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Study of Atezolizumab Combined With Split-dose Gemcitabine Plus Cisplatin in Urothelial Carcinoma (AUREA)

Primary Purpose

Locally Advanced or Metastatic Urothelial Carcinoma

Status
Active
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Atezolizumab 1200 mg/m2
Gemcitabine 1000 mg/m2
Cisplatin 70 mg/m2
Sponsored by
Spanish Oncology Genito-Urinary Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced or Metastatic Urothelial Carcinoma focused on measuring Cancer, Bladder, Urethra, Ureter, metastatic or locally advanced

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male or female subjects ≥ 18 years old.
  2. Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities.
  3. Patients with histologically documented, locally advanced (T4B, any N; or any T, N2-3) or metastatic urothelial carcinoma (M1, Stage IV)*.

    *Also termed transitional cell carcinoma (TCC) or Urothelial Cell Carcinoma (UCC) of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).

  4. Patients should not be eligible (unfit) for full dose of cisplatin, in the investigator's judgement, based on:

    a. Age older than 70 years. b. Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 2 or Karnofsky PS of 60 - 70% (only 15 patients will be included with ECOG 2). c. Measured creatinine clearance (ClCr) > 30 and < 60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for the determination of creatinine clearance:

    Males:

    Creatinine Clearance (CL) (mL/min) = Weight (kg) × (140 - Age) 72 x serum creatinine (mg/dL)

    Females:

    Creatinine CL (mL/min) =

    Weight (kg) × (140 - Age) ×0.85 72 x serum creatinine (mg/dL) d. Any other reason the physician considers but should specify in the Case Report Form (CRF) and discussed with the PI.

  5. At least one measurable lesion through radiographic tumor evaluation (CT scan or magnetic resonance imaging/MRI) as defined by RECIST version 1.1, that has not been previously irradiated within 4 weeks prior to the study enrolment.
  6. Patients with an archival or de novo tumor biopsy (representative formalin-fixed paraffin-embedded (FFPE) paraffin block obtained within 6 months prior to inclusion) with an associated pathology report, for testing of PD-L1 expression prior to study enrollment. Samples in unstained slides could be acceptable (at least 15 slides).
  7. Patients with adequate normal organ and marrow function as defined below:

    1. Haemoglobin ≥ 9.0 g/dL.
    2. Absolute neutrophil count (ANC) > 1500 per mm
    3. Platelet count ≥ 100,000 per mm
    4. Serum bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤ 2X ULN. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology); however, they will be allowed only in consultation with their physician.
    5. Serum transaminases (ALT, AST and GGT) ≤ 2.5X institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 3X ULN.
  8. No major active bleeding.
  9. Female subjects of childbearing potential (not surgically sterile or at least 2 years postmenopausal) must provide a negative urine pregnancy test at screening, and use a medically accepted double barrier method of contraception. In addition, they must agree to continue the use of this double barrier method for the duration of the study and for 6 months after participation in the study.
  10. Males should agree to abstain from sexual intercourse with a female partner or agree to use a double barrier method of contraception (i.e. condom with spermicide, in addition to having their female partner use some contraceptive measures such as oral contraceptive drugs, intrauterine device (IUD) hormonal contraception, or cervical caps), for the duration of the study and for 6 months after participation in the study
  11. Willingness and ability of patients to comply with the protocol for the duration of the study including undergoing treatment as well as availability for scheduled visits and examinations including follow up.

Exclusion Criteria:

  1. Prior treatment with any immune checkpoint inhibitor therapy (e.g., CTLA4, PD-1, or PD-L1 targeting agent).*
  2. Presence of active second malignancy and/or prior malignancy in the last 2 years is allowed except for the following:

    1. adequately treated basal cell or squamous cell skin cancer,
    2. adequately treated Stage I or II cancer from which the patient is currently in complete remission per investigators' clinical judgment.
  3. Patient receiving radiation therapy within 4 weeks before inclusion.
  4. 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.

