Phase 2 Study of Study of Tesevatinib in Subjects With NSCLC and Brain or Leptomeningeal Metastases

• Sponsor: Kadmon Corporation, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02616393
• Collaborator: (none)
• Enrollment: 36
• Locations: 7
• Arms: 3
• Duration (Months): 29
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

A study to assess the activity of tesevatinib in subjects with non-small cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations who have disease progression with Brain Metastases (BM) or Leptomeningeal Metastases (LM) or who have either BM or LM at initial presentation (IP)

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer; Leptomeningeal Metastases; Brain Metastases	Drug: Tesevatinib	Phase 2

Detailed Description

This was a multicenter, phase 2, open-label study to assess the activity of tesevatinib, in subjects with non-small cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations, and brain metastases (BM) or leptomeningeal metastases (LM).

After completion of the screening assessments and confirmation of study eligibility, tesevatinib was orally administered to all subjects at a dose of 300 mg once daily (QD). Tumor response, both in the central nervous system (CNS) and outside the central nervous system (non-CNS), was assessed after the second cycle of treatment and then at the end of every two cycles of treatment thereafter. Subjects were treated with tesevatinib 300 mg QD until disease progression or the subject experienced unacceptable toxicity.

Subjects who discontinued tesevatinib therapy were followed for survival.

Subjects with NSCLC + EGFR mutations were assigned to one of three cohorts:

• Cohort A: Brain Metastases (BM). Subjects had progressed with BM.

• Cohort B: Leptomeningeal Metastases (LM). Subjects had initially presented or progressed with LM.

• Cohort C: Brain Metastases at Initial Presentation (BM-IP). Subjects had no prior systemic therapy.

Each of the three cohorts was to have 20 subjects, for a total of 60 subjects. All three cohorts were enrolled simultaneously.

The primary objectives were to include:

• Clinical activity of tesevatinib of subjects in Cohort A (BM) and Cohort C (BM-IP) as measured by Response Criteria in Solid Tumors (RECIST) version 1.1 which evaluated changes in BM size.

• Clinical activity of tesevatinib of subjects in Cohort B (LM) as measured by improvement in Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 symptoms and signs.

Efficacy assessments included response to treatment using RECIST criteria, progression-free survival (PFS), time to progression (TTP), overall survival (OS), and Quality of Life (QOL) questionnaires. Safety assessments included adverse event (AE) monitoring, electrocardiogram (ECG), Eastern Cooperative Oncology Group (ECOG) Performance Status, laboratory testing, physical examination, vital signs, and pregnancy testing. In addition, pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed.

An End of Treatment Visit occurred within 3 days after the subject's last dose of study drug. This could have occurred at the visit when disease progression was diagnosed. Subjects were continued to be followed for disease progression and survival.

A follow-up visit occurred 30 days (± 5 days) after the last dose of study drug. This visit may have occurred prior to 30 days if a new therapy was started within 30 days of last dose of study drug.

For long-term follow-up, after subjects withdrew from the active treatment portion of the study, they were contacted by telephone every 8 weeks to assess survival status and any subsequent anti-cancer treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter Study of Tesevatinib in Subjects With Non-Small Cell Lung Cancer, EGFR Activating Mutation, Prior Treatment With a Tyrosine Kinase Inhibitor, and Brain Metastases or Leptomeningeal Metastases
• Study Start Date: Nov 1, 2015
• Actual Primary Completion Date: Apr 3, 2018
• Actual Study Completion Date: Apr 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: Brain Metastases (BM) Tesevatinib 300 mg orally (PO) once daily (QD) administered to subjects with NSCLC who had progressed with brain metastases (BM)	Drug: Tesevatinib; Other Names: KD019, XL647
Experimental: Cohort B: Leptomeningeal Metastases (LM) Tesevatinib 300 mg PO QD administered to subjects with NSCLC who had progressed with leptomeningeal metastases (LM)	Drug: Tesevatinib; Other Names: KD019, XL647
Experimental: Cohort C: Brain Metastases at Initial Presentation (BM-IP) Tesevatinib 300 mg PO QD administered NSCLC who presented initially with BM at initial presentation	Drug: Tesevatinib; Other Names: KD019, XL647

Outcome Measures

Primary Outcome Measures

1. Best Overall Response Rate (ORR) of Subjects With BM [Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first]

   The best overall response rates (ORRs) of subjects who had brain tumors and exhibited either a complete response (CR) or a partial responder (PR) to therapy divided by the total number of subjects treated with tesevatinib 300 mg PO QD. Response rates are in accordance with RECIST Version 1.1 criteria. Since such brain metastases (BM) tumors can either affect the central nervous system (CNS) or not affect the CNS (non-CNS), they were categorized into CNS and non-CNS subsets. Because leptomeningeal metastases (LM) only are considered cancer cell migration from the breast, lung, or some other part of the body to the cerebrospinal fluid (CSF), analysis of CNS are not appropriate, so Cohort B is excluded.

2. Best ORR of Subjects With LM [Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first]

   The best overall response rates (ORRs) of subjects who had leptomeningeal tumors and exhibited either a complete response (CR) or a partial responder (PR) to therapy divided by the total number of subjects treated with tesevatinib 300 mg PO QD. Response rates are in accordance with RECIST Version 1.1 criteria. Since leptomeningeal metastases (LM) are only considered cancer cell migration from the breast, lung, or some other part of the body to the cerebrospinal fluid (CSF), analysis of CNS are not appropriate, so Cohorts A and C are excluded.

