Clinical Trials /

A Study of Abemaciclib in Combination With Sunitinib in Metastatic Renal Cell Carcinoma

NCT03905889

Description:

The purpose of this study is to determine the safety, tolerability, and maximal tolerated dose (MTD) of the combination of Abemaciclib and Sunitinib administered orally in patients with advanced and metastatic renal cell carcinoma. This study consists of two parts: Dose Escalation and Dose Expansion. During the dose escalation phase, participants will be sequentially enrolled in a standard 3 x 3 dose escalation study design to receive oral Abemaciclib in Combination with Sunitinib. The purpose of this dose escalation is to determine the maximal tolerated dose based on assessment of any dose limiting toxicity. The Dose Expansion Phase will enroll additional participants at the established maximal tolerated dose to further evaluate safety, tolerability, as well as the pharmacokinetics and pharmacodynamics of this combination drug regimen.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Abemaciclib in Combination With Sunitinib in Metastatic Renal Cell Carcinoma
  • Official Title: Targeting PIM1 and CDK4/6 Kinases in Renal Cell Carcinoma (PICKRCC): A Phase Ib Study of Abemaciclib (VerzenioTM) in Combination With Sunitinib in Metastatic Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: PSCI-18-055
  • NCT ID: NCT03905889

Conditions

  • Renal Cell Carcinoma Metastatic

Interventions

DrugSynonymsArms
AbemaciclibVerzenioExperimental Abemaciclib and Sunitinib
SunitinibSutentExperimental Abemaciclib and Sunitinib

Purpose

The purpose of this study is to determine the safety, tolerability, and maximal tolerated dose (MTD) of the combination of Abemaciclib and Sunitinib administered orally in patients with advanced and metastatic renal cell carcinoma. This study consists of two parts: Dose Escalation and Dose Expansion. During the dose escalation phase, participants will be sequentially enrolled in a standard 3 x 3 dose escalation study design to receive oral Abemaciclib in Combination with Sunitinib. The purpose of this dose escalation is to determine the maximal tolerated dose based on assessment of any dose limiting toxicity. The Dose Expansion Phase will enroll additional participants at the established maximal tolerated dose to further evaluate safety, tolerability, as well as the pharmacokinetics and pharmacodynamics of this combination drug regimen.

Detailed Description

      Renal cell carcinoma (RCC) accounted for about 64, 000 new cancer diagnoses in the USA in
      2018. Up to 30% of those diagnoses will be patients with metastatic disease. Additionally, up
      to 50% of patients who undergo partial or radical nephrectomy will develop metastatic
      disease.. There is no cure for metastatic RCC, thus, metastatic RCC represents a significant
      cancer burden. Numerous directed therapies are available to improve overall survival but
      these do not result in durable complete responses. However, recent pre-clinical studies of
      RCC have demonstrated that Abemaciclib, a CDK4/6 and PIM1 kinase inhibitor, induces rapid,
      dramatic, and sustained tumor regression when used in combination with Sunitinib.

      Our objectives for this study are as follows:

      Primary Objectives:

        -  Determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of
           the combination of Abemaciclib with Sunitinib for patients with metastatic renal cell
           carcinoma. Additionally, determine pharmacokinetics (serum trough levels) of Abemaciclib
           and Sunitinib at steady state.

        -  Continued safety assessment of the combination of Abemaciclib and Sunitinib at the
           established maximum tolerated dose (i.e. the recommended Phase II dose)

      Secondary Objectives:

      Determine any anti-tumor activity in the dose expansion phase of the study. Tumor related
      activity will be assessed by:

        -  Length of progression free survival

        -  Disease response rate

        -  Time to disease response

        -  Disease control rate

        -  Duration of response

        -  Overall survival and progression free survival
    

Trial Arms

NameTypeDescriptionInterventions
Experimental Abemaciclib and SunitinibExperimentalFor the dose escalation phase, Subjects will receive a 21-day cycle of continuous oral daily Sunitinib in combination with Abemaciclib every 12 hours for 14 days followed by 7 days off. Using a traditional 3 x 3 study design assessing dose limiting toxicity, if the initial prescribed dosing of these 2 medications (Dose Level 1) is tolerated by the first 3 subjects, the study will pause for a 30 day time period between cohorts to assess toxicity. If no dose limiting toxicity is identified, the next cohort of 3 new subjects will be treated at the next higher dose level (Dose Level 2). If the original cohort treated at Dose Level 1 do not tolerate the combination of medications, the medication regimen will be modified to a lower dose (Dose Level - 1). A dose expansion phase is included which will evaluate the combination of Abemaciclib in combination with Sunitinib when given at the maximum tolerated dose as determined from the from dose escalation phase.
  • Abemaciclib
  • Sunitinib

Eligibility Criteria

        Inclusion Criteria:

          1. Has histologic or cytologic evidence of metastatic renal cell carcinoma with histology
             predominantly (>50%) clear cell renal cell carcinoma solid neoplasm.

          2. Has evidence of metastatic disease. Intermediate and poor risk patients according to
             International Metastatic Renal Cell Carcinoma Database criteria (IMDC) must have
             received prior combination ipilimumab and nivolumab therapy and subsequently
             experienced disease progression, or been offered ipilimumab and nivolumab combination
             therapy and refused, or be ineligible for combination ipilimumab and nivolumab
             therapy. Patients with favorable risk disease have no eligibility requirement for
             prior use of ipilimumab and nivolumab immunotherapy.

          3. Intermediate and poor risk patients (according to IMDC criteria) must also have
             received prior cabozantinib therapy and subsequently experienced disease progression,
             or been offered cabozantinib therapy and refused, or be ineligible for cabozantinib
             therapy. Patients with favorable risk disease have no eligibility requirement for
             prior use of cabozantinib. Cytoreductive nephrectomy is allowed but not mandatory.

          4. Has in the opinion of the investigator, a predicted life expectancy of more than 3
             months.

          5. Has presence of at least 1 lesion that is measurable or evaluable using RECIST v1.1.
             This is defined in at least one dimension as ≥20 mm with conventional techniques or as
             ≥10 mm with spiral CT, MRI or calipers by clinical exam

          6. Has either archival tissue for analysis or will require confirmation of disease with
             fresh biopsy. Tissue will not be required pre/post treatment for biomarker analysis.

          7. Has an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2.

          8. Patients with central nervous system metastases must have received surgical and/or
             radiation treatment, the metastases must be neurologically stable, and patients must
             be off corticosteroids or receiving a stable low-dose regimen of corticosteroids
             (i.e., a daily dose of 10 mg or less of prednisone or equivalent) for at least 4 weeks
             prior to the first dose of study drug.

          9. Has completed any prior anticancer treatment and must have recovered from any acute
             toxicities. The period between the last dose of prior treatment and the first dose of
             study drug treatment must be at least 1 week for radiotherapy, at least 3-4 weeks from
             prior VEGFR/mTOR/ or immunotherapy or any other tyrosine kinase inhibitor (TKI)
             therapy, and at least 4 weeks for treatment with investigational drugs

         10. Must be able to swallow capsules and tablets.

         11. Has adequate organ function (i.e. lung, liver, kidney, bone marrow), as evidenced by
             multiple laboratory value results within specific parameters.

         12. Women of childbearing potential (WOCP) as defined as not surgically sterile or not
             postmenopausal) must have a negative result for a serum pregnancy test before study
             drug administration on cycle 1 day 1. WOCP must use a medically accepted method of
             contraception and must agree to continue use this method for the duration of the study
             and for 30 days after discontinuation of study drug.

         13. If male, is surgically sterile, or, if capable of producing offspring, is currently
             using an approved method of birth control and agrees to continued use of this method
             for the duration of the study (and for 30 days after taking the last dose of study
             drug because of the possible effects on spermatogenesis).

