A Phase 1b/2 Study of PLX3397 + Radiation Therapy + Temozolomide in Patients With Newly Diagnosed Glioblastoma

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01790503
• Collaborator: Plexxikon (Industry)
• Enrollment: 65
• Locations: 9
• Arms: 4
• Actual Duration (Months): 79.5
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study objectives are to assess the potential for PLX3397 to improve the efficacy of standard of care radiation therapy (RT) + temozolomide in patients with newly diagnosed glioblastoma (GBM).

Condition or Disease	Intervention/Treatment	Phase
Patients With Newly Diagnosed Glioblastoma	Drug: PLX3397; Radiation: Radiation Therapy; Drug: Temozolomide	Phase 1/Phase 2

Detailed Description

Study drug will be administered twice daily for 7 days prior to the initiation of RT (radiation therapy)and will continue twice daily during the course of RT. The RT schedule will be once daily for 5 days per week for 6 weeks (total radiation dose of 60 Gy. Oral temozolomide will be administered once daily (7 days per week) for the duration of RT. Four weeks after the completion of the course of RT, patients will be started on once-daily adjuvant temozolomide (Day 1-5 of a 28 day cycle) and PLX3397 twice daily (28 days of a 28 day cycle) for up to 12 cycles in the absence of progressive disease or unacceptable toxicities. After discontinuation of study drug, patients will continue to be followed for OS every 6 months. For patients participating in the run-in Phase 1b of the study, intra patient dose escalation will be permitted after a RP2D has been established. The Phase 2 portion of the study will enroll patients to be treated with PLX3397 at RP2D.

For the Phase 1b portion of the study, 2 cohorts (800 mg/day and 1000 mg/day) are planned to be enrolled at approximately 7-10 sites. Each cohort will consist of approximately 7 patients. Therefore, a minimum of 14 patients are planned to be enrolled in Phase 1b. Additional patients may be required for replacement patients, or if lower dose cohorts (600 mg or 400 mg) are required. For the Phase 2 portion of the study, enrollment is planned to include approximately 44 patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Phase 1b/2 Study of Orally Administered PLX3397 in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma
• Actual Study Start Date: Jul 18, 2013
• Actual Primary Completion Date: Nov 3, 2017
• Actual Study Completion Date: Mar 4, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b dose escalation - 600mg/day PLX3397 cohort 600mg/day PLX3397, Radiation Therapy, and Temozolomide	Drug: PLX3397; Other Names: Pexidartinib ; Radiation: Radiation Therapy; Drug: Temozolomide; Other Names: TMZ Temodar
Experimental: Phase 1b dose escalation - 800mg/day PLX3397 800mg/day PLX3397, Radiation Therapy, and Temozolomide	Drug: PLX3397; Other Names: Pexidartinib ; Radiation: Radiation Therapy; Drug: Temozolomide; Other Names: TMZ Temodar
Experimental: Phase 1b dose escalation - 1000 mg/day PLX3397 cohort 1000 mg/day PLX3397, Radiation Therapy, and Temozolomide	Drug: PLX3397; Other Names: Pexidartinib ; Radiation: Radiation Therapy; Drug: Temozolomide; Other Names: TMZ Temodar
Experimental: Phase 2 - Recommended phase 2 dose of PLX3397 Recommended phase 2 dose of PLX3397 (800mg/day), Radiation therapy, and Temozolomide	Drug: PLX3397; Other Names: Pexidartinib ; Radiation: Radiation Therapy; Drug: Temozolomide; Other Names: TMZ Temodar

Outcome Measures

Primary Outcome Measures

1. Summary of the Median Progression-free Survival (mPFS) in the Combined 800 mg, 5 Days/Week Dose Group [Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months.]

   Progression was determined by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS) was analyzed based on the non-parametric Kaplan-Meier method.

2. Summary of the Median Progression-free Survival (mPFS) in the Study Group Compared With Historical Control From Medical Literature [Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months.]

   mPFS was based on model parameters estimated by maximum likelihood with a Newton-Raphson algorithm. The Radiation Therapy Oncology Group (RTOG) 0525 study was the main historical control used for statistical analysis. Additionally, RTOG-0825 was also used to support this outcome measure.

Secondary Outcome Measures

1. Summary of the Median Progression-free Survival (mPFS) by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose [Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months.]

   Progression was determined by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS) was analyzed based on the non-parametric Kaplan-Meier method. mPFS was analyzed by age group, extent of surgery, baseline Karnofsky Performance Status (KPS), and O6-methylguanine-DNA methyltransferase status (MGMT). The scale range for the baseline Karnofsky Performance Status is from 0-100, with 0 indicating that the participant is dead and 100 indicating that the participant is Normal no complaints, no evidence of disease. The higher the number, the better the outcome.

2. Summary of the Overall Survival in The Study Population [Assessed from date of first dose administered to date of death from any cause, assessed up to 4 years 4 months]

   Overall Survival (OS) was defined as the number of days from the first day of treatment (C1D1) to the date of death and analyzed using a non-parametric Kaplan Meier method.

3. Summary of the Overall Survival in the Study Group Compared With Historical Control From Medical Literature [Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.]

   Overall Survival was calculated using a parametric model. The Radiation Therapy Oncology Group (RTOG) 0525 study was the main historical control used for statistical analysis. Additionally, RTOG-0825 was also used to support this outcome measure

4. Summary of the Overall Survival by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose [Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.]

   Overall Survival was calculated using a non-parametric Kaplan-Meier analysis method. Median OS was analyzed by age group, extent of surgery, baseline Karnofsky Performance Status (KPS), and O6-methylguanine-DNA methyltransferase status (MGMT). The scale range for the baseline Karnofsky Performance Status is from 0-100, with 0 indicating that the participant is dead and 100 indicating that the participant is Normal no complaints, no evidence of disease. The higher the number, the better the outcome.

