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Trial record 1 of 1 for:    NCT02495103
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Vandetanib in Combination With Metformin in People With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma

This study is currently recruiting participants.
Verified May 17, 2017 by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Sponsor:
ClinicalTrials.gov Identifier:
NCT02495103
First Posted: July 13, 2015
Last Update Posted: October 19, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
  Purpose

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.
  • 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 Intervention Phase
Renal Cell Carcinoma Hereditary Leiomyomatosis and Renal Cell Cancer Papillary Renal Cell Carcinoma, Sporadic Drug: Vandetanib Drug: Metformin Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 73
Study Start Date: July 8, 2015
Estimated Study Completion Date: May 1, 2022
Estimated Primary Completion Date: May 1, 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 2
Phase II Component: Patients with advanced sporadic/non-HLRCC papillary RCC.
Drug: Vandetanib
Vandetanib is commercially available under the trade name CAPRELSA, but will be supplied by the manufacturer (AstraZeneca Pharmaceuticals, Wilmington, DE) for the purposes of the study.
Drug: Metformin
Metformin is commercially available and manufactured by Bristol-Myers Squibb Company (Princeton, NJ) under the trade name GLUCOPHAGE.
Experimental: Cohort 1
Phase II Component: Patients with advanced HLRCC or SDH associated RCC.
Drug: Vandetanib
Vandetanib is commercially available under the trade name CAPRELSA, but will be supplied by the manufacturer (AstraZeneca Pharmaceuticals, Wilmington, DE) for the purposes of the study.
Drug: Metformin
Metformin is commercially available and manufactured by Bristol-Myers Squibb Company (Princeton, NJ) under the trade name GLUCOPHAGE.
Experimental: 1
Phase I Component: Patients with advanced RCC.
Drug: Vandetanib
Vandetanib is commercially available under the trade name CAPRELSA, but will be supplied by the manufacturer (AstraZeneca Pharmaceuticals, Wilmington, DE) for the purposes of the study.
Drug: Metformin
Metformin is commercially available and manufactured by Bristol-Myers Squibb Company (Princeton, NJ) under the trade name GLUCOPHAGE.

  Hide Detailed Description

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 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 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.

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 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.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 100 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Diagnosis/Histology

      1. Phase I Component Histologically confirmed advanced RCC of any subtype.
      2. Phase II Component Advanced RCC associated with 1) HLRCC or SDH (Cohort 1); OR 2) advanced non HLRCC-related papillary RCC (Cohort 2).
    2. Phase 1: Patients must have evaluable disease

Phase 2: Patients must have measurable disease based on 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 CT scan or MRI (except for lymph nodes, which must be >15 mm).

3. Prior Therapy

  1. Phase 1- Patients with clear cell RCC must have either declined, be ineligible to receive, have progressed on, or be intolerant to high dose IL-2, or standard first and second line VEGF, or mTOR targeted agents. As there is no standard therapy for metastatic non-clear cell RCC, no prior therapy is required.
  2. Phase 2- No more than two prior VEGF-pathway targeted agents
  3. No previous treatment with vandetanib. Previous or ongoing treatment with metformin is allowed.

    4. Age greater than or equal to18 years.

    5. 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)

    AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal

    eGFR (CKD-EPI) greater than or equal to 50 mL/min/1.73 m2

    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.

    EXCLUSION CRITERIA:

    1. Known serious allergic reaction to vandetanib or metformin.
    2. 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.
    3. 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.
    4. 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).
    5. Unacceptable electrolyte values, including:

      • Potassium <4.0 mmol/L despite supplementation, or elevated potassium above the CTCAE Grade 1 upper limit.
      • 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.
    6. 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.
    7. 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.
    8. Hypertension not controlled by medical therapy (systolic blood pressure greater than 140 millimeter of mercury [mmHg] or diastolic blood pressure greater than 90 mmHg).
    9. 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.
    10. Proteinuria > 1gram/24 hrs
    11. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.
    12. 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 QT syndrome.

    14 Any concomitant medications that are known to be associated with Torsades de Pointes Drugs that in the investigator s 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 QTcF correction unmeasurable or >450 ms on screening 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. 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 GI bleeding or those with bleeding diathesis

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02495103


Contacts
Contact: Martha Ninos, R.N. (301) 435-8897 mninos@mail.nih.gov

Locations
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      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Ramaprasad Srinivasan, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02495103     History of Changes
Other Study ID Numbers: 150157
15-C-0157
First Submitted: July 8, 2015
First Posted: July 13, 2015
Last Update Posted: October 19, 2017
Last Verified: May 17, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Dose-Escalation
Maximum Tolerated Dose
Safety
Overall Response

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Kidney Neoplasms
Leiomyomatosis
Skin Neoplasms
Uterine Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Leiomyoma
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Skin Diseases
Genital Neoplasms, Female
Uterine Diseases
Genital Diseases, Female
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs