Vandetanib in Combination With Metformin in People With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma

NCT02495103 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 15015715-C-0157
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

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.

Conditions

Renal Cell Carcinoma; Hereditary Leiomyomatosis; Renal Cell Cancer

Keywords

Dose-Escalation; Maximum Tolerated Dose; Overall Response

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  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)

  Time from start of treatment to time of progression or death, whichever occurs first

• Phase 2 Component - Time to Progression (TTP)

  Approximately 8 weeks after initiation of therapy, every 8 weeks thereafter for the first 32 weeks, and then every 12 weeks while on treatment

Other Outcomes (2)

• Phase 1 Component - Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

  Approximately 24 months

• Phase 1 Component - Number of Participants With a Dose Limiting Toxicity (DLT)

  Cycle 1 or 42 days from the time the intended dose of metformin is reached for a given dose level

Study Arms (2)

Phase I Component - Vandetanib

EXPERIMENTAL

Phase I Component

Drug: Vandetanib; Drug: Metformin

Phase II Component- Vandetanib/Metformin

EXPERIMENTAL

Phase II Component

Drug: Vandetanib/Metformin

Interventions

Vandetanib DRUG

PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin.

Also known as: Caprelsa

Phase I Component - Vandetanib

Metformin DRUG

Phase I: Metformin starting dose 250mg by mouth (PO) daily in combination with Vandetanib

Also known as: Glucophage

Phase I Component - Vandetanib

Vandetanib/Metformin DRUG

Phase II: Vandetanib and metformin by mouth (PO) daily at determined maximum tolerated dose (MTD).

Phase II Component- Vandetanib/Metformin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• \. 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.
• \. Age greater than or equal to18 years.
• \. Eastern Cooperative Oncology Group (ECOG) performance status \<2 (Karnofsky \>60%).
• \. Negative pregnancy test (urine or serum) for female patients of childbearing potential.
• \. 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

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

vandetanib; Metformin

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Dr. Ramaprasad Srinivasan
• Organization: National Cancer Institute

ramasrin@mail.nih.gov

240-760-6251

Study Officials

• Ramaprasad Srinivasan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 8, 2015
• First Posted: July 13, 2015
• Study Start: August 26, 2015
• Primary Completion: February 6, 2020
• Study Completion: February 6, 2020
• Last Updated: January 26, 2021
• Results First Posted: January 26, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)