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Bladder AdenocarcinomaPhase 2NCT03912818

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

A Phase 2 study testing Carboplatin, Cisplatin and Cystectomy in people with Bladder Adenocarcinoma and Bladder Mixed Adenocarcinoma, run by Stanford University at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Carboplatin, Cisplatin and Cystectomy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
7 participants
Where
1 siteUnited States
Study dates
10 Apr 2019to 11 Aug 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).
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  • 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.
  • Consent to provide a formalin fixed paraffin embedded (FFPE) tissue block and 1 hematoxylin and eosin (H and E) slide (preferred) or one of the following:
  • 10 unstained slides and 1 H and E slide OR
  • Tissue block punches and 1 H and E slide, OR
  • 4 to 6 cores and 1 H and E slide.
  • Willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations including follow up.
  • For female subjects:
  • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation induced menopause with last menses > 1 year ago, had chemotherapy induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

Who cannot join

  • 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.
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  • 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:
  • Subjects with vitiligo or alopecia
  • Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Subjects with celiac disease controlled by diet alone.
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events (AEs) or compromise the ability of the subject to give written informed consent.
  • History of active primary immunodeficiency.
  • Active infection including:
  • Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice)
  • Hepatitis B (known positive hepatitis B virus (HBV) surface antigen (HBsAg) result)
  • Hepatitis C
  • Human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies).
  • Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody (anti HBc) and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of study medication. Note: subjects, if enrolled, should not receive live vaccine while receiving study medication and up to 30 days after the last dose of study medication.
  • Pregnant or lactating.
  • Male or female subject of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
  • Known allergy or hypersensitivity to any of the study medications or any of the study medication excipients.
  • Judgment by the investigator that the subject is unsuitable to participate in the study and the subject is unlikely to comply with study procedures, restrictions and requirements.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Stanford Cancer Institute Palo Alto

    Palo Alto, California, 94304

Other trials in United States

About this study

Official title: Phase 2 Open Label Study of Durvalumab With Neoadjuvant Chemotherapy in Variant Histology Bladder Cancer

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To assess the safety and tolerability of durvalumab in combination with chemotherapy in subjects with variant histology bladder cancer.

SECONDARY OBJECTIVES:

  1. To determine the percent of subjects post-neoadjuvant chemo-immunotherapy who achieve tumor stage of pT2 N0 M0 or better (pT1 N0 or pT0) at cystectomy.

II. To assess the response rate (RR) in post-neoadjuvant chemo immunotherapy as assessed by the investigator using imaging at screening and post treatment.

III. To assess the molecular characterization of tumor tissue pre-neoadjuvant therapy and at post treatment cystectomy (for subject who have persistent disease).

IV. To determine circulating free deoxyribonucleic acid (DNA) (cfDNA) (cell free DNA) at baseline, during treatment and following post treatment cystectomy using Natera sequencing platform.

OUTLINE: Patients are assigned to 1 of 3 cohorts.

COHORT I: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1. Chemotherapeutic agents will be administered as an IV infusion according to prescribing information or treatment guidance in general use by the Investigating site. Methotrexate on day 1, vinblastine IV on day 2, doxorubicin IV on day 2, and cisplatin IV on day 2. Cycles repeat every 14 days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy within 6 weeks.

COHORT II: Patients receive durvalumab IV over 60 minutes on day 1. Chemotherapeutic agents will be administered as an IV infusion according to prescribing information or treatment guidance in general use by the Investigating site. Cisplatin IV over 60 minutes on day 1, and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy within 6 weeks.

COHORT III: Patients receive durvalumab IV over 60 minutes on day 1.Chemotherapeutic agents will be administered as an IV infusion according to prescribing information or treatment guidance in general use by the Investigating site. Carboplatin IV on day 1, and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy within 6 weeks.

After surgery, patients are followed up at 30 and 90 days.

Being tested
Carboplatin, Cisplatin, Cystectomy, Doxorubicin, Durvalumab

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CarboplatinDrug

    Also called Carboplat, Carboplatino, Carbosol, Paraplatin

    Given IV

  • CisplatinDrug

    Also called Abiplatin, Briplatin, Cis-platinum, Cismaplat

    Given IV

  • CystectomyProcedure or surgery

    Undergo cystectomy

  • DoxorubicinDrug

    Also called Adriablastin, Hydroxyl Daunorubicin, Rubex

    Given IV

  • DurvalumabBiological

    Also called Imfinzi, MEDI-4736

    Given IV

  • GemcitabineDrug

    Also called Difluorodeoxycytidine, Gemzar

    Given IV

  • MethotrexateDrug

    Also called Abitrexate, Amethopterin, Brimexate, Methotrexate Methylaminopterin

    Given IV

  • VinblastineDrug

    Also called Vincaleucoblastine, Vinblastine Sulfate, vincaleukoblastine, sulfate

    Given IV

Study groups in NCT03912818
Study groupRoleWhat they receive
Cohort II (durvalumab, cis-gem)ExperimentalDurvalumab (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.
Receives: Drug: Cisplatin; Procedure: Cystectomy; Biological: Durvalumab; Drug: Gemcitabine
Cohort III (Durvalumab, carbo-gem)ExperimentalDurvalumab (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.
Receives: Drug: Carboplatin; Procedure: Cystectomy; Biological: Durvalumab; Drug: Gemcitabine
Cohort I (durvalumab, DD MVAC)ExperimentalDurvalumab (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.
Receives: Drug: Cisplatin; Procedure: Cystectomy; Drug: Doxorubicin; Biological: Durvalumab; Drug: Methotrexate; Drug: Vinblastine

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: At 120 days

Secondary outcomes (1)

  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

    Achievement of tumor staging will be determined by pathologist at cystectomy and reported by treatment cohort. Assessed per National Comprehensive Cancer Network bladder cancer guidelines.

    • T0 N0 M0 = No evidence of primary tumor
    • T1 N0 M0 = Tumor staging by pathological assessment detected in lamina propria (T0), with no tumor positive nodes (N0).
    • T2 N0 M0 = Tumor staging by pathological assessment detected in muscularis propria (pT2), with no tumor positive nodes (N0) or tumor metastases (M0) observed.

    Measured: At 20 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Apr 2019
  2. Study start10 Apr 2019
  3. Primary completion11 Aug 2022
  4. Study completion11 Aug 2022

Why it stopped: Difficulty with enrollment

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
7 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03912818
Sponsor's protocol ID
IRB-48062
Other IDs
NCI-2019-01364, BLDR0028
Status last verified
Aug 2023
First submitted
8 Apr 2019
Last updated
11 Sep 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Carboplatin, Cisplatin and Cystectomy in people with Bladder Adenocarcinoma and Bladder Mixed Adenocarcinoma, run by Stanford University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 11 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Sep 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of Grade 3-5 Adverse Events (time frame: At 120 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03912818.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2023.

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