5. Summary of Best Overall Response by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose [Assessed from Baseline and every 8 weeks, up to 4 years 4 months]

   Best Overall Response (based on the RANO response) was defined as the highest overall response recorded from the start of study treatment until the end of treatment. Per the Response Assessment in Neuro-Oncology (RANO) criteria for measurable lesions and assessed by Cranial MRI scan, summarized as: Complete Response (CR), Disappearance of all enhancing disease (measurable and non-measurable); Partial Response (PR), >=50% decrease of all measurable enhancing lesions; Stable disease, does not qualify for complete response, partial response, or progression, and progression, >25% increase in enhancing lesions despite stable or increasing steroid use or any new lesions.

6. Overview of Most Frequent System Organ Classes Reported in Phase 1b of the Modified Intent-To-Treat Population [Baseline up to 30 days after last dose, up to 4 years 4 months]

7. Overview of Most Frequent System Organ Classes Reported in Phase 2 of the Modified Intent-To-Treat Population [Baseline up to 30 days after last dose, up to 4 years 4 months]

8. Number of Patients With Clinically Significant Abnormal Chemistry and Hematology Values Reported as Adverse Events by Preferred Term in Phase 1b of the Modified Intent-To-Treat Population [Baseline up to 30 days after last dose, up to 4 years 4 months]

9. Number of Patients With Clinically Significant Abnormal Chemistry and Hematology Values Reported as Adverse Events by Preferred Term in Phase 2, the Combined RP2D Groups in Phase 1b, and in the Study Overall Modified Intent-To-Treat Population [Baseline up to 30 days after last dose, up to 4 years 4 months]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female patients ≥18 years old.

• Histologically confirmed definitive GBM or gliosarcoma by partial or complete surgical resection (i.e. not by biopsy only) within 5 weeks prior to PLX3397 administration (C1D1). Tumor must have a supratentorial component. For all patients, availability of a surgical paraffin tumor block sufficient to generate at least 20 unstained slides; or, if a paraffin tumor block is unavailable, at least 20 unstained slides.

• The patient must have recovered from the effects of surgery, post-operative infection, and other complications before study registration.

• A diagnostic contrast-enhanced MRI or CT scan of the brain must be performed preoperatively and postoperatively prior to the initiation of radiotherapy, within 28 days (preferably 14 days) prior to C1D1.

• Patients unable to undergo MR imaging because of non-compatible devices can be enrolled, provided pre- and post-operative contrast-enhanced CT scans are obtained and are of sufficient quality.

• Patients must receive RT at the participating institution.

• Women of child-bearing potential must have a negative pregnancy test within 14 days of initiation of dosing and must agree to use an acceptable method of birth control while on study drug and for 3 months after the last dose. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. Men of child-bearing potential must also agree to use an acceptable method of birth control while on study drug, and for 3 months after the last dose.

• Karnofsky performance status of ≥70.

• Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.5x 109/L, Hgb >10 g/dL, platelet count ≥100 x 109/L, AST/ALT ≤2.5x ULN, creatinine ≤1.5x ULN).

• Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements.

Exclusion Criteria:

• Evidence of recurrent GBM or metastases detected outside of the cranial vault.

• Investigational drug use within 28 days of the first dose of PLX3397 or concurrently.

• Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment.

• Prior radiation or chemotherapy for glioblastoma or glioma.

• Prior chemotherapy or radiosensitizers for cancer of the head and neck (except for T1 glottic cancer) that would result in an overlap of radiation fields.

• Prior allergic reaction to temozolomide.

• History of Grade 2 (CTCAE v4) or greater acute intracranial hemorrhage.

• Active cancer (either concurrent or within the last 3 years) that requires non-surgical therapy (e.g. chemotherapy or radiation therapy), with the exception of surgically treated basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix.

• Chronic active hepatitis B or C.

• Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel resection that would preclude adequate absorption of study drug.

• Patients with serious illnesses, uncontrolled infection, medical conditions, or other medical history including abnormal laboratory results, which in the investigator's opinion would be likely to interfere with a patient's participation in the study, or with the interpretation of the results.

• Women of child-bearing potential who are pregnant or breast feeding.

• At Screening QTcF ≥450 msec for males and ≥470 msec for females.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611
2	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
4	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
5	Henry Ford Hospital	Detroit	Michigan	United States	48202
6	Columbia University Medical Center	New York	New York	United States	10032
7	James Cancer Hospital/Ohio State University	Columbia	Ohio	United States	43210
8	Huntsman Cancer Institute University of Utah	Salt Lake City	Utah	United States	84132
9	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Daiichi Sankyo, Inc.
• Plexxikon

Investigators

• Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 14, 2017

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT01790503
• Other Study ID Numbers: PLX108-08
• First Posted: Feb 13, 2013
• Last Update Posted: Jun 30, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Daiichi Sankyo, Inc.: glioblastoma; GBM
• Additional relevant MeSH terms: Glioblastoma; Temozolomide

Study Results

Participant Flow

Recruitment Details	A total of 65 participants (22 in Phase 1b; 43 in Phase 2) who met all inclusion criteria and no exclusion criteria were enrolled and treated in the study at 10 clinic sites in the United States.
Pre-assignment Detail	This study included Phase 1b dose escalation where 5 cohorts were planned to be enrolled, each with approximately 7 participants (3+3 design) and Phase 2 where 37 participants were planned to be enrolled with the 7 participants treated at the RP2D level determined in the Phase 1b dose escalation phase yielding approximately 44 participants.