  5. Active or prior documented inflammatory bowel disease (e.g.., Crohn's disease and ulcerative colitis).
  6. History of allogeneic organ transplant.
  7. Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment.
  8. Current or prior use of immunosuppressive medication within 7 days prior to enrolment, except the following:

    a. Intranasal, inhaled, topical steroids, or local steroid injections i. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent; ii. Steroids as premedication for hypersensitivity reactions

  9. The subject has uncontrolled, significant intercurrent or recent illness (within 6 months prior to inclusion) including, but not limited to, the following conditions:

    a. Cardiovascular disorders: i. Class 3 or 4 congestive heart failure as defined by the New York Heart Association, unstable angina pectoris, and serious cardiac arrhythmias. ii. Uncontrolled hypertension defined as sustained blood press > 150 mm hg systolic or > 100 mm hg diastolic despite optimal antihypertensive treatment. iii. Stroke (including Transient Ischemic Attack (TIA)), myocardial infarction, other ischemic event, or thromboembolic event within 6 months before inclusion. Subjects with a more recent diagnosis of Deep Vein Thrombosis (DVT) are allowed if stable, asymptomatic, and treated with Low Molecular Weight Heparin (LMWH) for at least 6 weeks before study treatment.

    b. Gastrointestinal disorders (e.g., malabsorption syndrome or gastric outlet obstruction) including those associated with a high risk of perforation or fistula formulation: i. Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction. ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before inclusion. Note: complete healing of an intra-abdominal abscess must be confirmed prior to start of the treatment.

    c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (> 2.5 ml) of red blood or history of other significant bleeding within 3 months before treatment.

    d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.

    e. Lesions invading major pulmonary blood vessels.

    f. Other clinically significant disorders such as: i. Active infection requiring systemic treatment, infection with human immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or chronic hepatitis B or C infection.

    ii. Serious non-healing wound/ulcer/bone fracture. iii. Malabsorption syndrome. iv. Moderate to severe hepatic impairment (child-pugh B or C). v. Requirement for hemodialysis or peritoneal dialysis. vi. Uncontrolled diabetes mellitus.

  10. Major surgery (e.g., GI surgery and removal or biopsy of brain metastasis) within 8 weeks before inclusion. Complete wound healing from major surgery must have occurred 4 weeks before study treatment and from minor surgery at least 10 days before study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
  11. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
  12. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection.
  13. Women who are pregnant or are breastfeeding.
  14. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy.
  15. Any of the following within 6 months prior to study entry: myocardial infarction, uncontrolled angina, uncontrolled hypertension, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack.
  16. Previously identified allergy or hypersensitivity to components of the study treatment formulations.

Sites / Locations

  • Hospital de la Santa Creu i Sant Pau
  • ICO Hospitalet- Hospital Duran i Reynals
  • Hospital Provincial de Castellón
  • Hospital Universitario de Jaén
  • Complejo Hospitalario Universitario Insular Marterno Infantil
  • Hospital Clínico Universitario San Carlos
  • Hospital Universitario 12 de Octubre
  • Hospital Universitario La Paz
  • Complejo Hospitalario Universitario Ourense
  • Hospital Universitario Central de Asturias
  • Hospital Son Llàtzer
  • Hospital Virgen de la Salud

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

AUREA single-arm

Arm Description

Atezolizumab (1200 mg) intravenously administered every 21 days (one cycle) up to disease progression, unacceptable toxicity or absence of clinical benefit. Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle plus Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles.

Outcomes

Primary Outcome Measures

Overall Response Rate (ORR)
Percentage/proportion of patients with confirmed complete response (CR) or partial response (PR) as their overall best response throughout the study period according to RECIST 1.1 criteria. Evaluated by Computed tomography scans (CT scan).

Secondary Outcome Measures

Duration of response (DoR)
Time from first confirmed response (CR or PR) to the date of the documented PD as determined using RECIST 1.1 criteria or death due to any cause, whichever occurs first.
Time to response (TtR)
Time from first dosing date to the date of the documented ORR as determined using RECIST 1.1 criteria.
Clinical Benefit Rate (CBR)
Percentage/proportion of patients with confirmed complete response (CR) or partial response (PR), or stable disease (SD) as their overall best response throughout the study period.
Overall Survival (OS)
Time from first dosing date to the date of death. A subject who has not died will be censored at the last known date alive.
Progression-Free Survival (PFS)
Time from first dosing date to the date of confirmed PD. A subject who has not died will be censored at the last known date alive.
6 months Progression-Free Survival (PFS)
Proportion of patients free of PD at 6 months since start of treatment. A subject who has not died will be censored at the last known date alive.
Adverse Events frequency (safety)
Frequency of adverse events reported classified by type and severity.
Treatment-related Adverse Events frequency (safety)
Frequency of treatment-related adverse events reported classified by type and severity.

