BIBF 1120 for Recurrent High-Grade Gliomas

• Sponsor: Patrick Y. Wen, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT01380782
• Collaborator: Boehringer Ingelheim (Industry), Wake Forest University Health Sciences (Other), University of Virginia (Other), Massachusetts General Hospital (Other), The Cleveland Clinic (Other)
• Enrollment: 37
• Locations: 4
• Arms: 2
• Duration (Months): 26
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

BIBF 1120 is a newly discovered compound that may stop cancer cells from growing abnormally. This drug is currently being used in treatment for other cancers in research studies and information from those other research studies suggests that this agent, BIBF 1120, may help to stop recurrent malignant glioma cells from multiplying and it may also prevent the growth of new blood vessels at the site of the tumor. In this research study, the investigators are looking to see how well BIBF 1120 works in patients with recurrent malignant gliomas.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma; Gliosarcoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Oligoastrocytoma	Drug: BIBF 1120	Phase 2

Detailed Description

This is a two arm, multicenter, open label phase II trial in adult patients with recurrent supratentorial high-grade glioma. One arm (the "bevacizumab naïve" arm) will enroll patients who have not received prior bevacizumab therapy, and the other arm (the "post-bevacizumab" arm) will enroll patients who have experienced progression on bevacizumab.

All subjects will receive BIBF 1120 at 200mg orally, twice daily in cycles of 28 days. Subjects will come to the clinic on Day 1 of each cycle (or within 2 days prior) for blood and urine tests and a physical and neurologic exam. Bloods will also be checked within 2 days before or after Day 15 of Cycles 1 and 2. An additional blood sample will be taken on Days 1 and 8 of Cycle 1, at the start of every even-numbered cycle, and at the end of active study treatment. Subjects will have gadolinium-enhanced brain MRI scans performed with tumor measurements at screening, at the start of even-numbered cycles, and at the end of active study treatment(unless already obtained within 4 weeks of completing study treatment). 40 study subjects will have diffusion- and perfusion-weighted MRI at baseline, after 1 week on therapy (± 2 days), within 2 days prior to the start of every even-numbered cycle, and at the end of treatment (unless already obtained within 4 weeks of completing study treatment).

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Triple Receptor Tyrosine Kinase Receptor Inhibitor BIBF 1120 in Recurrent High-Grade Gliomas
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bevacizumab Naive Bevacizumab naive subjects	Drug: BIBF 1120; 200 mg BID oral for 28 day cycle
Experimental: Prior Bevacizumab Patients previously treated with bevacizumab	Drug: BIBF 1120; 200 mg BID oral for 28 day cycle

Outcome Measures

Primary Outcome Measures

1. 6-Month Progression Free Survival [Six months]

   To determine the efficacy of BIBF 1120 in bevacizumab-naive participants with recurrent glioblastoma (GBM) as measured by 6-month progression-free survival (PFS6).

2. 3-Month Progression Free Survival [3 months]

   To determine the efficacy of BIBF 1120 in bevacizumab-treated participants with recurrent GBM as measured by 3-month progression free survival (PFS3).

Secondary Outcome Measures

1. Proportion of Participants Experiencing Stable Disease (SD) as Their Best Radiographic Response [2 years]

   Best radiographic response in both populations. There were no participants with partial or complete responses, so the results are being reported in the proportion of participants who experienced stable disease (SD) as their best response (as opposed to progressive disease).

2. Overall Survival [2 years]

   Overall survival in both populations

3. Time-to-tumor Progression [2 years]

   Time-to-tumor progression in both populations.

4. Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) [2 years]

   Safety profile in both populations - as adverse events are posted separately in detail, these results will demonstrate serious adverse events (defined as grades 3-5) that were judged at least possibly related to Nintedanib (BIBF 1120).

Other Outcome Measures

1. Exploratory Objective #1: Progression-free Survival at 3- and 6-months for Participants With Recurrent Anaplastic Gliomas (AG) [Arm A - 6 months; Arm B - 3 months]

   To explore the efficacy of BIBF 1120 in bevacizumab-naïve and bevacizumab-treated participants with recurrent anaplastic gliomas (AG) survival was assessed at 6 months for Arm A and 3 months for Arm B.

2. Exploratory Objective #2: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Tumor Genotype and/or Expression Profile [2 years]

   To explore the extent to which the tumor's genotype and expression profile correlate with outcome.

3. Exploratory Objective #3: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Serum Angiogenic Peptides, Circulating Endothelial Cells, and/or Circulating Progenitor Cells [2 years]

   To explore the correlation between serum angiogenic peptides, circulating endothelial cells, and circulating progenitor cells with response to therapy.

4. Exploratory Objective #4: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Perfusion MRI, Diffusion MRI [2 years]

   To explore the correlation between perfusion MRI, diffusion MRI and response to therapy.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histopathologically-confirmed, supratentorial, recurrent glioblastoma; subjects with an initial diagnosis of a lower grade glioma are eligible if a subsequent biopsy is determined to be glioblastoma

• Demonstration of recurrent disease on MRI following prior therapy

• Development of progressive disease after having received prior RT, and must have an interval of at least 12 weeks from the completion of any radiation therapy to study entry (unless progressive tumor growth is outside the radiation field or there is histopathological confirmation of recurrent tumor).

• Bi-dimensionally measurable disease (minimum measurement of 1 cm in one dimension) on MRI performed within 14 days prior to first treatment. (If receiving corticosteroids, participants must be on a stable or decreasing dose of corticosteroids for at least 5 days prior to baseline MRI.)

• Life expectancy of at least 12 weeks

• KPS >/= 60

• Normal organ and marrow function as defined by protocol

• Recovered from toxic effects of prior therapy

• Sufficient tumor availability (at least 15-20 unstained paraffin slides from any prior surgery)

Exclusion Criteria:

• Receiving other investigational agent

• More than 2 prior relapses

• Prior therapy with inhibitor of VEGF, VEGFR, PDGFR, or FGFR (including bevacizumab)

• Pregnant or breast-feeding

• Unwilling to agree to adequate contraception, if subject is of child-bearing potential

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BIBF 1120

• Use of EIAEDs within 14 days of registration

• Evidence of recent hemorrhage on baseline MRI of the brain

• Uncontrolled intercurrent illness

• Uncontrolled hypertension

• History of hypertensive encephalopathy

• History of any of the following within 6 months prior to enrollment: myocardial infarction or unstable angina, stroke or transient ischemic attack, significant vascular disease or peripheral arterial thrombosis, abdominal fistula, gastrointestinal perforation, or intra-abdominal abcess, intracerebral abscess

• Evidence of bleeding diathesis or coagulopathy

• Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to the first treatment day, or anticipation of need for major surgical procedure during the course of the study

• Minor surgical procedures, stereotactic biopsy, fine needle aspiration, or core biopsy within 7 days prior to the first treatment day

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

• History of a different malignancy unless disease-free for at least 5 years (unless cervical cancer in situ, or basal cell or squamous cell carcinoma of the skin)

• HIV positive

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
3	Cleveland Clinic	Cleveland	Ohio	United States	44195
4	University of Virginia	Charlottesville	Virginia	United States	22908-4324

Sponsors and Collaborators

• Patrick Y. Wen, MD
• Boehringer Ingelheim
• Wake Forest University Health Sciences
• University of Virginia
• Massachusetts General Hospital
• The Cleveland Clinic

Investigators

• Principal Investigator: Patrick Y Wen, M.D., Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Patrick Y. Wen, MD, Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01380782
• Other Study ID Numbers: 11-055; BIBF 1199.94
• First Posted: Jun 27, 2011
• Last Update Posted: Aug 18, 2014
• Last Verified: Aug 1, 2014

• Keywords provided by Patrick Y. Wen, MD, Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute: brain tumor; recurrent disease
• Additional relevant MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Nintedanib

Study Results

Participant Flow

Recruitment Details	Study activated at Dana-Farber Cancer Institute in May 2012 and was eventually activated at Massachusetts General Hospital, Cleveland Clinic, and University of Virginia. The bevacizumab-treated arm closed to accrual in December 2012 and the bevacizumab-naive arm closed in March 2013, both due to futility.

Arm/Group Title	Arm A (Bevacizumab-naive) - GBM	Arm A (Bevacizumab-naive) - AG	Arm B (Bevacizumab Treated) - GBM	Arm B (Bevacizumab Treated) - AG
Arm/Group Description	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was glioblastoma (GBM).	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was anaplastic glioma (AG).	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was glioblastoma (GBM).	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was anaplastic glioma (AG).
Period Title: Overall Study
STARTED	12	10	11	4
COMPLETED	0	0	0	0
NOT COMPLETED	12	10	11	4