Arm/Group Title	Phase 1b Dose Escalation - 600 mg/600 mg	Phase 1b Dose Escalation - 600 mg/800 mg	Phase 1b Dose Escalation - 600 mg/1000 mg	Phase 1b Dose Escalation - 600 mg	Phase 1b Dose Escalation - 800 mg/1000 mg	Phase 1b Dose Escalation - 800 mg (5 Days)	Phase 1b Dose Escalation - 800 mg/600 mg	Phase 1b Dose Escalation - 800 mg/800 mg	Phase 1b Dose Escalation - 800 mg (7 Days)	Phase 2 - 800 mg/800 mg	Phase 2 - 800 mg
Arm/Group Description	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 1000 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks). No adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks) followed by 1000 mg PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) No adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy, and temozolomide (5 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.
Period Title: Overall Study
STARTED	3	1	1	2	5	5	1	1	3	27	16
COMPLETED	0	0	0	0	0	0	0	0	0	1	0
NOT COMPLETED	3	1	1	2	5	5	1	1	3	26	16

Baseline Characteristics

Arm/Group Title	Phase 1b Dose Escalation - 600 mg/600 mg	Phase 1b Dose Escalation - 600 mg/800 mg	Phase 1b Dose Escalation - 600 mg/1000 mg	Phase 1b Dose Escalation - 600 mg	Phase 1b Dose Escalation - 800 mg/1000 mg	Phase 1b Dose Escalation - 800 mg (5 Days)	Phase 1b Dose Escalation - 800 mg/600 mg	Phase 1b Dose Escalation - 800 mg/800 mg	Phase 1b Dose Escation - 800 mg (7 Days)	Phase 2 - 800 mg/800 mg	Phase 2 - 800 mg	Total
Arm/Group Description	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 1000 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks). No adjuvant therapy thereafter	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks) followed by 1000 mg PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) No adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy, and temozolomide (5 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.	Total of all reporting groups
Overall Participants	3	1	1	2	5	5	1	1	3	27	16	65
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	1 100%	0 0%	2 100%	5 100%	4 80%	0 0%	1 100%	3 100%	7 25.9%	11 68.8%	37 56.9%
>=65 years	0 0%	0 0%	1 100%	0 0%	0 0%	1 20%	1 100%	0 0%	0 0%	20 74.1%	5 31.3%	28 43.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.3 (6.4)	23.0 (0)	73 (0)	48.0 (17.0)	50.8 (15.7)	60.8 (8.6)	30.0 (0)	51.0 (0)	53.3 (4.2)	55.7 (10.8)	59.0 (10.7)	55.3 (11.9)
Sex: Female, Male (Count of Participants)
Female	2 66.7%	0 0%	0 0%	1 50%	2 40%	3 60%	1 100%	0 0%	0 0%	8 29.6%	7 43.8%	24 36.9%
Male	1 33.3%	1 100%	1 100%	1 50%	3 60%	2 40%	0 0%	1 100%	3 100%	19 70.4%	9 56.3%	41 63.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 100%	0 0%	2 40%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	3 4.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 3.7%	0 0%	1 1.5%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	2 66.7%	1 100%	0 0%	2 100%	3 60%	4 80%	1 100%	1 100%	3 100%	25 92.6%	16 100%	58 89.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 33.3%	0 0%	0 0%	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	1 3.7%	0 0%	3 4.6%
Region of Enrollment (participants) [Number]
United States	3 100%	1 100%	1 100%	2 100%	5 100%	5 100%	1 100%	1 100%	3 100%	27 100%	16 100%	65 100%

Outcome Measures

1. Primary Outcome

Title	Summary of the Median Progression-free Survival (mPFS) in the Combined 800 mg, 5 Days/Week Dose Group
Description	Progression was determined by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS) was analyzed based on the non-parametric Kaplan-Meier method.
Time Frame	Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months.

Outcome Measure Data

Analysis Population Description

mPFS was assessed in the modified intent-to-treat RP2D and the per protocol (PP) populations.

Arm/Group Title	Combined 800 mg, 5 Days/Week
Arm/Group Description	All participants in Phase 1b or 2 who received 800 mg/day PLX3397 (5 days/week) during combination therapy.
Measure Participants	53
mITT RP2D	6.7
PP RP2D	6.9

2. Primary Outcome

Title	Summary of the Median Progression-free Survival (mPFS) in the Study Group Compared With Historical Control From Medical Literature
Description	mPFS was based on model parameters estimated by maximum likelihood with a Newton-Raphson algorithm. The Radiation Therapy Oncology Group (RTOG) 0525 study was the main historical control used for statistical analysis. Additionally, RTOG-0825 was also used to support this outcome measure.
Time Frame	Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months.

Outcome Measure Data

Analysis Population Description

mPFS was based on model parameters estimated by maximum likelihood with a Newton-Raphson algorithm. The Radiation Therapy Oncology Group (RTOG) 0525 study was the main historical control.

Arm/Group Title	RP2D	RP2D-0525 (Cycle 1, Day 1)	RP2D-0825	RP2D-0525 (Rest Period, Day 15)
Arm/Group Description	mPFS was assessed in the RP2D population at Cycle 1, Day 1.	mPFS was assessed in the RP2D population in the RTOG 0525 study at Cycle 1, Day 1.	mPFS was assessed in the RP2D population in the RTOG 0825 study at Cycle 2, Day 1.	mPFS was assessed in the RP2D population in the RTOG 0525 study at the Rest Period, Day 15.
Measure Participants	53	43	49	43
Median (95% Confidence Interval) [months]	7.7	7.6	7.0	6.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week, RP2D-0525 (Cycle 1, Day 1)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.456
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week, RP2D-0825
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.619
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week, RP2D-0525 (Rest Period, Day 15)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.272
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Summary of the Median Progression-free Survival (mPFS) by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose
Description	Progression was determined by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS) was analyzed based on the non-parametric Kaplan-Meier method. mPFS was analyzed by age group, extent of surgery, baseline Karnofsky Performance Status (KPS), and O6-methylguanine-DNA methyltransferase status (MGMT). The scale range for the baseline Karnofsky Performance Status is from 0-100, with 0 indicating that the participant is dead and 100 indicating that the participant is Normal no complaints, no evidence of disease. The higher the number, the better the outcome.
Time Frame	Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months.

Outcome Measure Data

Analysis Population Description

mPFS was assessed in the mITT RP2D population.

