Study of First Line MEDI4736 with or without Tremelimumab versus Standard of Care Chemotherapy in Advanced Unresectable Urothelial Cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Dec 2015 → 15 Apr 2025

Decision date (initial)

2025-01-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2024-513399-17-00

EudraCT number

2015-001633-24

ClinicalTrials.gov

NCT02516241

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Safety, Pharmacodynamic, Pharmacogenetic, Efficacy

1. To assess the efficacy of MEDI4736 + tremelimumab combination therapy versus SoC in terms of OS in patients with unresectable Stage IV UC;
2. To assess the efficacy of MEDI4736 monotherapy versus SoC in terms of OS in patients with unresectable Stage IV PD L1 High UC

Secondary objectives 1

1. 1. To assess the efficacy of MEDI4736 monotherapy compared to SoC in terms of PFS in patients with PD-L1-High UC. 2. To assess the efficacy of MEDI4736 + tremelimumab combination therapy versus SoC in terms of PFS in patients with UC. 3. To assess the efficacy of MEDI4736 monotherapy compared to SoC in terms of PFS and OS in patients with UC. 4. To assess the efficacy of MEDI4736 + tremelimumab combination therapy compared to SoC in terms of PFS and OS in patients with PD-L1-Low/Neg UC. 5. To assess the efficacy profile of MEDI4736 monotherapy in patients who are not cisplatin-eligible. 6. To further assess the efficacy of MEDI4736 + tremelimumab combination therapy compared to MEDI4736 monotherapy in terms of PFS, OS, OS24, APF12, ORR, DoR, DCR, and PFS2 in patients with PDL1-Low/Neg UC and all patients with UC. 7. To further assess the efficacy of MEDI4736 + tremelimumab combination therapy compared to SoC in terms of OS24, APF12, ORR, DoR, DCR, and PFS2 in patients with UC. 8. To further assess the efficacy of MEDI4736 monotherapy compared to SoC in terms of OS24, APF12, ORR, DoR, DCR, and PFS2 in patients with PD-L1-High UC. 9. To further assess the efficacy of MEDI4736 monotherapy compared to SoC in terms of OS24, APF12, ORR, DoR, DCR, and PFS2 in patients with UC. 10. To further assess the efficacy of MEDI4736 + tremelimumab combination therapy compared to SoC in terms of OS24, APF12, ORR, DoR, DCR, and PFS2 in patients with PD-L1-Low/Neg UC. 11. To further assess the efficacy of MEDI4736 + tremelimumab combination therapy compared to SoC in patients with PD-L1-High UC. 12. To assess disease-related symptoms and HRQoL in UC patients treated with MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy compared with SoC and each other using the FACT-BL questionnaire. 13. To assess the PK of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy. 14. To investigate the immunogenicity of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy.

Conditions and MedDRA coding

Adult patients (age ≥18 years) with histologically or cytologically documented transitional cell carcinoma (transitional cell and mixed transitional/non transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra), unresectable Stage IV, and who are chemotherapy-naïve.

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. 1. Age ≥18 years at the time of screening; 2. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. (For patients aged <20 years and enrolling in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.) 3.Patients with histologically or cytologically documented, unresectable, Stage IV (ie, T4b, any N; or any T, N2-N3 (Note: The Investigators will use their discretion to confirm the cause of N2 disease [reactive or inflammatory]); or M1) transitional cell carcinoma transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) (see NCCN Bladder Cancer Guidelines), who have not been previously treated with first-line chemotherapy. (Patients who have received prior definitive chemoradiation, adjuvant or neoadjuvant treatment for locally advanced disease, are eligible, provided that progression to Stage IV disease has occurred >6 months from last therapy [for chemoradiation and adjuvant treatment] r >6 months from last surgery [for neoadjuvant treatment].) 4. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis ≥15 mm) with a computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurements as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) guidelines. 5. Eastern Cooperative Oncology Group (ECOG) PS 0 or 1 6. Life expectancy ≥12 weeks (in the opinion of the Investigator) 7. Patients eligible or ineligible for cisplatin-based chemotherapy. Cisplatin ineligibility is defined as meeting one of the following criteria: - Creatinine clearance (CrCl) <60 mL/min calculated by Cockcroft-Gault equation (using actual body weight; see Appendix A) or by measured 24-hour urine collection. (In cases where both are performed, measured 24-hour urine collection will be used to determine eligibility, providing an adequate collection was performed.)*; - Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 audiometric hearing loss; - CTCAE Grade ≥2 peripheral neuropathy; - New York Heart Association ≥Class III heart failure 8. Tumor PD-L1 status, with IHC assay confirmed by a reference laboratory, must be known prior to randomization. As such, all patients must be able to provide a newly acquired tumor biopsy during screening (preferred) or provide an available tumor sample taken ≤3 years prior to screening. Tumor lesions used for newly acquired biopsies should not be target lesions, unless there are no other lesions suitable for biopsy. Samples with limited tumor content and fine needle aspirate specimens are not acceptable. Specimens from metastatic bone lesions are typically unacceptable unless there is a significant soft tissue component. The tumor specimen submitted to establish PD-L1 status should be of sufficient quantity to allow for PD-L1 IHC and other exploratory biomarker analyses and is preferred in formalin-fixed paraffin embedded blocks.
2. 9. Adequate organ and marrow function as defined below: - Hemoglobin ≥9 g/dL; - Absolute neutrophil count ≥1500/mm3; - Platelet count ≥100000/mm3; - Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician and AstraZeneca; - ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT, and AST ≤5 × ULN; - CrCl ≥30 mL/min calculated by Cockcroft-Gault equation (using actual body weight; see Appendix A) or by measured 24-hour urine collection for determination. (In cases where both are performed, measured 24-hour measured urine collection will be used to determine eligibility, providing an adequate collection was performed.) 10. Evidence of postmenopausal status or negative urinary or serum pregnancy test for female premenopausal patients. Women will be considered postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: - Women <50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy); - Women ≥50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments , had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

Exclusion criteria 3

1. "1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca/MedImmune staff and/or staff at the study site); 2. Previous investigational product (IP) assignment in the present study; 3. Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study; 4. Prior exposure to immune-mediated therapy (with exclusion of Bacillus Calmette Guerin), including but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines. Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days prior to the initiation of study treatment. 5. Any unresolved toxicity National Cancer Institute (NCI) CTCAE Version 4.03 Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: - Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with AstraZeneca; - Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with MEDI4736 or tremelimumab may be included after consultation with AstraZeneca 6. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. Note: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable (eg, local surgery or radiotherapy). 7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 28 days of the first dose of study drug 8. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 9. History of allogenic organ transplantation that requires use of immunosuppressive agents 10. Active or prior documented autoimmune or inflammatory disorders (including but not limited to inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, Wegener syndrome [granulomatosis with polyangiitis], Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc). The following are exceptions to this criterion: - Patients with vitiligo or alopecia; - Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement; - Any chronic skin condition that does not require systemic therapy; - Patients without active disease in the last 3 years may be included but only after consultation with AstraZeneca; - Patients with celiac disease controlled by diet alone may be included but only after consultation with AstraZeneca. 11. Uncontrolled intercurrent illnesses, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, uncontrolled diabetes, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
2. 12. Other malignancy within 5 years before first dose of IP, except for the following pending a discussion with AstraZeneca: - Patients with a history of prostate cancer (tumor/node/metastasis stage) of stage ≤T2cN0M0 without biochemical recurrence or progression and who in the opinion of the Investigator are not deemed to require active intervention; - Patients who have been adequately treated for a malignancy with a low potential risk for recurrence (eg, cervical carcinoma in situ, non-melanomatous carcinoma of the skin, or ductal carcinoma in situ of the breast that has been surgically cured) 13. History of leptomeningeal carcinomatosis 14. Brain metastases or spinal cord compression unless the patient’s condition is stable (asymptomatic, no evidence of new or emerging brain metastases) and off steroids for at least 14 days prior to the start of study treatment. Patients with suspected or known brain metastases at screening should have an MRI (preferred)/CT, preferably with IV contrast to access baseline disease status. 15. QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms calculated. Any clinically significant abnormalities detected require triplicate ECG results and a mean QTcF ≥470 ms calculated from 3 ECGs obtained over a brief period (eg, 30 minutes). 16. History of active primary immunodeficiency 17. Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B, hepatitis C, or human immunodeficiency virus (HIV, positive HIV 1 or 2 antibodies). Active hepatitis B virus (HBV) infection is defined by a positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core IgG antibody and the absence of HBsAg, deoxyribonucleic acid [DNA] negative) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
3. 18. Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion: - Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection); - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent; - Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) 19. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP. 20. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of MEDI4736 monotherapy or 180 days after the last dose of MEDI4736 + tremelimumab combination therapy 21. Known allergy or hypersensitivity to IP or any IP excipient, or to other humanized mAbs 22. Any medical contraindication to platinum (cisplatin or carboplatin)-based doublet chemotherapy 23. Patient <30 kg in weight

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. overall survival (OS)

Secondary endpoints 1

1. "1. Progression-free survival (PFS); 2. OS24; 3. Proportion of patients alive and progression-free at 12 months; 4. Objective response rate; 5. Duration of response; 6. Disease control rate; 7. Best objective response; 8. Time from randomization to second progression"

Investigational products

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

Test 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

2 EU/EEA countries · 2 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 13 files

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

Application history

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