Phase Ib/II Study of Concurrent Durvalumab And Radiation Therapy (DUART) Followed by Adjuvant Durvalumab in Patients With Urothelial Cancer (T2-4 N0-2 M0) of the Bladder: Big Ten Cancer Research Consortium BTCRC-GU15-023
Overview
- Phase
- Phase 1
- Intervention
- durvalumab
- Conditions
- Urothelial Cancer
- Sponsor
- Monika Joshi, MD
- Enrollment
- 26
- Locations
- 7
- Primary Endpoint
- Phase Ib: Safety Assessment - Evaluation of DLT (Dose Limiting Toxicity) Rate
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This is an open label, multi-institutional, single arm study of a phase Ib study, followed by a phase II study of durvalumab with radiation therapy (RT) in patients with urothelial cancer (UC). No randomization or blinding is involved.
Detailed Description
OUTLINE: This is a multi-center study. The phase Ib study will evaluate the safety of combining durvalumab with RT followed by adjuvant durvalumab. The phase II study will estimate the Progression Free Survival (PFS) and Disease Control Rate (DCR) with durvalumab plus RT followed by single agent durvalumab for patients with UC of bladder. PHASE Ib INVESTIGATIONAL TREATMENT: Cohort 1 will consist of up to 6 patients who will receive durvalumab 1500mg 2 doses Q4 weekly with RT to gross disease, 64.8 Gy, 36 fractions on weekdays over about 7 weeks. Durvalumab will be started on day 1; RT will be started on day 1 or 2. Three patients will be enrolled initially. If 2 or more patients (out of 3) experience dose-limiting toxicity (DLT), the combined treatment will be considered unsafe. Otherwise, an additional 3 patients will be treated at the same dose. If 0 or 1 patient experience DLT, the dose of durvalumab will be deemed safe for phase 2 part of the study. If, however, 2 or more patients (out of 6) experience DLT, the combined treatment will be considered unsafe. Post-concurrent durvalumab and RT, single agent durvalumab will be given1500mg every 4 weeks (±7 days) for a total period of up to 12 months. Adjuvant durvalumab treatment will be started 3-4 weeks post completion of durvalumab and RT. PHASE II INVESTIGATIONAL TREATMENT: Subjects will receive durvalumab 1500mg 2 doses Q4 weekly with RT to gross disease, 64.8 Gy, 36 fractions on weekdays over about 7 weeks. Durvalumab will start on Day 1. RT to start on Day 1 or 2. Post-concurrent durvalumab and RT, single agent durvalumab will be given1500mg every 4 weeks (±7 days) for a total period of up to 12 months. Adjuvant durvalumab monotherapy will be started 3-4 weeks post completion of durvalumab and RT. Life expectancy of \>6 months per treating physician. Adequate organ and marrow function as defined below: 1. Hemoglobin ≥ 9.0 g/dL 2. Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (\> 1500 per mm\^3) 3. Platelet count ≥ 100 x 10\^9/L (\>100,000 per mm\^3) 4. 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. 5. 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. 6. Serum creatinine CL\>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
Investigators
Monika Joshi, MD
M.D.
Big Ten Cancer Research Consortium
Eligibility Criteria
Inclusion Criteria
- •Phase Ib subjects must meet the following inclusion criteria:
- •Locally advanced urothelial cancer of bladder with any of the following:
- •T3-4, N0-2 M0, OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR medically unfit for surgery, OR cisplatin ineligible. T3 N0 M0 patients can be included if they are cisplatin ineligible.
- •Patients who have T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 post-neoadjuvant chemotherapy who become unresectable OR medically unfit for surgery.
- •Phase II subjects must meet the following inclusion criteria:
- •Locally advanced urothelial cancer of bladder with any of the following:
- •T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR medically unfit for surgery OR cisplatin ineligible. T3 N0 M0 patients can be included if they are cisplatin ineligible.
- •T3-4, N0-1 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 patients post-neoadjuvant chemotherapy who become unresectable OR medically unfit for surgery.
- •T2, N0, M0 who are ineligible to get cisplatin based chemotherapy.