Full Information

First Posted
October 6, 2020
Last Updated
March 24, 2022
Sponsor
Spanish Oncology Genito-Urinary Group
Collaborators
Roche Pharma AG
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1. Study Identification

Unique Protocol Identification Number
NCT04602078
Brief Title
Study of Atezolizumab Combined With Split-dose Gemcitabine Plus Cisplatin in Urothelial Carcinoma
Acronym
AUREA
Official Title
Phase II, Multicenter, Non-randomized, Single-arm, Open-label Trial of Atezolizumab in Combination of Split-doses of Gemcitabine Plus Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 23, 2020 (Actual)
Primary Completion Date
January 2023 (Anticipated)
Study Completion Date
January 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Spanish Oncology Genito-Urinary Group
Collaborators
Roche Pharma AG

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Phase II, multicenter, non-randomized, single-arm, open-label trial of atezolizumab in combination of split-doses of gemcitabine plus cisplatin in patients with locally advanced or metastatic urothelial carcinoma. The Aurea trial aims to evaluate the preliminary efficacy of atezolizumab plus split-dose gemcitabine and cisplatin (GC) for the first-line setting, in patients with histologically confirmed advanced (locally advanced and metastatic) urothelial cancer in terms of overall response rate (ORR) assessed by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary objectives include: efficacy (clinical benefit rate, duration of response, time to response, overall survival and progression-free survival); safety (frequency and severity of adverse events assessed by NCI CTCAE v5.0) and exploratory endpoints ( correlation of prognostic biomarkers/factors with efficacy and relationship between the expression of PD-L1 and microbiome with ORR and PFS). At least 66 patients will be included. The treatment schedule is as follows: Atezolizumab at a fixed dose of 1200 mg/m2 by intravenous (IV) infusion on D1 of each 21-day cycle up to disease progression, unacceptable toxicity or absence of clinical benefit. Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle plus Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles.
Detailed Description
The results of trials combining checkpoint inhibitors or platinum-based chemotherapy plus PD-1/PD-L1 inhibitors are eagerly awaited. The combination of split cisplatin with atezolizumab is a feasible treatment that may provide better outcomes than carboplatin/based combinations. In the IMvigor130, 52% of patients considered cisplatin eligible at the entry of the study were treated with carboplatin. Subanalysis presented at European Society of Medical Oncology (ESMO) 2019 (Grande E, et al. 2019) has also shown a longer median OS are achieved with cisplatin-based chemotherapy combined with atezolizumab (21.7 months) when compared to the carboplatin-based chemotherapy plus atezolizumab (14.2 months), with similar findings when it comes to PFS 8.8 months with cisplatin/gemcitabine/atezolizumab vs 7.1 months carboplatin/gemcitabine/atezolizumab. A reasonable strategy may be the use of split cisplatin with atezolizumab to increase the number of patients receiving cisplatin. The AUREA study is a multicenter, open labelled, single arm, multicohort Phase II clinical trial of of atezolizumab in combination of split-dose cisplatin plus gemcitabine in patients with locally advanced or metastatic urothelial carcinoma (additional details on the eligibility criteria of the study are found in section 6 of this protocol). The design includes screening phase, combined treatment initial phase, monotherapy treatment phase, follow-up phase and translational research with biopsies, blood samples and faecal samples. The dose scheme includes the initial dose of atezolizumab (1200 mg) intravenously administered every 21 days (one cycle) up to disease progression, unacceptable toxicity or absence of clinical benefit. Dose adjustment or dose reductions of atezolizumab are not expected. AUREA is an Investigator Initiated Study, the Sponsor will supply Atezolizumab for up to 24 months of treatment for each patient. For those patients in which the PI considers that the best option for the patient is continuing atezolizumab for more than 24 months, available commercial Site supplies should be used, after managed local administrative regulation. Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle plus Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles. Study treatment will begin as soon as possible after signing the informed consent. Before each treatment administration chemotherapy/atezolizumab administration laboratory, medical consulting and other determinations will be performed to ensure that treatment can be safely administered. A CT Scan or MRI will be performed at baseline, on week 9, week 18 and then every 12 weeks (q12w) ± 1w until objective disease progression as per PI's criteria or death (whichever comes first). Blood samples for biomarkers studies should be collected before administration of cycle 4 and at the time of Progression Disease (PD) (end of treatment if applicable). For patients with progression reported as per RECIST criteria at week 9, continuity of treatment with atezolizumab should be evaluated by the PI of each site as per clinical benefit criteria.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced or Metastatic Urothelial Carcinoma
Keywords
Cancer, Bladder, Urethra, Ureter, metastatic or locally advanced

