Trial Outcomes & Findings for Vandetanib in Combination With Metformin in People With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma (NCT NCT02495103)

Last Updated: 2021-01-26

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

7 participants

Primary outcome timeframe

42 days after the last patient starts therapy.

Results posted on

2021-01-26

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I, Dose Level 1 - Metformin 250mg Daily/Vandetanib 300mg Daily Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) daily in combination with Vandetanib	Phase I, Dose Level 2 - Metformin 250mg Twice Daily/Vandetanib 300mg Daily Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) twice daily in combination with Vandetanib
Overall Study STARTED	3	4
Overall Study COMPLETED	3	4
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I, Dose Level 1 - Metformin 250mg Daily/Vandetanib 300mg Daily n=3 Participants Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) daily in combination with Vandetanib	Phase I, Dose Level 2 - Metformin 250mg Twice Daily/Vandetanib 300mg Daily n=4 Participants Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) twice daily in combination with Vandetanib	Total n=7 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	44.2 years STANDARD_DEVIATION 4.77 • n=5 Participants	57.9 years STANDARD_DEVIATION 3.07 • n=7 Participants	52.03 years STANDARD_DEVIATION 8.12 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants

PRIMARY outcome

Timeframe: 42 days after the last patient starts therapy.

Outcome measures

Outcome measures
Measure	All Participants n=7 Participants All participants that received Phase I, Dose Level 1 - Metformin 250mg daily/Vandetanib 300mg daily; and Phase I, Dose Level 2 - Metformin 250mg twice daily/Vandetanib 300mg daily.	Phase I, Dose Level 2 - Metformin 250mg Twice Daily/Vandetanib 300mg Daily Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) twice daily in combination with Vandetanib
Phase 1 Component - Maximum Tolerated Dose (MTD) of Vandetanib and Metformin When Used in Combination in Patients With Metastatic Renal Cell Carcinoma (RCC)	NA mg MTD was not reached because accrual was halted before sufficient number of patients could be enrolled for adequate MTD.	—

PRIMARY outcome

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

Population: This outcome measure was not done because we did not enter the phase II portion of the study, thus this endpoint was not evaluated. Vandetanib is no longer available as Sanofi has decided not to provide additional drug.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

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

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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Approximately 24 months

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Outcome measures

Outcome measures
Measure	All Participants n=3 Participants All participants that received Phase I, Dose Level 1 - Metformin 250mg daily/Vandetanib 300mg daily; and Phase I, Dose Level 2 - Metformin 250mg twice daily/Vandetanib 300mg daily.	Phase I, Dose Level 2 - Metformin 250mg Twice Daily/Vandetanib 300mg Daily n=4 Participants Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) twice daily in combination with Vandetanib
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).	3 Participants	4 Participants

OTHER_PRE_SPECIFIED outcome

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

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.

Outcome measures

Outcome measures
Measure	All Participants n=3 Participants All participants that received Phase I, Dose Level 1 - Metformin 250mg daily/Vandetanib 300mg daily; and Phase I, Dose Level 2 - Metformin 250mg twice daily/Vandetanib 300mg daily.	Phase I, Dose Level 2 - Metformin 250mg Twice Daily/Vandetanib 300mg Daily n=4 Participants Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) twice daily in combination with Vandetanib
Phase 1 Component - Number of Participants With a Dose Limiting Toxicity (DLT)	0 Participants	0 Participants

Adverse Events

Phase I, Dose Level 1 - Metformin 250mg Daily/Vandetanib 300mg Daily

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Phase I, Dose Level 2 - Metformin 250mg Twice Daily/Vandetanib 300mg Daily

Serious events: 2 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase I, Dose Level 1 - Metformin 250mg Daily/Vandetanib 300mg Daily n=3 participants at risk Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) daily in combination with Vandetanib	Phase I, Dose Level 2 - Metformin 250mg Twice Daily/Vandetanib 300mg Daily n=4 participants at risk Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) twice daily in combination with Vandetanib
Gastrointestinal disorders Vomiting	33.3% 1/3 • Number of events 1 • Approximately 24 months.	0.00% 0/4 • Approximately 24 months.
Vascular disorders Hypotension	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
General disorders Pain	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.

