A Phase 1 Study of TPI 287 Concurrent With Fractionated Stereotactic Radiotherapy (FSRT) in Treatment of Brain Metastases From Advanced Breast and Non-Small Cell Lung (NSCL) Cancer
Phase: PHASE1
Conditions: Brain Metastases, Generalized Malignancy, Primary, Brain Lesions
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 A Phase 1 Study of TPI 287 Concurrent with Fractionated Stereotactic 
Radiotherapy (FSRT) in Treatment of Brain Metastases from Advanced Breast and 
Non-Small Cell Lung (NSCL) Cancer 
NCT02187822 
Version 1.6 
July 7, 2014 

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Title: 
A Phase 1 Study of TPI 287 Concurrent with Fractionated Stereotactic 
Radiotherapy (FSRT) in Treatment of Brain Metastases from Advanced 
Breast and Non-Small Cell Lung (NSCL) Cancer  
Protocol Number: 
MCC 17816 
IND Number: 
 
123010 
Sponsor:  
H. Lee Moffitt Cancer Center & Research Institute, Inc. 
(Moffitt Cancer Center), Investigator Initiated Trial 
Investigational Product: TPI 287 
Principal Investigators:  
Solmaz Sahebjam, MD 
Department of Neuro-Oncology, Moffitt Cancer Center 
12902 Magnolia Drive 
Tampa, FL 33612 
 
 
  
Co-Investigators:  
Nikhil G. Rao, MD 
Prakash Chinnaiyan, MD 
Thomas J. Dilling, MD 
Peter Forsyth, MD 
Jhanelle Gray, MD 
Hyo S. Han, MD 
Amit Mahipal, MD 
Susan E. Minton, DO 
Hatem Soliman, MD 
Nam D. Tran, MD, PhD 
Statistician: 
 
Original Protocol: 
July 7
th, 2014

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PROTOCOL SYNOPSIS 
 
TITLE 
A Phase 1 Study of TPI 287 Concurrent with Fractionated Stereotactic 
Radiotherapy (FSRT) in Treatment of Brain Metastases from 
Advanced Breast and Non-Small Cell Lung (NSCL) Cancer  
 
STUDY PHASE 
I 
PRIMARY 
OBJECTIVES 
To evaluate the safety, tolerability, and to determine the maximum 
tolerated dose (MTD) of TPI 287 given concurrently with fractionated 
stereotactic radiotherapy (FSRT) to treat brain metastases from 
advanced breast and  non-small cell lung cancer. 
 
SECONDARY 
OBJECTIVES 
To characterize the pharmacokinetics and anti-tumor effect of TPI 287 
administered concurrently with FSRT in the treatment of patients with 
breast and NSCL cancers metastatic to the brain; and to evaluate the 
effect of treatment on measures of quality of life. 
 
HYPOTHESES 
TPI 287, given concurrently with FSRT, will improve local control 
and decrease distant brain failure in patients with brain metastases 
from advanced breast and NSCL cancers. 
 
STUDY DESIGN 
Dose escalation phase: The MTD for TPI 287 given concurrently with 
FSRT will be determined using the standard 3+3 study design. 
 
Dose expansion phase: Patients will be treated with TPI 287 at MTD 
given concurrently with FSRT to further assess toxicity and tumor 
response. 
 
PRIMARY 
ENDPOINTS AND 
SECONDARY 
ENDPOINTS 
Primary endpoints: 
 To determine the maximum tolerated dose (MTD) of TPI 287 
given concurrently with FSRT to treat brain metastases from 
advanced breast and NSCL cancers and to determine the 
recommended phase 2 dose (RP2D) 
 To determine the safety and toxicity of TPI 287 given 
concurrently with FSRT to treat brain metastases from 
advanced breast and NSCL cancers 
 
Secondary endpoints: 
 
 To determine the local control rate  
 To determine the distant intra-cranial control rate 
 To determine the short-term (≤ 30 days post-treatment) and 
long-term (> 30 days post treatment) adverse effects 
 To determine the PFS  
 To evaluate the effect of concurrent therapy with TPI 287 and 

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FSRT on measures of quality of life 
SAMPLE SIZE 
The maximum number for the dose escalation phase will be 36 
patients. In the dose expansion phase, a total of 10 patients (including 
patients treated at the MTD from dose escalation phase) will be 
enrolled to confirm the safety and to assess radiologic response. 
 
SUMMARY OF 
SUBJECT 
ELIGIBILITY 
Major inclusion criteria:  
 Patients age 18 years and older with brain metastasis (up to 3 
metastatic brain lesions) from histologically proven advanced 
breast and NSCL cancers which have not been treated with 
previous brain radiation. 
 Maximum diameter of each brain lesion ≤ 5 cm and maximum 
tumor volume ≤ 120 cc 
 Adequate organ function 
 Systemic chemotherapy washout period ≥ 7 days. For 
investigational drugs and monoclonal antibodies washout 
period ≥ 5x drug half-life.  
 ECOG ≤ 2 
 
Major exclusion criteria: 
 Previous treatment of the target lesions with radiation therapy 
 Previous whole brain radiotherapy  
 Pregnant and nursing women 
 Patients who are unable to give informed consent 
INVESTIGATIONAL 
TREATMENT 
TPI 287 will be administered intravenously prior to treatment of brain 
metastasis with FSRT on day 1 and will be given for 2 more weekly 
doses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation Phase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Expansion Phase 
 
                                              Dose Escalation Schedule 
Dose Level 
Dose 
TPI 287 IV  
Radiotherapy 
Level -1 
7 mg/m2/dose 
5 Gy daily fraction 
Level 1 
14 mg/m2/dose
 
5 Gy daily fraction 
Level 2 
28 mg/m2/dose
 
5 Gy daily fraction 
Level 3 
56 mg/m2/dose
 
5 Gy daily fraction 
Level 4 
85 mg/m2/dose 
5 Gy daily fraction 
Level 5 
113 mg/m2/dose 
5 Gy daily fraction 
Level 6 
127.5 mg/m2/dose 
5 Gy daily fraction 
Patients will be treated with TPI 287 at MTD 
 (from dose escalation phase) and FSRT to metastatic brain disease 
Patients with advanced 
breast and NSCL cancers 
metastatic to brain not 
amenable to surgical 
resection or radiosurgery 
TPI 287 
concurrent with FSRT                  
(25 Gy in 5 fractions)  
on day 1 
Single agent TPI 287 
 on day 8, and day 15  
Clinical and radiologic 
assessment every 3 
months until the patient is 
off-study or reaches  
18-month study 
completion date 

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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ..........................................................................................................2 
SCHEMA ...................................................................................................................................4 
1.   OBJECTIVES 
............................................................................................................................7 
1.1 Phase 1 Primary Objectives 
........................................................................................7 
1.2 Secondary Objectives...................................................................................................7 
2.    BACKGROUND 
......................................................................................................................7 
2.1 Brain Metastases 
..........................................................................................................7 
2.2 TPI 287 
..........................................................................................................................8 
2.3 Concurrent Radiotherapy with TPI 287 
...................................................................9 
2.4 Rationale 
.......................................................................................................................9 
2.5 Correlative Studies Background ..............................................................................10 
3.     PATIENT SELECTION 
........................................................................................................10 
3.1 Eligibility Criteria 
......................................................................................................10 
3.2 Exclusion Criteria 
................................
......................................................................11 
3.3 Inclusion of Women and Minorities 
.........................................................................12 
4.     INFORMED CONSENT PROCESS 
.....................................................................................12 
5.     TREATMENT PLAN 
...........................................................................................................12 
5.1 Pretreatment Evaluation 
...........................................................................................12 
5.2 Fractionated stereotactic radiotherapy (FSRT) 
......................................................12 
5.3 Drug therapy 
................................
..............................................................................13 
5.4 Definition of Dose-Limiting Toxicity 
........................................................................15 
5.5 General Concomitant Medication and Supportive Care Guidelines 
....................17 
5.6 Duration of Therapy 
..................................................................................................17 
5.7 Duration of Follow Up 
...............................................................................................17 
5.8 Criteria for Removal from Study 
.............................................................................18 
5.9 Stopping Rules 
...........................................................................................................19 
6.     DOSING DELAYS/DOSE MODIFICATIONS/TREATMENT DISCONTINUATION ....19 
7.     ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
................................21 
7.1 Potential Adverse Events 
...........................................................................................21 
7.2 Adverse Event Characteristics..................................................................................23 
7.3 Recording & Reporting Adverse Events 
..................................................................23 
7.4 Adverse Event Reporting Period 
..............................................................................23 
7.5 Immediate Reporting of Serious Adverse Event 
.....................................................23 
7.6 Second Malignancy 
................................................................................................... 26 
7.7 Pregnancy 
...................................................................................................................26 

