DISCUS: A Randomised Phase II Study Comparing 3 vs 6 Cycles of Platinum-based Chemotherapy Prior to Maintenance Avelumab in Advanced Urothelial Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Queen Mary University Of London

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Apr 2022 → ongoing

Decision date (initial)

2024-11-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Healthcare KGaA

External identifiers

EU CT number

2024-518244-20-01

EudraCT number

2021-001975-17

ISRCTN

ISRCTN15750433

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the effect of 3 vs 6 cycles platinum-based, front-line chemotherapy followed by maintenance avelumab based on patient-reported outcomes (PROs) in the study population.

Secondary objectives 4

1. 1. To evaluate the effect of 3 vs 6 cycles platinum-based, front-line chemotherapy followed by maintenance avelumab based on additional patient-reported outcomes (PROs) in the study population.
2. 2. To evaluate the effect of 3 vs 6 cycles platinum-based, front-line chemotherapy followed by maintenance avelumab based on clinician reported outcomes.
3. 4. To assess the efficacy of 3 vs 6 cycles platinum based, front-line chemotherapy followed by maintenance avelumab in patients with advanced UC.
4. 3. To evaluate the safety and tolerability of 3 vs 6 cycles of platinum-based, front-line chemotherapy followed by maintenance avelumab therapy.

Conditions and MedDRA coding

Urothelial Carcinoma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. Willing and able to provide written informed consent.
2. 2. Ability to comply with the protocol, including but not limited to, the repeated completion of the EORTC QLQ-C30 questionnaires.
3. 3. Age ≥ 18 years.
4. 4. Histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous or sarcomatoid differentiation or mixed cell types are eligible but a component of urothelial cancer is required.
5. 5. Measurable disease by RECIST v1.1.
6. 6. Eligible for gemcitabine/ cisplatin or gemcitabine/carboplatin. Patients meeting any of the following criteria or considered ineligible for cisplatin as per investigator discretion, should be considered for gemcitabine/carboplatin (as per local standard practice): a. GFR <60 mL/min (measured by the Cockcroft-Gault formula or by local accepted standards). Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgement. Subjects are required to have a GFR ≥30 mL/min (measured by the Cockcroft-Gault formula or by local accepted standards) to receive carboplatin. b. ECOG or WHO performance status of 2. c. NCI CTCAE Grade ≥2 audiometric hearing loss. d. NYHA Class III heart failure.
7. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.
8. 8. Adequate haematologic and organ function as defined below: a. Haemoglobin ≥ 9.0g/dL b. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500/µL) without growth factor support c. Platelet count ≥ 100 x 109 /L (≥100,000/µL) d. Total serum bilirubin ≤1.5 x institutional upper limit of normal (ULN) (this will not apply to subjects with confirmed Gilbert’s syndrome [persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology], who will be allowed only in consultation with their physician. e. Serum transaminases (AST/ALT) ≤2.5 x the institutional ULN with the following exception in patients with documented liver metastases: AST and/or ALT ≤5 × ULN f. GFR ≥30mL/min measured by Cockcroft-Gault formula, or locally accepted standards.
9. 9. Negative serum or urine pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential only. Non-childbearing potential is defined as either: a. Postmenopausal ≥ 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments OR b. Documented irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation OR c. <50 years of age who have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels within local institution postmenopausal ranges
10. 10. Agreement to use adequate contraceptive measures (Refer to section 11.30 for full details).
11. FRANCE SPECIFIC CRITERIA: 11. Patients affiliated to the social security system.