Arm/Group Title	Combined 800 mg, 5 Days/Week
Arm/Group Description	All participants in Phase 1b or 2 who received 800 mg/day PLX3397 (5 days/week) during combination therapy.
Measure Participants	53
Age: 18-64 years	6
Age: 65+ years	10
Extent of surgery: complete resection	6
Extent of surgery: partial resection	9
Baseline KPS: 70-89	4
Baseline KPS: 90-100	11
MGMT status: methylated	10
MGMT status: unmethylated	4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between age subgroups: 18-64 years vs 65+ years
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.440
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between extent of surgery subgroups: complete resection vs partial resection
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.699
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between baseline KPS subgroups: 70-89 vs 90-100
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between MGMT status subgroups: methylated vs unmethylated
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.201
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Summary of the Overall Survival in The Study Population
Description	Overall Survival (OS) was defined as the number of days from the first day of treatment (C1D1) to the date of death and analyzed using a non-parametric Kaplan Meier method.
Time Frame	Assessed from date of first dose administered to date of death from any cause, assessed up to 4 years 4 months

Outcome Measure Data

Analysis Population Description

OS was assessed in the mITT RP2D and PP RP2D populations.

Arm/Group Title	Combined 800 mg, 5 Days/Week
Arm/Group Description	All participants in Phase 1b or 2 who received 800 mg/day PLX3397 (5 days/week) during combination therapy.
Measure Participants	53
mITT RP2D	13.1
PP RP2D	12.4

5. Secondary Outcome

Title	Summary of the Overall Survival in the Study Group Compared With Historical Control From Medical Literature
Description	Overall Survival was calculated using a parametric model. The Radiation Therapy Oncology Group (RTOG) 0525 study was the main historical control used for statistical analysis. Additionally, RTOG-0825 was also used to support this outcome measure
Time Frame	Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.

Outcome Measure Data

Analysis Population Description

Median OS was based on model parameters estimated by maximum likelihood with a Newton-Raphson algorithm. The Radiation Therapy Oncology Group (RTOG) 0525 study was the main historical control.

Arm/Group Title	RP2D	RP2D-0525 (Cycle 1, Day 1)	RP2D-0825	RP2D-0525 (Rest Period, Day 15)
Arm/Group Description	OS was assessed in the RP2D population at Cycle 1, Day 1.	OS was assessed in the RP2D population in the RTOG 0525 study at Cycle 1, Day 1.	OS was assessed in the RP2D population in the RTOG 0825 study at Cycle 2, Day 1.	OS was assessed in the RP2D population in the RTOG 0525 study at the Rest Period, Day 15.
Measure Participants	53	43	49	43
Median (95% Confidence Interval) [months]	18.8	20.2	17.0	16.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week, RP2D-0525 (Cycle 1, Day 1)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.389
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.60 to 1.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week, RP2D-0825
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.393
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.63 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week, RP2D-0525 (Rest Period, Day 15)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.469
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.63 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Summary of the Overall Survival by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose
Description	Overall Survival was calculated using a non-parametric Kaplan-Meier analysis method. Median OS was analyzed by age group, extent of surgery, baseline Karnofsky Performance Status (KPS), and O6-methylguanine-DNA methyltransferase status (MGMT). The scale range for the baseline Karnofsky Performance Status is from 0-100, with 0 indicating that the participant is dead and 100 indicating that the participant is Normal no complaints, no evidence of disease. The higher the number, the better the outcome.
Time Frame	Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.

Outcome Measure Data

Analysis Population Description

OS was assessed in the mITT RP2D population.

Arm/Group Title	Combined 800 mg, 5 Days/Week
Arm/Group Description	All participants in Phase 1b or 2 who received 800 mg/day PLX3397 (5 days/week) during combination therapy.
Measure Participants	53
Age group: 18-64 years	14.3
Age group: 65+ years	11
Extent of surgery: complete resection	14
Extent of surgery: partial resection	13
Basline KPS: 70-89	8
Baseline KPS: 90-100	24
MGMT status: methylated	15
MGMT: unmethylated	12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between age subgroups: 18-64 years vs 65+ years
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.063
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between extent of surgery subgroups: complete resection vs partial resection
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.969
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between baseline KPS subgroups: 70-89 vs 90-100
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between MGMT status subgroups: methylated vs unmethylated
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.501
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Summary of Best Overall Response by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose
Description	Best Overall Response (based on the RANO response) was defined as the highest overall response recorded from the start of study treatment until the end of treatment. Per the Response Assessment in Neuro-Oncology (RANO) criteria for measurable lesions and assessed by Cranial MRI scan, summarized as: Complete Response (CR), Disappearance of all enhancing disease (measurable and non-measurable); Partial Response (PR), >=50% decrease of all measurable enhancing lesions; Stable disease, does not qualify for complete response, partial response, or progression, and progression, >25% increase in enhancing lesions despite stable or increasing steroid use or any new lesions.
Time Frame	Assessed from Baseline and every 8 weeks, up to 4 years 4 months

Outcome Measure Data

Analysis Population Description

Best Overall Response was assessed in the mITT RP2D population.

