NEOadjuvant chemotherapy study of Nintedanib with Gemcitabine and Cisplatin in locally advanced muscle invasive BLADder cancEr

ISRCTN	ISRCTN56349930
DOI	https://doi.org/10.1186/ISRCTN56349930
EudraCT/CTIS number	2012-004895-01
Secondary identifying numbers	16091

Submission date: 23/04/2014
Registration date: 23/04/2014
Last edited: 21/01/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

http://www.cancerresearchuk.org/about-cancer/trials/a-trial-chemotherapy-nintedanib-people-invasive-bladder-cancer-neoblade

Contact information

Dr Siobhan Cosgrave
Scientific

Cancer Research UK Liverpool Cancer Trials Unit
University of Liverpool
1st floor Block C, Waterhouse Building
3 Brownlow Street
Liverpool
L69 3GL
United Kingdom

Email	a.s.cosgrave@liv.ac.uk

Study information

Study design	Randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	Phase II randomised placebo controlled NEOadjuvant chemotherapy study of Nintedanib with Gemcitabine and Cisplatin in locally advanced muscle invasive BLADder cancEr
Study acronym	NEOBLADE
Study hypothesis	The primary research question of the main study will investigate if treatment with a new drug called Nintedanib, used in combination with standard treatment, helps to improve the removal of cancer cells (measured from the sample of bladder tissue taken from the patient) compared to if the patient were to receive standard treatment alone. The primary research question of the safety sub-study will determine if patients with poor kidney function can tolerate Nintedanib and at what dose so that these types of patients can also be included in the main study. The secondary research questions of this study will investigate whether the time in which the disease does not get any worse can be extended for a patient by using this new drug called Nintedanib (used in combination with standard treatment) compared to if the patient were to receive standard treatment alone. Also, does treatment with Nintedanib (used in combination with standard treatment) help to prolong how long a patient lives for compared to if the patient were to receive standard treatment alone. The study will also evaluate the toxicity of Nintedanib.
Ethics approval(s)	13/NW/0134; First MREC approval date 23/04/2013
Condition	Topic: Cancer; Subtopic: Bladder Cancer; Disease: Bladder (advanced)
Intervention	Nintedanib, Triple Kinase Inhibitor; Nintedanib/Placebo, Triple Kinase Inhibitor or Inactive Placebo The visit schedule and assessments for the safety sub-study and the main study are the same. Initially patients will go for a screening visit to provide consent and check if they are eligible for the study. If patients are eligible they will be registered/randomised depending on their kidney function which is measured by Glomerular Filtration Rate (GFR). For both studies, there are two stages of treatment. The first stage for all patients consists of neo-adjuvant treatment with three different drugs together (Gemcitabine and Cisplatin, intravenously, which would normally be given as standard care, plus the new drug: Nintedanib/placebo, orally). For the main study patients with normal GFR > 60ml/min will be treated with Gemcitabine 1000 mg/m2 (Day 1 and Day 8 of each cycle) and standard Cisplatin 70 mg/m2 (Day 1 of each cycle) with 200 mg Nintedanib or placebo twice a day. For the main study patients with poor GFR 40- 60ml/min will be treated with Gemcitabine 1000 mg/m2 and split dose Cisplatin 70 mg/m2 (35mg/m2 on Day 1 and Day 8 of each cycle) with Nintedanib or placebo (the concentration of this will be determined by the safety sub-study). Patients on the safety sub-study will only receive Nintedanib and will receive the split dose Cisplatin regime. Following 3 x 21 day cycles of neo-adjuvant chemotherapy, patients will undergo response assessment MRI scan and cystoscopic evaluation with tumour bed biopsy. Patients will then receive a 4th cycle of neoadjuvant chemotherapy before receiving radical treatment which is the second stage of treatment and will be either cystectomy or organ preservation treatment with chemoradiotherapy or radiotherapy based on patient and clinician discretion. After radical treatment patients will then be followed up at 3, 6 and 12 months and then annually for up to 5 years.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Nintedanib with Gemcitabine
Primary outcome measure	1. Pathological complete response; Timepoint(s): Baseline (standard diagnostic biopsy) End of cycle 3 of neoadjuvant treatment Following neoa
Secondary outcome measures	1. Primary outcome (Safety Sub-study): MTD of Nintedanib to be confirmed for renally impaired patients; Timepoint(s): 6 months 2. Secondary outcomes (Phase II Main study): 2.1. Overall Survival; Timepoint(s): 5 years 2.2. Progression free survival; Timepoint(s): 5 years 2.3. Toxicity; Timepoint(s): 5 years
Overall study start date	15/05/2014
Overall study end date	30/11/2016

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 132; UK Sample Size: 132; Description: 120 (Main study) up to 12 (Safety Sub-Study)
Total final enrolment	120
Participant inclusion criteria	1. Aged 18 or over 2. Histologically proven invasive TCC of bladder 3. Localised muscle invasive carcinoma either surgically or by imaging (T2-T4a N0 M0 ) 4. ECOG performance status grade 0 to 1 5. Adequate haematological function as evidenced by: 5.1. Haemoglobin >10.0g/dl 5.2. White blood cell count >3.0 x10 9/L 5.3. Absolute neutrophil count >1.5 x10 9/L 5.4. Platelet count >100,000/mm3 6. Adequate Hepatic function as evidenced by: 6.1. Total Bilirubin <1.5 xULN 6.2. Alkaline Phosphatase (ALP) levels <2 xULN 6.3. Aspartate transaminase (AST)/Alanine transaminase (ALT) levels <3.0 xULN 7. Glomerular Filtration Rate (GFR) > 60ml/min* measured by either: 7.1. EDTA clearance 7.2. 24 hr Urine collection 7.3. The Cockcroft-Gault calculation As per local standard practice; Available for 12month follow up 8. Agree to use adequate contraception which they agree to continue for 3 months after the study treatment 9. Suitable for treatment with Gemcitabine and Cisplatin 10. Able to receive radical treatment 11. Able to provide written informed consent *Following safety review from the safety substudy, the ISDMC and the funder will decide whether the data indicates that it is suitable for patients with impaired GFR (40-60 ml/minute) to be included in the trial using split dose cisplatin 35 mg/m2 on day 1 and day 8 and which dose of Nintedanib/Placebo will be used for the main study.
Participant exclusion criteria	1. Pregnant or breast feeding 2. Concomitant or previous malignancy which is likely to interfere with protocol treatment 3. Evidence of significant clinical disorder, or laboratory finding which, in the opinion of the investigator, makes it undesirable for the patient to participate in the trial. 4. Male and female patients (of childbearing potential* not using adequate contraception and do not agree to do so for 3 months following Nintedanib treatment 5. Evidence of metastatic disease * Patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or postmenopausal for at least two years. Note: Patients with hydronephrosis can be included if the kidney/ureter has been stented, or nephrostomy has been inserted, and renal function has been maintained to allow neoadjuvant chemotherapy to be administered satisfactorily
Recruitment start date	15/05/2014
Recruitment end date	30/11/2016

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Cancer Research UK Liverpool Cancer Trials Unit

Liverpool
L69 3GL
United Kingdom

Sponsor information

Clatterbridge Centre for Oncology NHS Trust (UK)
Hospital/treatment centre

Clatterbridge Hospital
Clatterbridge Road
Wirral
CH63 4JY
England
United Kingdom

"ROR"	https://ror.org/05gcq4j10

Funders

Funder type

Industry

Boehringer Ingelheim Ltd (UK)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Abstract results	results presented at ASCO	20/02/2020	17/08/2020	No	No
Results article		11/04/2022	19/04/2022	Yes	No
HRA research summary			28/06/2023	No	No
Plain English results			21/01/2025	No	Yes

Editorial Notes

21/01/2025: Cancer Research UK plain English results link added.
19/04/2022: Publication reference added.
17/08/2020: The following changes have been made:
1. Publication reference added.
2. The final enrolment number has been added from the reference.