Trial Outcomes & Findings for Tandutinib in Treating Patients With Recurrent or Progressive Glioblastoma (NCT NCT00379080)

NCT ID: NCT00379080

Last Updated: 2017-04-07

Results Overview

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 60 participants
• Primary outcome timeframe: cycle 1 - 28 days
• Results posted on: 2017-04-07

Participant Flow

Patients enrolled from 4/2007 through 6/2010. Patients accrued in the outpatient clinical setting. The first part of study was for patients who required surgery. Hence these patients were treated in-patient.

Participant milestones

Measure	Arm 1- Phase 0 Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. conventional surgery oral tandutinib Pharmacological study Tissue samples	Arm 2 - Phase 1 Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. tandutinib: Given orally pharmacological study: Correlative studies	Arm 3 - Phase 2 Patients receive tandutinib as in phase I at the MTD determined in phase I. 600mg was the determined MTD in Dose Escalation oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies
Overall Study STARTED	6	19	31
Overall Study COMPLETED	6	15	31
Overall Study NOT COMPLETED	0	4	0

Reasons for withdrawal

Measure	Arm 1- Phase 0 Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. conventional surgery oral tandutinib Pharmacological study Tissue samples	Arm 2 - Phase 1 Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. tandutinib: Given orally pharmacological study: Correlative studies	Arm 3 - Phase 2 Patients receive tandutinib as in phase I at the MTD determined in phase I. 600mg was the determined MTD in Dose Escalation oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies
Overall Study Withdrawal by Subject	0	4	0

Baseline Characteristics

Tandutinib in Treating Patients With Recurrent or Progressive Glioblastoma

Baseline characteristics by cohort

Measure	Arm 1 - Phase 0 n=6 Participants Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. conventional surgery oral tandutinib Pharmacological study Tissue samples	Arm 2 - Phase 1 n=19 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. tandutinib: Given orally pharmacological study: Correlative studies	Arm 3 - Phase 2 n=31 Participants Patients receive tandutinib as in phase I at the MTD determined in phase I. 600mg was the determined MTD in Dose Escalation oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Total n=56 Participants Total of all reporting groups
Age, Continuous	61 years n=5 Participants	56 years n=7 Participants	54 years n=5 Participants	56 years n=4 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants	13 Participants n=4 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	15 Participants n=7 Participants	24 Participants n=5 Participants	43 Participants n=4 Participants
Karnofsky Performance Status	80 Percentage n=5 Participants	90 Percentage n=7 Participants	90 Percentage n=5 Participants	90 Percentage n=4 Participants
Mini Mental Score	29 units on a scale n=5 Participants	30 units on a scale n=7 Participants	29 units on a scale n=5 Participants	29 units on a scale n=4 Participants
Steroids Yes	5 participants n=5 Participants	10 participants n=7 Participants	8 participants n=5 Participants	23 participants n=4 Participants
Steroids No	1 participants n=5 Participants	9 participants n=7 Participants	23 participants n=5 Participants	33 participants n=4 Participants

PRIMARY outcome

Timeframe: cycle 1 - 28 days

Population: 19 patients enrolled in dose escalation but 4 were removed for reasons other than drug related toxicity

Outcome measures

Measure	Level 2 - 600mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=15 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Maximum Tolerated Dose of Tandutinib Defined by Dose Limiting Toxicities (Phase 1)	—	—	600 mg BID	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 7 days prior to surgery including surgery

Population: a tandutinib tumor:plasma ratio of \>/=0.33 was the objective in a minimum of 3/6 subjects in order to proceed with Phase 1/2 study. 6 samples received, but 2 samples were found to be thawed at receipt and not used in analysis

participants are administered tandutinib (500mg BID) for 7 days prior to surgery and then undergo resection for recurrent glioblastoma. Tissue samples will be collected for correlative studies - determine tumor/plasma ratio.