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8.    PHARMACEUTICAL INFORMATION 
...............................................................................26 
9.    CORRELATIVE STUDIES 
...................................................................................................26 
9.1 Laboratory Correlative Studies 
................................................................................27 
10.  STUDY CALENDAR ............................................................................................................28 
11.  MEASUREMENT OF EFFECT.............................................................................................29 
11.1 Antitumor Effect  
.....................................................................................................29 
11.2 Criteria for Evaluation of Therapy Effectiveness 
.................................................30 
12.  ETHICAL AND REGULATORY CONSIDERATIONS 
......................................................31 
12.1 Protocol and Regulatory Compliance 
....................................................................31 
12.2 Document Audits and Monitoring 
..........................................................................31  
12.3 Protocol Amendments .............................................................................................32 
12.4 Reulatory Binder 
.....................................................................................................32 
12.5 Informed Consent 
....................................................................................................32  
12.6 Institutional Review Boards 
....................................................................................32 
12.7 Institutional Review Boards/Independent Ethics Committee .............................33 
12.8 Curriculum Vitae and Medical Licenses 
...............................................................33 
12.9 Patient Confidentiality.............................................................................................33 
12.10 Financial Disclosure 
...............................................................................................34 
  
13.       DATA MANAGEMENT AND RECORD KEEPING…..………………………………34         
14.       STATISTICAL CONSIDERATIONS...............................................................................34 
14.1 Study Design/Endpoints 
..........................................................................................34 
14.2 Sample Size/Accrual Rate 
.......................................................................................35 
14.3 Data Analysis 
...........................................................................................................35 
REFERENCES ..............................................................................................................................36 
APPENDIX A PERFORMANCE STATUS CRITERIA 
..............................................................38 
APPENDIX B List OF PROHIBITED DRUGS ...........................................................................39   
 
 
 

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1. OBJECTIVES 
 
1.1 Phase 1 Primary Objectives 
 
The primary objectives of this study are to evaluate the safety, tolerability, and to 
determine the maximum tolerated dose (MTD) of TPI 287 given concurrently with 
fractionated stereotactic radiotherapy (FSRT) to treat brain metastases from advanced 
breast and NSCL cancers. 
 
1.2 Secondary Objectives 
 
    
The secondary objectives are to characterize the pharmacokinetics and anti-tumor effect         
    
of TPI 287 administered concurrently with FSRT in the treatment of patients with breast   
    
and NSCL cancers metastatic to the brain; and to evaluate the effect of treatment on  
    
measures of quality of life. 
 
2. BACKGROUND 
 
2.1 Brain Metastases 
 
Brain metastases are a grave complication of cancer. They exceed the number of primary brain 
tumours by at least four times and occur in about 25% of all cancer patients totalling 
approximately 170,000 new cases each year in the United States.1,2 Brain metastases may 
originate from lung (40–50%), breast (15–25%), melanoma (5–20%), and kidney (5–10%) 
primary sites.2 Moreover, there is evidence that the overall incidence of brain metastases is 
increasing as a result of improvements in systemic treatments. While these treatments increase 
the longevity of patients with advanced disease, they do not effectively cross the blood-brain 
barrier (BBB).1  
 
Surgery or radiosurgery (SRS) are important modalities for patients with a single brain 
metastasis, particularly when favorable prognostic factors and systemic disease control are 
present. However, more than 70% of patients with brain metastases have multiple lesions at the 
time of presentation which are not considered to be surgically resectable.
3 Radiation therapy, 
either as SRS, fractionated stereotactic radiotherapy (FSRT) or whole brain radiotherapy 
(WBRT) remains the standard of care for treatment of these patients with unresectable brain 
metastases (NCCN Clinical Practice Guidelines in Oncology, version 2.2013).  
 
FSRT remains an attractive therapeutic strategy for large brain metastases (>2cm diameter) 
and/or for those located in eloquent critical locations in the brain. SRS for the treatment of these 
lesions may lead to an unacceptable rate of late toxicity including brain necrosis.
4 Fractionating 
the radiotherapy allows one to deliver a total dose close to that used in SRS while allowing for a 
decrease in normal tissue injury. However, this treatment modality is not optimal and response 
rate ranges from 60-80% for FSRT are seen.
5,6 Radiosensitization may help improve the control 
of brain metastases treated with FSRT. This strategy may be particularly helpful for those 
patients who are less likely to have optimal control with FSRT alone.7  

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2.2 TPI 287 
 
Taxanes have well established anti-cancer properties in wide spectrum of malignancies including 
breast and lung cancer. First generation taxanes (paclitaxel and docetaxel) are one of the main 
chemotherapeutic agents for the treatment of breast and non-small cell lung cancers. Although 
these agents are very effective in treatment of extra-cranial disease, minimum efficacy has been 
shown with their use for intracranial involvement. The efficacy of first generation taxanes on 
brain metastases is impacted by their inability to permeate the brain. A major limiting factor for 
their penetration across the BBB is the active efflux back into the circulation by the 
overexpression of the multidrug-resistant gene product 1 (MDR1) or P-glycoprotein (P-gp).8  
 
TPI 287, a new member of taxanes diterpenoid (taxoid) family, is a microtubule-inhibitor with 
significant cytotoxic activity and brain permeability.
9 TPI 287 has shown comparable (within 2-
fold) or increased cytotoxicity/growth inhibition compared to standard chemotherapeutic agents 
in human cell lines derived from the following tumors: breast (including a brain metastatic breast 
cancer cell line), lung, squamous cell carcinoma, pancreas, hepatocellular, colon, uterine, 
ovarian, prostate, Burkitt’s lymphoma, head/neck, neuroblastoma, glioblastoma, and 
medulloblastoma (Investigator’s brochure). TPI 287 was shown to be active (TGI > 58%) in 
mouse xenograft models of the following human tumors: breast adenocarcinoma, colon 
adenocarcinoma, prostate adenocarcinoma, pancreatic adenocarcinoma, head/neck tumor, 
glioblastoma, neuroblastoma, and ovarian tumor (Investigator’s brochure). Moreover, activity 
exceeding that of the comparator chemotherapeutic agent has been observed in multiple MDR+ 
tumor models, including breast, colon, head/neck, and neuroblastoma (Investigator’s brochure). 
 
TPI 287 has been investigated in 2 phase 1 clinical trials. The initial phase 1 clinical trial used 
the once weekly for 3 weeks with the fourth week off treatment schedule in subjects with 
recurrent or refractory cancers. In this study, 48 patients were enrolled and the MTD of weekly 
TPI 287 was determined to be 127.5 mg/m2. Another phase I trial of single agent TPI 287, 
investigated once every 3 week treatment schedule in 21 patients. In this schedule MTD was 160 
mg/m2. Overall, the most frequent adverse events (≥10%) considered possibly, probably, or 
definitely related to TPI 287 were peripheral neuropathy (48%), anemia (38%), diarrhea (29%), 
neutropenia and nausea (24%), fatigue and myalgia (19%), vomiting, asthenia, pyrexia, 
neuropathy, and alopecia (14%), and leukopenia, thrombocytopenia, abdominal pain, 
constipation, anorexia, back pain, bone pain, pain in extremity, hypoesthesia, and flushing (10%) 
(Investigator’s brochure). 
 
TPI 287 is a poor substrate for P-gp efflux pump resulting in high brain-to-plasma ratios in the 
animal models. Brain-to-plasma ratio of this agent after a single injection were as high as 63.8 in 
the rat and 14.1 in the mouse. Moreover, when used in preclinical model of brain metastasis from 
breast cancer, TPI 287 resulted in 55% reduction in the formation of large brain metastasis from 
breast cancer.9 Hence, this agent rises as a promising compound for treatment of patients with 
brain metastasis from primary tumors such as breast and non-small cell lung cancer which are 
deemed taxane-sensitive. 
 
 

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2.3 Concurrent Radiotherapy with TPI 287 
 