Secondary Outcome Measures

1. Median Progression-free Survival (PFS) [Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first]

   Median duration of survival without progression of subjects treated with tesevatinib 300 mg PO QD.

2. Probability of PFS at 12 Weeks and 24 Weeks--Cohort A (BM Only) and Cohort B (LM Only) [24 weeks (6 months)]

   Probability that subjects with brain metastases (BM) or leptomeningeal metastases (LM) would not progress, i.e., progression-free survival (PFS) after 12 weeks (3 months) and after 24 weeks (6 months) of treatment with tesevatinib 300 mg PO QD

3. Probability of PFS at 24 Weeks--Cohort C (BM-IP Only) [24 weeks (6 months)]

   Probability that subjects with brain metastases at initial presentation (BM-IP) would not progress, i.e., progression-free survival (PFS) after 24 weeks (6 months) of treatment with tesevatinib 300 mg PO QD

4. Probability of OS at 12 Weeks and at 24 Weeks--Cohort A (BM Only) and Cohort B (LM Only) [24 weeks (6 months)]

   Probability that subjects with brain metastases (BM) or leptomeningeal metastases (LM) survived (overall survival [OS]) after 12 weeks (3 months) and after 24 weeks (6 months) of treatment with tesevatinib 300 mg PO QD

5. Median Time to Progression (TTP)--Cohort A (BM), Cohort B (LM), Cohort C (BM-IP) [Until disease progression, death, unacceptable toxicity, or up to 2 years, whichever occurred first]

   Median time to the development of disease progression (TTP) for subjects in Cohort A, Cohort B and Cohort C who were treated with tesevatinib 300 mg PO QD

6. Probability of TTP at 12 Weeks and 24 Weeks--Non-CNS Cohort A (BM Only) and Cohort B (LM Only) [24 weeks (6 months)]

   Probability that the time to progression (TTP) for subjects with no metastases to the central nervous system (non-CNS) in Cohort A (brain metastases only) or Cohort B (leptomeningeal metastases only) would be at 12 weeks (3 months) and at 24 weeks (6 months) of therapy with tesevatinib 300 mg PO QD. There were an insufficient number of subjects in Cohort C (brain metastases at initial presentation) who had events.

7. Probability of TTP at 24 Weeks--CNS [24 weeks (6 months)]

   Probability that the time to progression (TTP) for subjects with metastases to the central nervous system (CNS) would be at 24 weeks (6 months) of therapy with tesevatinib 300 mg PO QD.

8. Quality of Life (QoL): Mean Change From Baseline in EORTC-QLQ-C30 Questionnaire Scores [Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first]

   The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Cancer 30 (C30) is a 30-question assessment composed of both multi-item scales and single-item measures: 5 functional scales, 3 symptom scales, 1 global QoL scale, and 6 single items. Ratings are on a 4-point scale (not at all, a little quite a bit, very much), with scoring from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. The outcome measure is the mean change in the EORTC-QLQ-C30 from baseline to a visit.

9. Quality of Life (QoL): Mean Change From Baseline in EORTC-QLQ-BN20 Questionnaire Scores [Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first]

   The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Cancer BN20 Questionnaire is a 20-question assessment of symptomatology based on a categorical scale (Not at all = 1; A little = 2; Quite a bit = 3; and Very much = 4). For 20 questions: minimum score = 20 and maximum score = 80. Higher scores indicate greater level of symptomatology/problems. The outcome measure is the mean change in the EORTC-QLQ-BN20 from baseline to a visit.

Eligibility Criteria

Criteria

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

Cohort A

Inclusion Criteria:

• History of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation or an EGFR activating mutation that has had a clinical response to erlotinib, afatinib, or gefitinib in the patient being enrolled

• Occurrence or progression of BM while receiving first-line therapy (either erlotinib, afatinib, or gefitinib) for at least 14 days. Patients may have received osimertinib (or other agents inhibiting the T790M EGFR mutation) as second line therapy. If BM progression occurs after osimertinib, patient will be eligible.

• At least one measurable BM by RECIST 1.1 criteria (≥ 10 mm in longest diameter). Target lesions must not have received stereotactic radiotherapy (SRS). If a subject had prior whole brain radiotherapy (WBRT), progression in any measurable BM lesion must have occurred at least 3 months after the end of WBRT. Subjects with asymptomatic brain metastases may have been enrolled without prior radiation therapy to the brain. Subjects with minimally symptomatic brain metastases may have been enrolled without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant

• Subjects in Cohort A may have had asymptomatic LM detected by MRI. (Subjects with symptoms or signs attributed to LM were enrolled in Cohort B whether or not they have brain metastases)

• No clinically significant progression outside of the CNS on most recent EGFR inhibitor therapy

• ECOG Score ≤ 2

• No history of another malignancy in the 5 years prior to study entry, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma in situ of the cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and have not recurred

• Adequate organ and bone marrow functions

• Serum potassium and magnesium levels above the lower limit of normal

• No coexisting medical problems of sufficient severity to limit compliance with the study

• Willing and able to sign written informed consent and able to comply with the study protocol for the duration of the study

• Women of childbearing potential (i.e., menstruating women) must have had a negative urine pregnancy test (positive urine tests confirmed by serum test)

Exclusion Criteria:

• First day of dosing with tesevatinib less than 2 weeks from the last treatment of cytotoxic chemotherapy, biological therapy, or immunotherapy, and less than 6 weeks for nitrosoureas and mitomycin C. Surgical procedures must have been performed at least 2 weeks prior to the start of study treatment. Subjects must have recovered from the reversible effects of prior lung cancer treatments, including surgery and radiation therapy (excluding alopecia).

