Phase II Study of BKM120 for Subjects With Recurrent Glioblastoma

• Sponsor: Patrick Y. Wen, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT01339052
• Collaborator: Brigham and Women's Hospital (Other), Massachusetts General Hospital (Other), Novartis Pharmaceuticals (Industry), M.D. Anderson Cancer Center (Other), Memorial Sloan Kettering Cancer Center (Other), University of California, San Francisco (Other), University of California, Los Angeles (Other), University of Utah (Other)
• Enrollment: 65
• Locations: 7
• Arms: 2
• Actual Duration (Months): 89
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

BKM120 is a newly discovered drug that has been used in other research studies. Information from those other research studies suggests that BKM120 may help to slow or stop the growth of malignant gliomas. The purpose of this study is to see how well BKM120 works in patients with malignant gliomas. Patients on this study will be treated in two groups: patients who are going to receive surgery and those who will not receive surgery. This study is trying to determine how effective BKM120 is in stopping cancer cells from growing. For patients receiving surgery the research will also try to determine if an effective level of BKM120 can penetrate the brain before surgery.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma	Drug: BKM120; Procedure: Surgery	Phase 2

Detailed Description

OBJECTIVES:

Cohort 1

Primary Objectives

• Evaluate PI3K pathway modulation due to BKM120 in tumor tissue

• Evaluate BKM120 concentration in tumor tissue, plasma, and cerebrospinal fluid

Secondary Objectives

• Evaluate effects of BKM120 on tumor cell proliferation and tumor cell death

• Investigate the safety profile of BKM120 in this population

• Investigate pharmacokinetics of BKM120 in this population

Exploratory Objectives

• Correlate FDG-PET and FLT-PET with pharmacodynamic effects and 6-month progressive-free survival (PFS6)

• Determine the effects of BKM120 on primary GBM cell lines derived from participants and correlate with participant benefit from BKM120 treatment

Cohort 2

Primary Objective

• Investigate the treatment efficacy as measured by 6-month progressive-free survival (PFS6)

Secondary Objectives

• Investigate the radiographic response, progression free survival, overall survival

• Investigate the safety profile efficacy of BKM120 in this population

Exploratory Objectives

• Correlate benefit from BKM120 treatment with molecular genotype of tumor (using immunohistochemistry, mutation analysis and RNA expression profiling), and whole blood proteomics

• Correlate benefit from BKM120 treatment with circulating angiogenic biomarkers

• Utilize advance MRI (perfusion, permeability, diffusion imaging) to determine the effects of BKM120 on tumor vasculature and to correlate with benefit from BKM120 treatment

STATISTICAL DESIGN:

Cohort 1

The primary endpoint for Cohort 1 is modulation of PI3 kinase pathway based on change in immunohistochemistry (IHC) scoring for pAKT. Modulation in scoring as measured by reduction of staining intensity score of one degree or more was reported as a positive response to drug. This portion of the trial would be considered a success if 9 or more participants of 15 participants showed a response. There was a 94% chance of this occurring if the true response rate was 75% and only a 10% chance of this occurring if the true response rate was 40%.

Cohort 2

The primary endpoint for Cohort 2 is the proportion of participants progression free at 6 months (PFS6). Historical comparison data suggest that ineffective therapies in recurrent GBM have a PFS6 rate of approximately 9-16% (Wong 1999; Lamborn 2008). This trial was sized to differentiate between a 15% versus a 32% PFS6. With a total sample size of 50 participants, this design yields at least 90% power with a one sided alpha < 0.1 to detect a true PFS6 rate of at least 32%. If the number of successes was ≥ 12, the therapy would be considered worthy of further study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of BKM 120 for Patients With Recurrent Glioblastoma and Activated PI3K Pathway
• Actual Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Oct 1, 2016
• Actual Study Completion Date: Feb 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: Surgical subjects Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Patients continued treatment until disease progression or unacceptable toxicity.	Drug: BKM120; Other Names: Busparlisib ; Procedure: Surgery; Surgery
Experimental: Cohort 2: Non-surgical subjects Subjects not candidates for surgery BKM120: 100 mg once daily, orally, for 28-day cycles Patients continued treatment until disease progression or unacceptable toxicity.	Drug: BKM120; Other Names: Busparlisib

Outcome Measures

Primary Outcome Measures

1. Change in pAKT (S473) Immunohistochemistry (IHC) Score From Baseline to Surgery [Cohort 1] [Samples were collected at baseline and at surgery (resected surgical tumor specimen) which occurred after up to 12 days of BKM120 treatment.]

   pAKT response was determined by pathologist-performed semi-quantitative IHC scoring for pAKT using previously established methods for glioblastoma (GBM) patients. Sample staining scored for intensity on a 0-2+ scale (0 none, 1+ weak positive, 2+ strong positive). Change in pAKT IHC score was the difference in score from baseline to surgery. Participants were classified into 3 groups: a reduction of staining score of one degree or more (considered a response), an increase in score and no change in score.

2. 6-Month Progression-Free Survival (PFS6) [Cohort 2] [Participants were assessed radiologically every other cycle on treatment; Relevant for this outcome is up to month 6 evaluation.]

   PFS6 is the proportion of participants remaining alive and progression-free at 6-months from cycle 1 day 1 of BKM120 treatment. Progressive disease is defined using RANO (Response Assessment in Neuro-Oncology) criteria (Wen et al JCO 2010), which takes modified Macdonald Criteria and adds assessment of non-enhancing lesions. Per RANO, progressive disease (PD) is defined either as > 25% increase in sum of the products of perpendicular diameters of enhancing lesions on stable or increasing doses of corticosteroids, or one or more of the of the following: 1) Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids steroids not due to co-morbid events; 2) Any new lesion; 3) Clear clinical deterioration not attributable to other causes apart from the tumor; or 4) Failure to return for evaluation due to death or deteriorating condition.