        Exclusion Criteria:

          1. Predominately non-clear cell renal cell carcinoma histology (i.e. >50%)

          2. Has had chemotherapy within 4 weeks or radiotherapy within 1 week prior to first dose
             of study drug or those who have not recovered from toxicities due to agents
             administered more than 4 weeks earlier.

          3. Has ongoing or active infection requiring parenteral antibiotics.

          4. Has uncontrolled hypertension despite adequate therapy (i.e., systolic blood pressure
             higher than 150 mm Hg or diastolic blood pressure higher than 90 mm Hg found on 2
             separate occasions separated by 1 week).

          5. Has diabetes mellitus with occurrence of more than 2 episodes of ketoacidosis in the
             12 months prior to the first dose of study drug.

          6. Has an active second malignancy other than curatively resected basal cell carcinoma of
             the skin, squamous cell carcinoma of the skin, in situ carcinoma of the cervix, or
             other cancers for which they are treated with curative intent, and no known active
             disease in the 3 years prior to enrollment.

          7. Has a primary brain tumor or has brain metastases from a non-renal cell cancer.

          8. Has a QTcF interval greater than 470 msec, has a known history of QTcF prolongation,
             or has a history of torsade de pointes.

          9. Has a known history of human immunodeficiency virus (HIV), hepatitis B or hepatitis C.

         10. Has a known history of pulmonary fibrosis or any other restrictive lung disorder.

         11. Has any other concurrent conditions including a medical, psychiatric, or social
             condition that, in the opinion of the investigator, could preclude the patient's
             participation in the study, pose an undue medical hazard, or interfere with the
             interpretation of the study results, including, but not limited to, patients with
             congestive heart failure (New York Heart Association [NYHA] Class III or IV), cardiac
             arrhythmia, or acute coronary syndromes within 6 months of enrollment.

         12. Has used an investigational drug within 4 weeks prior to first dose of study drug or
             is currently participating in another investigational study.

         13. Has any disorder that may interfere with drug absorption, distribution, metabolism, or
             excretion (including gastrointestinal surgery or bariatric surgery).

         14. Has a history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to Abemaciclib or Sunitinib.

         15. Has previous use of a CDK4/6 kinase inhibitor (eg. ribociclib, palbociclib)

         16. Has previous use of a PIM1 kinase inhibitor
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:At the end of Cycle 1 (each cycle is 21 days)
Safety Issue:
Description:A standard 3+3 trial design will be used to determine the safest maximal tolerated dose of the combination of Abemaciclib with Sunitinib. Doses of each medication will be increased or decreased based on upon tolerability and assessment of any dose limiting toxicity(ies) that may occur in study subjects. Safety and toxicity will be evaluated using the NCI Common Toxicity Criteria.

Secondary Outcome Measures

Measure:Disease Control Rate
Time Frame:54 weeks
Safety Issue:
Description:The number of subjects achieving a response (complete response, partial response, stable disease) on the combination regimen of Abemaciclib and Sunitinib at 6, 12, 24, 36, 45, and 54 weeks post initiation of treatment.
Measure:Progression Free Survival
Time Frame:3 years
Safety Issue:
Description:The duration of time from the date of start of treatment until the criteria for disease progression is met by RECIST v1.1 criteria.
Measure:Overall Survival
Time Frame:3 years
Safety Issue:
Description:Overall Survival rate from initiation of Abemaciclib and Sunitinib to completion of the protocol prescribed drug regimen and required follow up time period.
Measure:Median Progression Free Survival
Time Frame:3 years
Safety Issue:
Description:The median number of days of progression free survival from initiation of Abemaciclib and Sunitinib to completion of the protocol prescribed drug regimen and required follow up time period.
Measure:Median Overall Survival
Time Frame:3 years
Safety Issue:
Description:The median number of days of survival from initiation of Abemaciclib and Sunitinib to completion of the protocol prescribed drug regimen and required follow up time period.
Measure:Duration of Response
Time Frame:3 years
Safety Issue:
Description:The period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Milton S. Hershey Medical Center

Trial Keywords

  • Renal cell carcinoma
  • Abemaciclib
  • Sunitinib

Last Updated

November 14, 2019