• First day of dosing with tesevatinib less than 4 weeks from the last radiotherapy of the brain or spinal cord/cauda equina

• First day of dosing with tesevatinib less than 2 weeks from treatment with another investigational agent

• Treatment with erlotinib must have been discontinued at least 3 days prior to first dose of tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor must have been discontinued at least 3 days prior to first dose of tesevatinib

• Any concurrent therapy for BM other than the specified treatment in this study

• Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or any drugs that are CYP3A4 inducers (including anti-epileptic agents such as phenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the selective serotonin uptake inhibitor (SSRI) class was allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine)

• Taking any drugs associated with torsades de pointes or known to moderately or severely prolong the QTc(F) interval

• Evidence of active heart disease such as myocardial infarction within the 3 months prior to study entry; symptomatic coronary insufficiency congestive heart failure; moderate or severe pulmonary dysfunction

• History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or congenital long QT syndrome. Subjects with a history of atrial arrhythmias were discussed with the medical monitor

• Had an active infectious process

• Female subject pregnant or lactating

• Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body

• Marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval > 470 msec) using the Fridericia method of correction for heart rate

• Gastrointestinal (GI) condition interfering with drug absorption

• Non-malignant neurological disease that would interfere with evaluation of symptoms or signs of brain metastases

Cohort B

Inclusion Criteria:

• History of NSCLC with EGFR mutation (either exon 19 deletion or L858R mutation) or, if previously treated, history of an activating EGFR mutation that had a clinical response to erlotinib, afatinib, or gefitinib in the subject being enrolled).

• Presentation with LM at initial presentation with no prior systemic treatment, or occurrence or progression of LM while receiving first-line therapy (either erlotinib, afatinib, or gefitinib) for at least 14 days. Patients may have received osimertinib (or other agents inhibiting the T790M EGFR mutation) as second line therapy. If LM progression occurred after osimertinib, subjects were eligible.

• Presence of at least one CTCAE 4.03 symptom/sign of at least Grade 1 attributed by the investigator to LM

• Diagnosis of LM by:

1. Cytological evidence in cerebrospinal fluid (CSF) sample of LM due to NSCLC, and/or

2. Findings on gadolinium-enhanced MRI

• No clinically significant progression outside of the CNS on most recent EGFR inhibitor therapy

• Concomitant brain metastases and brain metastases previously treated with radiation therapy were allowed. (Subjects with symptoms or signs attributed to LM will be enrolled in Cohort B whether or not they have brain metastases)

• ECOG Score ≤ 2

• No history of another malignancy in the 5 years prior to study entry, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma in situ of the cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and had not recurred

• Adequate organ and bone marrow functions

• Serum potassium and magnesium levels above the lower limit of normal (LLN)

• No coexisting medical problems of sufficient severity to limit compliance with the study

• Willing and able to sign written informed consent and able to comply with the study protocol for the duration of the study

• Women of childbearing potential (i.e., menstruating women) must have had a negative urine pregnancy test (positive urine tests confirmed by serum test)

Exclusion Criteria:

• First day of dosing with tesevatinib less than 2 weeks from the last treatment of cytotoxic chemotherapy, biological therapy, or immunotherapy, and less than 6 weeks for nitrosoureas and mitomycin C. Surgical procedures must have been performed at least 2 weeks prior to the start of study treatment. Subjects must have recovered from the reversible effects of prior lung cancer treatments, including surgery and radiation therapy (excluding alopecia).

• First day of dosing with tesevatinib less than 4 weeks from the last radiotherapy of the brain or spinal cord/cauda equina

• First day of dosing with tesevatinib less than 2 weeks from treatment with another investigational agent

• Treatment with erlotinib must have been discontinued at least 3 days prior to first dose of tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor must have been discontinued at least 3 days prior to first dose of tesevatinib

• Any concurrent therapy for LM other than the specified treatment in this study

• Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or any drugs that are CYP3A4 inducers (including anti-epileptic agents such as phenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class was allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine)

• Taking any drugs associated with torsades de pointes or known to moderately or severely prolong the QTc(F) interval

• Evidence of active heart disease such as myocardial infarction within the 3 months prior to study entry; symptomatic coronary insufficiency congestive heart failure; moderate or severe pulmonary dysfunction

• History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or congenital long QT syndrome. Subjects with a history of atrial arrhythmias were discussed with the medical monitor.

• Has an active infectious process

• Female subject pregnant or lactating

• Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body

• Marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval > 470 msec) using the Fridericia method of correction for heart rate

• GI condition that would interfere with drug absorption

• Non-malignant neurological disease that would interfere with evaluation of symptoms or signs of leptomeningeal metastases

• Contraindications to lumbar puncture:

1. International Normalized Ratio (INR) > 1.5

2. Platelets < 50 × 10^{9/L (Note that platelets are required to be ≥100× 10}9/L at screening)

3. Therapeutic anticoagulant treatment that can't be held for 24 hours. Low dose low molecular weight heparin given for deep vein thrombosis (DVT) prophylaxis was allowed.

4. CNS lesions considered to be at risk for cerebral herniation, myelocompression, or conus/cauda compression

Cohort C

Inclusion Criteria:

• NSCLC with EGFR activating mutation

• No prior systemic treatment for NSCLC. Treatment with systemic steroids was not considered systemic treatment for NSCLC

• No prior radiation therapy to the CNS (brain or spinal cord)

• At least one measurable BM by RECIST 1.1 criteria (≥ 10 mm in longest diameter) in a subject with asymptomatic or minimally symptomatic brain metastases who did not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant.

• Subjects in Cohort C may have had asymptomatic LM detected by MRI

• ECOG Score ≤ 2

• No history of another malignancy in the 5 years prior to study entry, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma in situ of the cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and have not recurred

• Adequate organ and bone marrow functions

• Serum potassium and magnesium levels above the LLN

• No coexisting medical problems of sufficient severity to limit compliance with the study.

• Willing and able to sign written informed consent and able to comply with the study protocol for the duration of the study

• Women of childbearing potential (i.e., menstruating women) must have had a negative urine pregnancy test (positive urine tests are to be confirmed by serum test)

Exclusion Criteria:

• Surgical procedures performed less than 2 weeks prior to the start of study treatment

• Any concurrent therapy for BM other than the specified treatment in this study

• Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or any drugs that are CYP3A4 inducers (including anti-epileptic agents such as phenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class was allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine)

• Taking any drugs associated with torsades de pointes or known to moderately or severely prolong the QTc(F) interval

• Evidence of active heart disease such as myocardial infarction within the 3 months prior to study entry; symptomatic coronary insufficiency congestive heart failure; moderate or severe pulmonary dysfunction

• History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first-degree block, being PR interval only), or congenital long QT syndrome. Subjects with a history of atrial arrhythmias were discussed with the medical monitor

• An active infectious process

• Female subject pregnant or lactating

• Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body

• Marked prolongation of QTc(F) interval at screening or Cycle 1 Day 1 (QTc[F] interval

470 msec) using the Fridericia method of correction for heart rate

• GI condition interfering with drug absorption

• Non-malignant neurological disease that would interfere with evaluation of symptoms or signs of brain metastases

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beverly Hills Cancer Center	Beverly Hills	California	United States	90211
2	USC Norris Oncology/Hematology Newport Beach	Newport Beach	California	United States	92663
3	John Wayne Cancer Institute	Santa Monica	California	United States	90404
4	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
5	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
6	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
7	UT M.D. Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• Kadmon Corporation, LLC

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Oct 3, 2017
• Statistical Analysis Plan - Oct 5, 2018

More Information

Publications

None provided.

• Responsible Party: Kadmon Corporation, LLC
• ClinicalTrials.gov Identifier: NCT02616393
• Other Study ID Numbers: KD019-206
• First Posted: Nov 26, 2015
• Last Update Posted: Mar 16, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Neoplasms, Second Primary; Brain Neoplasms; Meningeal Carcinomatosis; XL647

Study Results

Participant Flow

Arm/Group Title	Cohort A (BM)	Cohort B (LM)	Cohort C (BM-IP)
Arm/Group Description	Subjects with brain metastases (BM) who received tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with leptomeningeal metastases (LM) who received tesevatinib 300 mg PO QD	Subjects with brain metastases at initial presentation (BM-IP) who received tesevatinib 300 mg PO QD
Period Title: Overall Study
STARTED	13	20	3
COMPLETED	0	0	0
NOT COMPLETED	13	20	3

Baseline Characteristics

Arm/Group Title	Cohort A - Brain Metastases	Cohort B - Leptomeningeal Metastases	Cohort C - Brain Metastases at Initial Presentation	Total
Arm/Group Description	Tesevatinib will be orally administered with a dose of 300 mg once daily to subjects with NSCLC who have progressed with BM Tesevatinib	Tesevatinib will be orally administered with a dose of 300 mg once daily to subjects with NSCLC who have progressed with LM Tesevatinib	Tesevatinib will be orally administered with a dose of 300 mg once daily to subjects with NSCLC with BM at initial presentation Tesevatinib	Total of all reporting groups
Overall Participants	13	20	3	36
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	60.7	56.3	64.7	58.6
Sex: Female, Male (Count of Participants)
Female	6 46.2%	15 75%	2 66.7%	23 63.9%
Male	7 53.8%	5 25%	1 33.3%	13 36.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 23.1%	1 5%	0 0%	4 11.1%
Not Hispanic or Latino	10 76.9%	19 95%	3 100%	32 88.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	3 23.1%	10 50%	0 0%	13 36.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	2 15.4%	2 10%	2 66.7%	6 16.7%
White	4 30.8%	8 40%	1 33.3%	13 36.1%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	4 30.8%	0 0%	0 0%	4 11.1%
EORTC-QLQ-C30 Questionnaire (Units (score) on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units (score) on a scale]	59.2 (20.48)	66.5 (12.84)	51.7 (5.51)	62.7 (60.6)
EORTC-QLQ-BN20 Questionnaire (Units (score) on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units (score) on a scale]	34.0 (15.71)	37.7 (8.64)	22.0 (2.00)	35.1 (11.89)

Outcome Measures

1. Primary Outcome

Title	Best Overall Response Rate (ORR) of Subjects With BM
Description	The best overall response rates (ORRs) of subjects who had brain tumors and exhibited either a complete response (CR) or a partial responder (PR) to therapy divided by the total number of subjects treated with tesevatinib 300 mg PO QD. Response rates are in accordance with RECIST Version 1.1 criteria. Since such brain metastases (BM) tumors can either affect the central nervous system (CNS) or not affect the CNS (non-CNS), they were categorized into CNS and non-CNS subsets. Because leptomeningeal metastases (LM) only are considered cancer cell migration from the breast, lung, or some other part of the body to the cerebrospinal fluid (CSF), analysis of CNS are not appropriate, so Cohort B is excluded.
Time Frame	Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first

Outcome Measure Data

Analysis Population Description

Subjects with BM only (Cohorts A and C). Subjects with LM (Cohort B) were excluded.

