Durvalumab and Standard Chemotherapy Before Surgery in Treating Patients With Variant Histology Bladder Cancer

NCT03912818 | Terminated Phase 2 Results DMC FDA Drug

• 3 other identifiers: IRB-48062NCI-2019-01364BLDR0028
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies the side effects of durvalumab and chemotherapy before surgery in treating patients with variant histology bladder cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as methotrexate, vinblastine, doxorubicin, cisplatin, gemcitabine, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving durvalumab in addition to standard chemotherapy may lead to better outcomes in patients with variant histology bladder cancer.

Conditions

Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant; Bladder Adenocarcinoma; Bladder Mixed Adenocarcinoma; Bladder Squamous Cell Carcinoma; Bladder Urothelial Carcinoma; Infiltrating Bladder Urothelial Carcinoma With Giant Cells; Infiltrating Bladder Urothelial Carcinoma With Glandular Differentiation; Infiltrating Bladder Urothelial Carcinoma With Trophoblastic Differentiation; Infiltrating Bladder Urothelial Carcinoma, Clear Cell Variant; Infiltrating Bladder Urothelial Carcinoma, Micropapillary Variant; Infiltrating Bladder Urothelial Carcinoma, Nested Variant; Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant

Outcome Measures

Primary Outcomes (1)

• Incidence of Grade 3-5 Adverse Events

  Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The safety and tolerability of durvalumab in combination with chemotherapy in subjects with variant histology bladder cancer who initiate study treatment will be assessed as the number, by treatment cohort, of grade 3, 4, or 5 adverse events, considered probably or definitely related by the investigator.

  At 120 days

Secondary Outcomes (1)

• Proportion of Subjects Who Initiate Study Treatment and Achieve Tumor Stage of pT2 N0 M0 or Better (e.g., pT0, pT1 N0) at Cystectomy

  At 20 weeks

Study Arms (3)

Cohort II (durvalumab, cis-gem)

EXPERIMENTAL

Durvalumab (MEDI4736), at 1500 mg fixed dose, administered intravenously (IV) over 60 minutes. Standard chemotherapy will be administered as an IV infusion during each of the 4 cycles. Cisplatin 70 mg/m2 on Cycle Day 2, and gemcitabine 1,000 mg/m2 on Cycle Day 1 and Day 8 in 21 day cycles (3 weeks). Patients undergo cystectomy within 6 weeks.

Drug: Cisplatin; Procedure: Cystectomy; Biological: Durvalumab; Drug: Gemcitabine

Cohort III (Durvalumab, carbo-gem)

EXPERIMENTAL

Durvalumab (MEDI4736), at 1500 mg fixed dose, administered intravenously (IV) over 60 minutes. Standard chemotherapy will be administered as an IV infusion during each of the 4 cycles. Carboplatin: AUC 5 on Cycle Day 1 and gemcitabine 1,000 mg/m2 on Cycle Day 1 and Day 8 in 21 day cycles (3 weeks). Patients undergo cystectomy within 6 weeks.

Drug: Carboplatin; Procedure: Cystectomy; Biological: Durvalumab; Drug: Gemcitabine

Cohort I (durvalumab, DD MVAC)

EXPERIMENTAL

Durvalumab (MEDI4736), at1500 mg fixed dose, administered intravenously (IV) over 60 minutes. Standard chemotherapy will be administered as an IV infusion during each of the 4 cycles. Dose Dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin (DD MVAC), in 14 day cycles (2 weeks), Methotrexate 30 mg/m2 on Cycle Day 1, Vinblastine 3 mg/m2 on Cycle Day 2, Doxorubicin 30 mg/m2 on Cycle Day 2 and Cisplatin 70 mg/m2 on Cycle Day 2. Patients undergo cystectomy within 6 weeks.

Drug: Cisplatin; Procedure: Cystectomy; Drug: Doxorubicin; Biological: Durvalumab; Drug: Methotrexate; Drug: Vinblastine

Interventions

Carboplatin DRUG

Given IV

Also known as: Carboplat, Carboplatino, Carbosol, Paraplatin, Paraplatine

Cohort III (Durvalumab, carbo-gem)

Cisplatin DRUG

Given IV

Also known as: Abiplatin, Briplatin, Cis-platinum, Cismaplat, Citoplatino, Plastistil, Platinol

Cohort I (durvalumab, DD MVAC); Cohort II (durvalumab, cis-gem)

Cystectomy PROCEDURE

Undergo cystectomy

Cohort I (durvalumab, DD MVAC); Cohort II (durvalumab, cis-gem); Cohort III (Durvalumab, carbo-gem)

Doxorubicin DRUG

Given IV

Also known as: Adriablastin, Hydroxyl Daunorubicin, Rubex

Cohort I (durvalumab, DD MVAC)

Durvalumab BIOLOGICAL

Given IV

Also known as: Imfinzi, MEDI-4736

Cohort I (durvalumab, DD MVAC); Cohort II (durvalumab, cis-gem); Cohort III (Durvalumab, carbo-gem)