Arm/Group Title	Combined 800 mg, 5 Days/Week
Arm/Group Description	All participants in Phase 1b or 2 who received 800 mg/day PLX3397 (5 days/week) during combination therapy.
Measure Participants	53
Complete response (CR)	2 66.7%
Partial response (PR)	4 133.3%
CR+PR	6 200%
Stable disease	18 600%
Progressive disease	9 300%
Unable to access	0 0%
Unknown	0 0%
Complete response (CR)	0 0%
Partial response (PR)	1 33.3%
CR+PR	1 33.3%
Stable disease	6 200%
Progressive disease	3 100%
Unable to access	0 0%
Unknown	0 0%
Complete response (CR)	1 33.3%
Partial response (PR)	2 66.7%
CR+PR	3 100%
Stable disease	10 333.3%
Progressive disease	5 166.7%
Unable to access	0 0%
Unknown	0 0%
Complete response (CR)	1 33.3%
Partial response (PR)	3 100%
CR+PR	4 133.3%
Stable disease	13 433.3%
Progressive disease	6 200%
Unable to access	0 0%
Unknown	0 0%
Complete response (CR)	0 0%
Partial response (PR)	1 33.3%
CR+PR	1 33.3%
Stable disease	7 233.3%
Progressive disease	8 266.7%
Unable to access	0 0%
Unknown	0 0%
Complete response (CR)	2 66.7%
Partial response (PR)	4 133.3%
CR+PR	6 200%
Stable disease	17 566.7%
Progressive disease	4 133.3%
Unable to access	0 0%
Unknown	0 0%
Complete response (CR)	1 33.3%
Partial response (PR)	3 100%
CR+PR	4 133.3%
Stable disease	11 366.7%
Progressive disease	3 100%
Unable to access	0 0%
Unknown	0 0%
Complete response (CR)	1 33.3%
Partial response (PR)	2 66.7%
CR+PR	3 100%
Stable disease	12 400%
Progressive disease	9 300%
Unable to access	0 0%
Unknown	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between age subgroups: 18-64 years vs 65+ years
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.705
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between extent of surgery subgroups: complete resection vs partial resection
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between baseline KPS subgroups: 70-89 vs 90-100
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.099
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined 800 mg, 5 Days/Week
	Comments	Comparison between MGMT status subgroups: methylated vs unmethylated
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.348
	Comments
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Overview of Most Frequent System Organ Classes Reported in Phase 1b of the Modified Intent-To-Treat Population
Time Frame	Baseline up to 30 days after last dose, up to 4 years 4 months

Outcome Measure Data

Analysis Population Description

Safety was assessed in the mITT population.

Arm/Group Title	Phase 1b Dose Escalation - 600 mg/600 mg	Phase 1b Dose Escalation - 600 mg/800 mg	Phase 1b Dose Escalation - 600 mg/1000 mg	Phase 1b Dose Escalation - 600 mg	Phase 1b Dose Escalation - 800 mg/1000 mg	Phase 1b Dose Escalation - 800 mg	Phase 1b Dose Escalation - 800 mg/600 mg	Phase 1b Dose Escalation - 800 mg/800 mg	Phase 1b Dose Escation - 800 mg
Arm/Group Description	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 1000 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks). No adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks) followed by 1000 mg PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.
Measure Participants	3	1	1	2	5	5	1	1	3
General Disorders and Administrative Site	2 66.7%	0 0%	1 100%	1 50%	5 100%	5 100%	1 100%	1 100%	3 100%
Nervous System Disorders	3 100%	1 100%	1 100%	2 100%	5 100%	4 80%	1 100%	0 0%	2 66.7%
Skin and Subcutaneous Tissue Disorders	3 100%	1 100%	1 100%	2 100%	5 100%	4 80%	0 0%	1 100%	1 33.3%
Gastrointestinal Disorders	3 100%	1 100%	1 100%	1 50%	5 100%	3 60%	0 0%	0 0%	2 66.7%
Metabolism and Nutrition Disorders	3 100%	1 100%	1 100%	1 50%	4 80%	2 40%	0 0%	1 100%	2 66.7%
Psychiatric Disorders	2 66.7%	1 100%	1 100%	2 100%	3 60%	1 20%	1 100%	0 0%	1 33.3%
Infections and Infestations	1 33.3%	0 0%	1 100%	1 50%	5 100%	1 20%	0 0%	0 0%	3 100%
Investigations	1 33.3%	0 0%	1 100%	1 50%	4 80%	2 40%	1 100%	0 0%	3 100%
Respiratory, Thoracic, and Mediastinal Disorders	1 33.3%	0 0%	1 100%	0 0%	3 60%	3 60%	0 0%	0 0%	2 66.7%
Musculoskeletal and Connective Tissue Disorders	0 0%	0 0%	0 0%	1 50%	2 40%	3 60%	1 100%	0 0%	1 33.3%
Blood and Lymphatic Tissue Disorders	1 33.3%	1 100%	1 100%	1 50%	1 20%	1 20%	0 0%	1 100%	1 33.3%
Vascular Disorders	0 0%	0 0%	0 0%	1 50%	3 60%	2 40%	0 0%	0 0%	2 66.7%
Renal and Urinary Disorders	1 33.3%	0 0%	0 0%	1 50%	3 60%	1 20%	0 0%	0 0%	1 33.3%
Eye Disorders	1 33.3%	0 0%	0 0%	0 0%	2 40%	1 20%	0 0%	0 0%	1 33.3%
Injury, Poisoning, and Procedural Complications	1 33.3%	0 0%	0 0%	1 50%	2 40%	0 0%	0 0%	0 0%	0 0%
Ear and Labyrinth	0 0%	0 0%	0 0%	1 50%	1 20%	0 0%	0 0%	0 0%	1 33.3%
Endocrine Disorders	0 0%	0 0%	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	1 33.3%
Cardiac Disorders	0 0%	0 0%	0 0%	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%
Hepatobiliary Disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%
Reproductive System and Breast Disorders	0 0%	0 0%	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%
Immune System Disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Neoplasms Benign, Malignant, and Unspecified	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

9. Secondary Outcome

Title	Overview of Most Frequent System Organ Classes Reported in Phase 2 of the Modified Intent-To-Treat Population
Time Frame	Baseline up to 30 days after last dose, up to 4 years 4 months

Outcome Measure Data

Analysis Population Description

Safety was assessed in the mITT population.

