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 hypoxia-inducible factor 1 (HIF 1-) and its downstream targets that promote glucose delivery and uptake to fuel aerobic glycolysis, and c) downregulation of 5' AMP-activated protein kinase (AMPK), resulting in activation of the mammalian target of rapamycin (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 Vascular endothelial growth-factor receptor (VEGFR)/estimated glomerular filtration rate (EGFR) inhibitor that reverses the metabolic phenotype associated with fumarate hydratase (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 the safety and maximum tolerated dose of the combination of vandetanib with metformin in patients with advanced RCC.
Phase II Component:
-Determine the overall response rate (Response Evaluation Criteria in Solid Tumors (RECIST 1.1) following treatment with combine vandetanib/metformin in patients with 1) advanced RCC associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) or succinate dehydrogenase renal cell carcinoma (SDH-RCC), and 2) advanced sporadic papillary renal cell carcinoma.
ELIGIBILITY:
Phase I Component:
* Diagnosis of advanced RCC
* Patients with clear cell RCC must have either declined, be unable to receive, progressed on, or be intolerant of high-dose IL-2 or established first and second line VEGF and/or mTOR targeted agents
* No prior therapy is required in patients with non-clear cell RCC, but prior therapy is allowed
Phase II Component:
* Diagnosis of advanced RCC associated with HLRCC or SDH-RCC (cohort 1) or sporadic/non-HLRCC papillary RCC (cohort 2)
* No more than 2 prior regimens with VEGF-pathway antagonists
General requirements for both Phase I and II:
* Age greater than or equal to18
* Brain metastases or spinal cord compression that requires treatment, unless the treatment ended at least 4 weeks before starting protocol therapy and the condition has been stable without steroid treatment for at least 10 days
* No major surgery within four weeks or inadequately healed wounds prior to study enrollment
* Adequate organ function
DESIGN:
Phase I Component:
* Combination vandetanib and metformin will be administered at starting doses of 300 mg every day (QD) and 250 mg twice a day (BID), respectively.
* The study design is based on a single arm, fixed order dose-escalation Phase 1 study using a modified Fibronacci schema.
* Up to 6 patients may be enrolled in a specific dose combination cohort. Based on the assumption that 3 dose levels will be evaluated, the total number of evaluable patients will be 18. To allow for a few patients who may be inevaluable, the accrual ceiling for this portion of the study will be set at 21. Based on how dose escalation proceeds and the adverse events seen, the total number of patients to be accrued may be changed via a protocol amendment.
Phase II Component:
* Once the maximum tolerated dose (MTD) is determined, the appropriate combination dose will be evaluated in the phase 2 component.
* Patients will be accrued into one of two independent, parallel cohorts:
* Cohort 1 Patients with advanced HLRCC or SDH associated RCC.
* Cohort 2 Patients with advanced sporadic/non-HLRCC papillary kidney cancer.
* Patients will be evaluated for response every 8-12 weeks using RECIST 1.1.
* The study is based on open label two-stage optimal phase II design.
* The accrual ceiling for this portion of the study will be 21 patients for each cohort.
