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Study of NIVOLUMAB/IPILIMUMAB Maintenance in Unresectable Locally Advanced or Metastatic Urothelial Cancer

Recruiting
18 years of age
Both
Phase 2

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Overview

Immunotherapy has improved clinical outcomes in metastatic urothelial carcinoma (mUC). Second-line treatment after progression to platinum-containing chemotherapy with immune checkpoint inhibitors (ICIs) have antitumor activity in advanced / metastatic UC and provide favorable safety profiles when compared with chemotherapy The study aims to determine if Nivolumab plus Ipilimumab maintenance therapy is effective in delaying disease progression in patients with unresectable locally advanced or metastatic urothelial cancer that did not progress during or following completion of first-line chemotherapy. Vexillum plans to recruit patients that achieve clinical benefit from first-line chemotherapy and may be candidates for maintenance immunotherapy to consolidate this benefit.

Description

All enrolled patients should have received first-line chemotherapy and not progressed. After a treatment-free interval of 3-12 weeks from chemotherapy, patients will receive maintenance therapy with 4 cycles of Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg every three weeks (Q3W)(induction phase) followed by Nivolumab 480 mg every 4 weeks (Q4W)(consolidation phase) until unacceptable toxicity, disease progression (PD), investigator ́s decision, patient's consent withdrawal or death by any cause, whichever occurs first.

  • Induction phase (Total of 4 cycles Q3W)
  • Nivolumab at 1 mg/kg by intravenous (IV) infusion on D1 of each cycle.
  • Ipilimumab at 3 mg/kg by intravenous (IV) infusion on D1 of each cycle.
  • Consolidation phase (Cycles Q4W) ○ Nivolumab at a fixed dose of 480 mg by intravenous (IV) infusion on D1 of each cycle. The maximum duration of treatment with nivolumab will be 2 years, and patients will discontinue treatment at any time in case of unacceptable toxicity, disease progression (PD), investigator ́s decision, patient's consent withdrawal or death by any cause, whichever occurs first.

Eligibility

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- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
        4- Histologically confirmed, unresectable locally advanced or metastatic transitional cell
        carcinoma of the urothelium.
          -  Also termed urothelial cell carcinoma [UCC] of the urinary tract; including renal
             pelvis, ureters, urinary bladder, and urethra).
             5- Stage IV disease (T4b, N0, M0; any T, N1-N3, M0; any T, any N, M1) at the start of
             first line chemotherapy.
             6- Prior first-line chemotherapy must have consisted of at least 4 cycles and no more
             than 6 cycles of gemcitabine plus cisplatin and/or gemcitabine plus carboplatin.
             7- Patient inclusion within the trial must occur within 3-12 weeks after the last dose
             of chemotherapy (3-12 weeks treatment-free interval).
             8- Only patients without progressive disease as per RECIST v1.1 guidelines after 4-6
             cycles of chemotherapy will be allowed to be included. Baseline CT scan before
             inclusion should confirm that patients are on CR, PR or SD according to RECIST 1.1
             criteria.
             9- Tumor tissue (formalin-fixed paraffin-embedded (FFPE) archival or recent
             acquisition) must be available at baseline.
        Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable. If an
        insufficient amount of tumor tissue from an unresectable or metastatic site is available
        prior to the start of the screening phase, subjects must consent to allow the acquisition
        of additional tumor tissue. This may be discussed with the PI if a new biopsy is feasible.
        10- Patients with adequate normal organ and marrow function as defined below:
          1. Haemoglobin ≥ 9.0 g/dL.
          2. Absolute neutrophil count (ANC) > 1500 per mm3.
          3. Platelet count ≥ 100,000 per mm3.
          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.
          6. Measured creatinine clearance (CL) > 30 mL/min or Calculated creatinine CL > 40 mL/min
             by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine
             collection for the determination of creatinine clearance.
             11- Female subjects of childbearing potential (WOCBP) must provide a negative urine
             pregnancy test at screening, and must agree to use a medically accepted and highly
             effective birth control method (i.e. those with a failure rate less than 1%; refer to
             ANNEX III) for the duration of the study treatment and for 5 months after the last
             dose of study treatment.
        A woman is considered of childbearing potential ( i.e. fertile) following menarche and
        until becoming post-menopausal unless permanently sterile. Women will be considered
        post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical
        cause. The following age-specific requirements apply:
          1. Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments
          2. Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol levels
             in the post-menopausal range
          3. Radiation induced oophorectomy with last menses >1 year ago
          4. Chemotherapy induced menopause with >1 year interval since last menses
          5. Surgical sterilization (bilateral oophorectomy or hysterectomy)
          6. 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)
          7. 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, or underwent surgical sterilization (bilateral oophorectomy, bilateral
             salpingectomy or hysterectomy).
             12- 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. ECOG performance status of >1 (Karnofsky < 70%).
               2. Patients whose disease progressed by RECIST v1.1 on or after first-line
                  chemotherapy for urothelial cancer in the advanced or metastatic setting.
               3. Prior immunotherapy with IL-2, IFN-a or treatment with any immune checkpoint
                  inhibitor therapy (e.g, CTLA4, PD-1, or PD-L1 targeting agent) for the
                  unresectable metastatic setting.
                  Note: Patients may have received immunotherapy in the adjuvant setting as long as
                  the last dose of adjuvant was administered at least 12 months prior to the first
                  dose of trial treatment.
               4. Receipt of any type of systemic chemotherapy or anticancer therapy within 3 weeks
                  before starting treatment.
               5. Previously identified allergy or hypersensitivity to components of the study
                  treatment formulations.
               6. History of allogeneic organ transplant.
               7. Any non-cancer treatment with vaccines used for the prevention of infectious
                  diseases (up to 1 month before or after any dose of ipilimumab and nivolumab).
               8. Major surgery (i.e. cystectomy) less than 28 days prior to the first dose of
                  study treatment.
               9. Patients with known symptomatic central nervous system (CNS) metastases requiring
                  steroids. Patients with previously diagnosed CNS metastases are eligible if they
                  have completed their treatment and have recovered from the acute effects of
                  radiation therapy or surgery prior to inclusion, have discontinued corticosteroid
                  treatment for these metastases for at least 4 weeks, and are neurologically
                  stable.
              10. Subjects that have 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, 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).
              11. Active or prior documented autoimmune disease within the past 2 years which
                  requires systemic therapy.
                  Note: Subjects with vitiligo, Grave's disease, or psoriasis not requiring
                  systemic treatment (within the past 2 years) are not excluded. Subjects with Type
                  I diabetes mellitus are not excluded.
              12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease and
                  ulcerative colitis).
              13. Inadequate haematological/organ function.
              14. Any of the following in the previous 6 months: myocardial infarction,
                  severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic
                  congestive heart failure, cerebrovascular accident, transient ischemic attack,
                  deep vein thrombosis, or symptomatic pulmonary embolism.
              15. Persistence of any toxicities attributed to prior anti-cancer therapy, other than
                  alopecia, that have not resolved to Grade 1 (NCI-CTCAE v5.0) or baseline before
                  administration of study treatment.
              16. Active hepatitis B virus or hepatitis C virus.
              17. Vaccination within 4 weeks of the first dose of study treatment and while on
                  trial is prohibited except for administration of inactivated vaccines (i.e.
                  SARS-CoV-2 and Influenza vaccines will be permitted).
              18. Patients who have a known secondary malignancy that is progressing or has
                  required active treatment within the past 2 years.
                  Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of
                  the skin, or carcinoma in situ that have undergone potentially curative therapy
                  are eligible.
              19. Pregnant or lactating females. Fertile and sexually active patients that are not
                  willing to use the appropriate highly effective contraceptive methods.
              20. Any underlying medical or psychiatric disorder, which, in the opinion of the
                  investigator, makes the administration of ipilimumab and nivolumab unsafe or
                  interferes with the informed consent process or trial procedures.
              21. Participation in other studies involving investigational drug(s) within 4 weeks
                  prior to inclusion. Observational studies are permitted.

Study details

Urothelial Cancer

NCT05219435

Spanish Oncology Genito-Urinary Group

25 January 2024

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