Arm/Group Title	Phase 2 - 800 mg/800 mg	Phase 2 - 800 mg	Phase 2 Total	Combined 800 mg, 5 Days/Week
Arm/Group Description	Participants received 800 mg/day PLX3397 in combination with radiation therapy, and temozolomide (5 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.	All participants in Phase 2 who received 800 mg/day PLX3397 in combination therapy.	All participants in Phase 1b or 2 who received 800 mg/day PLX3397 (5 days/week) during combination therapy.
Measure Participants	27	16	43	53
General Disorders and Administration Site	24 800%	13 1300%	37 3700%	47 2350%
Skin and Subcutaneous Tissue Disorders	24 800%	12 1200%	36 3600%	45 2250%
Nervous System Disorders	22 733.3%	12 1200%	34 3400%	43 2150%
Gastrointestinal Disorders	21 700%	12 1200%	33 3300%	41 2050%
Metabolism and Nutrition Disorders	16 533.3%	8 800%	24 2400%	30 1500%
Psychiatric Disorders	17 566.7%	6 600%	23 2300%	27 1350%
Investigations	12 400%	9 900%	21 2100%	27 1350%
Musculoskeletal and Connective Tissue Disorders	13 433.3%	7 700%	20 2000%	25 1250%
Blood and Lymphatic System Disorders	14 466.7%	2 200%	16 1600%	18 900%
Injury, Poisoning, and Procedural Complications	10 333.3%	6 600%	16 1600%	18 900%
Eye Disorders	7 233.3%	6 600%	13 1300%	16 800%
Vascular Disorders	9 300%	4 400%	13 1300%	18 900%
Respiratory, Thoracic, and Mediastinal Disorders	7 233.3%	3 300%	10 1000%	16 800%
Renal and Urinary Disorders	7 233.3%	2 200%	9 900%	13 650%
Cardiac Disorders	5 166.7%	2 200%	7 700%	8 400%
Endocrine Disorders	5 166.7%	1 100%	6 600%	7 350%
Ear and Labyrinth Disorders	3 100%	1 100%	4 400%	5 250%
Reproductive System and Breast Disorders	2 66.7%	0 0%	2 200%	3 150%
Neoplasms Benign, Malignant, and Unspecified	2 66.7%	0 0%	2 200%	2 100%
Hepatobiliary Disorders	0 0%	1 100%	1 100%	1 50%
Immune System Disorders	1 33.3%	0 0%	1 100%	1 50%

10. Secondary Outcome

Title	Number of Patients With Clinically Significant Abnormal Chemistry and Hematology Values Reported as Adverse Events by Preferred Term in Phase 1b of the Modified Intent-To-Treat Population
Time Frame	Baseline up to 30 days after last dose, up to 4 years 4 months

Outcome Measure Data

Analysis Population Description

Abnormal chemistry and hematology values were assessed in the mITT population.

Arm/Group Title	Phase 1b Dose Escalation - 600 mg/600 mg	Phase 1b Dose Escalation - 600 mg/800 mg	Phase 1b Dose Escalation - 600 mg/1000 mg	Phase 1b Dose Escalation - 600 mg	Phase 1b Dose Escalation - 800 mg/1000 mg	Phase 1b Dose Escalation - 800 mg (5 Days)	Phase 1b Dose Escalation - 800 mg/600 mg	Phase 1b Dose Escalation - 800 mg/800 mg	Phase 1b Dose Escation - 800 mg (No Adjuvant Therapy)
Arm/Group Description	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 1000 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks). No adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks) followed by 1000 mg PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) No adjuvant therapy thereafter.
Measure Participants	3	1	1	2	5	5	1	1	3
Thrombocytopenia	1 33.3%	1 100%	0 0%	0 0%	1 20%	1 20%	0 0%	1 100%	1 33.3%
Neutropenia	0 0%	1 100%	0 0%	0 0%	1 20%	1 20%	0 0%	0 0%	1 33.3%
Anaemia	1 33.3%	0 0%	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	1 33.3%
Lymphopenia	1 33.3%	1 100%	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%
AST increased	0 0%	0 0%	1 100%	0 0%	2 40%	0 0%	0 0%	0 0%	0 0%
Platelet count decreased	0 0%	0 0%	0 0%	0 0%	1 20%	1 20%	0 0%	0 0%	1 33.3%
Neutrophil count decreased	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 66.7%
Leukopenia	0 0%	1 100%	1 100%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Febrile neutropenia	0 0%	0 0%	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	1 33.3%
ALT increased	0 0%	0 0%	1 100%	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%
Bone marrow failure	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%
Haemolysis	0 0%	0 0%	0 0%	1 50%	0 0%	0 0%	0 0%	0 0%	0 0%
White blood cell decreased	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%
Lymphocyte count decreased	0 0%	0 0%	0 0%	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%

11. Secondary Outcome

Title	Number of Patients With Clinically Significant Abnormal Chemistry and Hematology Values Reported as Adverse Events by Preferred Term in Phase 2, the Combined RP2D Groups in Phase 1b, and in the Study Overall Modified Intent-To-Treat Population
Time Frame	Baseline up to 30 days after last dose, up to 4 years 4 months

Outcome Measure Data

Analysis Population Description

Abnormal chemistry and hematology values were assessed in the mITT population.

