| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic urothelial cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bladder or associated structures which has spread to other parts of the body. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10061620 |
| E.1.2 | Term | Adenocarcinoma with transitional cell carcinoma of bladder |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001213 |
| E.1.2 | Term | Adenocarcinoma with transitional cell carcinoma of bladder NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001214 |
| E.1.2 | Term | Adenocarcinoma with transitional cell carcinoma of bladder recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objectives of this trial are to compare progression-free survival (PFS, the time from starting the trial to the point at which the cancer starts to grow again or the patient dies, whichever comes first) in patients within different biomarker-defined subgroups (the treatment/placebo offered within each arm of the trial will be defined by specific molecular features of that individual patients tumour). Initially, patient urothelial tumour samples will be tested for Androgen Receptor (AR). Patients whose tumour is negative for AR will be offered the arm of the trial offering a drug called cabozantinib or placebo. The primary outcome will be PFS for patients for patients receiving each therapy. Further therapeutic arms (with additional options for treatment and molecular tumour testing) will be added in future throughout the trial. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this trial are to:
• Compare overall survival (OS) between the intervention arms and placebo arms for each component of the trial.
• Evaluate the safety and tolerability of enzalutamide and cabozantinib in this population.
• Compare the best response rate (RR, the proportion of patients whose tumours shrink whilst taking the trial medicine) between the intervention arm and placebo for each component of the trial.
• Compare the maximum reduction in the size of measurable tumourss between the study arms.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for ATLANTIS are as follows:
1 - Previously diagnosed stage IV urothelial cancer (UC) (T4b, Nany, Many; Tany, N1-3, M0; Tany, Nany, M1). 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.
2 - Able to commence the trial treatment within 10 weeks of completing chemotherapy.
3 - Adequate tissue for biomarker testing. Testing will occur centrally.
4 - 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.
5 - Adequate organ function as defined in drug specific appendices.
6 - ECOG performance status 0-2.
7 - Age ≥ 16 years.
8 -Female patients of childbearing potential must agree to comply with effective contraceptive measures, have been using adequate contraception since the last menses, will use adequate contraception during the trial, and have a negative pregnancy test within one week of trial entry.
9 -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.
10 - Written informed consent prior to admission to this trial.
11 -Meets all inclusion criteria for the relevant component subgroup listed in the appendices for each specific IMP. |
|
| E.4 | Principal exclusion criteria |
Exclusion creiteria for ATLANTIS are as follows:
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 scans 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 - Do not currently require second line chemotherapy in the opinion of the investigator.
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).
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 4 weeks prior to trial entry (palliative radiotherapy within >2 weeks 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure for this trial is progression free survival (PFS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 12 weeks for first 48 weeks, then every 16 weeks to 96 weeks then every 24 weeks thereafter until progression is documented or until the patient withdraws from follow up within the trial. |
|
| E.5.2 | Secondary end point(s) |
| The secondary endpoints of this trial are overall survival, response rate, maximum percentage decrease in measurable disease, safety and tolerability. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Overall survival, safety and tolerability will be recorded continuously until the end of the trial. Response rate and maximum percentage decrease in measurable disease will be recorded at the timepoints listed in 23-1 above. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 40 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
For the purpose of complying with UK Clinical Trials Regulations introduced in May 2004, the trial will be considered 'closed' when the follow-up point for the primary analysis of the final experimental arm has been reached. However, further observational follow-up of all patients enrolled in the trial will continue until all randomised patients have died.
This will initially be via the hospital, but in the longer term may employ national registers. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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