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
66 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AUREA single-arm
Arm Type
Experimental
Arm Description
Atezolizumab (1200 mg) intravenously administered every 21 days (one cycle) up to disease progression, unacceptable toxicity or absence of clinical benefit. Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle plus Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles.
Intervention Type
Drug
Intervention Name(s)
Atezolizumab 1200 mg/m2
Other Intervention Name(s)
Tecentriq
Intervention Description
Fixed dose of 1200 mg/m2 by intravenous (IV) infusion on D1 of each cycle up to disease progression, unacceptable toxicity or absence of clinical benefit.
Intervention Type
Drug
Intervention Name(s)
Gemcitabine 1000 mg/m2
Intervention Description
Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle for up to 6 cycles.
Intervention Type
Drug
Intervention Name(s)
Cisplatin 70 mg/m2
Intervention Description
Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles.
Primary Outcome Measure Information:
Title
Overall Response Rate (ORR)
Description
Percentage/proportion of patients with confirmed complete response (CR) or partial response (PR) as their overall best response throughout the study period according to RECIST 1.1 criteria. Evaluated by Computed tomography scans (CT scan).
Time Frame
Through study completion, average 2 years.
Secondary Outcome Measure Information:
Title
Duration of response (DoR)
Description
Time from first confirmed response (CR or PR) to the date of the documented PD as determined using RECIST 1.1 criteria or death due to any cause, whichever occurs first.
Time Frame
Through study completion, average 2 years. CT scans for evaluation will be performed at baseline, on week 9, week 18 and then every 12 weeks (q12w) ± 1w until objective disease progression as per PI's criteria or death (whichever comes first).
Title
Time to response (TtR)
Description
Time from first dosing date to the date of the documented ORR as determined using RECIST 1.1 criteria.
Time Frame
Through study completion, average 2 years. CT scans for evaluation will be performed at baseline, on week 9, week 18 and then every 12 weeks (q12w) ± 1w until objective disease progression as per PI's criteria or death (whichever comes first).
Title
Clinical Benefit Rate (CBR)
Description
Percentage/proportion of patients with confirmed complete response (CR) or partial response (PR), or stable disease (SD) as their overall best response throughout the study period.
Time Frame
Through study completion, average 2 years. CT scans for evaluation will be performed at baseline, on week 9, week 18 and then every 12 weeks (q12w) ± 1w until objective disease progression as per PI's criteria or death (whichever comes first).
Title
Overall Survival (OS)
Description
Time from first dosing date to the date of death. A subject who has not died will be censored at the last known date alive.
Time Frame
Through study completion, average 2 years.
Title
Progression-Free Survival (PFS)
Description
Time from first dosing date to the date of confirmed PD. A subject who has not died will be censored at the last known date alive.
Time Frame
Through study completion, average 2 years. CT scans for evaluation will be performed at baseline, on week 9, week 18 and then every 12 weeks (q12w) ± 1w until objective disease progression as per PI's criteria or death (whichever comes first).
Title
6 months Progression-Free Survival (PFS)
Description
Proportion of patients free of PD at 6 months since start of treatment. A subject who has not died will be censored at the last known date alive.
Time Frame
6 months from the first dose administration. CT scans for evaluation will be performed at baseline, on week 9, week 18 and then every 12 weeks
Title
Adverse Events frequency (safety)
Description
Frequency of adverse events reported classified by type and severity.
Time Frame
Through study completion, average 2 years
Title
Treatment-related Adverse Events frequency (safety)
Description
Frequency of treatment-related adverse events reported classified by type and severity.
Time Frame
Through study completion, average 2 years
Other Pre-specified Outcome Measures:
Title
Progression Free Survival measured by RECIST 1.1 in patients grouped according to their PD-L1 expression
Description
