Ignite Creation Date:
2025-12-24 @ 7:46 PM
Ignite Modification Date:
2026-01-03 @ 1:14 AM
Study NCT ID:
NCT02495103
Status:
TERMINATED
Last Update Posted:
2021-01-26
First Post:
2015-07-08
Is NOT Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Vandetanib in Combination With Metformin in People With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma
Sponsor:
National Cancer Institute (NCI)
Organization:
Study Overview
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
Status:
TERMINATED
Status Verified Date:
2021-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Vandetanib is no longer available as Sanofi has decided not to provide additional drug. All subjects are off-study.
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
* Magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) scan, and other imaging tests: they will lie in machines that take pictures of their body.
* Electrocardiogram (ECG): soft electrodes will be stuck to the skin. A machine will record the hearts 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.
\- 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
* Magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) scan, and other imaging tests: they will lie in machines that take pictures of their body.
* Electrocardiogram (ECG): soft electrodes will be stuck to the skin. A machine will record the hearts 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.
Detailed Description:
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.
* 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.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| 15-C-0157 | None | None | View |