An adaptive multi-arm phase II trial of maintenance targeted therapy after chemotherapy in metastatic urothelial cancer
| ISRCTN | ISRCTN25859465 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN25859465 |
| Clinical Trials Information System (CTIS) | 2015-003249-25 |
| Protocol serial number | ATLANTIS_2015 |
| Sponsors | NHS Greater Glasgow and Clyde, University of Glasgow |
| Funders | Cancer Research UK, Exelixis Inc |
- Submission date
- 12/09/2016
- Registration date
- 16/09/2016
- Last edited
- 28/12/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Plain English summary of protocol
Contact information
Public
CRUK CTU
Beatson West of Scotland Cancer Centre
Level 0
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
| Phone | +44 141 301 7184 |
|---|---|
| Eileen.Soulis@glasgow.ac.uk |
Scientific
CRUK CTU
Beatson West of Scotland Cancer Centre
Level 0
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
| Phone | +44 141 301 7184 |
|---|---|
| Eileen.Soulis@glasgow.ac.uk |
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Multi-centre randomised phase II trial |
| Secondary study design | Randomised controlled trial |
| Scientific title | An adaptive multi-arm phase II trial of maintenance targeted therapy after chemotherapy in metastatic urothelial cancer |
| Study acronym | ATLANTIS |
| Study objectives | The trial hypothesis is that the addition of biomarker-targeted novel agents used as maintenance therapy after chemotherapy will improve clinical efficacy in patients with metastatic urothelial cancer. |
| Ethics approval(s) | Approved 01/12/2016, West of Scotland Research Ethics Committee 1 (West of Scotland Research Ethics Service, Ward 11, Dykebar Hospital, Grahamston Road, Paisley, PA2 7DE, UK; +44 (0)141 3140213; WoSREC1@ggc.scot.nhs.uk), ref: 16/WX/0197 |
| Health condition(s) or problem(s) studied | Metastatic urothelial cancer |
| Intervention | Current interventions as of 14/07/2020: Multiple novel agents will be tested in parallel and patients will enter into particular ATLANTIS component subgroup studies dependent on their biomarker profile. The control arm will be placebo-controlled and double blind. Rucaparib drug subgroup: Patients will receive continuous daily dosing (days 1-28 of a 28 day cycle) until progression or acceptable toxicity. 1. Control arm: Matched placebo 600 mg twice daily and can be taken either with food or without food 2. Experimental arm: Rucaparib 600 mg twice daily and can be taken either with food or without food Dose reductions are recommended for events that, if persistent, could become serious or intolerable. The dose may be reduced (to 500 mg of rucaparib) due to treatment related toxicity. This should be clinically driven. Patients with grade 3 or 4 toxicity (as per CTCAE version 4.03) should be considered for a dose reduction, following recovery to grade 1 or baseline. Enzalutamide drug subgroup: Patients will receive continuous daily dosing (days 1-28 of a 28 day cycle) until progression or acceptable toxicity. 1. Control arm: Matched placebo 160 mg once daily 2. Experimental arm: Enzalutamide 160 mg once daily It is rarely necessary to reduce the dose of enzalutamide. Patients who experience grade 3 or 4 toxicity (as per CTCAE version 4.03), that cannot be ameliorated by the use of appropriate medical intervention, may interrupt enzalutamide until the toxicity improves to grade 2 or lower. Subsequent dosing may be restarted at the original dose (160mg) or a reduced dose of 80mg once daily. Cabozantinib drug subgroup: Patients will receive continuous daily dosing (days 1-28 of a 28 day cycle) until progression or unacceptable toxicity. 1. Control arm: Matched placebo 40mg once daily in the fasted state i.e. no food for at least 2 hours before through to 1 hour after taking. 2. Experimental arm: Cabozantinib 40mg once daily in the fasted state i.e. no food for at least 2 hours before through to 1 hour after taking. Dose reductions are recommended for events that, if persistent, could become serious or intolerable. The dose may be reduced (to 20mg of cabozantinib) due to treatment related toxicity. This should be clinically driven. Patients with grade 3 or 4 toxicity (as per CTCAE version 4.03) should be considered for a dose reduction, following recovery to grade 1 or baseline. Patients will continue to receive trial drug/placebo until progression, unacceptable toxicity, start of further systemic anticancer therapy, withdrawal of consent or the investigator decides it is not in the best interest of the patient to continue. Patients will be followed up for overall survival and further systemic anti-cancer treatments after progression has occurred. Data will be collected until 8 months after the last patient has been enrolled. Previous interventions: Multiple novel agents will be tested in parallel and patients will enter into particular ATLANTIS component subgroup studies dependent on their biomarker profile. The control arm will be placebo-controlled and double blind. The initial subgroup will investigate cabozantinib versus matched placebo at 40mg PO once daily. Cabozantinib drug subgroup: Patients will receive continuous daily dosing (days 1-28 of a 28 day cycle) until progression or unacceptable toxicity. 1. Control arm: Matched placebo 40 mg once daily in the fasted state i.e. no food for at least 2 hours before through to 1 hour after taking. 