Durvalumab And Radiation Therapy Followed by Adjuvant Durvalumab in Patients With Urothelial Cancer (T2-4 N0-2 M0) of the Bladder

NCT02891161 | Terminated Phase 1 Results DMC

• 1 other identifier: BTCRC-GU15-023
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 7

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.

Conditions

Urothelial Cancer

Keywords

durvalumab; MEDI4736; anti-PD-L1

Outcome Measures

Primary Outcomes (3)

• Phase Ib: Safety Assessment - Evaluation of DLT (Dose Limiting Toxicity) Rate

  To assess the safety of combining durvalumab with RT in that DLT rate is lower than than 33% based on CTCAEv4.0

  Begin W1 and every 2 chemotherapy cycles (2 weeks) thereafter, for up to 2 years or until unacceptable toxicity.

• All Phases: Progression Free Survival Rate at 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

  From C1D1 to Progression or until death for 1 year

• Phase II: Disease Control Rate to Concurrent durvaRT Followed by Durvalumab

  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

  From C1D1 until death or up to a maximum of 39 months.

Secondary Outcomes (4)

• 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.

Study Arms (2)

Arm A: Safety Run In Phase Ib

EXPERIMENTAL

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.

Drug: durvalumab; Radiation: Radiation Therapy

Arm B: Investigational Treatment Phase II

EXPERIMENTAL

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.

Drug: durvalumab; Radiation: Radiation Therapy

Interventions

durvalumab DRUG

1500 mg Q4 weekly

Arm A: Safety Run In Phase Ib; Arm B: Investigational Treatment Phase II

Radiation Therapy RADIATION

64.8 Gy, 36 daily fractions on weekdays over about 7 weeks

Also known as: RT

Arm A: Safety Run In Phase Ib; Arm B: Investigational Treatment Phase II

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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:
• Written informed consent and HIPAA authorization for personal health information, obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Life expectancy of \>6 months per treating physician.
• Subjects must have archival tissue available from previous TURBT (preferred) or lymph node core biopsy within 8 weeks of treatment or be assessed by the treating urologist to undergo maximal TURBT. The extent of TURBT may vary for each patient and will be determined by the treating urologist. Further, the treating urologist will decide if performing the TURBT is clinically appropriate. If the potential subject does not have tumor amenable to biopsy, there is insufficient tissue for PD-L1 testing or is not clinically appropriate for TURBT, enrollment must be discussed with the sponsor-investigator on a case by case basis.
• Histologically proven urothelial carcinoma of bladder with predominant transitional cell component. Adenocarcinoma, squamous cell differentiation, or other atypical histology (such as plasmacytoid or sarcomotoid) of the bladder will be allowed on the study, provided they form \<50% of the histology
• Females of childbearing potential must have a negative urine and serum pregnancy test within 3 days of study registration.
• NOTE: Female subjects are considered of child bearing potential unless they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are ≥60 years old and naturally postmenopausal for at least 12 consecutive months.

You may not qualify if:

• 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.
• 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.
• Any unresolved toxicity (\>CTCAE grade 2) from previous anti-cancer therapy. (Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripheral neuropathy).
• Any prior Grade ≥3 Immune-mediated adverse event (imAE) while receiving any previous immunotherapy agent, or any unresolved imAE \>Grade 1.
• Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Patients with h/o completely resolved childhood asthma or atopy will not be excluded. Patients with well-controlled hypothyroidism on thyroxine replacement will be eligible as well.
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).

Sponsors & Collaborators

• Monika Joshi, MD: lead
• AstraZeneca: collaborator

Study Sites (7)

University of Iowa Hospital and Clinics

Iowa City, Iowa, 52242, United States

Location

Nebraska Methodist Hospital

Omaha, Nebraska, 68114, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

Montefiore Medical Center

The Bronx, New York, 10641, United States

Location

Penn State Cancer Intsitute

Hershey, Pennsylvania, 17033, United States

Location

University of Wisconsin

Madison, Wisconsin, 53705, United States

Location

Froedtert & The Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Joshi M, Tuanquin L, Zhu J, Walter V, Schell T, Kaag M, Kilari D, Liao J, Holder SL, Emamekhoo H, Sankin A, Merrill S, Zheng H, Warrick J, Hauke R, Gartrel B, Stein M, Drabick J, Degraff DJ, Zakharia Y. Concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: results from phase II study, BTCRC-GU15-023. J Immunother Cancer. 2023 Feb;11(2):e006551. doi: 10.1136/jitc-2022-006551.

  PMID: 36822667 DERIVED

Related Links

• Big Ten Cancer Research Consortium Website

MeSH Terms

Interventions

durvalumab; Radiotherapy

Intervention Hierarchy (Ancestors)

Therapeutics

Results Point of Contact

• Title: Annesha Majumdar
• Organization: Hoosier Cancer Research Network

amajumdar@hoosiercancer.org

3179212050

Study Officials

• Monika Joshi, MD, MRCP

  Penn State Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: M.D.

Study Record Dates

• First Submitted: September 1, 2016
• First Posted: September 7, 2016
• Study Start: November 16, 2016
• Primary Completion: August 6, 2019
• Study Completion: April 27, 2022
• Last Updated: November 27, 2024
• Results First Posted: November 27, 2024

Record last verified: 2024-11

Locations

US (7)