3. BKM120 Brain-to-Plasma Ratio at Time of Surgery [Cohort 1] [Samples were collected at surgery (surgical tumor specimen and plasma sample) which occurred after up to 12 days of BKM120 treatment.]

   Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry. BKM120 tumor-to-plasma ratio at time of surgery was calculated based on these levels.

4. BKM120 Tumor Tissue Concentration at Time of Surgery [Cohort 1] [Samples were collected at surgery (resected surgical tumor specimen) which occurred after up to 12 days of BKM120 treatment.]

   Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry.

5. BKM120 Plasma Concentration at Time of Surgery [Cohort 1] [Samples were collected at surgery which occurred after up to 12 days of BKM120 treatment.]

   Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry.

Secondary Outcome Measures

1. % Ki-67 Reduction Using Immunohistochemistry (IHC) [Cohort 1] [Samples were collected at baseline (archival tumor specimen) and at surgery (surgical tumor specimen) which occurred after up to 12 days of BTK120 treatment.]

   Tumor cell proliferation and tumor cell death was using immunohistochemistry for Ki-67 based on established methods. Percent reduction was based on Ki-67 levels at baseline and at surgery.

2. Radiographic Response [Cohort 2] [Participants were assessed radiologically every other cycle on treatment. Cohort 2 participants were on treatment up to 9.2 months.]

   Radiographic response was based on RANO (Response Assessment in Neuro-Oncology) criteria. Per RANO, complete response (CR): 1) Complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks, 2) No new lesions, 3) All lesions assessed using the same techniques as baseline, 4) No steroid use (or on physiologic replacement doses only), 5) Stable or improved non-enhancing (T2/FLAIR) lesions and 6) Stable or improved clinically; partial response (PR): 1) >/= 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions (sum LD) sustained for at least 4 weeks and 2) No progression; progressive disease (PD): 1) > 25% increase sum LD and/or 2) significant increase in T2/FLAIR, 3) any new lesion, 4) clear clinical deterioration; stable disease (SD): none of the above.

3. Maximum Observed Plasma Concentrations (Cmax) of BKM120 Day 1 and Day 8 [Cohort 1] [On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.]

   Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. NOTE: This outcome measure was previously titled: "Investigate Pharmacokinetics of BKM120 in This Population by Comparing Maximum Plasma Concentrations (Cmax) From Day 1 to Day 8"

4. Cmax Accumulation Ratio of BKM120 Day 1 and Day 8 Ratio [Cohort 1] [On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.]

   Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. The accumulation ratio is day 8/day 1.

5. Area Under the Concentration Curve From Time 0 to Last Concentration (AUC0-5h) of BKM120 Day 1 and Day 8 [Cohort 1] [On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.]

   Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. NOTE: This outcome measure was previously titled: "Investigate Pharmacokinetics of BKM120 in This Population by Comparing the Drug Exposure Area Under the Curve (AUC0-5h) From Day 1 to Day 8"

6. AUC0-5h Accumulation Ratio of BKM120 Day 1 and Day 8 [Cohort 1] [On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.]

   Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. The accumulation ratio is day 8/day 1.

7. Time to Maximum Observed Plasma Concentration (Tmax) of BKM120 Day 1 and Day 8 [Cohort 1] [On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.]

   Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods.

8. Overall Survival (OS) [Cohort 2] [Participants were followed long-term for survival via medical record review. Cohort 2 participants were followed for survival up to 52 months in this study cohort.]

   Overall survival is defined as the time from date of first dose to death or date last known alive and estimated using Kaplan-Meier (KM) methods.

9. Progression-Free Survival (PFS) [Cohort 2] [Participants were assessed radiologically every other cycle on treatment and off-treatment via medical record review until death. Cohort 2 participants were followed for progression-free survival up to 12 months in this study cohort.]

   PFS is defined as the time from first dose to the earliest documentation of disease progression or death. Participants alive without evidence of PD were censored at the date of last disease assessment. Progressive disease was established based on Response Assessment in Neuro-Oncology (RANO) criteria (Wen et al JCO 2010). See outcome measure #2.

10. Grade 3-5 Treatment-Related Toxicity Rate [Adverse events experienced by participants are collected and reported throughout treatment with study drug (from initiation of study medication until 30 days after the last dose of BKM120), maximum timeframe was 2 years.]

    The percentage of patients who experienced any grade 3-5 treatment-related adverse event based on CTCAEv4 as reported on case report forms.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants must be able to understand and be willing to sign a written informed consent document.

• Subjects must be able to adhere to the dosing and visit schedules, and agree to record medication times accurately and consistently in a daily diary.

• Participants must be at least 18 years old.

• Participants must have a Karnofsky performance status (KPS) ≥ 60. Nature of illness and treatment history

• Participants must have histologically confirmed glioblastoma or variants. Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made.

• Participants may have had treatment for no more than 1 prior relapse(NOTE: Relapse is defined as progression following initial therapy (i.e., radiation ± chemotherapy)). The intent therefore is that patients had no more than 2 prior therapies (initial and treatment for 1 relapse). If the participant had a surgical resection for relapsed disease and no antitumor therapy was instituted for up to 12 weeks, and the participant undergoes another surgical resection, this is considered as a second relapse. For participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse).

• Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan.

• For Cohort 2, CT or MRI within 14 days prior to start of study drug. MRIs should include vascular imaging when possible. For Cohort 2, corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI or CT scan and the start of treatment, a new baseline MRI or CT is required. For Cohort 1 subjects, CT or MRI should be performed ideally within 14 days prior to study registration, but because the screening MRI for this subset of subjects will not be used for evaluation of response, it is acceptable for this MRI/CT to have been performed greater than 14 days prior to registration if unavoidable. Furthermore, for this same reason, fluctuation in corticosteroid dose around this MRI does not warrant repeat scan so long as there is documented unequivocal evidence of tumor progression available.

• For Cohort 2, Immunohistochemical or genetic analysis on tumor tissue from a prior surgery must demonstrate activation of the PI3K pathway through one of the following: PIK3CA mutation of PIK3R1 mutation, PTEN negativity (<10% of tumor cells staining) oh immunohistochemistry, PTEN mutation (any), homozygous deletion of PTEN

• Participants must have failed prior radiation therapy and must have an interval of at least 12 weeks from the completion of radiation therapy to study entry.

• Participants must have recovered to a grade 0 or 1 from the toxic effects of prior therapy (with the exception of lymphopenia which is common after therapy with temozolomide).

• From the projected start of scheduled study treatment, the following time periods must have elapsed: 4 weeks or 5 half-lives (whichever is shorter)from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies.

• Participants with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of progressive disease based upon nuclear imaging, MR spectroscopy, perfusion imaging or histopathology.

• Participants having undergone recent resection of recurrent or progressive tumor will be eligible for Cohort 2 as long as the following conditions apply: a) They have recovered from the effects of surgery; b) Residual disease following resection of recurrent tumor is not mandated for eligibility. To best assess the extent of residual disease postoperatively, an MRI or CT scan should ideally been performed no later than 96 hours following surgery or at least 28-days postoperatively, but scans performed outside of this window are considered acceptable if no alternative is available. In either case, the baseline/screening MRI must be performed within 14 days prior to registration. If the participant is taking corticosteroids, the dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI or CT scan and the start of treatment, a new baseline MRI or CT is required.

• Participants must have sufficient tissue from prior surgery for confirmation of diagnosis and correlative studies. Submission of tissue is to occur within 30 days after registration. The following amount of tissue is required: a) 25 unstained formalin fixed paraffin embedded (FFPE) sections (standard 4-5 micrometer thickness AND b)one of the following: i) At least 200 micrograms of frozen tissue OR ii)At least 10 (preferably 20) unstained FFPE sections of 10 micrometer thickness OR iii) At least 8 tissue cores from an FFPE block (200 micrometer total thickness of tissue from a block with a total surface area of 0.5 cm2)

• Clinical laboratory tests within 14 days prior to enrollment meeting the criteria listed in the protocol

• Cardiovascular assessment: baseline MUGA or Echocardiogram must demonstrate LVEF ≥ 50 %

• Electrocardiogram must demonstrate QTc interval of less than 480 msec

• Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective contraception (defined in protocol) during study treatment and for 16 weeks after study discontinuation.

• Women of child-bearing potential must have a negative serum pregnancy test at screening and within 48 hours prior to dosing with the study drug.

• Fertile males, defined as all males physiologically capable of conceiving offspring, must use condom during study treatment and for 16 weeks after study discontinuation and should not father a child in this period.

• Female partner of male study subject should use highly effective contraception while receiving study agent and for 16 weeks after final dose of study therapy.

Cohort 1 Inclusion Criteria (In addition to the general eligibility criteria, participants in the Cohort 1 preoperative portion of the study must meet the following criteria on screening examination to be eligible):

• A participant who is deemed by the site Investigator to be an appropriate candidate for surgical resection may be enrolled in the Cohort 1 preoperative study.

• There must be sufficient recurrent tumor to allow at least 400mg of tissue to be collected ( 2 X 0.5 cm3) for pharmacokinetic and pharmacodynamic analysis.

• Central Immunohistochemical analysis (by Dr. Ligon at DFCI) on tumor tissue from an earlier surgery must indicate pAKT positivity (1-2+ on a 0-2+ scale). [Cohort I patients' tissue may also demonstrate activation of the PI3K pathway via one of the criteria listed for Cohort 2 participants, but this is not mandatory.]

Exclusion Criteria:

• Participants who have received prior treatment with a P13K inhibitor, AKT inhibitor, mTOR inhibitor (e.g. rapamycin, MK2206, perifosine etc.).

• Participants who have received anti-angiogenic or anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL184, sunitinib etc).

• Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, and felbamate. Participant must be off any EIAEDs for at least two weeks prior to starting study drug. A list of EIAED and other inducers of CYP3A4 is provided in Table C-3 of Appendix C of the protocol.

• Participants taking a drug known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A (protoocol Appendix C). Participant must be off CYP3A inhibitors and inducers for at least two weeks prior to starting study drug. NOTE: participants must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to the first dose of study drug and during the entire study treatment period due to potential CYP3A4 interaction.

• Requirement of more than 8mg of dexamethasone daily.

• Participants taking drugs with known risk to promote QT prolongation and Torsades de Pointes (refer to protocol).

• Participants receiving any other investigational agents.

• Current use of herbal preparations/medications, including but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng. Participants should stop using these herbal medications 7 days prior to first dose of study drug.

• Current use of warfarin sodium or any other coumadin-derivative anticoagulant. Participant must be off Coumadin-derivative anticoagulants for at least 7 days prior to starting study drug. Low molecular weight heparin is allowed.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BKM120.

• History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician.

• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), chronic renal disease, pancreatitis, chronic pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements. Subjects must be free of any clinically relevant disease (other than glioma) that would, in the Investigator's opinion, interfere with the conduct of the study or study evaluations.

• Individuals with a history of a different malignancy except for the following circumstances: if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.

• Known diagnosis of human immunodeficiency virus (HIV) infection

• Participants with history of protocol specified mood disorders as judged by the Investigator or a psychiatrist, or as result of participant's screening mood assessment questionnaire

• Participants with diarrhea ≥ CTCAE grade 2

• Participant has active cardiac disease including any of the following: Angina pectoris that requires the use of anti-anginal medications; Ventricular arrhythmias except for benign premature ventricular contractions; Supraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication; Conduction abnormality requiring a pacemaker; Valvular disease with document compromise in cardiac function; Symptomatic pericarditis

• Participant has a history of cardiac dysfunction including any of the following: Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function; History of documented congestive heart failure (New York Heart Association functional classification III-IV; c)Documented cardiomyopathy; d) Congenital long QT syndrome

• Participants with poorly controlled diabetes mellitus (glycosylated hemoglobin > 8%) or poorly controlled steroid-induced diabetes mellitus (glycosylated hemoglobin > 8%)

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive small bowel resection). Participants with unresolved diarrhea will be excluded as previously indicated.

• Participants who have undergone major systemic surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Los Angeles	Los Angeles	California	United States	90095
2	University of California, San Francisco	San Francisco	California	United States	94143
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
5	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
6	UT, MD Anderson Cancer Center	Houston	Texas	United States	77030
7	Huntsman Cancer Institute, University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• Patrick Y. Wen, MD
• Brigham and Women's Hospital
• Massachusetts General Hospital
• Novartis Pharmaceuticals
• M.D. Anderson Cancer Center
• Memorial Sloan Kettering Cancer Center
• University of California, San Francisco
• University of California, Los Angeles
• University of Utah

Investigators

• Principal Investigator: Patrick Y Wen, MD, 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/Brigham and Women's Cancer Center
• ClinicalTrials.gov Identifier: NCT01339052
• Other Study ID Numbers: 11-033; CBKM120XUS07T
• First Posted: Apr 20, 2011
• Last Update Posted: Mar 19, 2019
• Last Verified: Mar 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Patrick Y. Wen, MD, Director, Center For Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center: BKM120; Brain tumor
• Additional relevant MeSH terms: Glioblastoma

Study Results

Participant Flow

Recruitment Details	Patients enrolled from September 2011 through February 2014.

Arm/Group Title	Cohort 1: Surgical Subjects	Cohort 2: Non-surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.	Subjects not candidates for surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	15	50
Measurable Disease	11	40
Evaluable Tumor Sample at Surgery	14	0
Evaluable Plasma Sample at Surgery	13	0
COMPLETED	0	0
NOT COMPLETED	15	50

Baseline Characteristics

Arm/Group Title	Cohort 1: Surgical Subjects	Cohort 2: Non-surgical Subjects	Total
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.	Subjects not candidates for surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	15	50	65
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	13 86.7%	43 86%	56 86.2%
>=65 years	2 13.3%	7 14%	9 13.8%
Sex: Female, Male (Count of Participants)
Female	4 26.7%	13 26%	17 26.2%
Male	11 73.3%	37 74%	48 73.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 4%	2 3.1%
Not Hispanic or Latino	11 73.3%	35 70%	46 70.8%
Unknown or Not Reported	4 26.7%	13 26%	17 26.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	3 6%	3 4.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	12 80%	32 64%	44 67.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 20%	15 30%	18 27.7%
Region of Enrollment (Count of Participants)
United States	15 100%	50 100%	65 100%
Karnofsky performance status (KPS) (Count of Participants)
70	1 6.7%	3 6%	4 6.2%
80	2 13.3%	15 30%	17 26.2%
90	10 66.7%	23 46%	33 50.8%
100	2 13.3%	9 18%	11 16.9%
Current Tumor Diagnosis (Count of Participants)
Glioblstoma Multiforme (GBM)	15 100%	47 94%	62 95.4%
Gliosarcoma	0 0%	3 6%	3 4.6%
Initial Tumor Diagnosis (Count of Participants)
Glioblastoma Multiforme (GBM)	13 86.7%	41 82%	54 83.1%
Anaplastic Astrocytoma (AA) merging w Glioblastoma	1 6.7%	0 0%	1 1.5%
Gr4 Right Parietal Glioma	1 6.7%	0 0%	1 1.5%
Astrocytoma	0 0%	1 2%	1 1.5%
Anaplastic Astrocytoma (AA)	0 0%	3 6%	3 4.6%
Gemistocytic Astrocyoma	0 0%	1 2%	1 1.5%
Glioma consistent w/ mixed Oligoastrocytoma	0 0%	1 2%	1 1.5%
Gliosarcoma	0 0%	1 2%	1 1.5%
High grade astrocytoma/glioblastoma	0 0%	1 2%	1 1.5%
Oligodendroglioma	0 0%	1 2%	1 1.5%
PTEN Status at Registration via Central Path Review (Count of Participants)
PTEN Negative	7 46.7%	34 68%	41 63.1%
Not PTEN Negative	8 53.3%	12 24%	20 30.8%
PTEN loss by FISH	0 0%	1 2%	1 1.5%
PTEN Mutant	0 0%	1 2%	1 1.5%
Unknown/Pending	0 0%	2 4%	2 3.1%
pAKT StatusStatus at Registration via Central Path Review (Count of Participants)
pAKT Positive	15 100%	39 78%	54 83.1%
pAKT Negative	0 0%	2 4%	2 3.1%
Unknown/Pending	0 0%	9 18%	9 13.8%
Mutation Status at Registration (Count of Participants)
PIK3CA mutation	1 6.7%	2 4%	3 4.6%
Negative	0 0%	1 2%	1 1.5%
Unknown/Pending	14 93.3%	47 94%	61 93.8%

Outcome Measures

1. Primary Outcome

Title	Change in pAKT (S473) Immunohistochemistry (IHC) Score From Baseline to Surgery [Cohort 1]
Description	pAKT response was determined by pathologist-performed semi-quantitative IHC scoring for pAKT using previously established methods for glioblastoma (GBM) patients. Sample staining scored for intensity on a 0-2+ scale (0 none, 1+ weak positive, 2+ strong positive). Change in pAKT IHC score was the difference in score from baseline to surgery. Participants were classified into 3 groups: a reduction of staining score of one degree or more (considered a response), an increase in score and no change in score.
Time Frame	Samples were collected at baseline and at surgery (resected surgical tumor specimen) which occurred after up to 12 days of BKM120 treatment.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated participants.

