Durvalumab and Standard Chemotherapy Before Surgery in Treating Patients With Variant Histology Bladder Cancer
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| ClinicalTrials.gov Identifier: NCT03912818 |
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Recruitment Status :
Active, not recruiting
First Posted : April 11, 2019
Last Update Posted : April 6, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Bladder Adenocarcinoma Bladder Mixed Adenocarcinoma Bladder Squamous Cell Carcinoma Bladder Urothelial Carcinoma Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant 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 | Drug: Carboplatin Drug: Cisplatin Procedure: Cystectomy Drug: Doxorubicin Biological: Durvalumab Drug: Gemcitabine Drug: Methotrexate Drug: Vinblastine | Phase 2 |
PRIMARY OBJECTIVES:
I. To assess the safety and tolerability of durvalumab in combination with chemotherapy in subjects with variant histology bladder cancer.
SECONDARY OBJECTIVES:
I. 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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 24 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase 2 Open Label Study of Durvalumab With Neoadjuvant Chemotherapy in Variant Histology Bladder Cancer |
| Actual Study Start Date : | April 10, 2019 |
| Estimated Primary Completion Date : | September 2022 |
| Estimated Study Completion Date : | September 2022 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Cohort II (durvalumab, cis-gem)
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.
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Drug: Cisplatin
Given IV
Other Names:
Procedure: Cystectomy Undergo cystectomy Biological: Durvalumab Given IV
Other Names:
Drug: Gemcitabine Given IV
Other Names:
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Experimental: Cohort III (Durvalumab, carbo-gem)
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.
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Drug: Carboplatin
Given IV
Other Names:
Procedure: Cystectomy Undergo cystectomy Biological: Durvalumab Given IV
Other Names:
Drug: Gemcitabine Given IV
Other Names:
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Experimental: Cohort I (durvalumab, DD MVAC)
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.
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Drug: Cisplatin
Given IV
Other Names:
Procedure: Cystectomy Undergo cystectomy Drug: Doxorubicin Given IV
Other Names:
Biological: Durvalumab Given IV
Other Names:
Drug: Methotrexate Given IV
Other Names:
Drug: Vinblastine Given IV
Other Names:
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- Incidence of grade 3-5 adverse events [ Time Frame: At 120 days ]Will be 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. The outcome will be reported as a number.
- Proportion of subjects who initiate study treatment and achieve tumor stage of pT2 N0 M0 or better (e.g., pT0, pT1 N0) at cystectomy [ Time Frame: At 20 weeks ]
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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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.
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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.
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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).
Exclusion Criteria:
- 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.
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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.
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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.
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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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03912818
| United States, California | |
| Stanford Cancer Institute Palo Alto | |
| Palo Alto, California, United States, 94304 | |
| Principal Investigator: | Sandy Srinivas | Stanford Cancer Institute Palo Alto |
Documents provided by Stanford University:
| Responsible Party: | Stanford University |
| ClinicalTrials.gov Identifier: | NCT03912818 |
| Other Study ID Numbers: |
IRB-48062 NCI-2019-01364 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) BLDR0028 ( Other Identifier: OnCore ) |
| First Posted: | April 11, 2019 Key Record Dates |
| Last Update Posted: | April 6, 2022 |
| Last Verified: | March 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | No |
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Carcinoma Adenocarcinoma Carcinoma, Transitional Cell Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Gemcitabine Carboplatin Doxorubicin Liposomal doxorubicin Methotrexate Durvalumab Daunorubicin Vinblastine Antineoplastic Agents |
Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antiviral Agents Anti-Infective Agents Enzyme Inhibitors Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antibiotics, Antineoplastic Topoisomerase II Inhibitors Topoisomerase Inhibitors Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents |