Urinary Bladder Neoplasms
Conditions
Keywords
Urinary Bladder Neoplasms
Brief summary
A Phase II, Randomized, Multi-Center, Double-Blind, Comparative Global Study to Determine the Efficacy and Safety of Durvalumab in Combination With Olaparib for First-Line Treatment in Platinum-Ineligible Patients With Unresectable Stage IV Urothelial Cancer
Detailed description
This is a Phase II, randomized, double-blind, placebo controlled, multi-center, comparative global study to determine the efficacy and safety of durvalumab + olaparib combination therapy versus durvalumab + placebo (durvalumab monotherapy) as first-line treatment in patients ineligible for platinum-based chemotherapy with unresectable Stage IV urothelial cancer (UC).
Interventions
DRUGDurvalumab
Durvalumab 1500 mg IV q4w
DRUGOlaparib
Olaparib PO 300 mg BID adjusted based on patient's creatinine clearance.
DRUGPlacebo
Matching placebo for oral tablet BID
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated, written ICF 2. Histologically or cytologically documented TCC/UC of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) also meeting the following: Unresectable, Stage IV disease; No prior systemic therapy for unresectable, Stage IV disease. 3. Ineligible for platinum-based chemotherapy defined as (i) in the opinion of the Investigator, unfit for carboplatin-based chemotherapy and (ii) meeting one of the following criteria: CrCl \<60 mL/min calculated by Cockcroft-Gault equation; Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 audiometric hearing loss (25 dB in 2 consecutive wave ranges); CTCAE Grade ≥2 peripheral neuropathy; New York Heart Association Class III heart failure; ECOG 2. 4. Known tumor HRR mutation status prior to randomization. 5. World Health Organization (WHO)/ECOG performance status of 0, 1, or 2. 6. Patients with at least 1 RECIST 1.1 target lesion at baseline. 7. Ability to swallow oral medications. 8. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients.
Exclusion criteria
1. Active or prior documented autoimmune or inflammatory disorders. 2. Other invasive malignancy within 5 years before the first dose of the IP. 3. Major surgical procedure within 28 days prior to the first dose 4. Brain metastases or spinal cord compression unless the patient's condition is stable and off steroid for at least 14 days 5. History of active primary immunodeficiency. 6. Active infection including tuberculosis (TB) 7. History of allogenic organ transplantation. 8. Uncontrolled intercurrent illness 9. Prior exposure to a PARP inhibitor or immune-mediated therapy. 10. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. 11. Current or prior use of immunosuppressive medication within 14 days before the first dose of the IP. 12. No radiation therapy is allowed, unless it is (1) definitive radiation that had been administered at least 12 months prior; (2) palliative radiation to the brain, with associated criteria for stability or lack of symptoms; or (3) palliative radiation to painful bony lesions (this must comprise less than 30% of the bone marrow) or symptomatic pelvic soft tissue mass(es). 13. Receipt of live attenuated vaccine within 30 days prior to the first dose of the IP. 14. Patients with a known hypersensitivity to durvalumab, olaparib, or any of the excipients of the products. 15. 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 durvalumab and 6 months for participants taking also Olaparib in case of female participants, 90 days after receipt of the last dose of the IP in case of male participants.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Assessments performed at baseline and every 8 weeks from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), assessed up to the data cut-off date (15 Oct 2020), up to a max. of 31 months | Progression-free survival based on investigator assessments according to RECIST 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From the date of randomization until the death due to any cause, assessed up to the data cut-off date (15 October 2020), to a maximum of 31 months | Number of Participants with Overall Survival (OS), where OS was defined as the time from the date of randomization until death due to any cause. |
| Objective Response Rate (ORR) | From the date of randomization to the date of progression or the last evaluable assessment in the absence of progression, assessed up to the data cut-off date (15 October 2020), to a maximum of 31 months | ORR (per RECIST 1.1 using Investigator assessments) is defined as the number (%) of patients with at least 1 visit response of complete response (CR) or partial response (PR). CR was defined as the disappearance of all target and non-target lesions; PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters |
| Duration of Response (DoR) | Tumor assessments every 8 weeks after randomization for the first 48 weeks and then every 12 weeks thereafter until the date of objective disease progression. Assessed up to the data cut-off date (15 October 2020), to a maximum of 31 months | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression |
Countries
Canada, Russia, South Korea, Spain, Taiwan, United States, Vietnam
Contacts
PRINCIPAL_INVESTIGATORJonathan Rosenberg, MD
Memorial Sloan Kettering Cancer Center
STUDY_DIRECTORMark Lanasa, MD
One MedImmune Way,Gaithersburg,Maryland,United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Durva + Olaparib Patients received a combination of durvalumab 1500mg intravenous (IV) every 4 weeks (q4w) with olaparib 300mg orally (PO) twice daily (BID) adjusted based on patient's creatinine clearance | 78 |
| Durva + Placebo Patients received durvalumab 1500mg IV q4w and placebo PO BID | 76 |
| Total | 154 |
Baseline characteristics
| Characteristic | Durva + Placebo | Total | Durva + Olaparib |
|---|---|---|---|
| Age, Continuous | 70.2 Years STANDARD_DEVIATION 10.26 | 71.9 Years STANDARD_DEVIATION 10.62 | 73.4 Years STANDARD_DEVIATION 10.8 |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 73 Participants | 148 Participants | 75 Participants |
| Sex: Female, Male Female | 21 Participants | 43 Participants | 22 Participants |
| Sex: Female, Male Male | 55 Participants | 111 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 52 / 78 | 46 / 76 |
| other Total, other adverse events | 65 / 76 | 63 / 76 |
| serious Total, serious adverse events | 37 / 76 | 26 / 76 |
Outcome results
Primary
Progression-free Survival (PFS)
Progression-free survival based on investigator assessments according to RECIST 1.1
Time frame: Assessments performed at baseline and every 8 weeks from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), assessed up to the data cut-off date (15 Oct 2020), up to a max. of 31 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Durva + Olaparib | Progression-free Survival (PFS) | 4.2 Months |
| Durva + Placebo | Progression-free Survival (PFS) | 3.5 Months |
p-value: 0.78995% CI: [0.641, 1.387]Regression, Cox
Secondary
Duration of Response (DoR)
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression
Time frame: Tumor assessments every 8 weeks after randomization for the first 48 weeks and then every 12 weeks thereafter until the date of objective disease progression. Assessed up to the data cut-off date (15 October 2020), to a maximum of 31 months
Population: Duration of Response (DoR) was calculated for all responders (N=36)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Durva + Olaparib | Duration of Response (DoR) | 8.9 Months |
| Durva + Placebo | Duration of Response (DoR) | 14.8 Months |
Secondary
Objective Response Rate (ORR)
ORR (per RECIST 1.1 using Investigator assessments) is defined as the number (%) of patients with at least 1 visit response of complete response (CR) or partial response (PR). CR was defined as the disappearance of all target and non-target lesions; PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters
Time frame: From the date of randomization to the date of progression or the last evaluable assessment in the absence of progression, assessed up to the data cut-off date (15 October 2020), to a maximum of 31 months
Population: Full analysis set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Durva + Olaparib | Objective Response Rate (ORR) | Response | 22 Participants |
| Durva + Olaparib | Objective Response Rate (ORR) | No Response | 56 Participants |
| Durva + Placebo | Objective Response Rate (ORR) | Response | 14 Participants |
| Durva + Placebo | Objective Response Rate (ORR) | No Response | 62 Participants |
p-value: 0.14295% CI: [0.821, 3.778]Regression, Logistic
Secondary
Overall Survival (OS)
Number of Participants with Overall Survival (OS), where OS was defined as the time from the date of randomization until death due to any cause.
Time frame: From the date of randomization until the death due to any cause, assessed up to the data cut-off date (15 October 2020), to a maximum of 31 months
Population: Full analysis set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Durva + Olaparib | Overall Survival (OS) | Died | 52 Participants |
| Durva + Olaparib | Overall Survival (OS) | Censored (includes subjects with unknown survival status or subjects who were lost to follow up) | 26 Participants |
| Durva + Placebo | Overall Survival (OS) | Died | 46 Participants |
| Durva + Placebo | Overall Survival (OS) | Censored (includes subjects with unknown survival status or subjects who were lost to follow up) | 30 Participants |
p-value: 0.72895% CI: [0.719, 1.606]Regression, Cox