Neoadjuvant treatment in rectal cancer with radiotherapy followed by atezolizumab and bevacizumab

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Digestive System Diseases [C06]

Trial duration

26 Sep 2019 → ongoing

Decision date (initial)

2024-10-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-517119-59-00

EudraCT number

2018-002463-25

ClinicalTrials.gov

NCT04017455

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To explore efficacy of neoadjuvant atezolizumab and bevacizumab following radiotherapy in low- to intermediate-risk rectal cancer

Secondary objectives 2

1. To evaluate safety/tolerability and pre-operative treatment-related complications with atezolizumab and bevacizumab following radiotherapy
2. To explore efficacy with regard to preventing/delaying disease relapse and to organ preservation

Conditions and MedDRA coding

Rectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Signed informed consent form
2. Age ≥18 years
3. Able to comply with the study protocol, in the investigator’s judgment
4. Histologically confirmed adenocarcinoma of the rectum
5. Patients with intermediate risk rectal cancer (cT1-3N1 or cT3c/dN0 MRF-) or low risk rectal cancer (cT1-3bN0 MRF-) in patients who wish to pursue organ preservation
6. Patients must be willing to undergo proctoscopy and biopsies prior to start of treatment and during treatment at defined timepoints
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
8. Evaluable disease, according to the international rectal cancer imaging guidelines and when possible RECIST 1.1
9. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment: o ANC higher then or equal to 1.5 x 10_9/L (1500/microL) without granulocyte colony-stimulating factor support o Platelet count higher or equal to 100 x 10_9/L (100,000/microL) without transfusion o Hemoglobin higher or equal to 5.6mmol/L (patients may be transfused to meet this criterion) o AST, ALT, and alkaline phosphatase (ALP) lower or equal to 2.5 x upper limit of normal (ULN) o Serum bilirubin lower or equal to 1.5 x ULN except for patients with known Gilbert disease: serum bilirubin level lower or equal to 3 x ULN o Serum creatinine lower or equal to 1.5 x ULN or Creatinine clearance higher or equal to 40 mL/min (calculated using the Cockcroft-Gault formula) o Serum albumin higher or equal to 25 g/L o For patients not receiving therapeutic anticoagulation: INR or aPTT lower or equal to 1.5 x ULN (patients receiving therapeutic anticoagulation must be on a stable regimen)
10. For women of childbearing potential: Negative serum pregnancy test within 14 days prior to screening. Agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of ≤ 1% per year during the treatment period and for at least 180 days after the last study treatment.
11. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm,

Exclusion criteria 26

1. Evidence of metastatic disease
2. Clinical symptoms or radiological suspicion of perforation
3. Distant metastases on CT of thorax and abdomen and MRI pelvis < 6 weeks to inclusion
4. Other malignancies within 3 years prior to registration with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ducal carcinoma in situ treated surgically with curative intent).
5. Prior radiation therapy for the disease under study or within 30 days prior to registration, , persistence of radiation-related adverse effects or previous radiation therapy preventing 5x5Gy as specified in this study
6. Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past
7. Spinal cord compression not definitively treated with surgery and/or radiation
8. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
9. Uncontrolled tumor pain. Patients who require narcotic pain medication during screening should be on a stable dose regimen prior to registration
10. Treatment with any investigational agent or approved therapy within 28 days or two investigational agent half-lives (whichever is longer) prior to registration
11. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-PD-1 and anti-PD-L1, or VEGF/VEGFR inhibitors
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any components of the atezolizumab or bevacizumab formulations
14. Current or recent (within 10 days of study enrollment) use of acetylsalicylic acid (> 325 mg/day), clopidogrel (> 75 mg/day)
15. History of clinically significant cardiac or pulmonary dysfunction including the following:  Inadequately controlled hypertension (that is defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg that is treated or untreated)  Prior history of hypertensive crisis or hypertensive encephalopathy  Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of registration  History of stroke or transient ischemic attack within 6 months prior to registration  Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 6 months prior to registration, severe cardiac arrhythmia requiring medication or severe conduction abnormalities, unstable arrhythmias, acute coronary syndromes (including unstable angina), or history of coronary angioplasty/stenting/bypass grafting within past 6 months. - Patients with known left ventricular ejection fraction (LVEF) < 40% will be excluded - Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
16. 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
17. Major surgical procedure, other than diagnostic laparoscopy, within 4 weeks prior to registration, or anticipation of need for a major surgical procedure during the course of the study
18. Serious non-healing wound, active ulcer or untreated bone fracture
19. History of abdominal fistula or gastrointestinal perforation within 6 months prior to registration
20. History of hemoptysis (≥ ½ teaspoon of bright red blood per episode), or any other serious hemorrhage or at risk of bleeding (gastrointestinal history of bleeds, gastrointestinal ulcers, etc.)
21. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding
22. Proteinuria at registration, by urine dipstick ≥ 2+ or 24-hour proteinuria > 1.0 g
23. Autoimmune conditions: History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain- Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 4 for a more comprehensive list of autoimmune diseases and immune deficiencies) with the following exceptions:  Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study  Patients with controlled Type 1 diabetes mellitus  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: - Rash must cover < 10% of body surface area - Disease is well controlled at baseline and requires only low-potency topical corticosteroids - No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months
24. Infectious diseases  Active infection requiring IV antibiotics at registration  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  Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening).  Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to C1D1.  Patients with active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA  Known HIV infection  Active tuberculosis  Influenza vaccination should be given during influenza season. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to registration or at any time during the study and for at least 5 months after the last dose of study drug.
25. Pregnant or lactating, or intending to become pregnant during the study. Women who are not post-menopausal (≥ 12 continuous months of amenorrhea with no identified cause other than menopause) or surgically sterile must have a negative serum pregnancy test within 14 days prior to registration
26. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of the investigational drugs, may affect the interpretation of the results, or may render the patient at high risk from treatment complications

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is clinical complete and near-complete response rate (c(n)CR) assessed at week 12 post-radiotherapy

Secondary endpoints 7

1. Safety: incidence and severity of AEs (with severity determined according to NCI CTCAE v5.0), vital signs and clinical laboratory test results.
2. Pre-operative treatment-related complications leading to delays in systemic treatment and/or surgery (excluding non-treatment-related and logistical reasons). Delays in surgery are defined as treatment-related delays beyond 4-6 weeks after the clinical decision has been made to operate
3. Relapse-free survival (RFS), defined as the time from study enrolment to disease recurrence or disease-related death during follow-up
4. Local recurrence rate (LRR) at 1 year follow-up
5. Proportion of patients who undergo organ preserving treatment defined as the patients who at evaluation at T12w are found to have a (near-) complete response and thus planned for watchful waiting or local excision.
6. Pathological complete and near-complete response (pCR), defined as Mandard TRG 1-2, if available
7. Radiological tumor regression using MRI (ESGAR consensus guidelines)

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

M. Chalabi

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

M. Chalabi

Locations

1 EU/EEA country · 2 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 3 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