Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) in resectable urothelial bladder cancer

Phase 1

• Conditions: Resectable urothelial bladder cancer; MedDRA version: 20.0Level: PTClassification code 10005003Term: Bladder cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-002765-22-ES
• Lead Sponsor: Spanish Oncology Genitourinary Group - SOGUG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2018-07-25
• Last Update Posted: 10 September 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 29

Inclusion Criteria

1. Written informed consent obtained from the subject prior to performing any protocol- related procedures, including screening evaluations
2. Age =18 years at time of study entry
3. Subjects with histological confirmation of T2-T4a urothelial bladder by transurethral resection
4. Patients aimed for cystectomy without neoadjuvant chemotherapy
5. Tumor tissue (archival or recent acquisition) from diagnostic TUR must be available (block or 5 - 15 unstained slides of FFPE tissue) for correlative studies.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
Life expectancy of > 16 weeks
8. Body weight >30kg
9. Normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
- Haemoglobin > 10.0 g/dL with no blood transfusion in the past 28 days
- Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3)
- Platelet count = 100 x 109/L (>100,000 per mm3)
- 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 hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
- AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be = 5x ULN
- Serum creatinine CL>51 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal subjects within 28 days of study treatment and confirmed prior to treatment on day 1. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
11. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
12. Male patients and their partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception in combination [see appendix 2 for acceptable methods], throughout the period of taking study treatment and for 180 days after last dose of study drug(s) to prevent pregnancy in a partner. Female patients of child bearing potential and male patients with partners of child bearing potential, who are sexually active, must agree to the use of two highly effective forms of contraception throughout period of taking study treatment and for 1 month (female patients) / 3 months (male patients) after last dose of study drug. For details refer to Appendix 2 Acceptable Birth Control Methods.
13. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT/MRI and is suitable for repeated assessment.
14. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer must be available for central testing. If there is not confirmation of the availability of an archived tumour sample prior to enrolment the patient is not eligible for the study.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 9

Exclusion Criteria

1. Participation in another clinical study with an investigational product during the last 4 weeks
2. Concurrent enrolment in another clinical study, unless it is an observational (non- interventional) clinical study or during the follow-up period of an interventional study
3. Prior therapy with anti-PD-1, anti-PD-L1 including durvalumab, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (or any other antibody or drug specifically targeting T-cell co- stimulation or checkpoint pathways).
4. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) = 28 days prior to the first dose of study drug.
5. Resting ECG with QTc> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
6. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
7. Any unresolved toxicity NCI CTCAE Grade =1 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
8. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions is acceptable.
9. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
10. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP and patients must have recovered from any effects of any major surgery. Note: Local surgery (like the TURBT) of isolated lesions for palliative intent is acceptable.
11. Previous allogenic bone marrow transplant or double umbilical cord blood transplant (dUCBT).
12. Whole blood transfusions in the last 120 days prior to entry to the study.
13. Active or prior documented autoimmune or inflammatory disorders, diverticulitis, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome.
14. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non- malignant systemic disease or active, uncontrolled infection.
15. Past medical history of Interstitial Lung Disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
16. Subjects with uncontrolled adrenal insufficiency
17. Known drug or alcohol abuse
18. History of another primary malignancy
19. Patients with symptomatic uncontrolled brain metastases.
20. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus.
21. Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment.
22. Female subjects who are pregnant or breastfeeding or male or female subjects of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of study treatment.
23. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
24. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
25. Prisoners or subjects w

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified