Clinical Trials /

(CLONEVO): Cell cycLe inhbitiON to Target the EVolution of UrOthelial Cancer

NCT03837821

Description:

Single-arm, open-label window-of-opportunity trial of neoadjuvant Abemaciclib in 20 patients, with tumor tissue obtained as standard of care at tumor resection (pre-Abemaciclib) and cystectomy (post-Abemaciclib)

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: (CLONEVO): Cell cycLe inhbitiON to Target the EVolution of UrOthelial Cancer
  • Official Title: A Window-of-opportunity Trial of Abemaciclib Followed by Radical Cystectomy in Patients With Platinum-ineligible Urothelial Carcinoma to Evaluate CDK4/6-dependent Phosphorylation of Pocket Proteins and Clonal Evolution Dynamics

Clinical Trial IDs

  • ORG STUDY ID: 1710018693
  • NCT ID: NCT03837821

Conditions

  • Bladder Cancer

Interventions

DrugSynonymsArms
AbemaciclibAll Subjects

Purpose

Single-arm, open-label window-of-opportunity trial of neoadjuvant Abemaciclib in 20 patients, with tumor tissue obtained as standard of care at tumor resection (pre-Abemaciclib) and cystectomy (post-Abemaciclib)

Detailed Description

      A Window-of-Opportunity Trial of Abemaciclib followed by radical cystectomy in patients with
      Platinum-Ineligible Urothelial Carcinoma to Evaluate CDK4/6-Dependent Phosphorylation of
      Pocket Proteins and Clonal Evolution Dynamics. Subjects will be treated with Abemaciclib at
      200 mg every 12 hours for at least 4 weeks (and likely slightly longer depending upon
      surgical date). Individual dose reductions will be made on the basis of the AEs observed. In
      the absence of treatment delays due to adverse event(s), treatment will be continued until
      the surgical date unless any of the following criteria applies: 1-Disease progression;
      2-Intercurrent illness that prevents further administration of treatment; 3-Unacceptable
      adverse event(s) as a result of Abemaciclib; 4- Patient decides to withdraw from the study;
      5-General or specific changes in the patient's condition render the patient unacceptable for
      further treatment in the judgment of the investigator. Patients will be followed with
      history, physical, and blood tests at each visit to monitor for toxicity. Patients will be
      followed for survival endpoints following completion of this study for 3 years after surgery
      or until death. Patients removed from study for unacceptable adverse events will be followed
      until resolution or stabilization of the adverse event.
    

Trial Arms

NameTypeDescriptionInterventions
All SubjectsExperimentalAbemaciclib 200 mg oral, every 12 hours
  • Abemaciclib

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years old at time of informed consent

          -  Histologically confirmed MIBC (T2-T4) pure or mixed histology urothelial carcinoma
             [urothelial carcinoma should be the dominant (>50%) histology].

          -  Refusing cisplatin-based chemotherapy or ineligible for cisplatin-based chemotherapy
             due to at least one of the following:

               1. Creatinine clearance < 60 mL/min (by Cockgroft-Gault calculation and/or measured
                  creatinine clearance)

               2. Hearing loss ≥ grade 2 by CTCAE criteria and/or;

               3. Neuropathy ≥ grade 2 by CTCAE criteria and/or

               4. Heart failure NYHA ≥ III

          -  Medically fit for TURBT and radical cystectomy

          -  Adequate organ and marrow function as defined below:

               1. Absolute neutrophil count ≥ 1.5 K/mm3

               2. White blood cell count (WBC) > 3.0 K/mm3

               3. Platelets ≥ 100 K/mm3

               4. Hemoglobin ≥ 9 g/dL

               5. Serum total bilirubin ≤ 1.5 x ULN

               6. ALT and AST ≤ 2.5 x ULN

               7. Serum creatinine clearance (CrCl) ≥ 30 ml/min using the Cockcroft-Gault or
                  measurement with 24 hour urine collection

        Exclusion Criteria:

          -  Patients with locally advanced unresectable or metastatic urothelial carcinoma as
             assessed on baseline radiographic imaging obtained within 28 days prior to study
             enrollment. Low volume (<1.5 cm) suspicious lymph node metastases in the pelvis are
             allowed if they are in the LN dissection template field. The required radiographic
             imaging includes:

               1. Abdomen/pelvis - CT/MRI

               2. Chest - chest x-ray or CT scan

               3. Bone scan or FDG-PET/CT in the presence of bone pain or unexplained elevated
                  alkaline phosphatase

          -  Patients with another active second malignancy other than non-melanoma skin cancers
             and localized prostate cancer. Patients that have completed all necessary therapy and
             are considered to be <30% risk of relapse are not considered to have an active second
             malignancy and are eligible for enrollment.

          -  Patients who have received anti-cancer therapy including chemotherapy, radiotherapy,
             immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or
             who have not recovered from the side effects of such therapy

          -  Patients with any concurrent severe and/or uncontrolled medical conditions which could
             compromise participation in the study

          -  Have an active systemic fungal and/or known viral infection (for example, human
             immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C
             antibodies).

          -  Subjects who received a strong CYP3A inhibitor within 7 days prior to the first dose
             of study drug, or patients who require continuous treatment with a strong CYP3A
             inhibitor

          -  Pregnant or breast-feeding women

          -  Women who do not agree to use a medically approved contraceptive method during the
             treatment period and for 3 months following the last dose of Abemaciclib

          -  Men who do not agree to use a reliable method of birth control and to not donate sperm
             during the study and for at least 3 months following the last dose of Abemaciclib

          -  Subjects unwilling or unable to comply with the protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in cell-cycle dynamics between pre- and post-Abemaciclib tumor samples assessed by immunohistochemistry of tumor tissues, circulating tumor DNA (ctDNA)
Time Frame:At baseline and post 4 week treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events (TEAEs) of Abemaciclib assessed by CTCAE 4.0
Time Frame:At baseline through 3 year follow up
Safety Issue:
Description:
Measure:Effect on tumor downstaging defined as <pT2 at time of cystectomy
Time Frame:At baseline and post 4 week treatment
Safety Issue:
Description:

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Weill Medical College of Cornell University

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