A phase 2 study to investigate the effectiveness of combination immunotherapy followed by chemoradiation of the tumor in patients with bladder cancer (Indi-blade).

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] - Male Urogenital Diseases [C12], Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

26 Jan 2022 → ongoing

Decision date (initial)

2024-10-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

BMS

External identifiers

EU CT number

2024-512211-41-00

EudraCT number

2021-004420-15

ClinicalTrials.gov

NCT05200988

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

 To establish efficacy of induction ipilimumab + nivolumab followed by CRT by determining bladder-intact event-free survival (BI-EFS) for the intention-to-treat population. Events are defined as:
- Muscle-invasive recurrence in the bladder or in the ureter, distal of the crossing with the common iliac artery
- Nodal or distant recurrence
- Cystectomy
- Death by any cause
- Switch to cisplatin-based chemotherapy

Secondary objectives 10

1. OS, defined as the time between the date of enrollment and the date of death. For subjects without documentation of death, OS will be censored on the last date the subject was known to be alive.  RFS, defined as time from start of therapy until the following events:- muscle-invasive recurrence in the bladder or in the ureter, distal of the crossing with the common iliac artery, nodal or distant recurrence, switch to cisplatin-based chemotherapy or death by any cause. A decision to switch to cystectomy is not an event, as RFS is meant to provide a measurement of induction therapy efficacy.  Rate of non muscle-invasive bladder cancer (NMIBC).  Feasibility to proceed to CRT: assessed by CT-scanning of the chest and abdomen, multiparametric MRI (mpMRI) of the bladder and cystoscopy after finalizing treatment with checkpoint inhibition, combined with clinical evaluation by the treating physician. When there is no progressive disease detected on imaging that would be prohibitive of bladder-sparing treatment (as judged by multidisciplinary assessment) and there are no medical contraindications to proceed with CRT, we consider CRT feasible.  BI-EFS in the population proceeding to CRT.  Safety of CRT as consolidative therapy after induction ipi/nivo: all grade AEs and treatment related all grade/gr 3-4 AEs will be provided.  Tumor evaluation by mpMRI to identify nonresponding patients, to select for treatment switch  Biomarkers – PD-L1, TMB, molecular subtypes and imaging biomarkers (AI) will be correlated with outcome (RFS and OS)  Predictive value of ctDNA In plasma: based on our work in NABUCCO, we aim to determine whether the absence of ctDNA in plasma after induction therapy is predictive of RFS and OS. Similarly, we aim to determine whether absence of ctDNA in plasma after CRT is predictive of response. In urine: we will explore whether clearance of urine ctDNA corresponds with bladder specific response  QoL and bladder function.
2. RFS, defined as time from start of therapy until the following events:- muscle-invasive recurrence in the bladder or in the ureter, distal of the crossing with the common iliac artery, nodal or distant recurrence, switch to cisplatin-based chemotherapy or death by any cause. A decision to switch to cystectomy is not an event, as RFS is meant to provide a measurement of induction therapy efficacy.
3. Rate of non muscle-invasive bladder cancer (NMIBC).
4. Feasibility to proceed to CRT: assessed by CT-scanning of the chest and abdomen, multiparametric MRI (mpMRI) of the bladder and cystoscopy after finalizing treatment with checkpoint inhibition, combined with clinical evaluation by the treating physician. When there is no progressive disease detected on imaging that would be prohibitive of bladder-sparing treatment (as judged by multidisciplinary assessment) and there are no medical contraindications to proceed with CRT, we consider CRT feasible.
5. BI-EFS in the population proceeding to CRT.
6. Safety of CRT as consolidative therapy after induction ipi/nivo: all grade AEs and treatment related all grade/gr 3-4 AEs will be provided.
7. Tumor evaluation by mpMRI to identify nonresponding patients, to select for treatment switch
8. Biomarkers – PD-L1, TMB, molecular subtypes and imaging biomarkers (AI) will be correlated with outcome (RFS and OS)
9. Predictive value of ctDNA In plasma: based on our work in NABUCCO, we aim to determine whether the absence of ctDNA in plasma after induction therapy is predictive of RFS and OS. Similarly, we aim to determine whether absence of ctDNA in plasma after CRT is predictive of response. In urine: we will explore whether clearance of urine ctDNA corresponds with bladder specific response
10. QoL and bladder function

Conditions and MedDRA coding

Urothelial carcinoma of the bladder and bladder cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Willing and able to provide informed consent
2. Age ≥ 18 years
3. Patients with cT2-4aN0-2M0 urothelial bladder cancer, seeking an alternative to radical cystectomy and/or patients who are medically unfit for surgery. Patients with suspected metastatic disease are not eligible.
4. Lymph node metastases should be amenable for inclusion into the radiation field according to the multidisciplinary tumor board and/or follow-up consultations between the treating physician and the radiation oncologist.
5. World Health Organization (WHO) performance Status 0 or 1.
6. Urothelial cancer is the dominant histology (>70%). A small cell component is not allowed.
7. Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from diagnostic TUR available.
8. Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.0x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, GFR>30 ml/min as per Cockcroft-Gault formula, AST ≤ 2.5 x ULN, ALT ≤2.5 x ULN, Bilirubin ≤1.5 X ULN with an exception for patients with Gilbert’s syndrome (Bilirubin ≤2 X ULN)
9. Negative pregnancy test (βHCG in urine or blood) for female patients of childbearing potential within 2 weeks prior to day 1 of start immunotherapy.
10. Highly effective contraception for both male and female subjects if the risk of conception exists. Female patients of childbearing potential must comply with contraception methods as requested by the study protocol (→ 4.4 Pregnancy, contraception and breastfeeding)

Exclusion criteria 18

1. Previous pelvic irradiation
2. Upper tract urothelial cancer
3. Extensive carcinoma in situ (CIS) of the bladder
4. Bilateral hydronephrosis
5. Previous intravenous chemotherapy for bladder cancer
6. Contra-indication to one of the study treatment components, or mpMRI
7. Subjects with active autoimmune disease in the past 2 years. Patients with diabetes mellitus, properly controlled hypothyroidism or hyperthyroidism, vitiligo, psoriasis or other mild skin disease can still be included.
8. Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis).
9. Prior CTLA-4 or PD-(L)1 -targeting immunotherapy.
10. Known history of Human Immunodeficiency Virus, active tuberculosis, or other active infection requiring therapy at the time of inclusion.
11. Positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA)
12. Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events
13. Medical condition requiring the use of immunosuppressive medications, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) will be allowed.
14. Use of other investigational drugs four weeks or five half-lives before study drug administration
15. Malignancy, other than urothelial cancer, in the previous 2 years, with a high chance of recurrence (estimated >10%). Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.
16. Pregnant and lactating female patients.
17. Major pelvic 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.
18. Severe infections within 2 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. efficacy defined as bladder-intact event-free survival (BI-EFS). Events consist of death by any cause; muscle-invasive recurrence in the bladder or in the ureter, distal of the crossing with the common iliac artery, nodal or distant recurrence, cystectomy, or switch to cisplatin-based chemotherapy.

Secondary endpoints 1

1. Overall survival (OS), recurrence-free survival (RFS), feasibility to proceed to CRT, safety, predictive value of ctDNA, QoL, and bladder function

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

Michiel van der Heijden

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Michiel van der Heijden

Locations

1 EU/EEA country · 3 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 13 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