Correlation between the expression of PD-L1 with PFS during experimental treatment. Patients will be grouped based on the PD-L1 expression levels in PD-L1 positive or negative patients. Progression free survival will be assessed in both groups of patients and compared to identify potential statistically significant differences between groups.
Time Frame
PD-L1 expression measured at the end of the trial. PFS assessed Through study completion, average 2 years
Title
ORR measured by RECIST 1.1. in patients grouped according to their PD-L1 expression
Description
Correlation between the expression of PD-L1 with ORR during experimental treatment. Patients will be grouped based on the PD-L1 expression levels in PD-L1 positive or negative patients. ORR will be assessed in both groups of patients and compared to identify potential statistically significant differences between groups.
Time Frame
PD-L1 expression measured at the end of the trial. ORR assessed Through study completion, average 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female subjects ≥ 18 years old. Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities. Patients with histologically documented, locally advanced (T4B, any N; or any T, N2-3) or metastatic urothelial carcinoma (M1, Stage IV)*. *Also termed transitional cell carcinoma (TCC) or Urothelial Cell Carcinoma (UCC) of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra). Patients should not be eligible (unfit) for full dose of cisplatin, in the investigator's judgement, based on: a. Age older than 70 years. b. Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 2 or Karnofsky PS of 60 - 70% (only 15 patients will be included with ECOG 2). c. Measured creatinine clearance (ClCr) > 30 and < 60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for the determination of creatinine clearance: Males: Creatinine Clearance (CL) (mL/min) = Weight (kg) × (140 - Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) × (140 - Age) ×0.85 72 x serum creatinine (mg/dL) d. Any other reason the physician considers but should specify in the Case Report Form (CRF) and discussed with the PI. At least one measurable lesion through radiographic tumor evaluation (CT scan or magnetic resonance imaging/MRI) as defined by RECIST version 1.1, that has not been previously irradiated within 4 weeks prior to the study enrolment. Patients with an archival or de novo tumor biopsy (representative formalin-fixed paraffin-embedded (FFPE) paraffin block obtained within 6 months prior to inclusion) with an associated pathology report, for testing of PD-L1 expression prior to study enrollment. Samples in unstained slides could be acceptable (at least 15 slides). Patients with adequate normal organ and marrow function as defined below: Haemoglobin ≥ 9.0 g/dL. Absolute neutrophil count (ANC) > 1500 per mm Platelet count ≥ 100,000 per mm Serum bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤ 2X ULN. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology); however, they will be allowed only in consultation with their physician. Serum transaminases (ALT, AST and GGT) ≤ 2.5X institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 3X ULN. No major active bleeding. Female subjects of childbearing potential (not surgically sterile or at least 2 years postmenopausal) must provide a negative urine pregnancy test at screening, and use a medically accepted double barrier method of contraception. In addition, they must agree to continue the use of this double barrier method for the duration of the study and for 6 months after participation in the study. Males should agree to abstain from sexual intercourse with a female partner or agree to use a double barrier method of contraception (i.e. condom with spermicide, in addition to having their female partner use some contraceptive measures such as oral contraceptive drugs, intrauterine device (IUD) hormonal contraception, or cervical caps), for the duration of the study and for 6 months after participation in the study Willingness and ability of patients to comply with the protocol for the duration of the study including undergoing treatment as well as availability for scheduled visits and examinations including follow up. Exclusion Criteria: Prior treatment with any immune checkpoint inhibitor therapy (e.g., CTLA4, PD-1, or PD-L1 targeting agent).* Presence of active second malignancy and/or prior malignancy in the last 2 years is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission per investigators' clinical judgment. Patient receiving radiation therapy within 4 weeks before inclusion. 