Gemcitabine DRUG

Given IV

Also known as: Difluorodeoxycytidine, Gemzar

Cohort II (durvalumab, cis-gem); Cohort III (Durvalumab, carbo-gem)

Methotrexate DRUG

Given IV

Also known as: Abitrexate, Amethopterin, Brimexate, Methotrexate Methylaminopterin, Metotrexato

Cohort I (durvalumab, DD MVAC)

Vinblastine DRUG

Given IV

Also known as: Vincaleucoblastine, Vinblastine Sulfate, vincaleukoblastine, sulfate

Cohort I (durvalumab, DD MVAC)

Eligibility Criteria

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

You may qualify if:

• Signed informed consent.
• Eastern Collaborative Oncology Group (ECOG) performance status score of 0 or 1.
• Body weight \> 30 kg.
• Absolute neutrophil count (ANC) \>= 1500 mm\^3 (within 28 days before the first study treatment).
• Hemoglobin \>= 9.0 g/dL (within 28 days before the first study treatment).
• Platelet count \>= 100,000 per mm\^3 (within 28 days before the first study treatment).
• Serum bilirubin =\< 1.5 X upper limit of normal (ULN) (within 28 days before the first study treatment). Subjects with Gilbert's syndrome will be considered after consultation with the principal investigator (PI).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 X ULN (within 28 days before the first study treatment).
• For subjects who will be treated with dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (DD MVAC) or cisplatin and gemcitabine (CG), creatinine clearance \>= 50 mL/min as measured based on Cockcroft-Gault glomerular filtration rate estimation (within 28 days before the first study treatment).
• For subjects who will be treated with carboplatin and gemcitabine (Carbo Gem), creatinine clearance \>= 30 mL/min as measured based on Cockcroft-Gault glomerular filtration rate estimation (within 28 days before the first study treatment).
• Anticipated life expectancy of \>= 12 weeks as assessed by the investigator.
• Histologically proven carcinoma of the bladder of variant urothelial carcinoma histologies which include squamous, adenocarcinoma, nested, plasmacytoid, micropapillary, glandular differentiation, lipid cell, clear cell, undifferentiated, giant cell, trophoblastic, sarcomatoid, carcinosarcoma; subjects with mixed cell types are eligible.
• Clinical T stage 2 (cT2) T4a, N0 N1, M0 disease. Clinical T stage is based on the transurethral resection of bladder tumor (TURBT) sample and imaging studies. Subjects must undergo cystoscopy and TURBT as part of screening within 30 days prior to registration.
• Abdominal/pelvic imaging by computed tomography (CT) or magnetic resonance imaging (MRI) scan; chest imaging by CT scan or x-ray (CT/positron emission tomography (PET) within 30 days prior to registration.
• Resting 12 lead electrocardiogram (ECG) documenting Fridericia's correction formula (QTcF) =\< 470 ms.

You may not qualify if:

• Prior treatment with systemic cytotoxic chemotherapy for muscle invasive bladder cancer (MIBC).
• Class III or IV heart failure, according to New York Heart Association Classifications. For patient on the dd MVAC or Cis-Gem arm, left ventricular ejection fraction of less than 50%
• Administration of an investigational therapeutic agent within 28 days of protocol registration.
• Current participation in a trial using an investigational agent. Subjects may participate in non-interventional, observational studies.
• Prior treatment with an anti-programmed cell death 1(PD1) or anti--programmed cell death ligand 1(PDL1) inhibitor including durvalumab.
• Receiving chronic systemic steroid therapy in dosing exceeding 10 mg daily of prednisone or equivalent per day within 7 days prior to the first dose of study treatment.
• History of another malignancy within 5 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Subjects with the following are allowed on study:
• 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.
• 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. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., 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 (e.g., CT scan premedication) or anti emetic during chemotherapy.
• History of allogenic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\]), diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc). The following are exceptions to this criterion:

Sponsors & Collaborators

• Stanford University: lead
• AstraZeneca: collaborator

Study Sites (1)

Stanford Cancer Institute Palo Alto

Palo Alto, California, 94304, United States

Location

MeSH Terms

Interventions

Carboplatin; Cisplatin; Cystectomy; Doxorubicin; durvalumab; Gemcitabine; Methotrexate; Vinblastine

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Urologic Surgical Procedures; Urogenital Surgical Procedures; Surgical Procedures, Operative; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines

Limitations and Caveats

The study did not achieve its planned enrollment size and did not achieve statistical power.

Results Point of Contact

• Title: Sandy Srinivas
• Organization: Stanford University

sandysri@stanford.edu

650-725-2078

Study Officials

• Sandy Srinivas

  Stanford Cancer Institute Palo Alto

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2019
• First Posted: April 11, 2019
• Study Start: April 10, 2019
• Primary Completion: August 11, 2022
• Study Completion: August 11, 2022
• Last Updated: September 11, 2023
• Results First Posted: September 11, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)