Renal Cell CarcinomaPhase 1/2NCT02495103
Vandetanib in Combination With Metformin in People With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma
A Phase 1/2 study testing Vandetanib, Metformin and Vandetanib/Metformin in people with Renal Cell Carcinoma and Hereditary Leiomyomatosis, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Renal Cell Carcinoma, Hereditary Leiomyomatosis, Renal Cell Cancer
- What is being tested?
- Vandetanib, Metformin and Vandetanib/Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 1 siteUnited States
- Study dates
- 26 Aug 2015to 6 Feb 2020
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis/Histology
- Phase I Component - Histologically confirmed advanced Renal Cell Carcinoma (RCC) of any subtype.
- Phase II Component - Advanced RCC associated with 1) Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) or Succinate dehydrogenase (SDH) (Cohort 1); OR 2) advanced non HLRCC-related papillary RCC (Cohort 2).
- Phase 1: Patients must have evaluable disease
- Phase 2: Patients must have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral computed tomography (CT) scan or magnetic resonance imaging (MRI) (except for lymph nodes, which must be >15 mm).
- 3. Prior Therapy
Show all 20Show fewer
- Phase 1- Patients with clear cell RCC must have either declined, be ineligible to receive, have progressed on, or be intolerant to high dose Interleukin 2 (IL-2), or standard first and second line Vascular endothelial growth factor (VEGF), or mammalian target of rapamycin (mTOR) targeted agents. As there is no standard therapy for metastatic non-clear cell RCC, no prior therapy is required.
- Phase 2- No more than two prior VEGF-pathway targeted agents
- No previous treatment with vandetanib. Previous or ongoing treatment with metformin is allowed.
- 4. Age greater than or equal to18 years.
- 5. Eastern Cooperative Oncology Group (ECOG) performance status <2 (Karnofsky >60%).
- 6. Negative pregnancy test (urine or serum) for female patients of childbearing potential.
- 7. Patients must have normal organ and marrow function as defined below:
- absolute neutrophil count greater than or equal to 1,500/mcL
- platelets greater than or equal to 100,000/mcL
- total bilirubin less than or equal to 1.5x upper limit of reference range ( < 3x upper limit of reference range in patients with Gilbert's disease)
- aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)(Serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5 X institutional upper limit of normal
- Estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) greater than or equal to 50 mL/min/1.73 m^2
- 8. Men and women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for at least 6 months after vandetanib/metformin therapy. Should a woman become pregnant (either a participant or the partner of a male participant) or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
- 9. Ability of subject to understand and the willingness to sign a written informed consent document.
Who cannot join
- Known serious allergic reaction to vandetanib or metformin.
- 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.
- Major surgery (includes any surgery that carries significant risk of blood loss, extended periods of general anesthesia, or requires at least an overnight hospital admission) within 28 days before starting treatment or inadequately healed incision/scar from prior surgery.
- Any unresolved chronic toxicity greater than Common Terminology Criteria for Adverse Event (CTCAE) Grade 2 or greater from previous anti-cancer therapy (this criterion does not apply to alopecia).
- Unacceptable electrolyte values, including:
- Potassium <4.0 mmol/L despite supplementation, or elevated potassium above the CTCAE Grade 1 upper limit.
Show all 25Show fewer
- Magnesium below the lower limit of normal range despite supplementation, or elevated magnesium above the CTCAE Grade 1 upper limit.
- Ionized calcium or corrected calcium values below the normal range or hypercalcemia above the CTCAE Grade 1 upper limit.
- Significant cardiac event (eg, myocardial infarction), New York Heart Association (NYHA) classification of heart disease greater than or equal to 2 within 12 weeks before starting treatment, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia.
- History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication are permitted.
- Hypertension not controlled by medical therapy (systolic blood pressure greater than 140 millimeter of mercury [mmHg] or diastolic blood pressure greater than 90 mmHg).
- Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease.
- Proteinuria > 1gram/24 hrs
- Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigators opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.
- Previous or current invasive malignancies of other histologies requiring treatment within the last 2 years, with the exception of adequately treated basal cell or squamous cell carcinoma of the skin (phase 2 only).
- 13 Congenital long Q wave T wave (QT) syndrome.
- 14 Any concomitant medications that are known to be associated with Torsades de Pointes Drugs that in the investigators opinion cannot be discontinued, are allowed however, must be monitored closely
- 15 .Any concomitant potent inducers of cytochrome P450 3A4 (CYP3A4) function (see http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a continually updated list of CYP3A4 inducers).
- 16 History of QT prolongation associated with other medications that required discontinuation of that medication.
- 17 Fridericia's (QTcF) correction unmeasurable or >450 ms on screening electrocardiogram (ECG) (Note: If a patient has a QTcF interval >450 ms on screening ECG, the screening ECG may be repeated twice [at least 24 hours apart] for a total of 3 ECGs. The average QTcF from the three
- screening ECGs must be less than or equal to 450 ms in order for the patient to be eligible for the study).