Exclusion criteria 28

1. 1. Prior treatment with a PD-(L)-1 inhibitor for any advanced malignancy. Treatment with PD-(L)-1 inhibitors in the neoadjuvant or adjuvant setting for UC are permitted.
2. 2. Prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: a platinum containing regimen (cisplatin or carboplatin) in the neoadjuvant or adjuvant setting if more than 6 months since last cycle have occurred. Patients who received adjuvant or neoadjuvant immune therapy for muscle invasive or non-muscle invasive disease are eligible.
3. 3. Pregnant and lactating female patients.
4. 4. Known history of active CNS metastases. Patients with treated CNS metastases are permitted on the study if all of the following are true: a. CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b. the subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks prior to C1D1 (if requiring steroid treatment); c. subject does not have leptomeningeal disease.
5. 5. Prior allogeneic stem cell or solid organ transplantation.
6. 6. Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study.
7. 7. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment (see section 11.26).
8. 8. Concurrent treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment.
9. 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, or superior vena cava syndrome).
10. 10. Malignancies other than urothelial carcinoma within 3 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive).
11. 11. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction or cerebral vascular accident/stroke within 6 months prior to enrolment, unstable arrhythmias, or unstable angina.
12. 12. Radiotherapy within 2 weeks prior to C1D1. Patients must have recovered adequately from toxicities resulting from the intervention prior to starting study treatment.
13. 13. Major surgery (defined as requiring general anaesthesia and >24-hour inpatient hospitalization) within 4 weeks prior to randomisation. Patients must have recovered adequately from complications from the intervention prior to starting study treatment.
14. 14. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).
15. 15. Active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.
16. 16. Positive HIV test.
17. 17. Active tuberculosis.
18. 18. Active autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
19. 19. History of autoimmune-related hypothyroidism, unless on a stable dose of thyroid replacement hormone.
20. 20. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies.
21. 21. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of avelumab.
22. 22. Active infection requiring systemic therapy.
23. 23. Persisting toxicity related to prior therapy (NCI CTCAE Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator’s judgment are acceptable.
24. 24. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
25. 25. Participants with previous or known history of allergic reaction to cisplatin, gemcitabine, carboplatin or other platinum containing compounds, or any component of the chemotherapy formulations.
26. 26. Patients with bleeding tumours
27. 27. Any other contraindication for gemcitabine/ cisplatin or gemcitabine/carboplatin treatment as per SmPC.
28. France Specific Criteria: 28. Person deprived of their liberty or under protective custody or guardianship.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in GHS/QoL scale scores from baseline to completion of 6 cycles of treatment. Patients who withdraw from treatment between Cycles 4 and 6 will be included, provided an EORTC QLQ-C30 questionnaire is completed within 14 days from the date of withdrawal.

Secondary endpoints 11

1. • Quality of Life assessment from baseline to the completion of 10 Cycles of treatment using the GHS/QOL scale score, as per the primary endpoint methodology.
2. • Quality of Life assessment from the beginning of cycle 5 to the completion of 10 Cycles of treatment using the GHS/QOL scale score, as per the primary endpoint methodology.
3. • Change in GHS/QOL scale scores from baseline to the end of assessment (wk54), as per the primary endpoint methodology.
4. • GHS/QoL scale score time to deterioration (TTD), where deterioration in the GHS/QoL scale score is defined as a decrease by ≥10 points at any time point after baseline with no subsequent observations with a <10 point decrease from baseline.
5. • Change in the GHS/QOL scale score from baseline as per the primary endpoint, but adjusted for baseline imbalances in GHS/QOL scale scores.
6. Performance status as measured by the Karnofsky Scale on completion of 6 cycles of treatment.
7. • Incidence, nature and severity of adverse events graded according to NCI-CTCAE v5.0 at the following timepoints: o Throughout treatment o On completion of Cycle 6 of treatment o Between Cycle 4 and the completion of Cycle 10. • Treatment discontinuation rate due to AEs.
8. Overall response rate in each randomised treatment arm defined as the proportion of patients who achieved complete response (CR) or partial response (PR) according to RECIST v1.1 recorded from randomisation until week 20. (investigator assessed unconfirmed best response)
9. Progression free survival rate at 20 weeks post randomisation (PFS rate) in each treatment arm defined as the proportion of patients who did not experience disease progression or death from any cause according to RECIST v1.1 recorded from randomisation until week 20.
10. Duration of response defined as the time from first documentation of CR or PR to disease progression (RECIST v1.1) or death from any cause, whichever occurs first.
11. Overall survival (OS), defined as the time between the date of randomisation and death due to any cause.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Queen Mary University Of London

Sponsor organisation

Queen Mary University Of London

Address

327 Mile End Road

City

London

Postcode

E1 4NS

Country

United Kingdom

Scientific contact point

Organisation

Queen Mary University Of London

Contact name

Dr. Mays Jawad

Public contact point

Organisation

Queen Mary University Of London

Contact name

Dr. Mays Jawad

Locations

2 EU/EEA countries · 32 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 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications