Clinical Trials /

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

NCT04602078

Description:

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.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Atezolizumab Combined With Split-dose Gemcitabine Plus Cisplatin in Urothelial Carcinoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: SOGUG-2020-IEC(VEJ)-1
  • SECONDARY ID: 2020-001326-65
  • NCT ID: NCT04602078

Conditions

  • Locally Advanced or Metastatic Urothelial Carcinoma

Interventions

DrugSynonymsArms
Atezolizumab 1200 mg/m2TecentriqAUREA single-arm
Gemcitabine 1000 mg/m2AUREA single-arm
Cisplatin 70 mg/m2AUREA single-arm

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
AUREA single-armExperimentalAtezolizumab (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.
  • Atezolizumab 1200 mg/m2
  • Gemcitabine 1000 mg/m2
  • Cisplatin 70 mg/m2

Eligibility Criteria

        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.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Through study completion, average 2 years.
Safety Issue:
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).

Secondary Outcome Measures

Measure:Duration of response (DoR)
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).
Safety Issue:
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.
Measure:Time to response (TtR)
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).
Safety Issue:
Description:Time from first dosing date to the date of the documented ORR as determined using RECIST 1.1 criteria.
Measure:Clinical Benefit Rate (CBR)
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).
Safety Issue:
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.
Measure:Overall Survival (OS)
Time Frame:Through study completion, average 2 years.
Safety Issue:
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.
Measure:Progression-Free Survival (PFS)
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).
Safety Issue:
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.
Measure:6 months Progression-Free Survival (PFS)
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
Safety Issue:
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.
Measure:Adverse Events frequency (safety)
Time Frame:Through study completion, average 2 years
Safety Issue:
Description:Frequency of adverse events reported classified by type and severity.
Measure:Treatment-related Adverse Events frequency (safety)
Time Frame:Through study completion, average 2 years
Safety Issue:
Description:Frequency of treatment-related adverse events reported classified by type and severity.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Spanish Oncology Genito-Urinary Group

Trial Keywords

  • Cancer
  • Bladder
  • Urethra
  • Ureter
  • metastatic or locally advanced

Last Updated

October 20, 2020