Phase 2 study of neoadjuvant immune checkpoint inhibitors in urothelial cancer (ABACUS-2)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Queen Mary University Of London

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Jun 2021 → ongoing

Decision date (initial)

2024-09-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-510750-28-00

EudraCT number

2019-004628-39

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy, Pharmacodynamic

To determine atezolizumab's ability to reduce the size of urothelial cancer in the bladder (rare histological subtypes) and upper urinary tract before surgery (measured as pathological complete response rate),and assess the impact of the drug on the body's immune system.

Secondary objectives 4

1. 1. Assess the safety and tolerability of atezolizumab in this patient population by collecting information about adverse events and surgical complications. 2. Assess the anti-tumour effect of atezolizumab by examining the radiological response (looking at pre- and posttreatment MRI/CT scan images), "disease free survival" rates, and overall patient survival.
2. 2. Assess the anti-tumour effect of atezolizumab by examining the radiological response (looking at pre- and posttreatment MRI/CT scan images), "disease free survival" rates, and overall patient survival.
3. 3. To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to anti-tumour effects based on Investigator assessed disease-free survival (DFS).
4. 4. To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to overall survival (OS).

Conditions and MedDRA coding

Tumours of the urothelial tract requiring surgery (T1 high grade-T4a of the bladder, rare histological subtypes) and upper urinary tract (high grade or high risk)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Willing and able to provide written informed consent
2. 2. Ability to comply with the protocol
3. 3. Age ≥ 18 años.
4. 4. Residual disease after TURBT or ureteroscopy (surgical opinion, cystoscopy/ ureteroscopy or radiological evidence).
5. 5. Fit and planned for cystectomy or radical surgery of the upper tract (according to local guidelines).
6. 6. N0-1 and M0 disease CT or MRI (within 4 weeks of registration).
7. 7. Representative formalin-fixed paraffin embedded (FFPE) tumour samples with an associated pathology report that are determined to be available and sufficient for central testing.
8. 8. Patients who refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin-based therapy is not appropriate.
9. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
10. 10. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
11. 11. For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 5 months after the last dose of atezolizumab.
12. 12. Adequate hematologic and end-organ function within 4 weeks prior to the first study treatment defined by the following: a. ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1) b. WBC counts > 2500/μL c. Lymphocyte count ≥ 500/μL d. Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1) e. Haemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion). f. AST or ALT and alkaline phosphatase ≤ 2.5 times the institutional upper limit of normal (ULN) and serum bilirubin level ≤ 1.5 times the institutional ULN (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled) g. INR and aPTT ≤ 1.5 × the institutional ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. h. Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula)

Exclusion criteria 25

1. 1. Pregnant and lactating female patients.
2. 2. Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
3. 3. Previously intravenous chemotherapy for urothelial cancer.
4. 4. Patients with prior allogeneic stem cell or solid organ transplantation.
5. 5. Prior treatment with CD137 agonists, anti-CTLA-4, anti PD-1, or anti−PD-L1 therapeutic antibody or pathway-targeting agents
6. 6. Patients must not have had oral or IV steroids for 14 days prior to study entry. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed
7. 7. Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to enrolment (Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible).
8. 8. Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study
9. 9. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment.
10. 10. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment.
11. 11. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome).
12. 12. Malignancies other than UC within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive).
13. 13. Severe infections within 4 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
14. 14. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina.
15. 15. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).
16. 16. Patients with uncontrolled Type 1 diabetes mellitus. Patients with Type 1 diabetes controlled on a stable insulin regimen are eligible.
17. 17. Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
18. 18. Positive test for HIV
19. 19. Patients with active tuberculosis
20. 20. History of gastrointestinal disorders which may interfere with the absorption of the study drug.
21. 21. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > the institutional ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while on study.
22. 22. 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-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
23. 23. Patients with a history of autoimmune-related hypothyroidism, unless on a stable dose of thyroid-replacement hormone.
24. 24. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
25. 25. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. This study has a clinical and a biological primary endpoint: Clinical: • Bladder Cohort rare histological subtypes: To assess the efficacy of atezolizumab pre-cystectomy with respect to pCR rate in patients with carcinoma of the urothelium of the bladder (T1 high grade-T4aN0-1M0) with mixed or rare histological subtypes • UTUC Cohort: To assess the efficacy of atezolizumab pre-surgery with respect to pCR rate in patients with high grade or high risk (N0-1M0) upper urinary tract urothelial ca

Secondary endpoints 4

1. 1).To evaluate the safety and tolerability of atezolizumab when given in neoadjuvant treatment
2. 2) To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to anti-tumour effects as measured by Investigator assessed radiological response (RR).
3. 3) To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to antitumour effects based on Investigator assessed disease-free survival (DFS).
4. 4) To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to overall survival (OS).

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Queen Mary University Of London

Sponsor organisation

Queen Mary University Of London

Address

Charterhouse Square

City

London

Postcode

EC1M 6BQ

Country

United Kingdom

Scientific contact point

Organisation

Queen Mary University Of London

Contact name

Apices Soluciones - Clinical Operations department

Public contact point

Organisation

Queen Mary University Of London

Contact name

Apices Soluciones - Clinical Operations department

Third parties 1

Locations

2 EU/EEA countries · 9 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

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