Baseline Characteristics

Arm/Group Title	Arm A Bevacizumab-naive	Arm B Bevacizumab-treated	Total
Arm/Group Description	Bevacizumab-naive participants	Bevacizumab-treated participants	Total of all reporting groups
Overall Participants	22	14	36
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54	52	52
Sex: Female, Male (Count of Participants)
Female	15 68.2%	3 21.4%	18 50%
Male	7 31.8%	11 78.6%	18 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 4.5%	0 0%	1 2.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	19 86.4%	11 78.6%	30 83.3%
More than one race	1 4.5%	0 0%	1 2.8%
Unknown or Not Reported	1 4.5%	3 21.4%	4 11.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 7.1%	1 2.8%
Not Hispanic or Latino	21 95.5%	12 85.7%	33 91.7%
Unknown or Not Reported	1 4.5%	1 7.1%	2 5.6%
Karnofsky Performance Status (Units on a scale) [Median (Full Range) ]
Median (Full Range) [Units on a scale]	90	90	90

Outcome Measures

1. Primary Outcome

Title	6-Month Progression Free Survival
Description	To determine the efficacy of BIBF 1120 in bevacizumab-naive participants with recurrent glioblastoma (GBM) as measured by 6-month progression-free survival (PFS6).
Time Frame	Six months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Bevacizumab-naive) - GBM
Arm/Group Description	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was glioblastoma (GBM).
Measure Participants	12
Number [percentage of participants]	0 0%

2. Primary Outcome

Title	3-Month Progression Free Survival
Description	To determine the efficacy of BIBF 1120 in bevacizumab-treated participants with recurrent GBM as measured by 3-month progression free survival (PFS3).
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm B (Bevacizumab Treated) - GBM
Arm/Group Description	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was glioblastoma (GBM).
Measure Participants	10
Number [percentage of participants]	0 0%

3. Secondary Outcome

Title	Proportion of Participants Experiencing Stable Disease (SD) as Their Best Radiographic Response
Description	Best radiographic response in both populations. There were no participants with partial or complete responses, so the results are being reported in the proportion of participants who experienced stable disease (SD) as their best response (as opposed to progressive disease).
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Bevacizumab-naive) - GBM	Arm A (Bevacizumab-naive) - AG	Arm B (Bevacizumab Treated) - GBM	Arm B (Bevacizumab Treated) - AG
Arm/Group Description	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was glioblastoma (GBM).	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was anaplastic glioma (AG).	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was glioblastoma (GBM).	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was anaplastic glioma (AG).
Measure Participants	12	10	10	4
Number [% of patients with best response SD]	33	40	10	25

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival in both populations
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Bevacizumab-naive) - GBM	Arm A (Bevacizumab-naive) - AG	Arm B (Bevacizumab Treated) - GBM	Arm B (Bevacizumab Treated) - AG
Arm/Group Description	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was glioblastoma (GBM).	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was anaplastic glioma (AG).	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was glioblastoma (GBM).	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was anaplastic glioma (AG).
Measure Participants	12	10	10	4
Median (95% Confidence Interval) [months]	6.9	11.3	2.6	7.3

5. Secondary Outcome

Title	Time-to-tumor Progression
Description	Time-to-tumor progression in both populations.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Bevacizumab-naive) - GBM	Arm A (Bevacizumab-naive) - AG	Arm B (Bevacizumab Treated) - GBM	Arm B (Bevacizumab Treated) - AG
Arm/Group Description	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was glioblastoma (GBM).	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was anaplastic glioma (AG).	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was glioblastoma (GBM).	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was anaplastic glioma (AG).
Measure Participants	12	10	10	4
Median (95% Confidence Interval) [days]	28	28	28	36

6. Secondary Outcome

Title	Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial)
Description	Safety profile in both populations - as adverse events are posted separately in detail, these results will demonstrate serious adverse events (defined as grades 3-5) that were judged at least possibly related to Nintedanib (BIBF 1120).
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants (Arm A and B)
Arm/Group Description
Measure Participants	37
Abdominal pain	1
Reversible transaminase elevation	8
Hypertension	1
Hypophosphatemia	3
Intracranial hemorrhage	1
Colonic perforation	2
Pulmonary embolism	1

7. Other Pre-specified Outcome

Title	Exploratory Objective #1: Progression-free Survival at 3- and 6-months for Participants With Recurrent Anaplastic Gliomas (AG)
Description	To explore the efficacy of BIBF 1120 in bevacizumab-naïve and bevacizumab-treated participants with recurrent anaplastic gliomas (AG) survival was assessed at 6 months for Arm A and 3 months for Arm B.
Time Frame	Arm A - 6 months; Arm B - 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Bevacizumab-naive) - AG	Arm B (Bevacizumab Treated) - AG
Arm/Group Description	Participants who had not been treated with bevacizumab prior to entering the study, and whose current histology was anaplastic glioma (AG).	Participants who had been previously treated with bevacizumab prior to entering the study, and whose currently histology was anaplastic glioma (AG).
Measure Participants	10	4
Number [percentage of participants]	0 0%	0 0%

8. Other Pre-specified Outcome

Title	Exploratory Objective #2: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Tumor Genotype and/or Expression Profile
Description	To explore the extent to which the tumor's genotype and expression profile correlate with outcome.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Exploratory Objective #3: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Serum Angiogenic Peptides, Circulating Endothelial Cells, and/or Circulating Progenitor Cells
Description	To explore the correlation between serum angiogenic peptides, circulating endothelial cells, and circulating progenitor cells with response to therapy.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Exploratory Objective #4: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Perfusion MRI, Diffusion MRI
Description	To explore the correlation between perfusion MRI, diffusion MRI and response to therapy.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse events were collected on each participant from the time the informed consent document was signed up until 30 days after the last dose of study drug.
Adverse Event Reporting Description	Abnormal laboratory values or diagnostic tests results constitute AEs only if they induce clinical signs or symptoms or require treatment or further diagnostic tests.
Arm/Group Title	Arm A		Arm B
Arm/Group Description	Bevacizumab-naive participants		Bevacizumab-treated participants
All Cause Mortality
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/22 (36.4%)		5/14 (35.7%)
Gastrointestinal disorders
Abdominal pain	0/22 (0%)	0	1/14 (7.1%)	1
Colonic perforation	1/22 (4.5%)	2	0/14 (0%)	0
Enterocolitis	0/22 (0%)	0	1/14 (7.1%)	2
General disorders
Death NOS	1/22 (4.5%)	1	2/14 (14.3%)	2
Investigations
Alanine aminotransferase increased	0/22 (0%)	0	1/14 (7.1%)	1
Aspartate aminotransferase increased	0/22 (0%)	0	1/14 (7.1%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness left-sided	0/22 (0%)	0	1/14 (7.1%)	1
Muscle weakness right-sided	1/22 (4.5%)	1	0/14 (0%)	0
Nervous system disorders
Dysphasia	1/22 (4.5%)	1	0/14 (0%)	0
Edema cerebral	1/22 (4.5%)	1	1/14 (7.1%)	1
Hydrocephalus	0/22 (0%)	0	1/14 (7.1%)	1
Intracranial hemorrhage	1/22 (4.5%)	2	0/14 (0%)	0
Psychiatric disorders
Agitation	1/22 (4.5%)	1	0/14 (0%)	0
Delirium	1/22 (4.5%)	1	0/14 (0%)	0
Depression	1/22 (4.5%)	1	0/14 (0%)	0
Suicidal ideation	1/22 (4.5%)	2	0/14 (0%)	0
Suicidal attempt	1/22 (4.5%)	1	0/14 (0%)	0
Vascular disorders
Thromboembolic event	1/22 (4.5%)	1	1/14 (7.1%)	1
Vascular disorders - Other	0/22 (0%)	0	1/14 (7.1%)	2
Other (Not Including Serious) Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/22 (100%)		14/14 (100%)
Cardiac disorders
Cardiac disorders - Other	0/22 (0%)	0	1/14 (7.1%)	1
Sinus bradycardia	0/22 (0%)	0	1/14 (7.1%)	1
Sinus tachycardia	0/22 (0%)	0	1/14 (7.1%)	1
Endocrine disorders
Cushingoid	0/22 (0%)	0	1/14 (7.1%)	1
Eye disorders
Eye disorders - Other	1/22 (4.5%)	1	1/14 (7.1%)	1
Gastrointestinal disorders
Abdominal pain	3/22 (13.6%)	3	1/14 (7.1%)	1
Constipation	2/22 (9.1%)	2	1/14 (7.1%)	1
Diarrhea	7/22 (31.8%)	9	4/14 (28.6%)	4