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. Active or prior documented inflammatory bowel disease (e.g.., Crohn's disease and ulcerative colitis). History of allogeneic organ transplant. Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment. Current or prior use of immunosuppressive medication within 7 days prior to enrolment, except the following: a. Intranasal, inhaled, topical steroids, or local steroid injections i. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent; ii. Steroids as premedication for hypersensitivity reactions The subject has uncontrolled, significant intercurrent or recent illness (within 6 months prior to inclusion) including, but not limited to, the following conditions: a. Cardiovascular disorders: i. Class 3 or 4 congestive heart failure as defined by the New York Heart Association, unstable angina pectoris, and serious cardiac arrhythmias. ii. Uncontrolled hypertension defined as sustained blood press > 150 mm hg systolic or > 100 mm hg diastolic despite optimal antihypertensive treatment. iii. Stroke (including Transient Ischemic Attack (TIA)), myocardial infarction, other ischemic event, or thromboembolic event within 6 months before inclusion. Subjects with a more recent diagnosis of Deep Vein Thrombosis (DVT) are allowed if stable, asymptomatic, and treated with Low Molecular Weight Heparin (LMWH) for at least 6 weeks before study treatment. b. Gastrointestinal disorders (e.g., malabsorption syndrome or gastric outlet obstruction) including those associated with a high risk of perforation or fistula formulation: i. Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction. ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before inclusion. Note: complete healing of an intra-abdominal abscess must be confirmed prior to start of the treatment. c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (> 2.5 ml) of red blood or history of other significant bleeding within 3 months before treatment. d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation. e. Lesions invading major pulmonary blood vessels. f. Other clinically significant disorders such as: i. Active infection requiring systemic treatment, infection with human immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or chronic hepatitis B or C infection. ii. Serious non-healing wound/ulcer/bone fracture. iii. Malabsorption syndrome. iv. Moderate to severe hepatic impairment (child-pugh B or C). v. Requirement for hemodialysis or peritoneal dialysis. vi. Uncontrolled diabetes mellitus. Major surgery (e.g., GI surgery and removal or biopsy of brain metastasis) within 8 weeks before inclusion. Complete wound healing from major surgery must have occurred 4 weeks before study treatment and from minor surgery at least 10 days before study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection. Women who are pregnant or are breastfeeding. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy. Any of the following within 6 months prior to study entry: myocardial infarction, uncontrolled angina, uncontrolled hypertension, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack. Previously identified allergy or hypersensitivity to components of the study treatment formulations.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Guillermo Velasco, M.D., Ph.D.
Organizational Affiliation
Hospital Universitario 12 de Octubre
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital de la Santa Creu i Sant Pau
City
Barcelona
ZIP/Postal Code
08041
Country
Spain
Facility Name
ICO Hospitalet- Hospital Duran i Reynals
City
Barcelona
ZIP/Postal Code
08908
Country
Spain
Facility Name
Hospital Provincial de Castellón
City
Castellón De La Plana
ZIP/Postal Code
12002
Country
Spain
Facility Name
Hospital Universitario de Jaén
City
Jaén
Country
Spain
Facility Name
Complejo Hospitalario Universitario Insular Marterno Infantil
City
Las Palmas De Gran Canaria
ZIP/Postal Code
35016
Country
Spain
Facility Name
Hospital Clínico Universitario San Carlos
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Complejo Hospitalario Universitario Ourense
City
Orense
Country
Spain
Facility Name
Hospital Universitario Central de Asturias
City
Oviedo
ZIP/Postal Code
33011
Country
Spain
Facility Name
Hospital Son Llàtzer
City
Palma De Mallorca
ZIP/Postal Code
07198
Country
Spain
Facility Name
Hospital Virgen de la Salud
City
Toledo
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Study of Atezolizumab Combined With Split-dose Gemcitabine Plus Cisplatin in Urothelial Carcinoma

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