An adaptive multi-arm phase II trial of maintenance targeted therapy after chemotherapy in metastatic urothelial cancer

• Register: ISRCTN
• Last refreshed on: 9 January 2023
• Main ID: ISRCTN25859465
• Date of registration: 16/09/2016
• Prospective Registration: Yes
• Primary sponsor: NHS Greater Glasgow and Clyde
• Public title: An adaptive multi-arm phase II trial of maintenance targeted therapy after chemotherapy in metastatic urothelial cancer
• Scientific title: An adaptive multi-arm phase II trial of maintenance targeted therapy after chemotherapy in metastatic urothelial cancer
• Date of first enrolment: 01/11/2016
• Target sample size: 140
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN25859465
• Study type: Interventional
• Study design: Multi-centre randomised phase II trial (Treatment)
• Phase: Phase II

Countries of recruitment

England, Scotland, United Kingdom, Wales

Contacts

• Name: Eileen Soulis

• Name: Eileen Soulis

Key inclusion & exclusion criteria

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.

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


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Metastatic urothelial cancer
Cancer

Intervention(s)

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 8

Primary Outcome(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

Secondary Outcome(s)

1. Overall survival - follow up by local investigator
2. Safety and tolerability - CTCAE assessment every 4 weeks whilst on study treatment
3. Response rate- RECIST 1.1 tumour measurements, assessed 12 weekly during trial treatment. Best response recorded from the start of treatment until disease progression
4. Maximum reduction in the size of measurable lesions - RECIST 1.1 tumour measurements, assessed 12 weekly during trial treatment. Maximum reduction recorded from the start of treatment until disease progression

Secondary ID(s)

2015-003249-25

ATLANTIS_2015

Source(s) of Monetary Support

Cancer Research UK, Exelixis Inc

Secondary Sponsor(s)

University of Glasgow

Ethics review

Status:
Approval date:
Contact:

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; [phone]; [e-mail]), ref: 16/WX/0197

Results

• Results available: Yes
• Date Completed: 17/05/2022