Outcome measures

Measure	Level 2 - 600mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=4 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
To Determine the Tumor/Plasma Ratio of in Subjects With Recurrent GBM Undergoing Resections (Phase 0)	—	—	13.1 ratio Standard Deviation 8.9	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 28 days

Population: all GBM, All prior treatment with RT. assessment was for 28 days, cycle 1. 3 dose levels 500, 600 and 700mg

cohorts of 3-6 pts will recieve oral tandutinib starting at 500mg BID with a dose escalation in each cohort. Each treatment cycle is 28 days. Evaluation period for MTD is 1st cycle - 28 days.

dose limiting toxicity defined as: grades 3-4 severity (except vomiting and diarrhea without sufficient prophylaxis delay of treatment > 14 days. ANC less/equal 500m/mm3; Plts less/equal 25,000/mm3; febrile neutropenia or delay of treatment > 14 days

Outcome measures

Measure	Level 2 - 600mg BID n=6 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID n=3 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=6 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Number of Dose Limiting Toxicities Per Dose Level	1 participants	2 participants	1 participants	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: Up to 4 years

Population: In the first stage, 31 patients would be enrolled and the trial would be terminated if 3 or fewer patients demonstrated objective responses (partial response or complete response)

pts receive a scan baseline and prior to every odd cycle. All responses are centrally reviewed Complete response Complete disappearance of all tumor on MRI scan, off all glucocorticoids with stable or improving neurological exam minimum of 4 wks Partial response Greater than or equal 50% reduction in tumor size on MRI, on sable or decreasing glucocorticoids with stable or improving neurological exam for a minimum of 4 wks.

Progressive disease Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion.

Stable disease Clinical status and MRI does not qualify for complete response, partial response or progression

Outcome measures

Measure	Level 2 - 600mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Tumor Response (Complete Response and Partial Response) Rate (Phase II)	—	—	1 participants with objective response	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 28 days

Population: 56 enrolled pts, 40 evaluable PK sample sets, parameters not estimated for 16 pts. (Sample collected after next dose taken 3pts;1st dose given before collecting redose sample 1 pt; concentration sample 24h after dosing \<LOQ 8 pts or samples not collected proper times 1pt. 2pts feasibility arm did not restart treatment post-surgery

pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2

Outcome measures

Measure	Level 2 - 600mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID n=3 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=6 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Pharmacokinetics (Max Concentration of Plasma) for Tandutinib in Phase 1 and Phase 2	486 ng/mL Standard Deviation 307	1285 ng/mL Standard Deviation 239	379 ng/mL Standard Deviation 193	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 28 days

Population: 56 enrolled pts, 40 evaluable PK sample sets, parameters not estimated for 16 pts. (Sample collected after next dose taken 3pts;1st dose given before collecting redose sample 1 pt; concentration sample 24h after dosing \<LOQ 8 pts or samples not collected proper times 1pt. 2pts feasibility arm did not restart treatment post-surgery

pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2

Outcome measures

Measure	Level 2 - 600mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID n=3 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=6 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Pharmacokinetics (Apparent Terminal Phase Half-life) for Tandutinib in Phase 1 and Phase 2	10.4 h Standard Deviation 2.5	13.2 h Standard Deviation 7.2	13.1 h Standard Deviation 1.1	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 28 days

Population: 56 enrolled pts, 40 evaluable PK sample sets, parameters not estimated for 16 pts. (Sample collected after next dose taken 3pts;1st dose given before collecting redose sample 1 pt; concentration sample 24h after dosing \<LOQ 8 pts or samples not collected proper times 1pt. 2pts feasibility arm did not restart treatment post-surgery

pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2

Outcome measures

Measure	Level 2 - 600mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID n=3 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=6 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Pharmacokinetics (Area Under the Plasma Concentration Time Profile From Zero to Infinity (AUC)) for Tandutinib in Phase 1 and Phase 2	4659 ng*h/mL Standard Deviation 1926	8193 ng*h/mL Standard Deviation 1915	3961 ng*h/mL Standard Deviation 1414	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 28 days