Arm/Group Title	Cohort 1: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	15
reduced pAKT (S473) IHC Score	6 40%
increased pAKT (S473) IHC Score	1 6.7%
no change in pAKT (S473) IHC Score	7 46.7%
Unevaluable	1 6.7%

2. Primary Outcome

Title	6-Month Progression-Free Survival (PFS6) [Cohort 2]
Description	PFS6 is the proportion of participants remaining alive and progression-free at 6-months from cycle 1 day 1 of BKM120 treatment. Progressive disease is defined using RANO (Response Assessment in Neuro-Oncology) criteria (Wen et al JCO 2010), which takes modified Macdonald Criteria and adds assessment of non-enhancing lesions. Per RANO, progressive disease (PD) is defined either as > 25% increase in sum of the products of perpendicular diameters of enhancing lesions on stable or increasing doses of corticosteroids, or one or more of the of the following: 1) Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids steroids not due to co-morbid events; 2) Any new lesion; 3) Clear clinical deterioration not attributable to other causes apart from the tumor; or 4) Failure to return for evaluation due to death or deteriorating condition.
Time Frame	Participants were assessed radiologically every other cycle on treatment; Relevant for this outcome is up to month 6 evaluation.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated participants.

Arm/Group Title	Cohort 2: Non-surgical Subjects
Arm/Group Description	Subjects not candidates for surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	50
Number (90% Confidence Interval) [proportion of participants]	0.08 0.5%

3. Primary Outcome

Title	BKM120 Brain-to-Plasma Ratio at Time of Surgery [Cohort 1]
Description	Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry. BKM120 tumor-to-plasma ratio at time of surgery was calculated based on these levels.
Time Frame	Samples were collected at surgery (surgical tumor specimen and plasma sample) which occurred after up to 12 days of BKM120 treatment.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of participants with a paired plasma and brain tumor sample (evaluable). Participants missing a brain tumor sample (n=1) or plasma sample (n=2) are excluded from the calculation.

Arm/Group Title	Cohort 1: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	13
Geometric Mean (Full Range) [ratio tumor-to-plasma]	1.00

4. Primary Outcome

Title	BKM120 Tumor Tissue Concentration at Time of Surgery [Cohort 1]
Description	Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry.
Time Frame	Samples were collected at surgery (resected surgical tumor specimen) which occurred after up to 12 days of BKM120 treatment.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all participants with a resected surgical tumor specimen (evaluable).

Arm/Group Title	Cohort 1: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	14
Geometric Mean (Full Range) [ng/gm]	590

5. Primary Outcome

Title	BKM120 Plasma Concentration at Time of Surgery [Cohort 1]
Description	Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry.
Time Frame	Samples were collected at surgery which occurred after up to 12 days of BKM120 treatment.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all participants with a plasma sample at surgery (evaluable).

Arm/Group Title	Cohort 1: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	13
Mean (Standard Deviation) [ng/mL]	585 (192)

6. Secondary Outcome

Title	% Ki-67 Reduction Using Immunohistochemistry (IHC) [Cohort 1]
Description	Tumor cell proliferation and tumor cell death was using immunohistochemistry for Ki-67 based on established methods. Percent reduction was based on Ki-67 levels at baseline and at surgery.
Time Frame	Samples were collected at baseline (archival tumor specimen) and at surgery (surgical tumor specimen) which occurred after up to 12 days of BTK120 treatment.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all participants with a resected surgical tumor specimen (evaluable).

Arm/Group Title	Cohort I: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	14
Median (Full Range) [% reduction]	11

7. Secondary Outcome

Title	Radiographic Response [Cohort 2]
Description	Radiographic response was based on RANO (Response Assessment in Neuro-Oncology) criteria. Per RANO, complete response (CR): 1) Complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks, 2) No new lesions, 3) All lesions assessed using the same techniques as baseline, 4) No steroid use (or on physiologic replacement doses only), 5) Stable or improved non-enhancing (T2/FLAIR) lesions and 6) Stable or improved clinically; partial response (PR): 1) >/= 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions (sum LD) sustained for at least 4 weeks and 2) No progression; progressive disease (PD): 1) > 25% increase sum LD and/or 2) significant increase in T2/FLAIR, 3) any new lesion, 4) clear clinical deterioration; stable disease (SD): none of the above.
Time Frame	Participants were assessed radiologically every other cycle on treatment. Cohort 2 participants were on treatment up to 9.2 months.

