Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00667394
• Collaborator: (none)
• Enrollment: 42
• Location: 1
• Arms: 2
• Duration (Months): 39
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

Background:

In order to survive, brain tumors must have a network of blood vessels to supply it with oxygen and nutrients. The tumors produce substances that enable new blood vessels to form.

Tandutinib and Bevacizumab are experimental drugs that may prevent new blood vessel formation and thereby slow or stop tumor growth in the brain.

Objectives:

To determine the safety and side effects of Tandutinib in combination with Bevacizumab in patients with brain tumors.

To evaluate the response of brain tumors to treatment with Tandutinib and Bevacizumab.

Eligibility:

Patients 18 years of age and older with a malignant brain tumor for whom standard treatments (surgery, radiation and chemotherapy) are no longer effective.

Design:

Patients receive treatment in 4-week cycles as follows: Tandutinib by mouth twice a day every day and intravenous (through a vein) infusions of Bevacizumab over 90 minutes (or less if well tolerated) every 2 weeks. Treatment may continue for up to 1 year, and possibly longer, as long as there are no signs of tumor growth or serious treatment side effects.

Patients are evaluated with magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scans before starting treatment and then periodically to determine the response to treatment.

Patients have physical and neurological examinations every 4 weeks and blood tests every 2 weeks. They complete quality of life questionnaires every 4 weeks.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma; Gliosarcoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Mixed Oligoastrocytoma	Biological: Bevacizumab; Drug: MLN-518 (Tandutinib); Procedure: Quality-of-life assessment	Phase 2

Detailed Description

Background

Bevacizumab is a monoclonal antibody directed against vascular- endothelial growth factor (VEGF), the major angiogenesis factor involved in high-grade glioma-mediated angiogenesis. Preclinical studies in our laboratory and others have shown potent antiglioma activity in vivo and early clinical trials of bevacizumab in combination with irinotecan and alone (National Institutes of Health (NIH) study) have demonstrated significant anti-vascular permeability and anti-glioma effects in patients with recurrent gliomas.

Tandutinib (MLN518) along with bevacizumab represents an attempt to further capitalize on the concept of targeting the tumor vasculature. Tandutinib is a small molecule inhibitor of fms-like tyrosine kinase receptor-3 (FLT3), platelet derived growth factor receptor (PDGFR), and cKIT (type III receptor tyrosine kinases). It has demonstrated anti-leukemic activity in patients with relapsed and refractory acute myeloid leukemia (AML) whose blasts contain an activating internal tandem duplication mutation of FLT3. However, in this study tandutinib is being added to bevacizumab primarily for its activity against the PDGFR and cKIT. Hannahan and colleagues have demonstrated the additional anti-tumor activity that results in vivo with combined inhibition of the vascular endothelial growth factor receptor (VEGFR) and PDGFR. The activity of PDGFR inhibition is hypothesized to result from its effect on pericytes, the cells that surround and support endothelial cells. These cells have abundant expression of PDGFR and require platelet-derived growth factor (PDGF)-PDGFR interaction for their normal function.

Objectives

To establish data regarding the anti-tumor activity of the combination of bevacizumab and tandutinib in patients with recurrent high-grade gliomas, as determined by progression-free-survival.

Eligibility

Patients with histologically proven recurrent malignant glioma are eligible for this study.

Design

Patients will receive tandutinib as a single agent at a daily dose of 500 mg PO bid for the first 14 days of treatment. Radiology: Prior to the first dose of tandutinib patients will undergo an MRI-perfusion scan and an FDG-PET scan. An MRI-perfusion scan will then be repeated between days 12-14 of the first 14 days of tandutinib monotherapy. On day 15, treatment with bevacizumab will be added to the ongoing treatment with tandutinib. Bevacizumab will be given intravenously in a dose of 10 mg/kg, repeated once every 2 weeks. After completion of the first 4 weeks of combined tandutinib and bevacizumab therapy (6 weeks after initiating treatment with tandutinib) considered the first cycle of therapy) the MRI-perfusion and fludeoxyglucose 18F-positron emission tomography (FDG-PET) scans will be repeated before the next dose of bevacizumab is given. Patients who are clinically/neurologically stable, and who have radiographically stable or responding disease at the end of that first cycle and every cycle thereafter (every 4 weeks), will continue treatment with tandutinib and bevacizumab. Magnetic resonance imaging (MRI)-perfusion scans will be repeated after the completion of every 4 weeks of therapy. A total of 80 patients will be enrolled to this study (GBM (glioblastoma multiforme)=40, AG=40)