Population: 56 enrolled pts, 40 evaluable PK sample sets, parameters not estimated for 16 pts. (Sample collected after next dose taken 3pts;1st dose given before collecting redose sample 1 pt; concentration sample 24h after dosing \<LOQ 8 pts or samples not collected proper times 1pt. 2pts feasibility arm did not restart treatment post surgery

pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2

Outcome measures

Measure	Level 2 - 600mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID n=3 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=6 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Pharmacokinetics; Apparent Oral Clearance for Tandutinib in Phase 1 and Phase 2	129 L/h Standard Deviation 54	85 L/h Standard Deviation 20	126 L/h Standard Deviation 45	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 28 days

Population: 56 enrolled pts, 40 evaluable PK sample sets, parameters not estimated for 16 pts. (Sample collected after next dose taken 3pts;1st dose given before collecting redose sample 1 pt; concentration sample 24h after dosing \<LOQ 8 pts or samples not collected proper times 1pt. 2pts feasibility arm did not restart treatment post-surgery

pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2

Outcome measures

Measure	Level 2 - 600mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID n=3 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=6 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Pharmacokinetics; Apparent Oral Total Body Volume of Distribution for Tandutinib in Phase 1 and Phase 2	1987 L Standard Deviation 1102	1764 L Standard Deviation 1242	2386 L Standard Deviation 934	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 28 days

Population: 56 enrolled pts, 40 evaluable PK sample sets, parameters not estimated for 16 pts. (Sample collected after next dose taken 3pts;1st dose given before collecting redose sample 1 pt; concentration sample 24h after dosing \<LOQ 8 pts or samples not collected proper times 1pt. 2pts feasibility arm did not restart treatment post-surgery

pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2

Outcome measures

Measure	Level 2 - 600mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID n=3 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=6 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Pharmacokinetics; Steady-state Trough Concentration for Tandutinib in Phase 1 and Phase 2	582 ng/mL Standard Deviation 381	971 ng/mL Standard Deviation 729	518 ng/mL Standard Deviation 182	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Up to 4 years

Population: Median time of survival along with 95% confidence interval will be estimated using Kaplan-Meier method. An overall failure rate will be estimated with 95% CI. The overall failure rate is expressed as hazard of failure per person-year of follow-up.

Median time of survival along with 95% confidence interval will be estimated using Kaplan-Meier method. An overall failure rate will be estimated with 95% CI.

Outcome measures

Measure	Level 2 - 600mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Overall Survival (Phase II)	—	—	8.8 months Interval 5.9 to 15.4	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: At 6 months

Population: The probability of 6-momth progression-free survival will be estimated using binomial distribution.

The probability of 6-momth progression-free survival will be estimated using binomial distribution.

Progression defined as: Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion.

Outcome measures

Measure	Level 2 - 600mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Six-month Progression-free Survival Rate (Phase II)	—	—	16 percent probability Interval 6.0 to 34.0	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: up to 4 years

The overall failure rate is expressed as hazard of failure per person-year of follow-up.

Outcome measures

Measure	Level 2 - 600mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Overall Failure Rate (Phase II)	—	—	0.82 failure per person-year Interval 0.57 to 1.19	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 2 year period

Grade 3 or 4 toxicities related to treatment as determined by the CTCAE

Outcome measures

Measure	Level 2 - 600mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=31 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Proportion of Patients With Serious or Life Threatening Toxicities	—	—	48 percentage of participants	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: baseline - cycle 2 (28 days)

Population: peripheral blood was obtained from 20 patients enrolled in the phase 2 portion of the study.

serial blood samples over multiple time points (prior to treatment, 2 days post treatment, 8 days post treatment, 10 days post treatment and 28 days post treatment.

statistical analyses presented for the comparisons that yielded a p-value <=0.05

Outcome measures

Measure	Level 2 - 600mg BID n=20 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Phase 2: MTD dose Patients receive tandutinib as in phase I at the MTD (600mg BID) determined in phase I. 600mg was the determined MTD in Dose Escalation dose for tandtinib is 600mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 3 - 700mg BID n=20 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 700mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Level 1 - 500mg BID n=20 Participants Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Association Between PFS Biomarker Day 2 / BL n=20 Participants Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 8 / BL n=19 Participants Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 8 / BL n=19 Participants Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 10 /BL n=18 Participants Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 10 / BL n=18 Participants Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between OS and Biomarker Day 28 / BL n=14 Participants Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood	Association Between PFS Biomarker Day 28 / BL n=14 Participants Patients receive tandutinib at 600mg as was the determined MTD in Dose Escalation oral tandutinib tandutinib: Given orally pharmacological study: Correlative studies Peripheral blood
Protein Expression Patterns Post Treatment - Loss or Gain SDF_1a	1.00 hazard ratio Interval 1.0 to 1.0	0.01 hazard ratio Interval 0.0 to 1.8	1.00 hazard ratio Interval 1.0 to 1.0	0.14 hazard ratio Interval 0.0 to 20.0	0.83 hazard ratio Interval 0.01 to 62.0	0.08 hazard ratio Interval 0.0 to 24.0	1.4 hazard ratio Interval 0.0 to 2531.0	1.68 hazard ratio Interval 0.0 to 3976.0	0.18 hazard ratio Interval 0.0 to 8.42	0.76 hazard ratio Interval 0.02 to 36.0
Protein Expression Patterns Post Treatment - Loss or Gain bFGF	1.01 hazard ratio Interval 1.0 to 1.02	0.72 hazard ratio Interval 0.42 to 1.23	1.00 hazard ratio Interval 0.99 to 1.01	0.52 hazard ratio Interval 0.27 to 1.04	1.03 hazard ratio Interval 0.61 to 1.74	0.88 hazard ratio Interval 0.53 to 1.47	0.65 hazard ratio Interval 0.36 to 1.17	0.60 hazard ratio Interval 0.31 to 1.14	0.84 hazard ratio Interval 0.44 to 1.61	0.70 hazard ratio Interval 0.37 to 1.3
Protein Expression Patterns Post Treatment - Loss or Gain PIGF	1.01 hazard ratio Interval 1.0 to 1.02	8.56 hazard ratio Interval 0.16 to 449.0	1.00 hazard ratio Interval 0.99 to 1.01	1.53 hazard ratio Interval 0.01 to 197.0	3.76 hazard ratio Interval 0.55 to 26.0	11.8 hazard ratio Interval 1.08 to 129.0	0.91 hazard ratio Interval 0.03 to 27.0	0.69 hazard ratio Interval 0.02 to 22.0	1.18 hazard ratio Interval 0.03 to 55.0	6.24 hazard ratio Interval 0.07 to 542.0
Protein Expression Patterns Post Treatment - Loss or Gain sFLT_1	1.00 hazard ratio Interval 1.0 to 1.0	1.08 hazard ratio Interval 0.08 to 1.45	1.00 hazard ratio Interval 1.0 to 1.0	1.22 hazard ratio Interval 0.89 to 1.66	1.03 hazard ratio Interval 0.86 to 1.23	1.12 hazard ratio Interval 0.92 to 1.36	1.06 hazard ratio Interval 0.08 to 1.41	1.13 hazard ratio Interval 0.82 to 1.55	61.5 hazard ratio Interval 1.0 to 3774.0	524 hazard ratio Interval 4.0 to 71128.0
Protein Expression Patterns Post Treatment - Loss or Gain VEGF	1.00 hazard ratio Interval 1.0 to 1.0	0.55 hazard ratio Interval 0.07 to 4.1	1.00 hazard ratio Interval 1.0 to 1.0	0.71 hazard ratio Interval 0.12 to 4.14	0.43 hazard ratio Interval 0.08 to 2.37	0.31 hazard ratio Interval 0.05 to 1.85	0.88 hazard ratio Interval 0.34 to 2.26	0.74 hazard ratio Interval 0.33 to 1.62	1.11 hazard ratio Interval 0.17 to 7.35	1.67 hazard ratio Interval 0.2 to 13.7
Protein Expression Patterns Post Treatment - Loss or Gain CAIX	1.00 hazard ratio Interval 1.0 to 1.0	1.16 hazard ratio Interval 0.23 to 5.85	1.00 hazard ratio Interval 1.0 to 1.01	0.38 hazard ratio Interval 0.05 to 3.19	1.53 hazard ratio Interval 0.99 to 2.36	1.74 hazard ratio Interval 1.11 to 2.72	1.24 hazard ratio Interval 0.76 to 2.01	0.80 hazard ratio Interval 0.44 to 1.45	1.41 hazard ratio Interval 0.83 to 2.41	0.89 hazard ratio Interval 0.53 to 1.48
Protein Expression Patterns Post Treatment - Loss or Gain VEGFR2	1.00 hazard ratio Interval 1.0 to 1.0	0.32 hazard ratio Interval 0.01 to 13.9	1.00 hazard ratio Interval 1.0 to 1.0	0.74 hazard ratio Interval 0.02 to 31.0	2.02 hazard ratio Interval 0.07 to 62.0	0.65 hazard ratio Interval 0.02 to 17.3	0.10 hazard ratio Interval 0.0 to 70.0	0.27 hazard ratio Interval 0.0 to 30.0	0.001 hazard ratio Interval 0.0 to 1.18	0.001 hazard ratio Interval 0.0 to 0.88
Protein Expression Patterns Post Treatment - Loss or Gain ANG_2	1.00 hazard ratio Interval 1.0 to 1.0	0.54 hazard ratio Interval 0.04 to 7.42	1.00 hazard ratio Interval 1.0 to 1.0	2.15 hazard ratio Interval 0.14 to 33.0	0.89 hazard ratio Interval 0.3 to 2.68	1.12 hazard ratio Interval 0.31 to 4.09	0.55 hazard ratio Interval 0.13 to 2.36	1.05 hazard ratio Interval 0.26 to 4.19	0.43 hazard ratio Interval 0.06 to 2.91	0.52 hazard ratio Interval 0.05 to 4.93