2. Experimental arm: Cabozantinib 40 mg once daily in the fasted state i.e. no food for at least 2 hours before through to 1 hour after taking. Dose reductions are recommended for events that, if persistent, could become serious or intolerable. The dose may be reduced (to 20 mg of cabozantinib) due to treatment-related toxicity. This should be clinically driven. Patients with grade 3 or 4 toxicity (as per CTCAE version 4.03) should be considered for a dose reduction, following recovery to grade 1 or baseline. Patients will continue to receive trial drug/placebo until progression, unacceptable toxicity, start of further systemic anticancer therapy, withdrawal of consent or the investigator decides it is not in the best interest of the patient to continue. Patients will be followed up for overall survival and further systemic anti-cancer treatments after progression has occurred. Data will be collected until 8 months after the last patient has been enrolled. |
| Intervention type | Drug |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Cabozantinib, enzalutamide, rucaparib |
| Primary outcome measure(s) |
Progression free survival- RECIST 1.1 tumour measurements, assessed 12 weekly during trial treatment. PFS is time from randomisation until progression or death, whichever occurs first |
| Key secondary outcome measure(s) |
1. Overall survival - follow up by local investigator |
| Completion date | 17/05/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | All |
| Target sample size at registration | 140 |
| Total final enrolment | 115 |
| Key inclusion criteria | 1. Previously diagnosed stage IV urothelial cancer (UC) (T4b, Nany, Many; Tany, N 1-3, M0; Tany, Nany, M1) see Appendix II) 2. Histologically confirmed urothelial cancer. This includes cancers of the urinary bladder, ureter, renal pelvis or urethra with transitional and/or squamous histology. A component of either or both of these histologies is adequate for entry 3. Able to commence the trial treatment within 10 weeks of completing chemotherapy 4. Adequate tissue for biomarker testing. Testing will occur centrally 5. Patients must have received between 4 and 8 cycles of first line chemotherapy for metastatic/advanced UC to be eligible **. Previous adjuvant or neoadjuvant chemotherapy does not count as a line of therapy 6. Adequate organ function as defined in the relevant subgroup specific appendix 7. ECOG performance status 0-2 8. Age ≥ 16 years 9. Female patients of childbearing potential must agree to comply with effective contraceptive measures, has been using adequate contraception since the last menses, will use adequate contraception during the trial, and has a negative pregnancy test within one week of trial entry. 10. Male patients with partners of child-bearing potential must agree to take measures not to father children by using one form of highly effective contraception, effective at the first administration of IMP and throughout the trial 11. Written informed consent prior to admission to this trial 12. Meets all inclusion criteria for the relevant component subgroup listed in the appendices **Standard chemotherapy consists of any widely accepted regimen. Patients who have had delays in treatment or dose reductions should not be excluded, providing they received at least 4 cycles of treatment. |
| Key exclusion criteria | 1. Progression during first-line chemotherapy for metastatic disease. This should be based on a radiological comparison between the pre-chemotherapy CT and end of treatment CT (local review). Patients may be permitted to enter the trial if their end of chemotherapy scan shows response or stable disease (local assessment using RECIST 1.1) when compared to their latest pre-chemotherapy scan, even if there is progression when compared to a nadir scan performed during chemotherapy. These patients should be discussed with the trial team 2. In the opinion of the Investigator requires second line chemotherapy 3. More than one line of chemotherapy for metastatic or locally advanced disease (where the regimen is changed during first-line treatment without evidence of progression (for example the patient changes from cisplatin to carboplatin due to toxicity) this will constitute a single line of chemotherapy). Prior adjuvant / neoadjuvant chemotherapy is permitted in addition 4. Patients receiving radical/curative surgery or radiotherapy at the end of first line treatment (palliative radiotherapy is allowed but must be > 2 weeks prior to trial entry) 5. Patients receiving less than 4 or more than 8 cycles of chemotherapy before randomisation and initiation of trial intervention (excluding any chemotherapy given as neo-adjuvant / adjuvant) 6. Treatment with any other investigational agent within 28 days prior to first dose of trial medication within ATLANTIS 7. Less than 3 or more than 10 weeks since the last infusion of first-line chemotherapy for advanced/metastatic UC at time of initiation of trial interventions 8. History of another malignancy in the last 2 years (other than treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated / biochemically stable, organ confined prostate cancer not requiring on-going androgen deprivation therapy) 9. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder) 10. Positive pregnancy test for females 11. Inadequate organ function as defined in drug-specific appendices 12. Ongoing therapy with prohibited medication which cannot be discontinued prior to starting trial specific intervention (as defined in drug-specific appendices) 13. Major surgery or any radiotherapy within 3 weeks prior to trial entry (palliative radiotherapy within >2 weeks prior to trial entry is permitted) 14. Significant comorbidity or serious intercurrent medical or psychiatric illness, including serious active infection which, in the opinion of the investigator would make it inappropriate for the patient to enter the trial 15. Women who are breast feeding 16. Meets any of the exclusion criteria listed in the relevant component subgroup specific appendix |
