Vandetanib in Combination With Metformin in People With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma
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|ClinicalTrials.gov Identifier: NCT02495103|
Recruitment Status : Recruiting
First Posted : July 13, 2015
Last Update Posted : April 4, 2018
- 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.
- 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.
- 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
- 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.
- ECG: soft electrodes will be stuck to the skin. A machine will record the heart s signals.
- Bone scan
- Some participants may have a gynecology evaluation or photos of skin tumors taken.
- Participants will have an optional tumor biopsy.
- After they stop taking the drugs, participants may have medical history, physical exam, and blood tests. They will be contacted once a year by phone to find out how they are doing.
|Condition or disease||Intervention/treatment||Phase|
|Renal Cell Carcinoma Hereditary Leiomyomatosis and Renal Cell Cancer Papillary Renal Cell Carcinoma, Sporadic||Drug: Vandetanib Drug: Metformin Drug: Vandetanib/Metformin||Phase 1 Phase 2|
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- 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.
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 (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.
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
Phase I Component:
- Combination vandetanib and metformin will be administered at starting doses of 300 mg QD and 250 mg 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 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||73 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|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|
|Study Start Date :||July 8, 2015|
|Estimated Primary Completion Date :||May 1, 2021|
|Estimated Study Completion Date :||May 1, 2022|
Phase II Component
Phase II: Vandetanib and metformin PO daily at determined MTD.
Phase I Component
PHASE I: Vandetanib PO daily at 300mg in combination with escalating doses of metformin.Drug: Metformin
Phase I: Metformin starting dose 250mg PO daily in combination with Vandetanib
- 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: 42 days after the last patient starts therapy. ]List of adverse events frequency and MTD
- 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: 3 years after the last patient finishes therapy. ]Percentage of patients who have a response to therapy.
- 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 ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02495103
|Contact: Martha Ninos, R.N.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937|
|Principal Investigator:||Ramaprasad Srinivasan, M.D.||National Cancer Institute (NCI)|