Adverse Events

Arm I - Feasibility

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Arm 2 - Dose Escalation (Phase 1)

Serious events: 3 serious events

Other events: 15 other events

Deaths: 0 deaths

Arm 3 - Phase 2

Serious events: 15 serious events

Other events: 28 other events

Deaths: 0 deaths

Serious adverse events

Measure	Arm I - Feasibility n=6 participants at risk Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. conventional surgery oral tandutinib Pharmacological study Tissue samples conventional surgery: Undergo surgery tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Arm 2 - Dose Escalation (Phase 1) n=15 participants at risk Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. the starting dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Arm 3 - Phase 2 n=31 participants at risk Patients receive tandutinib as in phase I at the MTD determined in phase I. 600mg was the determined MTD in Dose Escalation oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies
Nervous system disorders confusion	16.7% 1/6 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
Nervous system disorders Encephalopathy	16.7% 1/6 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
General disorders fatigue	33.3% 2/6 • Number of events 2 • Time of first dose until patient went off treatment. <4 years	6.7% 1/15 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	9.7% 3/31 • Number of events 3 • Time of first dose until patient went off treatment. <4 years
Nervous system disorders headache	16.7% 1/6 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
Vascular disorders hypertension	16.7% 1/6 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
Gastrointestinal disorders diarrhea	16.7% 1/6 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	3.2% 1/31 • Number of events 1 • Time of first dose until patient went off treatment. <4 years
Metabolism and nutrition disorders hypophosphatemia	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	13.3% 2/15 • Number of events 2 • Time of first dose until patient went off treatment. <4 years	16.1% 5/31 • Number of events 6 • Time of first dose until patient went off treatment. <4 years
Nervous system disorders somnolence	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	6.7% 1/15 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
Musculoskeletal and connective tissue disorders muscle weakness lower limb	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	6.7% 1/15 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
Gastrointestinal disorders vomiting	16.7% 1/6 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
Nervous system disorders intracranial hemorrhage	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	3.2% 1/31 • Number of events 1 • Time of first dose until patient went off treatment. <4 years
Metabolism and nutrition disorders alanine aminotransferase increased	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	3.2% 1/31 • Number of events 1 • Time of first dose until patient went off treatment. <4 years
Investigations electrocardiogram QT corrected interval prolonged	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	19.4% 6/31 • Number of events 8 • Time of first dose until patient went off treatment. <4 years
Musculoskeletal and connective tissue disorders generalized muscle weakness	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	3.2% 1/31 • Number of events 1 • Time of first dose until patient went off treatment. <4 years
Infections and infestations lung infection	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	3.2% 1/31 • Number of events 1 • Time of first dose until patient went off treatment. <4 years
Nervous system disorders peripheral motor neuropathy	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	3.2% 1/31 • Number of events 2 • Time of first dose until patient went off treatment. <4 years

Other adverse events

Measure	Arm I - Feasibility n=6 participants at risk Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. conventional surgery oral tandutinib Pharmacological study Tissue samples conventional surgery: Undergo surgery tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Arm 2 - Dose Escalation (Phase 1) n=15 participants at risk Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. the starting dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies	Arm 3 - Phase 2 n=31 participants at risk Patients receive tandutinib as in phase I at the MTD determined in phase I. 600mg was the determined MTD in Dose Escalation oral tandutinib Pharmacological study Tissue samples tandutinib: Given orally pharmacological study: Correlative studies Tissue samples: Correlative studies
General disorders fatigue	33.3% 2/6 • Number of events 3 • Time of first dose until patient went off treatment. <4 years	40.0% 6/15 • Number of events 8 • Time of first dose until patient went off treatment. <4 years	45.2% 14/31 • Number of events 18 • Time of first dose until patient went off treatment. <4 years
Investigations Platelet count decrease	33.3% 2/6 • Number of events 5 • Time of first dose until patient went off treatment. <4 years	13.3% 2/15 • Number of events 2 • Time of first dose until patient went off treatment. <4 years	19.4% 6/31 • Number of events 20 • Time of first dose until patient went off treatment. <4 years
Blood and lymphatic system disorders anemia	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	26.7% 4/15 • Number of events 19 • Time of first dose until patient went off treatment. <4 years	35.5% 11/31 • Number of events 74 • Time of first dose until patient went off treatment. <4 years
Cardiac disorders electrocardiogram QT corrected interval prolonged	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	20.0% 3/15 • Number of events 4 • Time of first dose until patient went off treatment. <4 years	29.0% 9/31 • Number of events 19 • Time of first dose until patient went off treatment. <4 years
Gastrointestinal disorders diarrhea	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	100.0% 15/15 • Number of events 19 • Time of first dose until patient went off treatment. <4 years	61.3% 19/31 • Number of events 37 • Time of first dose until patient went off treatment. <4 years
Gastrointestinal disorders nausea	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	80.0% 12/15 • Number of events 16 • Time of first dose until patient went off treatment. <4 years	61.3% 19/31 • Number of events 26 • Time of first dose until patient went off treatment. <4 years
Gastrointestinal disorders vomiting	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	46.7% 7/15 • Number of events 12 • Time of first dose until patient went off treatment. <4 years	45.2% 14/31 • Number of events 17 • Time of first dose until patient went off treatment. <4 years
General disorders edema face	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	20.0% 3/15 • Number of events 3 • Time of first dose until patient went off treatment. <4 years	19.4% 6/31 • Number of events 7 • Time of first dose until patient went off treatment. <4 years
General disorders edema limb	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	20.0% 3/15 • Number of events 3 • Time of first dose until patient went off treatment. <4 years	16.1% 5/31 • Number of events 7 • Time of first dose until patient went off treatment. <4 years
Investigations alanine aminotransferase increased	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	13.3% 2/15 • Number of events 7 • Time of first dose until patient went off treatment. <4 years	32.3% 10/31 • Number of events 23 • Time of first dose until patient went off treatment. <4 years
Investigations aspartate aminotransferase increased	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	33.3% 5/15 • Number of events 10 • Time of first dose until patient went off treatment. <4 years	25.8% 8/31 • Number of events 23 • Time of first dose until patient went off treatment. <4 years
Investigations white blood cell decreased	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	26.7% 4/15 • Number of events 10 • Time of first dose until patient went off treatment. <4 years	35.5% 11/31 • Number of events 45 • Time of first dose until patient went off treatment. <4 years