Arm/Group Title	Cohort A (BM)	Cohort C (BM-IP)	Overall BM
Arm/Group Description	Subjects with brain metastases (BM) who received tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with brain metastases at initial presentation (BM-IP) who received tesevatinib 300 mg PO QD	All subjects with brain metastases who received tesevatinib 300 mg PO QD
Measure Participants	13	3	16
CNS	15.4 118.5%	100 500%	31.3 1043.3%
non-CNS	0 0%	100 500%	18.8 626.7%
CNS + non-CNS	15.4 118.5%	100 500%	31.3 1043.3%

2. Primary Outcome

Title	Best ORR of Subjects With LM
Description	The best overall response rates (ORRs) of subjects who had leptomeningeal tumors and exhibited either a complete response (CR) or a partial responder (PR) to therapy divided by the total number of subjects treated with tesevatinib 300 mg PO QD. Response rates are in accordance with RECIST Version 1.1 criteria. Since leptomeningeal metastases (LM) are only considered cancer cell migration from the breast, lung, or some other part of the body to the cerebrospinal fluid (CSF), analysis of CNS are not appropriate, so Cohorts A and C are excluded.
Time Frame	Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort B (LM)
Arm/Group Description	Subjects with leptomeningeal metastases (LM) who received 300 mg PO QD
Measure Participants	20
Number [Percentage of participants (%)]	0 0%

3. Secondary Outcome

Title	Median Progression-free Survival (PFS)
Description	Median duration of survival without progression of subjects treated with tesevatinib 300 mg PO QD.
Time Frame	Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A (BM)	Cohort B (LM)	Cohort C (BM-IP)
Arm/Group Description	Subjects with brain metastases (BM) administered tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with leptomeningeal metastases (LM) administered tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with brain metastases at initial presentation (BM-IP) administered tesevatinib 300 mg orally (PO) once daily (QD)
Measure Participants	13	20	3
Median (95% Confidence Interval) [Weeks]	9.29	10.86	37.71

4. Secondary Outcome

Title	Probability of PFS at 12 Weeks and 24 Weeks--Cohort A (BM Only) and Cohort B (LM Only)
Description	Probability that subjects with brain metastases (BM) or leptomeningeal metastases (LM) would not progress, i.e., progression-free survival (PFS) after 12 weeks (3 months) and after 24 weeks (6 months) of treatment with tesevatinib 300 mg PO QD
Time Frame	24 weeks (6 months)

Outcome Measure Data

Analysis Population Description

Note: Cohort C (BM-IP) did not have a sufficient number of subjects with events to determine the PFS at 12 or 24 weeks.

Arm/Group Title	Cohort A (BM)	Cohort B (LM)
Arm/Group Description	Subjects with brain metastases (BM) administered tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with leptomeningeal metastases (LM) administered tesevatinib 300 mg orally (PO) once daily (QD)
Measure Participants	13	20
12 weeks (3 months)	0.4762	0.4737
24 weeks (6 months)	0.2857	0.2632

5. Secondary Outcome

Title	Probability of PFS at 24 Weeks--Cohort C (BM-IP Only)
Description	Probability that subjects with brain metastases at initial presentation (BM-IP) would not progress, i.e., progression-free survival (PFS) after 24 weeks (6 months) of treatment with tesevatinib 300 mg PO QD
Time Frame	24 weeks (6 months)

Outcome Measure Data

Analysis Population Description

Note: Insufficient data for PFS probability at 12 weeks

Arm/Group Title	Cohort C (BM-IP)
Arm/Group Description	Subjects with brain metastases at initial presentation (BM-IP) administered tesevatinib 300 mg orally (PO) once daily (QD)
Measure Participants	3
Number (95% Confidence Interval) [Probability]	0.6667

6. Secondary Outcome

Title	Probability of OS at 12 Weeks and at 24 Weeks--Cohort A (BM Only) and Cohort B (LM Only)
Description	Probability that subjects with brain metastases (BM) or leptomeningeal metastases (LM) survived (overall survival [OS]) after 12 weeks (3 months) and after 24 weeks (6 months) of treatment with tesevatinib 300 mg PO QD
Time Frame	24 weeks (6 months)

Outcome Measure Data

Analysis Population Description

Note: Cohort C did not have a sufficient number of subjects with events to determine the probability of survival at 12 or 24 weeks.

Arm/Group Title	Cohort A (BM)	Cohort B (LM)
Arm/Group Description	Subjects with brain metastases (BM) administered tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with leptomeningeal metastases (LM) administered tesevatinib 300 mg orally (PO) once daily (QD)
Measure Participants	13	20
12 weeks (3 months)	0.8462	0.8471
24 weeks (6 months)	0.7692	0.6353

7. Secondary Outcome

Title	Median Time to Progression (TTP)--Cohort A (BM), Cohort B (LM), Cohort C (BM-IP)
Description	Median time to the development of disease progression (TTP) for subjects in Cohort A, Cohort B and Cohort C who were treated with tesevatinib 300 mg PO QD
Time Frame	Until disease progression, death, unacceptable toxicity, or up to 2 years, whichever occurred first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A (BM)	Cohort B (LM)	Cohort C (BM-IP)
Arm/Group Description	subjects with brain metastases (BM) administered tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with leptomeningeal metastases (LM) who were administered tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with brain metastases at initial presentation who were administered 300 mg PO QD
Measure Participants	13	20	3
Median (95% Confidence Interval) [Weeks]	21.43	8.14	34.93