Nausea	3/22 (13.6%)	5	4/14 (28.6%)	5
Vomiting	5/22 (22.7%)	5	3/14 (21.4%)	3
Duodenal hemorrhage	0/22 (0%)	0	1/14 (7.1%)	1
General disorders
Edema limbs	2/22 (9.1%)	2	0/14 (0%)	0
Fatigue	4/22 (18.2%)	4	8/14 (57.1%)	10
Pain	1/22 (4.5%)	1	1/14 (7.1%)	1
Infusion site extravasation	0/22 (0%)	0	1/14 (7.1%)	1
Infections and infestations
Urinary tract infection	4/22 (18.2%)	4	1/14 (7.1%)	1
Lung infection	0/22 (0%)	0	1/14 (7.1%)	1
Injury, poisoning and procedural complications
Fall	2/22 (9.1%)	2	2/14 (14.3%)	3
Investigations
Alanine aminotransferase increased	4/22 (18.2%)	10	3/14 (21.4%)	4
Aspartate aminotransferase increased	4/22 (18.2%)	9	0/14 (0%)	0
Platelet count decreased	2/22 (9.1%)	2	3/14 (21.4%)	5
Weight loss	2/22 (9.1%)	4	0/14 (0%)	0
White blood cell decreased	2/22 (9.1%)	2	0/14 (0%)	0
Activated partial thromboplastic time prolonged	0/22 (0%)	0	1/14 (7.1%)	1
INR increased	0/22 (0%)	0	1/14 (7.1%)	1
Metabolism and nutrition disorders
Anorexia	2/22 (9.1%)	3	1/14 (7.1%)	1
Hypokalemia	1/22 (4.5%)	1	1/14 (7.1%)	1
Hypomagnesemia	1/22 (4.5%)	1	1/14 (7.1%)	1
Hypophosphatemia	4/22 (18.2%)	6	0/14 (0%)	0
Hyperglycemia	0/22 (0%)	0	2/14 (14.3%)	3
Hypocalcemia	0/22 (0%)	0	1/14 (7.1%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/22 (0%)	0	1/14 (7.1%)	1
Bone pain	0/22 (0%)	0	2/14 (14.3%)	2
Generalized muscle weakness	0/22 (0%)	0	2/14 (14.3%)	2
Muscle weakness left-sided	0/22 (0%)	0	1/14 (7.1%)	1
Muscle weakness lower limb	0/22 (0%)	0	1/14 (7.1%)	1
Muscle weakness right-sided	0/22 (0%)	0	1/14 (7.1%)	1
Pain in extremity	0/22 (0%)	0	2/14 (14.3%)	2
Nervous system disorders
Dysarthria	2/22 (9.1%)	2	0/14 (0%)	0
Headache	4/22 (18.2%)	4	2/14 (14.3%)	2
Seizure	2/22 (9.1%)	2	3/14 (21.4%)	4
Ataxia	0/22 (0%)	0	1/14 (7.1%)	1
Concentration impairment	0/22 (0%)	0	1/14 (7.1%)	1
Dysphasia	0/22 (0%)	0	3/14 (21.4%)	3
Encephalopathy	0/22 (0%)	0	1/14 (7.1%)	1
Paresthesia	0/22 (0%)	0	1/14 (7.1%)	1
Peripheral motor neuropathy	0/22 (0%)	0	1/14 (7.1%)	1
Psychiatric disorders
Agitation	1/22 (4.5%)	1	1/14 (7.1%)	1
Confusion	2/22 (9.1%)	3	3/14 (21.4%)	3
Depression	1/22 (4.5%)	1	1/14 (7.1%)	1
Personality change	2/22 (9.1%)	2	0/14 (0%)	0
Anxiety	0/22 (0%)	0	1/14 (7.1%)	1
Delirium	0/22 (0%)	0	1/14 (7.1%)	1
Insomnia	0/22 (0%)	0	2/14 (14.3%)	2
Renal and urinary disorders
Urinary incontinence	0/22 (0%)	0	1/14 (7.1%)	1
Reproductive system and breast disorders
Vaginal hemorrhage	0/22 (0%)	0	1/14 (7.1%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/22 (0%)	0	1/14 (7.1%)	1
Hoarseness	0/22 (0%)	0	1/14 (7.1%)	1
Respiratory failure	0/22 (0%)	0	1/14 (7.1%)	1
Respiratory, thoracic and mediastinal disorders - Other	0/22 (0%)	0	1/14 (7.1%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	2/22 (9.1%)	2	0/14 (0%)	0
Purpura	0/22 (0%)	0	1/14 (7.1%)	1
Vascular disorders
Hypertension	5/22 (22.7%)	6	6/14 (42.9%)	7

Limitations/Caveats

The trial intended to enroll 14 participants onto Arm A GBM, but only 10 enrolled due to futility. In addition, 10 AG participants were to be enrolled onto each Arm as exploratory cohorts, but again due to futility only 4 enrolled onto Arm B.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.