- •All subjects:
Exclusion Criteria
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- •Participation in another clinical study with an investigational product within 2 weeks prior to registration.
- •Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.
- •Previous systemic immunotherapy. Previous use of intravesical BCG is acceptable.
- •History of another primary malignancy except for:
- •Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence. However adequately treated prostate cancer \>3 years ago with no significant change in PSA for past 6 months can be included. Patients with a history of prostate cancer must not have any definitive radiation therapy to prostate area.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- •Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ.
- •Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) within14 days prior to the first dose of study drug (14 days prior to the first dose of study drug for subjects who have received prior TKIs \[e.g., erlotinib, gefitinib and crizotinib\] and within 6 weeks for nitrosourea or mitomycin C).
- •Mean QT interval corrected for heart rate (QTc) ≥470 ms on electrocardiogram (ECG) using Frediricia's Correction.
Arms & Interventions
Arm A: Safety Run In Phase Ib
Subjects will receive durvalumab 1500mg Q4 weekly with RT to gross disease over 36 fractions. Durvalumab will start on Day 1. RT to start on Day 1 or 2. Subjects will receive adjuvant durvalumab monotherapy Q4 week, up to 12 months. Durvalumab monotherapy to start 4 weeks post completion of durvalumab and RT.
Intervention: durvalumab
Arm A: Safety Run In Phase Ib
Subjects will receive durvalumab 1500mg Q4 weekly with RT to gross disease over 36 fractions. Durvalumab will start on Day 1. RT to start on Day 1 or 2. Subjects will receive adjuvant durvalumab monotherapy Q4 week, up to 12 months. Durvalumab monotherapy to start 4 weeks post completion of durvalumab and RT.
Intervention: Radiation Therapy
Arm B: Investigational Treatment Phase II
Subjects will receive durvalumab 1500mg Q4 weekly with RT to gross disease over 36 fractions. Durvalumab will start on Day 1. RT to start on Day 1 or 2.. Subjects will receive adjuvant durvalumab monotherapy Q4 week, up to 12 months. Adjuvant durvalumab monotherapy to start 4 weeks post completion of durvalumab and RT.
Intervention: durvalumab
Arm B: Investigational Treatment Phase II
Subjects will receive durvalumab 1500mg Q4 weekly with RT to gross disease over 36 fractions. Durvalumab will start on Day 1. RT to start on Day 1 or 2.. Subjects will receive adjuvant durvalumab monotherapy Q4 week, up to 12 months. Adjuvant durvalumab monotherapy to start 4 weeks post completion of durvalumab and RT.
Intervention: Radiation Therapy
Outcomes
Primary Outcomes
Phase Ib: Safety Assessment - Evaluation of DLT (Dose Limiting Toxicity) Rate
Time Frame: Begin W1 and every 2 chemotherapy cycles (2 weeks) thereafter, for up to 2 years or until unacceptable toxicity.
To assess the safety of combining durvalumab with RT in that DLT rate is lower than than 33% based on CTCAEv4.0
All Phases: Progression Free Survival Rate at 1 Year
Time Frame: From C1D1 to Progression or until death for 1 year
Progression free survival rate at one year is defined as the probability that a patient remains free of progression of disease (SD+CR+PR) by modified RECIST 1.1 and cystoscopy at 1 year from the start of durvalumab treatment, D1 of durvaRT. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Phase II: Disease Control Rate to Concurrent durvaRT Followed by Durvalumab
Time Frame: From C1D1 until death or up to a maximum of 39 months.
The number of all subjects is reported with stable disease (SD) for 8 weeks, or partial response (PR), or complete response (CR) according to modified RECIST 1.1 and cystoscopy, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease(SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started;Disease Control Rate (DCR) = CR + PR+SD
Secondary Outcomes
- All Phases: DCR Post Completion of Concurrent durvaRT(From C1D1 until death or up to a maximum of 39 months)
- All Phases : Median Progression Free Survival (PFS) Time(From C1D1 to PD or until death or up to a maximum of 37 months.)
- Phase II: Complete Remission(From C1D1 until CR or death or up to a maximum of 39 months.)
- All Phases: Overall Survival(From C1D1 until death or 39 months.)