8. Secondary Outcome

Title	Probability of TTP at 12 Weeks and 24 Weeks--Non-CNS Cohort A (BM Only) and Cohort B (LM Only)
Description	Probability that the time to progression (TTP) for subjects with no metastases to the central nervous system (non-CNS) in Cohort A (brain metastases only) or Cohort B (leptomeningeal metastases only) would be at 12 weeks (3 months) and at 24 weeks (6 months) of therapy with tesevatinib 300 mg PO QD. There were an insufficient number of subjects in Cohort C (brain metastases at initial presentation) who had events.
Time Frame	24 weeks (6 months)

Outcome Measure Data

Analysis Population Description

Note: Cohort C (BM-IP) did not have a sufficient number of subjects with events to determine the probability of TTP at 12 weeks or 24 weeks.

Arm/Group Title	Cohort A (BM)	Cohort B (LM)
Arm/Group Description	Subjects with brain metastases (BM) administered tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with leptomeningeal metastases (LM) administered tesevatinib 300 mg orally (PO) once daily (QD)
Measure Participants	13	20
Non-CNS at 12 weeks	0.5625	0.4396
Non-CNS at 24 weeks	0.2813	0.2637

9. Secondary Outcome

Title	Probability of TTP at 24 Weeks--CNS
Description	Probability that the time to progression (TTP) for subjects with metastases to the central nervous system (CNS) would be at 24 weeks (6 months) of therapy with tesevatinib 300 mg PO QD.
Time Frame	24 weeks (6 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A - Brain Metastases	Cohort B - Leptomeningeal Metastases	Cohort C - Brain Metastases at Initial Presentation
Arm/Group Description	Tesevatinib administered at a dose of 300 mg PO QD to subjects with NSCLC who progressed with BM	Tesevatinib administered at a dose of 300 mg PO QD to subjects with NSCLC who progressed with LM	Tesevatinib administered at a dose of 300 mg PO QD to subjects with NSCLC with BM at initial presentation
Measure Participants	13	20	3
Number (95% Confidence Interval) [Probability]	0.3636	0.4795	0.5000

10. Secondary Outcome

Title	Quality of Life (QoL): Mean Change From Baseline in EORTC-QLQ-C30 Questionnaire Scores
Description	The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Cancer 30 (C30) is a 30-question assessment composed of both multi-item scales and single-item measures: 5 functional scales, 3 symptom scales, 1 global QoL scale, and 6 single items. Ratings are on a 4-point scale (not at all, a little quite a bit, very much), with scoring from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. The outcome measure is the mean change in the EORTC-QLQ-C30 from baseline to a visit.
Time Frame	Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first

Outcome Measure Data

Analysis Population Description

Note: Not all subjects were available for analysis at all visits.

Arm/Group Title	Cohort A (BM)	Cohort B (LM)	Cohort C (BM-IP)	All Subjects (Cohorts A+B+C)
Arm/Group Description	Subjects with brain metastases (BM) who were administered tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with leptomeningeal metastases (LM) who were administered tesevatinib 300 mg PO QD	Subjects with brain metastases at initial presentation (BM-IP) who were administered tesevatinib 300 mg PO QD	All subjects with BM, LM or BM-IP who were administered tesevatinib 300 mg PO QD
Measure Participants	13	20	3	36
Baseline Score (35 subjects)	59.2 (20.48)	66.5 (12.84)	51.7 (5.51)	62.7 (15.91)
Mean Change--Cycle 3 Day 1 Change From Baseline	3.6 (5.22)	2.1 (12.09)	3.3 (0.58)	2.8 (8.64)
Mean Change from Baseline--Cycle 5 Day 1	2.8 (4.21)	5.5 (10.61)	1.0 (5.00)	2.8 (5.35)
Mean Change from Baseline to End-of-Study	2.9 (5.17)	7.2 (14.34)	15.0 (4.00)	6.7 (10.74)

11. Secondary Outcome

Title	Quality of Life (QoL): Mean Change From Baseline in EORTC-QLQ-BN20 Questionnaire Scores
Description	The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Cancer BN20 Questionnaire is a 20-question assessment of symptomatology based on a categorical scale (Not at all = 1; A little = 2; Quite a bit = 3; and Very much = 4). For 20 questions: minimum score = 20 and maximum score = 80. Higher scores indicate greater level of symptomatology/problems. The outcome measure is the mean change in the EORTC-QLQ-BN20 from baseline to a visit.
Time Frame	Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first

Outcome Measure Data

Analysis Population Description

Not all subjects were available for all analyses.

Arm/Group Title	Cohort A (BM)	Cohort B (LM)	Cohort C (BM-IP)	All Subjects (Cohorts A+B+C)
Arm/Group Description	Subjects with brain metastases (BM) who were administered tesevatinib 300 mg orally (PO) once daily (QD)	Subjects with leptomeningeal metastases (LM) who were administered tesevatinib 300 mg PO QD	Subjects with brain metastases at initial presentation (BM-IP) who were administered tesevatinib 300 mg PO QD	All subjects with BM, LM or BM-IP who were administered tesevatinib 300 mg PO QD
Measure Participants	13	20	3	36
Baseline Score (35 subjects)	34.0 (15.71)	37.7 (8.64)	22.0 (2.00)	35.1 (11.89)
Mean Change from Baseline--Cycle 3 Day 1 Change From Baseline	0.3 (4.89)	1.9 (6.66)	3.7 (2.08)	1.6 (5.44)
Mean Change from Baseline--Cycle 5 Day 1 Change From Baseline	-4.0 (5.34)	2.5 (12.02)	8.7 (8.96)	1.1 (8.97)
Mean Change from Baseline to End-of-Study	2.6 (3.05)	7.3 (12.35)	12.3 (10.26)	6.4 (9.73)