Other adverse events

Other adverse events
Measure	Phase I, Dose Level 1 - Metformin 250mg Daily/Vandetanib 300mg Daily n=3 participants at risk Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) daily in combination with Vandetanib	Phase I, Dose Level 2 - Metformin 250mg Twice Daily/Vandetanib 300mg Daily n=4 participants at risk Phase I Component Vandetanib: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. Metformin: Phase I: Metformin starting dose 250mg by mouth (PO) twice daily in combination with Vandetanib
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 4 • Approximately 24 months.
Investigations Activated partial thromboplastin time prolonged	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Investigations Alkaline phosphatase increased	33.3% 1/3 • Number of events 1 • Approximately 24 months.	50.0% 2/4 • Number of events 4 • Approximately 24 months.
Investigations Alanine aminotransferase increased	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 6 • Approximately 24 months.
Blood and lymphatic system disorders Anemia	33.3% 1/3 • Number of events 1 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Metabolism and nutrition disorders Anorexia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 3 • Approximately 24 months.
Psychiatric disorders Anxiety	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/3 • Approximately 24 months.	50.0% 2/4 • Number of events 3 • Approximately 24 months.
Investigations Aspartate aminotransferase increased	0.00% 0/3 • Approximately 24 months.	75.0% 3/4 • Number of events 7 • Approximately 24 months.
Nervous system disorders Ataxia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Nervous system disorders Cognitive disturbance	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Nervous system disorders Concentration impairment	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 2 • Approximately 24 months.
Gastrointestinal disorders Constipation	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 3 • Approximately 24 months.
Respiratory, thoracic and mediastinal disorders Cough	33.3% 1/3 • Number of events 1 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Investigations Creatinine increased	66.7% 2/3 • Number of events 5 • Approximately 24 months.	75.0% 3/4 • Number of events 8 • Approximately 24 months.
Gastrointestinal disorders Diarrhea	33.3% 1/3 • Number of events 1 • Approximately 24 months.	75.0% 3/4 • Number of events 7 • Approximately 24 months.
Nervous system disorders Dizziness	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 2 • Approximately 24 months.
Gastrointestinal disorders Dry mouth	33.3% 1/3 • Number of events 1 • Approximately 24 months.	0.00% 0/4 • Approximately 24 months.
Gastrointestinal disorders Dysphagia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
General disorders Edema trunk	33.3% 1/3 • Number of events 2 • Approximately 24 months.	0.00% 0/4 • Approximately 24 months.
Cardiac disorders Electrocardiogram QT corrected interval prolonged	66.7% 2/3 • Number of events 6 • Approximately 24 months.	75.0% 3/4 • Number of events 6 • Approximately 24 months.
Eye disorders Eye disorders - Other, specify	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Injury, poisoning and procedural complications Fall	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
General disorders Fatigue	33.3% 1/3 • Number of events 1 • Approximately 24 months.	50.0% 2/4 • Number of events 6 • Approximately 24 months.
Musculoskeletal and connective tissue disorders Flank pain	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Nervous system disorders Headache	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Renal and urinary disorders Hematuria	0.00% 0/3 • Approximately 24 months.	50.0% 2/4 • Number of events 6 • Approximately 24 months.
Renal and urinary disorders Hemoglobinuria	0.00% 0/3 • Approximately 24 months.	50.0% 2/4 • Number of events 5 • Approximately 24 months.
Metabolism and nutrition disorders Hypercalcemia	33.3% 1/3 • Number of events 1 • Approximately 24 months.	0.00% 0/4 • Approximately 24 months.
Metabolism and nutrition disorders Hyperkalemia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Vascular disorders Hypertension	33.3% 1/3 • Number of events 3 • Approximately 24 months.	50.0% 2/4 • Number of events 3 • Approximately 24 months.
Metabolism and nutrition disorders Hyperuricemia	66.7% 2/3 • Number of events 4 • Approximately 24 months.	25.0% 1/4 • Number of events 3 • Approximately 24 months.
Metabolism and nutrition disorders Hypoalbuminemia	33.3% 1/3 • Number of events 1 • Approximately 24 months.	100.0% 4/4 • Number of events 14 • Approximately 24 months.
Metabolism and nutrition disorders Hypocalcemia	66.7% 2/3 • Number of events 2 • Approximately 24 months.	50.0% 2/4 • Number of events 3 • Approximately 24 months.
Metabolism and nutrition disorders Hypoglycemia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 2 • Approximately 24 months.
Metabolism and nutrition disorders Hypomagnesemia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 4 • Approximately 24 months.
Metabolism and nutrition disorders Hyponatremia	33.3% 1/3 • Number of events 1 • Approximately 24 months.	75.0% 3/4 • Number of events 5 • Approximately 24 months.
Metabolism and nutrition disorders Hypophosphatemia	33.3% 1/3 • Number of events 1 • Approximately 24 months.	75.0% 3/4 • Number of events 5 • Approximately 24 months.
Endocrine disorders Hypothyroidism	33.3% 1/3 • Number of events 1 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Psychiatric disorders Insomnia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Investigations Lipase increased	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 8 • Approximately 24 months.
Investigations Lymphocyte count decreased	33.3% 1/3 • Number of events 2 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Nervous system disorders Memory impairment	0.00% 0/3 • Approximately 24 months.	50.0% 2/4 • Number of events 3 • Approximately 24 months.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 2 • Approximately 24 months.
Gastrointestinal disorders Nausea	33.3% 1/3 • Number of events 3 • Approximately 24 months.	75.0% 3/4 • Number of events 3 • Approximately 24 months.
Musculoskeletal and connective tissue disorders Non-cardiac chest pain	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
General disorders Pain	33.3% 1/3 • Number of events 1 • Approximately 24 months.	75.0% 3/4 • Number of events 12 • Approximately 24 months.
Nervous system disorders Paresthesia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Infections and infestations Paronychia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Skin and subcutaneous tissue disorders Photosensitivity	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Respiratory, thoracic and mediastinal disorders Pleural effusion	33.3% 1/3 • Number of events 1 • Approximately 24 months.	0.00% 0/4 • Approximately 24 months.
Renal and urinary disorders Proteinuria	66.7% 2/3 • Number of events 4 • Approximately 24 months.	100.0% 4/4 • Number of events 8 • Approximately 24 months.
Skin and subcutaneous tissue disorders Rash acneiform	33.3% 1/3 • Number of events 1 • Approximately 24 months.	75.0% 3/4 • Number of events 3 • Approximately 24 months.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Investigations Serum amylase increased	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 6 • Approximately 24 months.
Cardiac disorders Sinus bradycardia	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 2 • Approximately 24 months.
Nervous system disorders Somnolence	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Gastrointestinal disorders Toothache	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Renal and urinary disorders Urinary incontinence	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Infections and infestations Urinary tract infection	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.
Gastrointestinal disorders Vomiting	33.3% 1/3 • Number of events 1 • Approximately 24 months.	0.00% 0/4 • Approximately 24 months.
Investigations Weight loss	0.00% 0/3 • Approximately 24 months.	25.0% 1/4 • Number of events 1 • Approximately 24 months.

Additional Information

Dr. Ramaprasad Srinivasan

National Cancer Institute

Phone: 240-760-6251

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place