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Trial of Tandutinib in Combination With Bevacizumab for Patients With Recurrent High-Grade Gliomas
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tandutinib & Bevacizumab in GBM Patients GBM (glioblastoma multiforme) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.	Biological: Bevacizumab; Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.; Drug: MLN-518 (Tandutinib); Tandutinib 500 mg by mouth daily dose twice a day.; Procedure: Quality-of-life assessment; Forty-five one-sentence questionnaire to assess health related quality of life in patients with brain cancer.; Other Names: HRQL (health related quality of life)
Experimental: Tandutinib & Bevacizumab in AG Patients AG (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, and malignant astrocytoma NOS (not otherwise specified)) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.	Biological: Bevacizumab; Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.; Drug: MLN-518 (Tandutinib); Tandutinib 500 mg by mouth daily dose twice a day.; Procedure: Quality-of-life assessment; Forty-five one-sentence questionnaire to assess health related quality of life in patients with brain cancer.; Other Names: HRQL (health related quality of life)

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival at 6 Months [6 months]

   Percentage of participants with progression free survival at 6 months. Progression is defined as a 25% increase in the sum of all measurable lesions (or two largest lesions if too numerous) over the smallest sum observed (over baseline if no decrease), clear worsening of any evaluable disease, appearance of any new lesion/site, or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Secondary Outcome Measures

1. Number of Participants With Adverse Events [45 months]

   Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

• Patients with histologically proven intracranial malignant glioma will be eligible for this protocol.

Malignant glioma includes glioblastoma multiforme (GBM), gliosarcoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma NOS (not otherwise specified).

• Patients must have evidence for tumor progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan.

This scan should be performed within 14 days prior to registration and on a fixed dose of steroids for at least 5 days.

If the steroid dose is increased between the date of imaging and registration a new baseline MRI/CT is required.

The same type of scan, i.e. MRI or CT must be used throughout the period of protocol treatment for tumor measurement.

• Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:

• They have recovered from the effects of surgery.

• Residual disease following resection of recurrent tumor is not mandated for eligibility into the study.

To best assess the extent of residual disease post-operatively, a CT/ MRI should be done:

• no later than 96 hours in the immediate post-operative period or

• at least 4 weeks post-operatively, and

• within 14 days of registration, and

• on a steroid dosage that has been stable for at least 5 days.

• If the 96 hour scan is more than 21 days before registration, the scan needs to be repeated.

If the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days.

• Patients must have progressed after radiation therapy and must have an interval of greater than or equal to 4 weeks from the completion of radiation therapy to study entry.

• All patients or their previously designated durable power of attorney (DPA) (if the patient is deemed by the treating physician to be impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) must sign an informed consent indicating that they are aware of the investigational nature of this study.

• Patients must be greater than or equal to 18 years old, and with a life expectancy greater than 8 weeks.

• Patients must have a Karnofsky performance status of greater than or equal to 60.

• Patients must have recovered from the toxic effects of prior therapy: 2 weeks from any investigational agent, 4 weeks from prior cytotoxic therapy, two weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count). Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.

• Patients must have adequate bone marrow function (white blood cell (WBC) greater than or equal to 3,000/microl, Absolute neutrophil count (ANC) greater than or equal to 1,500/mm^{3, platelet count of greater than or equal to 100,000/mm}3, and hemoglobin greater than or equal to 10 gm/dl), adequate liver function (serum glutamic oxaloacetic transaminase (SGOT) and bilirubin less than 2 times upper limit of normal (ULN)), and adequate renal function (creatinine less than 1.5 mg/dL and/or creatinine clearance greater than or equal to 60 cc/min) before starting therapy.

Serum sodium, calcium, potassium, chloride, and magnesium must be in normal limits.

These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.

• Patients must not have any significant medical illnesses that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patients' ability to tolerate this therapy

• This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race. Minorities will actively be recruited to participate.

• Creatinine clearance or calculated creatinine clearance greater than or equal to 60 mL/minute.

• Patients must practice adequate contraception.

• Head CT Scan without contrast (to rule out significant acute hemorrhage) within 7 days prior to starting treatment.

• A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with corrected QT interval (QTc) less than 460 msec.

EXCLUSION CRITERIA:

• Patients who, in the view of the treating physician, have significant active cardiac, hepatic, renal, or psychiatric diseases are ineligible.

• No concurrent use of other standard chemotherapeutics or investigative agents.

• Patients known to have a malignancy that has required treatment in the last 12 months and/or is expected to require treatment in the next 12 months (except non-melanoma skin cancer or carcinoma in-situ in the cervix).

• Patients who have an active infection.

• Pregnant (positive pregnancy test) or nursing women. Fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of tandutinib plus bevacizumab therapy.

• Patients who have any disease that will obscure toxicity (i.e. vasculitis, congenital hypercoaguability syndromes, uncontrolled primary hypertension, idiopathic thrombocytopenia).

• Evidence of significant recent hemorrhage on mandatory CT scan (defined as 1 cm or more of acute blood) of the brain within 7 days of patient accrual with the following exceptions: resolving hemorrhagic changes related to surgery, and/or presence of punctate hemorrhages in the tumor.

• Concurrent anti-coagulation or anti-platelet medication (including aspirin, non-steroidal anti-inflammatories, cyclooxygenase -2 (COX-2) inhibitors).

• Serious or non-healing wound, ulcer or bone fracture.

• Proteinuria at screening as demonstrated by either:

• Urine protein:creatinine (UPC) ratio greater than or equal to 1.0 at screening OR

• Urine dipstick for proteinuria greater than or equal to 2+ (patients discovered to have greater than or equal to 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate less than or equal to 1g of protein in 24 hours to be eligible).

• History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months

• Invasive procedures defined as follows:

• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy

• Anticipation of need for major surgical procedures during the course of the study

• Core biopsy within 7 days prior to D1 therapy

• Patients with clinically significant cardiovascular disease

• History of cerebrovascular accident (CVA) or transient ischemic attack within 6 months

• Inadequately controlled hypertension (defined as systolic blood pressure greater than 160 and/or diastolic blood pressure greater than 100 mmHg on antihypertensive medications)

• Any prior history of hypertensive crisis or hypertensive encephalopathy

• Myocardial infarction or unstable angina within 6 months

• New York Heart Association Grade II or greater congestive heart failure

• Serious cardiac arrhythmia requiring medication

• Unstable angina pectoris

• Symptomatic peripheral vascular disease

• Evidence of bleeding diathesis or coagulopathy

• Prothrombin time (PT)/partial thromboplastin time (PTT) greater than1.5 time the upper limit of normal

• Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies

• Inability to take oral medication

• Known gastrointestinal disease or history of gastrointestinal surgery that could interfere with the absorption of orally administered medication.

• Ongoing vomiting

• Active cardiac disease as defined by:

• Significant cardiac event (including symptomatic heart failure or evidence of cardiac ischemia within 3 months of first dose or presence of any cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia.

• Clinically significant arrhythmia (multifocal premature ventricular contraction [PVC], bigeminy, trigeminy, ventricular tachycardia, bradycardia) that is symptomatic or requires treatment (Common Terminology Criteria for Adverse Events (CTCAE) grade 3), or asymptomatic sustained ventricular tachycardia.

• Previous history of QTc prolongation with other medication.

• Congenital long QT syndrome

• QTc with Bazett's correction that is unmeasurable, or greater than or equal to 460 msec on screening ECG. If a patient has QTc greater than or equal to 460 msec on screening ECG, a second screen ECG may be repeated at least 24 hours apart. The average QTc from the 2 screening ECGs must be less than 460 msec in order for the patient to be eligible for the study. If the patient meets eligibility requirements in this way, the 'baseline' QTc for this patient will be the average of the 3 ECGs (screen 1, screen 2, and pre- 1 first dose).

• Previous history of left ventricular ejection fraction (LVEF) less than 45 percent as measured by multi-gated acquisition scan (MUGA) or by echocardiogram (ECHO) for patients with previous anthracycline therapy (total dose greater than 450 mg/m^2 or significant cardiovascular disease or chest irradiation, as determined by the investigator.

• A cardiac arrhythmia serious enough to require therapy (i.e. drugs, acquired immune deficiency (AID)), angina, symptomatic congestive heart failure and/or a cardiac ejection fraction less than 45 percent.

• Prior serious cardiac disease defined as prior coronary bypass surgery, angioplasty, or prior myocardial infarction unless a recent cardiac evaluation (within the last 3 months) demonstrated no significant coronary artery disease (i.e. a negative stress test) and no myocardial wall dysfunction.

• Concurrent use of other standard chemotherapeutics or investigative agents or vasoconstrictors for the treatment of migraine (ergotamine, zolmitriptan, sumatriptan) because of the potential for exacerbation of coronary vasoconstriction.

• Known or suspected primary muscular or neuromuscular disease (e.g. muscular dystrophy, myasthenia gravis). This does not include steroid myopathy.

• Prior treatment with bevacizumab is not permitted.

• Concurrent use of other drugs that have been shown to potentially prolong the QTc interval.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Howard Fine, M.D., National Cancer Institute, National Institutes of Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Bigner SH, Bjerkvig R, Laerum OD. DNA content and chromosomal composition of malignant human gliomas. Neurol Clin. 1985 Nov;3(4):769-84. Review.
• Bovet P, Lob M. [Cancer mortality among the workers of a Swiss rubber goods factory. Epidemiological study, 1955-75]. Schweiz Med Wochenschr. 1980 Aug 30;110(35):1277-87. Review. French.
• Moss AR. Occupational exposure and brain tumors. J Toxicol Environ Health. 1985;16(5):703-11.

• Responsible Party: Katherine E. Warren, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00667394
• Other Study ID Numbers: 080101; 08-C-0101
• First Posted: Apr 28, 2008
• Last Update Posted: Nov 5, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Katherine E. Warren, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC): Brain Tumor; Chemotherapy; Radiation; Anti-Angiogenesis; Glioblastoma; Glioma
• Additional relevant MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Bevacizumab

Study Results

Participant Flow

Arm/Group Title	Tandutinib & Bevacizumab in GBM Patients	Tandutinib & Bevacizumab in AG Patients
Arm/Group Description	GBM (glioblastoma multiforme) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.	AG (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, and malignant astrocytoma NOS (not otherwise specified )) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks
Period Title: Overall Study
STARTED	41	1
COMPLETED	37	1
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	Tandutinib & Bevacizumab in GBM Patients	Tandutinib & Bevacizumab in AG Patients	Total
Arm/Group Description	GBM (glioblastoma multiforme) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.	AG (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, and malignant astrocytoma NOS (not otherwise specified )) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks	Total of all reporting groups
Overall Participants	41	1	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	36 87.8%	1 100%	37 88.1%
>=65 years	5 12.2%	0 0%	5 11.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.16 (11.52)	63 (0)	54.37 (11.46)
Sex: Female, Male (Count of Participants)
Female	12 29.3%	0 0%	12 28.6%
Male	29 70.7%	1 100%	30 71.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	38 92.7%	1 100%	39 92.9%
Unknown or Not Reported	3 7.3%	0 0%	3 7.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	3 7.3%	0 0%	3 7.1%
Native Hawaiian or Other Pacific Islander	1 2.4%	0 0%	1 2.4%
Black or African American	3 7.3%	0 0%	3 7.1%
White	32 78%	1 100%	33 78.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 4.9%	0 0%	2 4.8%
Region of Enrollment (participants) [Number]
United States	41 100%	1 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival at 6 Months
Description	Percentage of participants with progression free survival at 6 months. Progression is defined as a 25% increase in the sum of all measurable lesions (or two largest lesions if too numerous) over the smallest sum observed (over baseline if no decrease), clear worsening of any evaluable disease, appearance of any new lesion/site, or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tandutinib & Bevacizumab in GBM Patients	Tandutinib & Bevacizumab in AG Patients
Arm/Group Description	GBM (glioblastoma multiforme) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.	AG (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, and malignant astrocytoma NOS (not otherwise specified )) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks
Measure Participants	37	0
Median (95% Confidence Interval) [Percentage of participants]	23 56.1%

2. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time Frame	45 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tandutinib & Bevacizumab in GBM Patients	Tandutinib & Bevacizumab in AG Patients
Arm/Group Description	GBM (glioblastoma multiforme) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.	AG (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, and malignant astrocytoma NOS (not otherwise specified )) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks
Measure Participants	41	1
Number [Participants]	40 97.6%	1 100%

Adverse Events

Arm/Group Title	Tandutinib & Bevacizumab in GBM Patients		Tandutinib & Bevacizumab in AG Patients
Arm/Group Description	GBM (glioblastoma multiforme) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.		AG (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, and malignant astrocytoma NOS (not otherwise specified )) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks
All Cause Mortality
	Tandutinib & Bevacizumab in GBM Patients		Tandutinib & Bevacizumab in AG Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tandutinib & Bevacizumab in GBM Patients		Tandutinib & Bevacizumab in AG Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/41 (36.6%)		0/1 (0%)
Gastrointestinal disorders
Nausea	1/41 (2.4%)	1	0/1 (0%)	0
Perforation, GI::Stomach	1/41 (2.4%)	1	0/1 (0%)	0
Perforation, GI::Colon	1/41 (2.4%)	1	0/1 (0%)	0
General disorders
Death not associated with CTCAE term: Death Progression NOS	1/41 (2.4%)	1	0/1 (0%)	0
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils::Abdomen NOS	1/41 (2.4%)	1	0/1 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Colon	1/41 (2.4%)	1	0/1 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia)	1/41 (2.4%)	1	0/1 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Pleura (empyema)	1/41 (2.4%)	1	0/1 (0%)	0
Infection with unknown ANC::Lung (pneumonia)	1/41 (2.4%)	1	0/1 (0%)	0
Investigations
Platelets	1/41 (2.4%)	1	0/1 (0%)	0
Prolonged QTc interval	1/41 (2.4%)	1	0/1 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)::Extremity-lower	1/41 (2.4%)	1	0/1 (0%)	0
Pain-Other (Specify, lower extremities)	1/41 (2.4%)	1	0/1 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy)::Whole body/generalized	1/41 (2.4%)	1	0/1 (0%)	0
Nervous system disorders
Hemorrhage, CNS	3/41 (7.3%)	3	0/1 (0%)	0
Pain::Head/headache	1/41 (2.4%)	1	0/1 (0%)	0
Seizure	5/41 (12.2%)	7	0/1 (0%)	0
Psychiatric disorders
Psychosis (hallucinations/delusions)	1/41 (2.4%)	1	0/1 (0%)	0
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other (Specify, keratosis & dermal hematoma)	1/41 (2.4%)	1	0/1 (0%)	0
Rash: hand-foot skin reaction	1/41 (2.4%)	1	0/1 (0%)	0
Vascular disorders
Hypertension	1/41 (2.4%)	1	0/1 (0%)	0
Thrombosis/thrombus/embolism	1/41 (2.4%)	1	0/1 (0%)	0
Other (Not Including Serious) Adverse Events
	Tandutinib & Bevacizumab in GBM Patients		Tandutinib & Bevacizumab in AG Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/41 (100%)		1/1 (100%)
Blood and lymphatic system disorders
Blood/Bone marrow - Other (Specify, elevated eosinophils)	1/41 (2.4%)	1	0/1 (0%)	0
Petechiae/purpura (hemorrhage/bleeding into skin or mucosa)	1/41 (2.4%)	1	0/1 (0%)	0
Cardiac disorders
Supraventricular and nodal arrhythmia::Sinus tachycardia	1/41 (2.4%)	1	0/1 (0%)	0
Eye disorders
Hemorrhage/Bleeding - Other (hemorrhage into sclera)	1/41 (2.4%)	1	0/1 (0%)	0
Keratitis (corneal inflammatory/corneal ulceration)	1/41 (2.4%)	1	0/1 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy)::Extraocular	1/41 (2.4%)	1	0/1 (0%)	0
Vision-blurred vision	4/41 (9.8%)	4	0/1 (0%)	0
Gastrointestinal disorders
Diarrhea	31/41 (75.6%)	40	1/1 (100%)	1
Dry mouth/salivary gland (xerostomia)	1/41 (2.4%)	1	0/1 (0%)	0
Dysphagia (difficulty swallowing)	1/41 (2.4%)	1	0/1 (0%)	0
Gastritis (including bile reflux gastritis)	1/41 (2.4%)	1	0/1 (0%)	0
Hemorrhage, GI::Anus	1/41 (2.4%)	1	0/1 (0%)	0
Hemorrhage, GI::Rectum	2/41 (4.9%)	2	0/1 (0%)	0
Nausea	22/41 (53.7%)	27	1/1 (100%)	1
Vomiting	6/41 (14.6%)	6	0/1 (0%)	0
General disorders
Edema::head and neck	17/41 (41.5%)	21	0/1 (0%)	0
Edema: limb	9/41 (22%)	9	0/1 (0%)	0
Fatigue (asthenia, lethargy, malaise)	21/41 (51.2%)	30	0/1 (0%)	0
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	2/41 (4.9%)	2	0/1 (0%)	0
Infections and infestations
Infection with unknown ANC::Lip/perioral	1/41 (2.4%)	1	0/1 (0%)	0
Injury, poisoning and procedural complications
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	1/41 (2.4%)	1	0/1 (0%)	0
Wound complication, non-infectious	1/41 (2.4%)	1	0/1 (0%)	0
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	4/41 (9.8%)	6	0/1 (0%)	0
AST, SGOT(serum glutamic oxaloacetic transaminase)	16/41 (39%)	26	0/1 (0%)	0
Alkaline phosphatase	6/41 (14.6%)	7	0/1 (0%)	0
Bilirubin (hyperbilirubinemia)	4/41 (9.8%)	6	0/1 (0%)	0
Creatinine	2/41 (4.9%)	4	1/1 (100%)	1
Hemoglobin	14/41 (34.1%)	22	1/1 (100%)	2
Leukocytes (total WBC)	21/41 (51.2%)	69	0/1 (0%)	0
Lymphopenia	23/41 (56.1%)	73	0/1 (0%)	0
Neutrophils/granulocytes (ANC/AGC)	13/41 (31.7%)	49	0/1 (0%)	0
Platelets	17/41 (41.5%)	31	0/1 (0%)	0
Prolonged QTc interval	21/41 (51.2%)	51	0/1 (0%)	0
Weight gain	1/41 (2.4%)	1	0/1 (0%)	0
Weight loss	1/41 (2.4%)	1	0/1 (0%)	0
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	1/41 (2.4%)	1	0/1 (0%)	0
Anorexia	2/41 (4.9%)	2	0/1 (0%)	0
Calcium, serum-high (hypercalcemia)	1/41 (2.4%)	1	0/1 (0%)	0
Calcium, serum-low (hypocalcemia)	1/41 (2.4%)	1	0/1 (0%)	0
Dehydration	1/41 (2.4%)	1	0/1 (0%)	0
Glucose, serum-low (hyperglycemia)	1/41 (2.4%)	1	0/1 (0%)	0
Magnesium, serum-high (hypermagnesemia)	6/41 (14.6%)	6	0/1 (0%)	0
Magnesium, serum-low (hypomagnesemia)	1/41 (2.4%)	4	0/1 (0%)	0
Phosphate, serum-low (hypophosphatemia)	15/41 (36.6%)	35	1/1 (100%)	3
Sodium, serum-low (hypernatremia)	3/41 (7.3%)	4	0/1 (0%)	0
Sodium, serum-low (hyponatremia)	2/41 (4.9%)	2	0/1 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)::Extremity-lower	3/41 (7.3%)	5	0/1 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy)::Whole body/generalized	7/41 (17.1%)	12	0/1 (0%)	0
Pain::Other (Specify, left arm (phlebotomy pain))	1/41 (2.4%)	1	0/1 (0%)	0
Pain::Chest wall	3/41 (7.3%)	3	0/1 (0%)	0
Pain::Muscle	1/41 (2.4%)	1	0/1 (0%)	0
Pain::Neck	1/41 (2.4%)	1	0/1 (0%)	0
Nervous system disorders
Dizziness	2/41 (4.9%)	2	0/1 (0%)	0
Pain::Head/headache	6/41 (14.6%)	7	0/1 (0%)	0
Pyramidal tract dysfunction (e.g., increased tone, hyperflexia, positive Babinski, decreased fine mo	1/41 (2.4%)	1	0/1 (0%)	0
Renal and urinary disorders
Hemoglobinuria	1/41 (2.4%)	1	0/1 (0%)	0
Proteinuria	18/41 (43.9%)	21	1/1 (100%)	2
Urinary frequency/urgency	2/41 (4.9%)	4	0/1 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hemorrhage, pulmonary/upper respiratory::Nose	1/41 (2.4%)	1	1/1 (100%)	1
Pain::Throat/pharynx/larynx	1/41 (2.4%)	1	0/1 (0%)	0
Voice changes/dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis)	2/41 (4.9%)	2	0/1 (0%)	0
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other (Specify,hyperpigmentation 1; laceration)	1/41 (2.4%)	1	0/1 (0%)	0
Hair loss/alopecia (scalp or body)	1/41 (2.4%)	1	0/1 (0%)	0
Hypopigmentation	1/41 (2.4%)	1	0/1 (0%)	0
Nail changes	2/41 (4.9%)	2	0/1 (0%)	0
Rash/desquamation	1/41 (2.4%)	1	0/1 (0%)	0
Rash: acne/acneiform	6/41 (14.6%)	6	0/1 (0%)	0
Rash: hand-foot skin reaction	3/41 (7.3%)	3	0/1 (0%)	0
Vascular disorders
Flushing	1/41 (2.4%)	1	0/1 (0%)	0
Hypertension	16/41 (39%)	24	1/1 (100%)	1
Lymphedema-related fibrosis	1/41 (2.4%)	1	0/1 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.