff [(White blood cell count ≥ 3.0 x 10^6/mL (Inclusion is also possible if 2,5 10^6/mL < White blood cell > 3.0 x 10^6/mL, in which case the neutrophils must be >= 1.5 x10^6/ml and the lymphocytes >= 0.5 x10^6/ml))
10. INR < 1.5 ULN and PTT < 1.5 ULN within 7 days prior to registration
11. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
12. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly-effective contraception

Exclusion criteria 30

1. Severe infection within 4 weeks prior to registration
2. Distant metastases or residual disease
3. Neoadjuvant radiotherapy or radio-chemotherapy (rectal cancer patients without prior radio- or radio-chemotherapy allowed); prior neoadjuvant radio-chemotherapy or radiotherapy for rectal cancer is allowed if >5 years and secondary colorectal cancer
4. Prior adjuvant chemotherapy for colorectal cancer; allowed if >5 years and secondary colorectal cancer
5. Prior treatment with atezolizumab or any other checkpoint inhibitor
6. Treatment with systemic immunosuppressive medication within 2 weeks prior to treatment start, or anticipation of need for systemic immunosuppressive medication during study treatment
7. Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment
8. History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins
9. Known hypersensitivity to CHO cell products or any component of the atezolizumab formulation
10. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
11. Active HBV infection (chronic or acute), defined as having a positive HBsAg test at screening
12. Anti-viral therapy against HCV during the trial (allowed prior to trial)
13. Positive HIV test. As an exception, known HIV+ patients may be included if they have: A stable regimen of HAART; No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections; A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests
14. Treatment with a live, attenuated vaccine within 4 weeks prior to first dose of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the last dose of study treatment.
15. Treatment with any vaccine during screening and the first cycle of treatment.
16. Active tuberculosis
17. Active or history of autoimmune disease or immune deficiency e.g. 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
18. Prior (<3 years) or concurrent malignancy that either progresses or requires active treatment. Exceptions: basal cell cancer of the skin, preinvasive cancer of the cervix, T1a or T1b prostate carcinoma, superficial urinary bladder tumor
19. History of hypersensitivity to any of the study drugs or any excipient IMM-101
20. Prior allogeneic stem cell or solid organ transplantation requiring immunosuppressive therapy or other major immunosuppressive therapy
21. Severe non-healing wounds, ulcers or bone fractions
22. Evidence of bleeding diathesis or coagulopathy
23. Major gastrointestinal bleeding within 4 weeks prior to treatment start, unless cause of bleeding was resected tumor
24. Major surgical procedures other than primary tumor resection, except open biopsy, nor significant traumatic injury within 28 days prior to registration, or anticipation of the need for major surgical procedure during the course of the study except for surgery of central intravenous line placement for chemotherapy administration
25. Medication that is known to interfere with any of the agents applied in the trial
26. Female subjects who are pregnant or breast-feeding; male or female patients of reproductive potential who are not employing an effective method of birth control as listed in the protocol) (failure rate of less than 1% per year, see protocol section 6.1.3). Women of childbearing potential must have a negative pregnancy test
27. Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study treatment or affect patient safety or study results
28. Participation in another clinical study with an investigational drug within 28 days prior to treatment start or 7 half-lives of previously used trial medication, whichever is longer
29. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities
30. Affected persons who might be dependent on the sponsor or the investigator

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. The primary efficacy endpoint is disease-free survival (DFS) rate at 3 years, defined as the proportion of patients without relapse or tumor-related death from any cause 3 years after start of treatment in the intention-to-treat population.
2. For the sub-study: Pathological complete (pCR) or subtotal (<10% vital tumor cells) regression (measured in resected tumors) after completion of 5 weeks of neoadjuvant treatment.
3. incidence, severity and causality/ relationship of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESI)

Secondary endpoints 4

1. DFS including 1-, and 2-year tumor-specific DFS rates
2. Overall Survival (OS) including 1-, 2- and 3-year OS rates
3. Rate of patients without detectable ctDNA after 12 months. ctDNA-free is defined as a ctDNA level below the lowest limit of detection of the respective Liquid Biopsy Assay
4. QoL

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AIO-Studien gGmbH

Sponsor organisation

AIO-Studien gGmbH

Address

Kuno-Fischer-Strasse 8, Charlottenburg Charlottenburg

City

Berlin

Postcode

14057

Country

Germany

Scientific contact point

Organisation

AIO-Studien gGmbH

Contact name

Prof. Dr. med. Stefan Kasper-Virchow

Public contact point

Organisation

AIO-Studien gGmbH

Contact name

Katrin Krause

Locations

1 EU/EEA country · 17 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

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

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