Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient DNA mismatch repair (ATOMIC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

National Cancer Institute, AIO-Studien gGmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-09-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-517269-18-00

EudraCT number

2019-003562-40

ClinicalTrials.gov

NCT02912559

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

To determine whether atezolizumab combined with FOLFOX and its continuation as monotherapy can significantly improve DFS compared to FOLFOX alone in patients with stage III colon cancers and dMMR.

Secondary objectives 1

1. To determine whether atezolizumab combined with FOLFOX and its continuation as monotherapy can significantly improve overall survival compared to FOLFOX alone in patients with stage III colon cancers and dMMR. To assess the adverse events (AE) profile and safety of each treatment arm, using the CTCAE and PRO-CTCAE (among patients aged ≥ 18 years).

Conditions and MedDRA coding

stage III colon adenocarcinoma with deficient MMR

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C). Tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve)
2. Presence of deficient (d) DNA mismatch repair (dMMR). MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR. Note: loss of MLH1 and PMS2 commonly occur together. Patients who are known to have Lynch syndrome and have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate. Note that patients who did not show dMMR (loss of MMR protein) are not eligible to participate. Patients whose tumors show MSI-H by polymerase chain reaction (PCR)-based assay are not eligible to participate unless they also have MMR testing by IHC and are found to have dMMR (i.e. loss of one or more MMR proteins).
3. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue for subsequent retrospective central confirmation of dMMR status.
4. Tumor(s) completely resected. In patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented in the operative report or otherwise confirmed by the surgeon; near or positive radial margins are acceptable so long as en bloc resection was performed; proximal or distal margin positivity is not permitted
5. Entire tumor in the colon (rectal involvement is an exclusion). [Note: Surgeon confirmation that entire tumor was located in the colon is required only in cases where it is important to establish if the tumor is a colon versus (vs.) rectal primary.] Patients with more than one primary colon adenocarcinoma are eligible if the qualifying stage III tumor is confined to the colon, and not rectum, and the other cancers of lower stage are removed in the en bloc R0 resection. Based upon the operative report and other source documentation, the location of the primary tumor will be categorized as proximal or distal to the splenic flexure (included with distal), and further categorization will be as follows: cecum/ascending, transverse, descending, sigmoid colon, or rectosigmoid colon.
6. Age ≥ 18 years
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
8. Not pregnant and not nursing. For women of childbearing potential (WOCBP) only, a negative pregnancy test done ≤ 7 days prior to registration is required. A WOCBP is a sexually mature female who: 1) is not naturally postmenopausal (defined as at least 12 consecutive months with no menses without an alternative medical cause); OR 2) has not had a hysterectomy and/or bilateral oophorectomy (Note: Women with tubal ligation are still considered of child-bearing potential according to CTFG Guidance). Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial.
9. Absolute neutrophil count (ANC) ≥ 1500/mm³
10. Platelet count ≥ 100,000/mm³; platelets ≥ 75,000/mm³ required for patients who received cycle 1 of mFOLFOX6 prior to registration
11. Creatinine ≤ 1.5 x upper limit of normal (ULN) or Calculated creatinine clearance ≥ 45 mL/min by Cockcroft-Gault equation
12. Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except in the case of Gilbert disease
13. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
14. Thyroid-stimulating hormone (TSH) within normal limits (WNL). Supplementation is acceptable to achieve a TSH WNL. In patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible

Exclusion criteria 15

1. Evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging. The treating physician will determine if incidental lesions on imaging require workup to exclude metastatic disease. If based on review of images, the treating physician determines the patient to be stage III, then the patient is eligible.
2. Prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for the current colon cancer, except for one cycle of mFOLFOX6. Cycle 1 of mFOLFOX6 must have been administered per Appendix III of the main protocol.
3. Active known autoimmune disease, including colitis, inflammatory bowel disease (i.e. ulcerative colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency
4. Known active hepatitis B or C a. Active hepatitis B can be defined as: i. Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months; ii. Serum hepatitis B virus (HBV) DNA 20,000 IU/mL(105 copies/mL); lower values 2,000-20,000 IU/mL(104-105 copies/mL) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B; iii. Persistent or intermittent elevation in ALT/AST levels; iv. Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation. b. Active hepatitis C can be defined as: i. Hepatitis C antibody (AB) positive, AND ii. Presence of hepatitis C virus (HCV) RNA
5. Known active pulmonary disease with hypoxia defined as: a. Oxygen saturation < 85% on room air, or b. Oxygen saturation < 88% despite supplemental oxygen
6. Grade ≥ 2 peripheral motor or sensory neuropathy
7. HIV-positivity, unless all of the following are met: a. A stable regimen of highly active anti-retroviral therapy (HAART) b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections c. A CD4 count above 250 cells/μL, and an undetectable HIV viral load on standard PCR-based tests
8. Other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
9. Systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration
10. Known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins
11. Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation
12. Contraindications against any of the chemotherapeutic agents of the mFOLFOX6 regimen including but not limited to known allergy to 5-fluorouracil, oxaliplatin, or folinic acid
13. Inability to provide consent because the patient does not understand the nature, significance, and/or implications of the clinical trial and therefore cannot form a rational intention in the light of the facts (e.g. patients with psychiatric illness).
14. Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
15. A “currently active” second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Guidance: a. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for ≥ 3 years, had a gastric or bowel carcinoid < 1 cm, or DCIS/LCIS of the breast without invasive cancer, or endometrial dysplasia/carcinoma in situ. b. Patients are not considered to have a “currently active” malignancy if they had a sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma) that was noninvasive.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Disease-free survival (DFS), defined as the time from randomization to first documentation of disease recurrence (primary tumor relapse) or death.

Investigational products

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

Test 1

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

National Cancer Institute

Sponsor organisation

National Cancer Institute

Address

Building 37

City

Bethesda

Postcode

20892

Country

United States

Scientific contact point

Organisation

National Cancer Institute

Contact name

Frank A. Sinicrope, MD

Public contact point

Organisation

National Cancer Institute

Contact name

Stacy N. Reeves MBA, MPH

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. Anke Reinacher-Schick

Public contact point

Organisation

AIO-Studien gGmbH

Contact name

Katrin Krause

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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