Clinical Trial: Vandetanib in Combination With Metformin in People With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Phase I/II Trial of Vandetanib in Combination With Metformin in Subjects With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma

Brief Summary:

Background:

- There are no established treatments for people with certain advanced kidney cancers. These tumors often don t respond well to currently available treatments. Researchers believe that two drugs that treat other diseases metformin and vandetanib could help people with advanced kidney cancer.

Objective:

- To test the combination of metformin and vandetanib in people with advanced kidney cancer. Phase I of the study will determine a safe dose for the drugs. Phase II will test this dose in people with certain kidney cancers.

Eligibility:

  • For Phase I, people 18 and over with advanced kidney cancer
  • For Phase II, people 18 and over with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC), succinate dehydrogenase renal cell carcinoma (SDH-RCC), or advanced papillary renal cell carcinoma not related to a hereditary syndrome

Design:

  • The study will last many months.
  • Participants will be screened with medical history and physical exam.
  • Participants will take the study drugs by mouth every day.
  • Participants will measure and record their blood pressure every day.
  • Participants will have many tests:
  • Blood and urine tests
  • MRI, CT, PET scan, and other imaging tests: they will lie in machines that take pictures of their body.

  • Detailed Summary:

    BACKGROUND:

    • The management of advanced renal cell carcinoma (RCC) continues to remain a challenge, particularly for patients with papillary and non-clear cell variants of RCC, for whom there is no standard therapy of proven benefit.
    • Inactivation of the Krebs cycle enzyme Fumarate Hydratase (FH) in tumors associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) results in a metabolic shift characterized by a) reliance on aerobic glycolysis for energy production, b) upregulation of HIF 1- and its downstream targets that promote glucose delivery and uptake to fuel aerobic glycolysis, and c) downregulation of AMPK, resulting in activation of the mTOR pathway and increased macromolecule synthesis.
    • Inactivation of another Krebs cycle enzyme, Succinate Dehydrogenase (SDH), is also associated with a familial form of kidney cancer which shares some of the above metabolic features.
    • Vandetanib is a dual VEGFR/EGFR inhibitor that reverses the metabolic phenotype associated with FH (and SDH) inactivation and has potent preclinical activity in FH-/- and SDH -/- tumors. Metformin activates AMPK and has demonstrated potent synergy when combined with vandetanib, in preclinical models of FH -/- tumors.
    • In this phase 1/2 trial, we first propose to establish the safety and dosing parameters of combined vandetanib and metformin therapy. We then propose to test the activity of vandetanib in combination with metformin in patients with HLRCC or SDH-associated RCC, as well as those with sporadic forms of papillary RCC.

    OBJECTIVE:

    Phase I Component:

    -Establish
    Sponsor: National Cancer Institute (NCI)

    Current Primary Outcome:

    • Phase 1 Component: To establish the safety and maximum tolerated dose (MTD) of vandetanib and metformin when used in combination in patients with metastatic RCC. [ Time Frame: 1- 2 years ]
    • Phase 2 Component: To determine the overall response rate (RECIST 1.1) following treatment with the combination of vandetanib and metformin in patients with 1) advanced RCC associated with HLRCC or SDH, and 2) advanced sporadic/non-HLRCC papilla... [ Time Frame: 2- 3 years ]


    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Phase 1 Component: Evaluate the clinical activity of the combination of vandetanib and metformin [ Time Frame: 2-3 years ]
    • Phase 1 Component: Evaluate modulation of the biochemical and metabolic phenotype following therapy using paired pre- and on-treatment tumor biopsies (when available) [ Time Frame: 2-3 years ]
    • Phase 1 Component: Identify drug interaction between metformin and vandetanib at clinically-relevant doses [ Time Frame: 2-3 years ]
    • Phase 2 Component: Assess duration of response, progression-free survival and overall survival with this combination [ Time Frame: 2-3 years ]
    • Phase 2 Component: Investigate the effect of vandetanib/metformin on potential biomarkers of angiogenesis in plasma such as VEGF and soluble VEGFR2 [ Time Frame: 2-3 years ]
    • Phase 2 Component: Evaluate modulation of the biochemical and metabolic phenotype following therapy using paired pre- and on-treatment tumor biopsies (when available) [ Time Frame: 2-3 years ]
    • Phase 2 Component: Evaluate the prevalence of somatic fumarate hydratase (FH) and succinate dehydrogenase (SDH)mutations/inactivation as well as activation of/mutations in theNRF2/KEAP1/CUL3 pathway in patients with sporadic papillary RCC and... [ Time Frame: 2-3 years ]


    Original Secondary Outcome:

    Information By: National Institutes of Health Clinical Center (CC)

    Dates:
    Date Received: July 8, 2015
    Date Started: June 30, 2015
    Date Completion: May 1, 2022
    Last Updated: May 12, 2017
    Last Verified: October 4, 2016