Investigations creatinine increased	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	6.7% 1/15 • Number of events 3 • Time of first dose until patient went off treatment. <4 years	9.7% 3/31 • Number of events 4 • Time of first dose until patient went off treatment. <4 years
Metabolism and nutrition disorders hypoalbuminemia	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	13.3% 2/15 • Number of events 4 • Time of first dose until patient went off treatment. <4 years	6.5% 2/31 • Number of events 3 • Time of first dose until patient went off treatment. <4 years
Metabolism and nutrition disorders hypophosphatemia	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	26.7% 4/15 • Number of events 6 • Time of first dose until patient went off treatment. <4 years	48.4% 15/31 • Number of events 37 • Time of first dose until patient went off treatment. <4 years
Musculoskeletal and connective tissue disorders muscle weakness lower limb	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	6.7% 1/15 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
Nervous system disorders somnolence	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	6.7% 1/15 • Number of events 1 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
Skin and subcutaneous tissue disorders rash maculopapular	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	20.0% 3/15 • Number of events 3 • Time of first dose until patient went off treatment. <4 years	0.00% 0/31 • Time of first dose until patient went off treatment. <4 years
Investigations blood bilirubin increase	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	13.3% 2/15 • Number of events 2 • Time of first dose until patient went off treatment. <4 years	6.5% 2/31 • Number of events 2 • Time of first dose until patient went off treatment. <4 years
Investigations neutrophil count decrease	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	13.3% 2/15 • Number of events 2 • Time of first dose until patient went off treatment. <4 years	12.9% 4/31 • Number of events 12 • Time of first dose until patient went off treatment. <4 years
Investigations alkaline phosphatase increase	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	16.1% 5/31 • Number of events 9 • Time of first dose until patient went off treatment. <4 years
Ear and labyrinth disorders blurred vision	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	6.5% 2/31 • Number of events 2 • Time of first dose until patient went off treatment. <4 years
Psychiatric disorders confusion	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	9.7% 3/31 • Number of events 3 • Time of first dose until patient went off treatment. <4 years
Nervous system disorders dizziness	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	16.1% 5/31 • Number of events 6 • Time of first dose until patient went off treatment. <4 years
Musculoskeletal and connective tissue disorders generalized muscle weakness	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	16.1% 5/31 • Number of events 5 • Time of first dose until patient went off treatment. <4 years
Nervous system disorders headache	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	6.5% 2/31 • Number of events 2 • Time of first dose until patient went off treatment. <4 years
Metabolism and nutrition disorders hyperglycemia	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	6.5% 2/31 • Number of events 3 • Time of first dose until patient went off treatment. <4 years
Metabolism and nutrition disorders hypocalcemia	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	16.1% 5/31 • Number of events 13 • Time of first dose until patient went off treatment. <4 years
Psychiatric disorders insomnia	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	6.5% 2/31 • Number of events 2 • Time of first dose until patient went off treatment. <4 years
Respiratory, thoracic and mediastinal disorders pharyngolaryngeal pain	0.00% 0/6 • Time of first dose until patient went off treatment. <4 years	0.00% 0/15 • Time of first dose until patient went off treatment. <4 years	6.5% 2/31 • Number of events 2 • Time of first dose until patient went off treatment. <4 years

Additional Information

Stuart A Grossman, MD Director of ABTC

Adult Brain Tumor Consortium

Phone: 410-955-8837

Email: grossman@jhmi.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60