| Date of first enrolment | 01/11/2016 |
| Date of final enrolment | 17/05/2022 |
Locations
Countries of recruitment
- United Kingdom
- England
- Scotland
- Wales
Study participating centres
Glasgow
G12 0YN
United Kingdom
London
EC1A 7BE
United Kingdom
London
SE1 7EH
United Kingdom
Southampton
SO16 6YD
United Kingdom
Clatterbridge Rd
Wirral
CH63 4JY
United Kingdom
Lancaster
LA1 4RP
United Kingdom
Parc
Nantgarw
Cardiff
CF14 2TL
United Kingdom
Manchester
M20 4BX
United Kingdom
Sutton
SM2 5PT
United Kingdom
Leeds
LS9 7TF
United Kingdom
London
NW1 2PG
United Kingdom
Newcastle
NE7 7DN
United Kingdom
Headington
Oxford
OX3 7LE
United Kingdom
Taunton
TA1 5DA
United Kingdom
Nottingham
NH5 1PB
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Bristol
BS2 8HW
United Kingdom
Romford
RM7 0AG
United Kingdom
Portsmouth
PO6 3LY
United Kingdom
Leicester
LE1 5WW
United Kingdom
Derby
DE22 3NE
United Kingdom
Edinburgh
EH4 2XU
United Kingdom
Maidstone
ME16 9QQ
United Kingdom
Bournemouth
BH7 7DW
United Kingdom
Sutton-in-Ashfield
NG17 4JL
United Kingdom
Hammersmith
London
W6 8RF
United Kingdom
Plymouth
PL6 8DH
United Kingdom
Fulwood
Preston
PR2 9HT
United Kingdom
Shrewsbury
SY3 8XQ
United Kingdom
Blackburn
BB2 3HH
United Kingdom
Wakefield
WF1 4DG
United Kingdom
Broomhill
Sheffield
S10 2SJ
United Kingdom
Sunderland
SR4 7TP
United Kingdom
Results and Publications
| Individual participant data (IPD) Intention to share | No |
|---|---|
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| IPD sharing plan | The current data sharing plans for this study are unknown and will be available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | Rucaparib results | 01/01/2023 | 28/12/2022 | Yes | No |
| Protocol article | 19/04/2020 | 28/12/2022 | Yes | No | |
| Abstract results | Cabozantinib results | 08/06/2022 | 28/12/2022 | No | No |
| Plain English results | Early results for participants in group 2 | 22/02/2022 | 23/02/2022 | No | Yes |
| Protocol file | version 2.7 | 17/05/2022 | 21/09/2022 | No | No |
Additional files
- 32564 ATLANTIS Protocol_Version 2.7_17May2022.pdf
- Protocol file
Editorial Notes
28/12/2022: Publication references added.
21/09/2022: The following changes were made to the trial record:
1. The overall end date was changed from 30/04/2023 to 17/05/2022.
2. The total final enrolment was added.
3. The ethics approval was added.
4. Uploaded protocol (not peer-reviewed) as an additional file.
10/08/2022: The ATLANTIS platform has been closed, and will not be opening any new drug comparison arms as of 17th May 2022. The recruitment end date has been changed from 30/07/2022 to 17/05/2022.
23/02/2022: The Cancer Research UK lay results summary of early results has been added.
23/07/2020: The trial participting centre "Barts and the London NHS Trust" was changed to "Barts Health NHS Trust" and the trial participating centres "The Christie Hospital ", "The Royal Marsden Hospital ", "St James’ Hospital", "University College London Hospitals ", "The Freeman Hospital", "The Churchill Hospital ", "Musgrove Park Hospital", "Nottingham University Hospital", "Aberdeen Royal Infirmary", "Bristol University Hospitals", "Queens Hospital Romford", "Portsmouth Hospital ", "Leicester Royal Infirmary", "Derby Hospitals ", "Western General Hospital", "Maidstone Hospital", "Royal Bournemouth & Christchurch Hospitals", "Kings Mill Hospital", "Charing Cross Hospital", "Derriford Hospital", "Royal Preston Hospital", "Shrewsbury Hospital", "Royal Blackburn Hospital", "Pinderfields Hospital", "Weston Park Hospital", and "Sunderland Royal Hospital" have been added.
14/07/2020: Recruitment for this study is no longer paused as of 30/06/2020 and the interventions have been updated.
14/04/2020: Due to current public health guidance, recruitment for this study has been paused. Additionally, the following changes have been made:
1. The recruitment end date has been changed from 31/12/2020 to 30/07/2022.
2. The overall trial end date has been changed from 01/08/2021 to 30/04/2023.
3. The intention to publish date has been changed from 01/08/2022 to 31/12/2024.
12/12/2018: The following changes have been made:
1. The recruitment end date has been updated from 30/11/2018 to 31/12/2020.
2. The overall trial end date has been updated from 01/07/2019 to 01/08/2021.
3. The intention to publish date has been updated from 01/07/2020 to 01/08/2022.
10/12/2018: The public and scientific contact has been changed from Anna Morris to Eileen Soulis.
31/10/2017: Internal review.
11/08/2017: Internal review.
16/05/2017: Cancer Help UK lay summary link added to plain English summary field.
10/04/2017: Internal review.