- 18. Women that are currently breast feeding.
- 19. Active treatment-refractory diarrhea that may affect the ability of the patient to absorb the trial agents or tolerate further diarrhea.
- 20. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with vandetanib/metformin.
- 21. Patients with active hemoptysis, clinically significant non hemorrhoidal gastrointestinal (GI) bleeding or those with bleeding diathesis
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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
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.
Read more
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.
Read the 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.
- Being tested
- Vandetanib, Metformin, Vandetanib/Metformin
- Keywords
- Dose-Escalation, Maximum Tolerated Dose, Overall Response
- Medical subject headings
- Carcinoma, Renal Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VandetanibDrug
Also called Caprelsa
PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin.
MetforminDrug
Also called Glucophage
Phase I: Metformin starting dose 250mg by mouth (PO) daily in combination with Vandetanib
Vandetanib/MetforminDrug
Phase II: Vandetanib and metformin by mouth (PO) daily at determined maximum tolerated dose (MTD).
| Study group | Role | What they receive |
|---|---|---|
| Phase I Component - Vandetanib | Experimental | Phase I Component Receives: Drug: Vandetanib; Drug: Metformin |
| Phase II Component- Vandetanib/Metformin | Experimental | Phase II Component Receives: Drug: Vandetanib/Metformin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 1 Component - Maximum Tolerated Dose (MTD) of Vandetanib and Metformin When Used in Combination in Patients With Metastatic Renal Cell Carcinoma (RCC)
MTD is the dose level at which no more than 1 of up to 6 patients experience dose limiting toxicity (DLT) during 1 cycle of treatment (42 days from the time the intended dose of metformin is reached for a given dose level), and the dose below that at which at least 2 (of ≤6) patients have DLT as a result of the experimental regimen. A DLT is defined as grade III or greater diarrhea leading to hospitalization or lasting > 48 hours despite optimal anti-diarrheal medication; grade IV diarrhea despite optimal anti-diarrheal prophylaxis; grade III or greater nausea or vomiting despite optimal antiemetics; grade III hypertension that is not controlled (to 140/90 mmHg or below) despite optimal antihypertensive therapy; grade III elevated serum creatinine that cannot be corrected to grade 1 or better with hydration within 48 hours; and electrolyte abnormalities that cannot be corrected with medical management within 72 hours.
Measured: 42 days after the last patient starts therapy.
Phase 2 Component - Percentage of Participants With an Overall Response Rate Following Treatment With the Combination of Vandetanib and Metformin
Percentage of participants with an overall response rate following treatment with the combination of vandetanib and metformin in patients with 1) advanced Renal Cell Carcinoma (RCC) associated with Hereditary leiomyomatosis and renal cell cancer (HLRCC) or Succinate Dehydrogenase (SDH), and 2) advanced sporadic/non-HLRCC Papillary Renal Cell Carcinoma assessed by the Response Evaluation Criteria in SOlid Tumors (RECIST) v1.1.
Measured: Approximately 8 weeks after initiation of therapy, every 8 weeks thereafter for the first 32 weeks, and then every 12 weeks while on treatment
Secondary outcomes (2)
Phase 2 Component - Progression Free Survival (PFS)
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was assessed by the and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.
Measured: Time from start of treatment to time of progression or death, whichever occurs first
Phase 2 Component - Time to Progression (TTP)
Time to progression is the time between the first day of treatment to the day of disease progression. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.
Measured: Approximately 8 weeks after initiation of therapy, every 8 weeks thereafter for the first 32 weeks, and then every 12 weeks while on treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jul 2015 (estimated)
- Study start26 Aug 2015
- Primary completion6 Feb 2020
- Study completion6 Feb 2020
Why it stopped: Vandetanib is no longer available as Sanofi has decided not to provide additional drug. All subjects are off-study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Renal Cell CarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 7 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Ramaprasad Srinivasan, M.D., National Cancer Institute (NCI)
- Investigators
- Ramaprasad Srinivasan, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02495103
- Sponsor's protocol ID
- 150157
- Other IDs
- 15-C-0157
- Status last verified
- Jan 2021
- First submitted
- 8 Jul 2015
- Last updated
- 26 Jan 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02495103
- Acronym / sponsor ID
- 150157
- Keywords
- Dose-Escalation, Maximum Tolerated Dose, Overall Response
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Vandetanib is no longer available as Sanofi has decided not to provide additional drug. All subjects are off-study.