Arm/Group Title	Phase 2 - 800 mg/800 mg	Phase 2 - 800 mg	Phase 2 Total	Combined 800 mg, 5 Days/Week
Arm/Group Description	Participants received 800 mg/day PLX3397 in combination with radiation therapy, and temozolomide (5 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.	Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.	All participants in Phase 2 who received 800 mg/day PLX3397 in combination therapy.	All participants in Phase 1b or 2 who received 800 mg/day PLX3397 (5 days/week) during combination therapy.
Measure Participants	27	16	43	53
Neutropenia	6 200%	1 100%	7 700%	9 450%
Thrombocytopenia	3 100%	1 100%	4 400%	6 300%
Anaemia	5 166.7%	1 100%	6 600%	7 350%
ALT increased	2 66.7%	5 500%	7 700%	8 400%
AST increased	2 66.7%	4 400%	6 600%	8 400%
Platelet count decreased	4 133.3%	1 100%	5 500%	7 350%
Lymphopenia	2 66.7%	1 100%	3 300%	4 200%
White blood cell count decreased	4 133.3%	1 100%	5 500%	5 250%
Neutrophil count decreased	2 66.7%	0 0%	2 200%	2 100%
Leukopenia	1 33.3%	1 100%	2 200%	2 100%
Febrile neutropenia	0 0%	1 100%	1 100%	2 100%
Lymphocyte count decreased	1 33.3%	1 100%	2 200%	3 150%
Blood alkaline phosphatase increased	0 0%	3 300%	3 300%	3 150%
Blood creatinine increased	2 66.7%	1 100%	3 300%	3 150%
DRESS	0 0%	1 100%	1 100%	1 50%
Liver function test abnormal	0 0%	1 100%	1 100%	1 50%
Bone marrow failure	0 0%	0 0%	0 0%	0 0%
Haemolysis	0 0%	0 0%	0 0%	1 50%
Blood bilirubin increased	0 0%	1 100%	1 100%	1 50%
Blood iron decreased	1 33.3%	0 0%	1 100%	1 50%