Adverse Events

Time Frame	Subjects were treated with tesevatinib 300 mg QD until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first.
Arm/Group Title	Cohort A - Brain Metastases		Cohort B - Leptomeningeal Metastases		Cohort C - Brain Metastases at Initial Presentation		All Subjects (Cohorts A+B+C)
Arm/Group Description	Tesevatinib 300 mg administered orally (PO) once daily (QD) to subjects with NSCLC who have progressed with BM		Tesevatinib 300 mg administered PO to subjects with NSCLC who have progressed with LM		Tesevatinib 300 mg administered PO to subjects with NSCLC who presented initially with brain metastases		Tesevatinib 300 mg administered PO to all subjects with NSCLC who had brain metastases and who had leptomeningeal metastases
All Cause Mortality
	Cohort A - Brain Metastases		Cohort B - Leptomeningeal Metastases		Cohort C - Brain Metastases at Initial Presentation		All Subjects (Cohorts A+B+C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/13 (38.5%)		12/20 (60%)		1/3 (33.3%)		18/36 (50%)
Serious Adverse Events
	Cohort A - Brain Metastases		Cohort B - Leptomeningeal Metastases		Cohort C - Brain Metastases at Initial Presentation		All Subjects (Cohorts A+B+C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/13 (46.2%)		13/20 (65%)		2/3 (66.7%)		21/36 (58.3%)
Gastrointestinal disorders
Abdominal pain	0/13 (0%)		0/20 (0%)		1/3 (33.3%)		1/36 (2.8%)
Dysphagia	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Nausea	1/13 (7.7%)		0/20 (0%)		0/3 (0%)		1/36 (2.8%)
General disorders
Disease progression	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Fatigue	1/13 (7.7%)		0/20 (0%)		0/3 (0%)		1/36 (2.8%)
Gait disturbance	1/13 (7.7%)		0/20 (0%)		0/3 (0%)		1/36 (2.8%)
Hepatobiliary disorders
Drug-induced liver injury	0/13 (0%)		0/20 (0%)		1/3 (33.3%)		1/36 (2.8%)
Infections and infestations
Urinary tract infection	1/13 (7.7%)		2/20 (10%)		0/3 (0%)		3/36 (8.3%)
Enterocolitis infectious	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Pneumonia	1/13 (7.7%)		0/20 (0%)		0/3 (0%)		1/36 (2.8%)
Postoperative wound infection	1/13 (7.7%)		0/20 (0%)		0/3 (0%)		1/36 (2.8%)
Sepsis	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Injury, poisoning and procedural complications
Subdural hematoma	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Metabolism and nutrition disorders
Dehydration	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Failure to thrive	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Hypercalcemia	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Hypokalemia	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Hyponatremia	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Nervous system disorders
Encephalopathy	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Dysarthria	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Headache	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Seizure	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Psychiatric disorders
Confusional state	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Renal and urinary disorders
Acute kidney injury	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	1/13 (7.7%)		0/20 (0%)		0/3 (0%)		1/36 (2.8%)
Pneumonthorax	0/13 (0%)		1/20 (5%)		0/3 (0%)		1/36 (2.8%)
Vascular disorders
Embolism	0/13 (0%)		0/20 (0%)		1/3 (33.3%)		1/36 (2.8%)
Other (Not Including Serious) Adverse Events
	Cohort A - Brain Metastases		Cohort B - Leptomeningeal Metastases		Cohort C - Brain Metastases at Initial Presentation		All Subjects (Cohorts A+B+C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		20/20 (100%)		3/3 (100%)		36/36 (100%)
Blood and lymphatic system disorders
Anemia	0/13 (0%)		1/20 (5%)		1/3 (33.3%)		2/36 (5.6%)
Cardiac disorders
Bradycardia	2/13 (15.4%)		0/20 (0%)		1/3 (33.3%)		3/36 (8.3%)
Tachycardia	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Ear and labyrinth disorders
Tinnitus	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Eye disorders
Diplopia	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Vision blurred	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Gastrointestinal disorders
Diarrhea	10/13 (76.9%)		14/20 (70%)		0/3 (0%)		24/36 (66.7%)
Vomiting	3/13 (23.1%)		5/20 (25%)		1/3 (33.3%)		9/36 (25%)
Abdominal pain	1/13 (7.7%)		2/20 (10%)		2/3 (66.7%)		5/36 (13.9%)
Anal incontinence	1/13 (7.7%)		3/20 (15%)		0/3 (0%)		4/36 (11.1%)
Dysphagia	0/13 (0%)		4/20 (20%)		0/3 (0%)		4/36 (11.1%)
Constipation	1/13 (7.7%)		2/20 (10%)		0/3 (0%)		3/36 (8.3%)
Dry mouth	0/13 (0%)		1/20 (5%)		1/3 (33.3%)		2/36 (5.6%)
General disorders
Fatigue	5/13 (38.5%)		8/20 (40%)		3/3 (100%)		16/36 (44.4%)
Nausea	7/13 (53.8%)		5/20 (25%)		1/3 (33.3%)		36/36 (100%)
Gait disturbance	2/13 (15.4%)		3/20 (15%)		0/3 (0%)		5/36 (13.9%)
Asthenia	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Chest discomfort	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Edema peripheral	2/13 (15.4%)		0/20 (0%)		0/3 (0%)		2/36 (5.6%)
Peripheral swelling	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Infections and infestations
Urinary tract infection	4/13 (30.8%)		5/20 (25%)		1/3 (33.3%)		10/36 (27.8%)
Upper respiratory infection	1/13 (7.7%)		2/20 (10%)		0/3 (0%)		3/36 (8.3%)
Oral candidiasis	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Rhinitis	0/13 (0%)		1/20 (5%)		1/3 (33.3%)		2/36 (5.6%)
Sepsis	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Viral upper respiratory tract infection	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Injury, poisoning and procedural complications
Fall	2/13 (15.4%)		3/20 (15%)		0/3 (0%)		5/36 (13.9%)
Investigations
QT Prolongation	5/13 (38.5%)		9/20 (45%)		1/3 (33.3%)		15/36 (41.7%)
Alanine aminotransaminase (ALT) increased	1/13 (7.7%)		3/20 (15%)		0/3 (0%)		4/36 (11.1%)
Aspartate aminotransferase (AST) increased	2/13 (15.4%)		1/20 (5%)		0/3 (0%)		3/36 (8.3%)
Weight decreased	2/13 (15.4%)		1/20 (5%)		0/3 (0%)		3/36 (8.3%)
Blood creatinine increased	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Lipase increased	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Metabolism and nutrition disorders
Decreased appetite	3/13 (23.1%)		2/20 (10%)		3/3 (100%)		8/36 (22.2%)
Hypokalemia	1/13 (7.7%)		4/20 (20%)		1/3 (33.3%)		6/36 (16.7%)
Dehydration	3/13 (23.1%)		2/20 (10%)		0/3 (0%)		5/36 (13.9%)
Failure to thrive	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Hypoalbuminemia	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Hyponatremia	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Musculoskeletal and connective tissue disorders
Back pain	5/13 (38.5%)		1/20 (5%)		1/3 (33.3%)		7/36 (19.4%)
Muscle spasms	1/13 (7.7%)		2/20 (10%)		1/3 (33.3%)		4/36 (11.1%)
Muscular weakness	1/13 (7.7%)		3/20 (15%)		0/3 (0%)		4/36 (11.1%)
Pain in extremity	1/13 (7.7%)		3/20 (15%)		0/3 (0%)		4/36 (11.1%)
Arthralgia	3/13 (23.1%)		0/20 (0%)		0/3 (0%)		3/36 (8.3%)
Neck pain	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Nervous system disorders
Headache	2/13 (15.4%)		5/20 (25%)		0/3 (0%)		7/36 (19.4%)
Dizziness	1/13 (7.7%)		2/20 (10%)		2/3 (66.7%)		5/36 (13.9%)
Dysarthria	0/13 (0%)		5/20 (25%)		0/3 (0%)		5/36 (13.9%)
Paresthesia	3/13 (23.1%)		2/20 (10%)		0/3 (0%)		5/36 (13.9%)
Dysgeusia	0/13 (0%)		1/20 (5%)		2/3 (66.7%)		3/36 (8.3%)
Neuropathy peripheral	0/13 (0%)		2/20 (10%)		1/3 (33.3%)		3/36 (8.3%)
Balance disorder	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Encephalopathy	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Facial paresis	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Hypoesthesia	0/13 (0%)		1/20 (5%)		1/3 (33.3%)		2/36 (5.6%)
Seizure	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Psychiatric disorders
Confusional state	1/13 (7.7%)		2/20 (10%)		0/3 (0%)		3/36 (8.3%)
Anxiety	0/13 (0%)		0/20 (0%)		2/3 (66.7%)		2/36 (5.6%)
Insomnia	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Renal and urinary disorders
Urinary retention	1/13 (7.7%)		2/20 (10%)		0/3 (0%)		3/36 (8.3%)
Acute kidney injury	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Proteinuria	2/13 (15.4%)		0/20 (0%)		0/3 (0%)		2/36 (5.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/13 (15.4%)		4/20 (20%)		2/3 (66.7%)		8/36 (22.2%)
Pleural effusion	2/13 (15.4%)		2/20 (10%)		0/3 (0%)		4/36 (11.1%)
Cough	2/13 (15.4%)		1/20 (5%)		0/3 (0%)		3/36 (8.3%)
Dysphonia	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Dyspnea exertional	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Epistaxis	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Nasal congestion	0/13 (0%)		1/20 (5%)		1/3 (33.3%)		2/36 (5.6%)
Skin and subcutaneous tissue disorders
Rash	6/13 (46.2%)		2/20 (10%)		3/3 (100%)		11/36 (30.6%)
Dermatitis acneiform	1/13 (7.7%)		4/20 (20%)		0/3 (0%)		5/36 (13.9%)
Dry skin	1/13 (7.7%)		3/20 (15%)		0/3 (0%)		4/36 (11.1%)
Alopecia	0/13 (0%)		1/20 (5%)		1/3 (33.3%)		2/36 (5.6%)
Decubitus ulcer	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)
Ecchymosis	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Pruritus	1/13 (7.7%)		0/20 (0%)		1/3 (33.3%)		2/36 (5.6%)
Rash macular	0/13 (0%)		2/20 (10%)		0/3 (0%)		2/36 (5.6%)
Vascular disorders
Hypertension	3/13 (23.1%)		2/20 (10%)		0/3 (0%)		5/36 (13.9%)
Hypotension	1/13 (7.7%)		1/20 (5%)		0/3 (0%)		2/36 (5.6%)

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.