- Enrolment
- 7 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 26 Aug 2015 (actual)
- Primary completion
- 6 Feb 2020 (actual)
- Study completion
- 6 Feb 2020 (actual)
- First posted
- 13 Jul 2015 (estimated)
- Results
- Posted 26 Jan 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Phase I Component - Vandetanib | Experimental | Drug: Vandetanib, Drug: MetforminPhase I Component |
| Phase II Component- Vandetanib/Metformin | Experimental | Drug: Vandetanib/MetforminPhase II Component |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- Phase 2: Patients must have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral computed tomography (CT) scan or magnetic resonance imaging (MRI) (except for lymph nodes, which must be >15 mm).
- 3. Prior Therapy
- Phase 1- Patients with clear cell RCC must have either declined, be ineligible to receive, have progressed on, or be intolerant to high dose Interleukin 2 (IL-2), or standard first and second line Vascular endothelial growth factor (VEGF), or mammalian target of rapamycin (mTOR) targeted agents. As there is no standard therapy for metastatic non-clear cell RCC, no prior therapy is required.
- Phase 2- No more than two prior VEGF-pathway targeted agents
- No previous treatment with vandetanib. Previous or ongoing treatment with metformin is allowed.
Key exclusion criteria (25 listed)
- 13 Congenital long Q wave T wave (QT) syndrome.
- 14 Any concomitant medications that are known to be associated with Torsades de Pointes Drugs that in the investigators opinion cannot be discontinued, are allowed however, must be monitored closely
- 15 .Any concomitant potent inducers of cytochrome P450 3A4 (CYP3A4) function (see http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a continually updated list of CYP3A4 inducers).
- 16 History of QT prolongation associated with other medications that required discontinuation of that medication.
- 17 Fridericia's (QTcF) correction unmeasurable or >450 ms on screening electrocardiogram (ECG) (Note: If a patient has a QTcF interval >450 ms on screening ECG, the screening ECG may be repeated twice [at least 24 hours apart] for a total of 3 ECGs. The average QTcF from the three
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VandetanibAlso: CaprelsaPHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. | Drug | Phase I Component - Vandetanib |
| MetforminAlso: GlucophagePhase I: Metformin starting dose 250mg by mouth (PO) daily in combination with Vandetanib | Drug | Phase I Component - Vandetanib |
| Vandetanib/MetforminPhase II: Vandetanib and metformin by mouth (PO) daily at determined maximum tolerated dose (MTD). | Drug | Phase II Component- Vandetanib/Metformin |
Primary outcome
Phase 1 Component - Maximum Tolerated Dose (MTD) of Vandetanib and Metformin When Used in Combination in Patients With Metastatic Renal Cell Carcinoma (RCC)
Time frame: 42 days after the last patient starts therapy.
MTD is the dose level at which no more than 1 of up to 6 patients experience dose limiting toxicity (DLT) during 1 cycle of treatment (42 days from the time the intended dose of metformin is reached for a given dose level), and the dose below that at which at least 2 (of ≤6) patients have DLT as a result of the experimental regimen. A DLT is defined as grade III or greater diarrhea leading to hospitalization or lasting > 48 hours despite optimal anti-diarrheal medication; grade IV diarrhea despite optimal anti-diarrheal prophylaxis; grade III or greater nausea or vomiting despite optimal antiemetics; grade III hypertension that is not controlled (to 140/90 mmHg or below) despite optimal antihypertensive therapy; grade III elevated serum creatinine that cannot be corrected to grade 1 or better with hydration within 48 hours; and electrolyte abnormalities that cannot be corrected with medical management within 72 hours.
Phase 2 Component - Percentage of Participants With an Overall Response Rate Following Treatment With the Combination of Vandetanib and Metformin
Time frame: Approximately 8 weeks after initiation of therapy, every 8 weeks thereafter for the first 32 weeks, and then every 12 weeks while on treatment
Percentage of participants with an overall response rate following treatment with the combination of vandetanib and metformin in patients with 1) advanced Renal Cell Carcinoma (RCC) associated with Hereditary leiomyomatosis and renal cell cancer (HLRCC) or Succinate Dehydrogenase (SDH), and 2) advanced sporadic/non-HLRCC Papillary Renal Cell Carcinoma assessed by the Response Evaluation Criteria in SOlid Tumors (RECIST) v1.1.
2 secondary outcomes
Phase 2 Component - Progression Free Survival (PFS)
Time frame: Time from start of treatment to time of progression or death, whichever occurs first
Phase 2 Component - Time to Progression (TTP)
Time frame: Approximately 8 weeks after initiation of therapy, every 8 weeks thereafter for the first 32 weeks, and then every 12 weeks while on treatment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jan 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ramaprasad Srinivasan, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Vandetanib, Metformin and Vandetanib/Metformin in people with Renal Cell Carcinoma and Hereditary Leiomyomatosis, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Jan 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1 Component - Maximum Tolerated Dose (MTD) of Vandetanib and Metformin When Used in Combination in Patients With Metastatic Renal Cell Carcinoma (RCC) (time frame: 42 days after the last patient starts therapy.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jan 2021.