Adverse Events

Time Frame	Adverse event data were collected from baseline up to 30 days after the last dose, up to 4 years 4 months.
Adverse Event Reporting Description	Adverse events that emerge (or worsen) after the first dose of study drug and within 28 days after the last dose. For the Other (Not Including Serious) Adverse Events data reported, data available are AEs who meet the Common Toxicity Criteria for Adverse Events (CTCAE) >=3 criteria (which is for severity, rather than frequency).
Arm/Group Title	Phase 1b Dose Escalation - 600 mg/600 mg		Phase 1b Dose Escalation - 600 mg/800 mg		Phase 1b Dose Escalation - 600 mg/1000 mg		Phase 1b Dose Escalation - 600 mg		Phase 1b Dose Escalation - 800 mg/1000 mg		Phase 1b Dose Escalation - 800 mg (5 Days)		Phase 1b Dose Escalation - 800 mg/600 mg		Phase 1b Dose Escalation - 800 mg/800 mg		Phase 1b Dose Escation - 800 mg (7 Days)		Phase 2 - 800 mg/800 mg		Phase 2 - 800 mg
Arm/Group Description	Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.		Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.		Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks), followed by 1000 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.		Participants received 600 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks). No adjuvant therapy thereafter.		Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks) followed by 1000 mg PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.		Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.		Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 600 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.		Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.		Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (7 days per week for six weeks) No adjuvant therapy thereafter.		Participants received 800 mg/day PLX3397 in combination with radiation therapy, and temozolomide (5 days per week for six weeks) followed by 800 mg/day PLX3397 (daily dosing) and temozolomide (once daily on days 1-5 of each 28 day cycle) adjuvant therapy thereafter.		Participants received 800 mg/day PLX3397 in combination with radiation therapy and temozolomide (5 days per week for six weeks). No adjuvant therapy thereafter.
All Cause Mortality
	Phase 1b Dose Escalation - 600 mg/600 mg		Phase 1b Dose Escalation - 600 mg/800 mg		Phase 1b Dose Escalation - 600 mg/1000 mg		Phase 1b Dose Escalation - 600 mg		Phase 1b Dose Escalation - 800 mg/1000 mg		Phase 1b Dose Escalation - 800 mg (5 Days)		Phase 1b Dose Escalation - 800 mg/600 mg		Phase 1b Dose Escalation - 800 mg/800 mg		Phase 1b Dose Escation - 800 mg (7 Days)		Phase 2 - 800 mg/800 mg		Phase 2 - 800 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Serious Adverse Events
	Phase 1b Dose Escalation - 600 mg/600 mg		Phase 1b Dose Escalation - 600 mg/800 mg		Phase 1b Dose Escalation - 600 mg/1000 mg		Phase 1b Dose Escalation - 600 mg		Phase 1b Dose Escalation - 800 mg/1000 mg		Phase 1b Dose Escalation - 800 mg (5 Days)		Phase 1b Dose Escalation - 800 mg/600 mg		Phase 1b Dose Escalation - 800 mg/800 mg		Phase 1b Dose Escation - 800 mg (7 Days)		Phase 2 - 800 mg/800 mg		Phase 2 - 800 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		0/1 (0%)		0/1 (0%)		2/2 (100%)		2/5 (40%)		2/5 (40%)		0/1 (0%)		0/1 (0%)		3/3 (100%)		13/27 (48.1%)		9/16 (56.3%)
Blood and lymphatic system disorders
Thrombocytopenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		0/27 (0%)		0/16 (0%)
Neutropenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		0/27 (0%)		1/16 (6.3%)
Febrile neutropenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Neutrophil count decreased	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		1/27 (3.7%)		0/16 (0%)
Platelet count decreased	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)
Leukopenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Lymphopenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
White blood cell count decreased	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Cardiac disorders
Tachycardia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Gastrointestinal disorders
Colitis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Diverticular perforation	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
General disorders
Pyrexia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		1/27 (3.7%)		1/16 (6.3%)
Fatigue	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		2/27 (7.4%)		0/16 (0%)
Asthenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Drug reaction with eosinophilia and systemic symptoms	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Hepatobiliary disorders
Cholestasis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Infections and infestations
Urinary tract infection	1/3 (33.3%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Necrotising fasciitis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		0/27 (0%)		0/16 (0%)
Pneumonia aspiration	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Corona virus infection	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Cystitis noninfective	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Respirovirus test positive	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Wound infection	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Injury, poisoning and procedural complications
Fall	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Investigations
Alanine aminotransferase increased	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Aspartate aminotransferase increased	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Metabolism and nutrition disorders
Dehydration	1/3 (33.3%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Hyperglycaemia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Musculoskeletal and connective tissue disorders
Hemiparesis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Myopathy	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Nervous system disorders
Aphasia	0/3 (0%)		0/1 (0%)		0/1 (0%)		1/2 (50%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Apraxia	0/3 (0%)		0/1 (0%)		0/1 (0%)		1/2 (50%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Convulsion	1/3 (33.3%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		4/27 (14.8%)		1/16 (6.3%)
Grand mal convulsion	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		0/27 (0%)		0/16 (0%)
Haemorrhage intracranial	0/3 (0%)		0/1 (0%)		0/1 (0%)		1/2 (50%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)
Headache	0/3 (0%)		0/1 (0%)		0/1 (0%)		1/2 (50%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		2/27 (7.4%)		0/16 (0%)
Hydrocephalus	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		0/27 (0%)		1/16 (6.3%)
Brain oedema	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Central nervous system necrosis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Cerebral haemorrhage	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Herpes simplex encephalitis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Meningitis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Psychiatric disorders
Mental status changes	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)
Confusional state	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Somnolence	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Renal and urinary disorders
Urinary retention	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		1/27 (3.7%)		0/16 (0%)
Vascular disorders
Hypotension	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Embolism	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)
Deep vein thrombosis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Phase 1b Dose Escalation - 600 mg/600 mg		Phase 1b Dose Escalation - 600 mg/800 mg		Phase 1b Dose Escalation - 600 mg/1000 mg		Phase 1b Dose Escalation - 600 mg		Phase 1b Dose Escalation - 800 mg/1000 mg		Phase 1b Dose Escalation - 800 mg (5 Days)		Phase 1b Dose Escalation - 800 mg/600 mg		Phase 1b Dose Escalation - 800 mg/800 mg		Phase 1b Dose Escation - 800 mg (7 Days)		Phase 2 - 800 mg/800 mg		Phase 2 - 800 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		1/1 (100%)		1/1 (100%)		2/2 (100%)		5/5 (100%)		5/5 (100%)		0/1 (0%)		1/1 (100%)		3/3 (100%)		18/27 (66.7%)		13/16 (81.3%)
Blood and lymphatic system disorders
Thrombocytopenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		1/5 (20%)		0/1 (0%)		1/1 (100%)		1/3 (33.3%)		2/27 (7.4%)		1/16 (6.3%)
Lymphopenia	1/3 (33.3%)		1/1 (100%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		2/27 (7.4%)		1/16 (6.3%)
Neutropenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		4/27 (14.8%)		1/16 (6.3%)
Neutrophil count decreased	1/3 (33.3%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		2/3 (66.7%)		1/27 (3.7%)		0/16 (0%)
Anaemia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		3/27 (11.1%)		1/16 (6.3%)
Febrile neutropenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		0/27 (0%)		1/16 (6.3%)
Platelet count decreased	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		2/27 (7.4%)		1/16 (6.3%)
Haemolysis	0/3 (0%)		0/1 (0%)		0/1 (0%)		1/2 (50%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
White blood cell count decreased	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		3/27 (11.1%)		1/16 (6.3%)
Leukopenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Cardiac disorders
Tachycardia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Atrial fibrillation	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Colitis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Vomiting	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Diarrhoea	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Diverticular perforation	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
General disorders
Gait disturbance	0/3 (0%)		0/1 (0%)		0/1 (0%)		1/2 (50%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Fatigue	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		2/27 (7.4%)		1/16 (6.3%)
Pyrexia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		0/27 (0%)		0/16 (0%)
Asthenia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)
Drug reaction with eosinophilia and systemic symptoms	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Hepatobiliary disorders
Cholestasis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Liver function abnormal	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Infections and infestations
Necrotising fasciitis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		0/27 (0%)		0/16 (0%)
Pneumonia aspiration	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Urinary tract infection	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Corona virus infection	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Cystitis noninfective	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Injury, poisoning and procedural complications
Fall	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Investigations
Alanine aminotransferase increased	0/3 (0%)		0/1 (0%)		1/1 (100%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		4/16 (25%)
Aspartate aminotransferase increased	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		3/16 (18.8%)
Blood bilirubin increased	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Metabolism and nutrition disorders
Dehydration	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Hyponatraemia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		1/27 (3.7%)		0/16 (0%)
Hypophosphataemia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Hyperglycaemia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Hypoglycaemia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Hypokalaemia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Musculoskeletal and connective tissue disorders
Hemiparesis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)
Myopathy	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Nervous system disorders
Aphasia	0/3 (0%)		0/1 (0%)		0/1 (0%)		1/2 (50%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Apraxia	0/3 (0%)		0/1 (0%)		0/1 (0%)		1/2 (50%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Motor dysfunction	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Syncope	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		2/27 (7.4%)		1/16 (6.3%)
Brain oedema	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		2/27 (7.4%)		0/16 (0%)
Convulsion	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		2/27 (7.4%)		0/16 (0%)
Cerebral haemorrhage	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Haemorrhage intracranial	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Headache	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Herpes simplex encephalitis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Hydrocephalus	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		1/16 (6.3%)
Meningitis	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Vasogenic cerebral oedema	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Psychiatric disorders
Confusional state	1/3 (33.3%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)
Mental status changes	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)
Depression	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Hypoxia	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		0/27 (0%)		0/16 (0%)
Pulmonary embolism	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		2/27 (7.4%)		0/16 (0%)
Skin and subcutaneous tissue disorders
Petechiae	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Rash generalized	1/3 (33.3%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Rash pruritic	0/3 (0%)		0/1 (0%)		1/1 (100%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Rash	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)
Rash maculo-papular	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		2/16 (12.5%)
Vascular disorders
Hypertension	0/3 (0%)		0/1 (0%)		0/1 (0%)		1/2 (50%)		1/5 (20%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		2/27 (7.4%)		0/16 (0%)
Hypotension	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/27 (0%)		0/16 (0%)
Embolism	0/3 (0%)		0/1 (0%)		0/1 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		1/27 (3.7%)		1/16 (6.3%)

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.