Outcome Measure Data

Analysis Population Description

Only those participants who had measurable disease present at baseline and received at least one dose of therapy are considered evaluable for radiographic response

Arm/Group Title	Cohort 2: Non-surgical Subjects
Arm/Group Description	Subjects not candidates for surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	40
Stable Disease	16 106.7%
Progressive Disease	22 146.7%
Not Evaluable	2 13.3%

8. Secondary Outcome

Title	Maximum Observed Plasma Concentrations (Cmax) of BKM120 Day 1 and Day 8 [Cohort 1]
Description	Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. NOTE: This outcome measure was previously titled: "Investigate Pharmacokinetics of BKM120 in This Population by Comparing Maximum Plasma Concentrations (Cmax) From Day 1 to Day 8"
Time Frame	On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	Cohort 1: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	15
Day 1	471 (147)
Day 8	820 (192)

9. Secondary Outcome

Title	Cmax Accumulation Ratio of BKM120 Day 1 and Day 8 Ratio [Cohort 1]
Description	Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. The accumulation ratio is day 8/day 1.
Time Frame	On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	Cohort I: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	15
Mean (Full Range) [ratio day 8/day 1]	1.88

10. Secondary Outcome

Title	Area Under the Concentration Curve From Time 0 to Last Concentration (AUC0-5h) of BKM120 Day 1 and Day 8 [Cohort 1]
Description	Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. NOTE: This outcome measure was previously titled: "Investigate Pharmacokinetics of BKM120 in This Population by Comparing the Drug Exposure Area Under the Curve (AUC0-5h) From Day 1 to Day 8"
Time Frame	On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	Cohort 1: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	15
Day 1	1.42 (0.50)
Day 8	3.27 (1.43)

11. Secondary Outcome

Title	AUC0-5h Accumulation Ratio of BKM120 Day 1 and Day 8 [Cohort 1]
Description	Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. The accumulation ratio is day 8/day 1.
Time Frame	On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	Cohort I: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	15
Mean (Full Range) [ratio day 8/day 1]	2.42

12. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) of BKM120 Day 1 and Day 8 [Cohort 1]
Description	Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods.
Time Frame	On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	Cohort 1: Surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	15
Day 1	1.5
Day 8	1.5

13. Secondary Outcome

Title	Overall Survival (OS) [Cohort 2]
Description	Overall survival is defined as the time from date of first dose to death or date last known alive and estimated using Kaplan-Meier (KM) methods.
Time Frame	Participants were followed long-term for survival via medical record review. Cohort 2 participants were followed for survival up to 52 months in this study cohort.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated participants.

Arm/Group Title	Cohort 2: Non-surgical Subjects
Arm/Group Description	Subjects not candidates for surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	50
Median (95% Confidence Interval) [months]	9.8

14. Secondary Outcome

Title	Progression-Free Survival (PFS) [Cohort 2]
Description	PFS is defined as the time from first dose to the earliest documentation of disease progression or death. Participants alive without evidence of PD were censored at the date of last disease assessment. Progressive disease was established based on Response Assessment in Neuro-Oncology (RANO) criteria (Wen et al JCO 2010). See outcome measure #2.
Time Frame	Participants were assessed radiologically every other cycle on treatment and off-treatment via medical record review until death. Cohort 2 participants were followed for progression-free survival up to 12 months in this study cohort.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated participants.

Arm/Group Title	Cohort 2: Non-surgical Subjects
Arm/Group Description	Subjects not candidates for surgery BKM120: 100 mg once daily, orally, for 28-day cycles Participants continued treatment until disease progression or unacceptable toxicity.
Measure Participants	50
Median (95% Confidence Interval) [months]	1.7

15. Secondary Outcome

Title	Grade 3-5 Treatment-Related Toxicity Rate
Description	The percentage of patients who experienced any grade 3-5 treatment-related adverse event based on CTCAEv4 as reported on case report forms.
Time Frame	Adverse events experienced by participants are collected and reported throughout treatment with study drug (from initiation of study medication until 30 days after the last dose of BKM120), maximum timeframe was 2 years.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	Cohorts 1: Surgical Subjects	Cohorts 2: Non-surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Patients continued treatment until disease progression or unacceptable toxicity.	Subjects not candidates for surgery BKM120: 100 mg once daily, orally, for 28-day cycles Patients continued treatment until disease progression or unacceptable toxicity.
Measure Participants	15	50
Number (90% Confidence Interval) [percentage of patients]	40.0	32.0

Adverse Events

Time Frame	Adverse events experienced by participants are collected and reported throughout treatment with study drug (from initiation of study medication until 30 days after the last dose of BKM120), maximum timeframe was 2 years.
Adverse Event Reporting Description	The following are considered 'serious' adverse events (SAEs) per protocol: ALL Grade 5 (fatal) Events ALL Grade 4 (life threatening or disabling) Events - Unless both Expected AND specifically listed in protocol as not requiring reporting ANY Grade 2 (moderate) or Grade 3 (severe) Event that is both Unexpected and deemed at least Possibly Related to study intervention Other AEs: Remaining AEs (maximum grade by toxicity type) without regard to treatment attribution.
Arm/Group Title	Cohorts 1: Surgical Subjects		Cohorts 2: Non-surgical Subjects
Arm/Group Description	Subjects scheduled for surgery BKM120: 100 mg once daily, orally, for 8-12 days prior to surgery Surgery: Surgery BKM120: 100 mg once daily, orally, for 28-day cycles Patients continued treatment until disease progression or unacceptable toxicity.		Subjects not candidates for surgery BKM120: 100 mg once daily, orally, for 28-day cycles Patients continued treatment until disease progression or unacceptable toxicity.
All Cause Mortality
	Cohorts 1: Surgical Subjects		Cohorts 2: Non-surgical Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		2/50 (4%)
Serious Adverse Events
	Cohorts 1: Surgical Subjects		Cohorts 2: Non-surgical Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/15 (33.3%)		12/50 (24%)
Ear and labyrinth disorders
Tinnitus	1/15 (6.7%)	1	0/50 (0%)	0
Vestibular disorder	1/15 (6.7%)	1	0/50 (0%)	0
Gastrointestinal disorders
Constipation	0/15 (0%)	0	1/50 (2%)	1
Infections and infestations
Wound Infection	0/15 (0%)	0	1/50 (2%)	1
Investigations
Lipase Increased	0/15 (0%)	0	3/50 (6%)	3
Lymphocyte count decreased	1/15 (6.7%)	1	0/50 (0%)	0
Platelet count decreased	1/15 (6.7%)	1	0/50 (0%)	0
Serum amylase increased	1/15 (6.7%)	2	2/50 (4%)	3
Weight loss	1/15 (6.7%)	1	0/50 (0%)	0
White blood cell decreased	1/15 (6.7%)	1	0/50 (0%)	0
Metabolism and nutrition disorders
Hypophosphatemia	0/15 (0%)	0	2/50 (4%)	3
Musculoskeletal and connective tissue disorders
Chest wall pain	0/15 (0%)	0	1/50 (2%)	1
Nervous system disorders
Edema cerebral	0/15 (0%)	0	1/50 (2%)	1
Headache	1/15 (6.7%)	1	0/50 (0%)	0
Leukoencephalopathy	0/15 (0%)	0	1/50 (2%)	1
Seizure	1/15 (6.7%)	2	0/50 (0%)	0
Spasticity	0/15 (0%)	0	1/50 (2%)	1
Psychiatric disorders
Psychosis	0/15 (0%)	0	1/50 (2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/15 (0%)	0	1/50 (2%)	1
Cough	0/15 (0%)	0	1/50 (2%)	1
Skin and subcutaneous tissue disorders
Photosensitivity	0/15 (0%)	0	1/50 (2%)	2
Vascular disorders
Thromboembolic event	0/15 (0%)	0	1/50 (2%)	1
Other (Not Including Serious) Adverse Events
	Cohorts 1: Surgical Subjects		Cohorts 2: Non-surgical Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/15 (100%)		50/50 (100%)
Blood and lymphatic system disorders
Anemia	1/15 (6.7%)	6	0/50 (0%)	0
Cardiac disorders
Sinus bradycardia	2/15 (13.3%)	2	1/50 (2%)	1
Ear and labyrinth disorders
Hearing Impaired	2/15 (13.3%)	2	2/50 (4%)	2
Tinnitus	0/15 (0%)	0	2/50 (4%)	2
Endocrine disorders
Hypothyroidism	1/15 (6.7%)	1	0/50 (0%)	0
Cushingoid	0/15 (0%)	0	2/50 (4%)	2
Eye disorders
Blurred vision	1/15 (6.7%)	1	4/50 (8%)	5
Cataract	1/15 (6.7%)	1	1/50 (2%)	1
Eye disorders - Other, specify: Left visual field cut/difficulty	1/15 (6.7%)	1	1/50 (2%)	1
Eye disorders - Other, specify: Eye Disorder:Dyplopia-Double Vision	1/15 (6.7%)	1	0/50 (0%)	0
Eye disorders - Other, specify: Quadranopsia, right	1/15 (6.7%)	1	0/50 (0%)	0
Optic nerve disorder	0/15 (0%)	0	2/50 (4%)	2
Gastrointestinal disorders
Constipation	2/15 (13.3%)	4	8/50 (16%)	8
Diarrhea	5/15 (33.3%)	8	12/50 (24%)	15
Mucositis oral	3/15 (20%)	3	6/50 (12%)	6
Nausea	6/15 (40%)	6	8/50 (16%)	8
Dyspepsia	1/15 (6.7%)	1	0/50 (0%)	0
Abdominal pain	0/15 (0%)	0	3/50 (6%)	3
Vomiting	0/15 (0%)	0	3/50 (6%)	4
Fecal incontinence	0/15 (0%)	0	4/50 (8%)	4
General disorders
Fatigue	11/15 (73.3%)	23	28/50 (56%)	41
Irritability	1/15 (6.7%)	1	3/50 (6%)	3
Chills	0/15 (0%)	0	2/50 (4%)	2
Edema face	1/15 (6.7%)	1	2/50 (4%)	2
Fever	1/15 (6.7%)	1	0/50 (0%)	0
Pain	3/15 (20%)	3	0/50 (0%)	0
Gait disturbance	0/15 (0%)	0	9/50 (18%)	10
Infections and infestations
Conjunctivitis infective	1/15 (6.7%)	1	0/50 (0%)	0
Papulopustular rash	1/15 (6.7%)	1	0/50 (0%)	0
Infections and infestations - Other, specify: varicella-zoster virus infection	1/15 (6.7%)	1	0/50 (0%)	0
Mucosal infection	1/15 (6.7%)	1	0/50 (0%)	0
Upper respiratory infection	1/15 (6.7%)	1	1/50 (2%)	1
Urinary tract infection	0/15 (0%)	0	2/50 (4%)	2
Wound infection	0/15 (0%)	0	2/50 (4%)	2
Injury, poisoning and procedural complications
Bruising	0/15 (0%)	0	2/50 (4%)	3
Fall	2/15 (13.3%)	2	4/50 (8%)	5
Investigations
Alanine aminotransferase increased	2/15 (13.3%)	2	7/50 (14%)	15
Aspartate aminotransferase increased	1/15 (6.7%)	1	4/50 (8%)	9
Lipase increased	2/15 (13.3%)	2	8/50 (16%)	9
Lymphocyte count decreased	2/15 (13.3%)	5	2/50 (4%)	2
Platelet count decreased	3/15 (20%)	4	7/50 (14%)	15
Serum amylase increased	3/15 (20%)	3	5/50 (10%)	8
White blood cell decreased	2/15 (13.3%)	2	5/50 (10%)	5
Alkaline phosphatase increased	1/15 (6.7%)	1	1/50 (2%)	1
Blood bilirubin increased	1/15 (6.7%)	1	1/50 (2%)	1
Neutrophil count decreased	1/15 (6.7%)	1	0/50 (0%)	0
Weight loss	1/15 (6.7%)	1	0/50 (0%)	0
Weight gain	0/15 (0%)	0	2/50 (4%)	3
Metabolism and nutrition disorders
Anorexia	2/15 (13.3%)	3	3/50 (6%)	3
Hyperglycemia	6/15 (40%)	9	25/50 (50%)	66
Hypophosphatemia	2/15 (13.3%)	7	2/50 (4%)	3
Hyperkalemia	1/15 (6.7%)	1	1/50 (2%)	1
Dehydration	2/15 (13.3%)	2	0/50 (0%)	0
Hypoalbuminemia	1/15 (6.7%)	2	0/50 (0%)	0
Hypocalcemia	1/15 (6.7%)	1	0/50 (0%)	0
Hypokalemia	3/15 (20%)	4	1/50 (2%)	3
Hypomagnesemia	1/15 (6.7%)	1	0/50 (0%)	0
Hyponatremia	1/15 (6.7%)	2	2/50 (4%)	2
Musculoskeletal and connective tissue disorders
Chest wall pain	0/15 (0%)	0	2/50 (4%)	2
Neck pain	0/15 (0%)	0	2/50 (4%)	2
Arthralgia	1/15 (6.7%)	1	1/50 (2%)	1
Back pain	2/15 (13.3%)	3	3/50 (6%)	3
Generalized muscle weakness	2/15 (13.3%)	2	5/50 (10%)	7
Muscle weakness left-sided	1/15 (6.7%)	1	2/50 (4%)	3
Muscle weakness right-sided	1/15 (6.7%)	1	1/50 (2%)	1
Nervous system disorders
Ataxia	3/15 (20%)	4	2/50 (4%)	2
Cognitive disturbance	1/15 (6.7%)	1	7/50 (14%)	7
Dizziness	2/15 (13.3%)	2	4/50 (8%)	4
Dysarthria	1/15 (6.7%)	1	1/50 (2%)	1
Dysesthesia	1/15 (6.7%)	1	1/50 (2%)	1
Dysphasia	2/15 (13.3%)	2	9/50 (18%)	10
Headache	2/15 (13.3%)	2	17/50 (34%)	21
Intracranial hemorrhage	1/15 (6.7%)	1	0/50 (0%)	0
Memory impairment	1/15 (6.7%)	1	9/50 (18%)	10
Nervous system disorders - Other, specify: left tongue deviation	1/15 (6.7%)	1	0/50 (0%)	0
Neuralgia	1/15 (6.7%)	1	0/50 (0%)	0
Seizure	4/15 (26.7%)	6	11/50 (22%)	14
Stroke	1/15 (6.7%)	1	0/50 (0%)	0
Concentration impairment	0/15 (0%)	0	2/50 (4%)	2
Lethargy	0/15 (0%)	0	2/50 (4%)	3
Pyramidal tract syndrome	0/15 (0%)	0	4/50 (8%)	4
Somnolence	0/15 (0%)	0	2/50 (4%)	2
Nervous system disorders - Other, specify: Aphasia	0/15 (0%)	0	3/50 (6%)	3
Psychiatric disorders
Agitation	1/15 (6.7%)	1	6/50 (12%)	6
Anxiety	3/15 (20%)	6	11/50 (22%)	18
Depression	6/15 (40%)	9	11/50 (22%)	20
Confusion	1/15 (6.7%)	2	6/50 (12%)	6
Insomnia	1/15 (6.7%)	1	5/50 (10%)	7
Libido decreased	1/15 (6.7%)	1	0/50 (0%)	0
Personality change	0/15 (0%)	0	2/50 (4%)	2
Renal and urinary disorders
Urinary frequency	1/15 (6.7%)	1	5/50 (10%)	6
Renal calculi	1/15 (6.7%)	1	0/50 (0%)	0
Urinary incontinence	1/15 (6.7%)	1	5/50 (10%)	7
Respiratory, thoracic and mediastinal disorders
Cough	0/15 (0%)	0	3/50 (6%)	3
Sore throat	0/15 (0%)	0	2/50 (4%)	2
Skin and subcutaneous tissue disorders
Dry skin	0/15 (0%)	0	4/50 (8%)	4
Pruritis	0/15 (0%)	0	5/50 (10%)	6
Rash acneiform	4/15 (26.7%)	9	5/50 (10%)	10
Rash maculo-papular	1/15 (6.7%)	2	4/50 (8%)	6
Photosensitivity	1/15 (6.7%)	1	1/50 (2%)	2
Purpura	1/15 (6.7%)	2	0/50 (0%)	0
Skin and subcutaneous tissue disorders - Other, specify: Rash, unspecified	1/15 (6.7%)	1	2/50 (4%)	2
Skin/subcutaneous tissue disorders; Other, specify: Significant confluent erythema covering essentia	1/15 (6.7%)	1	0/50 (0%)	0
Erythema multiforme	0/15 (0%)	0	3/50 (6%)	3
Scalp pain	1/15 (6.7%)	1	0/50 (0%)	0
Skin and subcutaneous tissue disorders - Other, specify: mild pain at incision site	1/15 (6.7%)	1	0/50 (0%)	0
Skin and subcutaneous tissue disorders - Other, specify: Fungal Rash	1/15 (6.7%)	1	0/50 (0%)	0
Surgical and medical procedures
Surgical and medical procedures - Other, specify: Surgery (post-treatment craniotomy)	0/15 (0%)	0	2/50 (4%)	2
Vascular disorders
Hypertension	0/15 (0%)	0	7/50 (14%)	15
Thromboembolic event	1/15 (6.7%)	1	3/50 (6%)	3
Hypotension	1/15 (6.7%)	1	0/50 (0%)	0

Limitations/Caveats

[Not Specified]

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.