First generation taxanes are potent radiosensitizers and have been widely used as radiosensitizers 
in various tumors.
10,11 Preclinical data have shown that taxanes can enhance radiation sensitivity 
through two major mechanisms: reoxygenation of radioresistant hypoxic cells and cell arrest in 
in the radiosensitive G2/M phase of the cell cycle.
12 In vivo studies have shown that taxanes can 
strongly enhance tumor radioresponse, producing enhancement factors of 1.2 to more than 2.0. 
12. Concurrent use of docetaxel and paclitaxel with radiation therapy has shown to be feasible 
and clinically beneficial in treatment of wide range of malignancies including non-small cell 
lung cancer, nasopharyngeal cancer, esophageal squamous cell cancer, bladder cancer, and 
gynecologic cancers.13-20 RTOG-9705 trial has studied the use of postoperative adjuvant 
paclitaxel/carboplatin concurrent with thoracic radiotherapy in resected stage II and IIIA non-
small cell lung cancer. 
21 This phase II trial showed that concurrent use of paclitaxel/carboplatin 
with radiation therapy to lung is safe and increases progression free survival and overall survival 
in this group of patients. 
21 Similar results have been demonstrated in another phase II trial by 
Feigenberg et al.22 Based on these trials concurrent thoracic radiotherapy with 
paclitaxel/carboplatin has been recommended by NCCN guidelines (version 4.2014) for 
treatment of resected stage II and IIIA non-small cell lung cancer. 
Concurrent chemoradiotherapy to brain has been shown to be feasible and safe and has been 
established as standard of care for treatment of primary brain tumors such as glioblastoma.
23 
However, this potential treatment strategy has not been well developed for metastatic brain 
disease. 
Given the failure rate of FSRT in treating brain metastasis, concurrent chemoradiotherapy could 
be a potential treatment strategy to overcome resistance to radiotherapy alone. However, brain 
tissue penetrance has been the limiting factor for the use of taxanes in this setting. With current 
evidence showing promising data on brain concentration of TPI 287, it would be of great interest 
to investigate radiosensitizing effect of this agent when used concurrently with radiation therapy 
for metastatic brain lesions. 
 
2.4 Rationale 
 
In summary brain metastases are grave and challenging complication in patients with metastatic 
breast and NSCL cancer and result in limited survival. TPI 287 possesses a favorable efficacy 
and pharmacokinetic profile in pre-clinical models. TPI 287 has been observed preclinically to 
cross the blood-brain barrier and reach a notable concentration in brain tissue and cerebrospinal 
fluid.
9 Furthermore, the use of TPI 287 has resulted in reduction of brain metastasis formation in 
animal models of breast cancer.9 
 
Based on available safety pharmacology, toxicology and pharmacokinetic data from phase 1 
study of TPI 287, it can be concluded that TPI 287 has been adequately characterized to support 
the initiation of this phase 1 trial in combination with radiation in patients with metastatic brain 
lesions from breast and NSCL cancers. 
 
If the combination is tolerable, further studies of efficacy will be warranted to assess whether the 

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addition of TPI 287 can potentially increase tumor response, maintain neurologic function, 
improve quality of life, and extend survival. 
 
2.5 Correlative Studies Background 
 
Pharmacokinetic data in animal models indicate that TPI 287 crosses the blood brain barrier and 
reaches the brain tissue and cerebrospinal fluid (CSF).
9 However, the permeability of this 
compound through blood-brain barrier has not been investigated in human studies.  
 
3. PATIENT SELECTION 
 
3.1 Eligibility Criteria  
 
 Patients must have histologically or cytologically confirmed non-central nervous     
system primary breast or non-small cell lung cancer. 
 
 Patients must have pathologically or radiologically confirmed metastatic disease in the 
brain.  
 
 Patients with up to 3 brain metastases (symptomatic and non-symptomatic) can be treated 
on this study. Maximum diameter of each brain lesion should be ≤ 5 cm. Maximum 
tumor volume ≤ 120 cc 
 
 Age ≥18 years. 
 
 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
 Life expectancy of greater than 12 weeks. 
 
 Patients requiring treatment with corticosteroids are eligible. 
 
 Treatment with non-enzyme inducing anti-seizure medications is allowed. 
 
 Patients must have normal organ and marrow function as defined below: 
 leukocytes ≥3,000/mcL 
 absolute neutrophil count ≥1,500/mcL 
 platelets ≥100,000/mcL 
 total bilirubin within normal institutional limits 
 AS T(SGOT)/ALT (SGPT) ≤2.5 × institutional upper limit of normal 
 creatinine within normal institutional limits  OR 
 calculated creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
   
 Systemic chemotherapy washout period ≥ 7 days. For investigational dugs and 
monoclonal antibodies washout period ≥ 5x drug half-life. There are no limitations on 

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number of prior treatment regimens. 
 
 The effects of TPI 287on the developing human fetus is unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, 
and 4 months after completion of TPI 287 administration. 
 
 Prior brain surgery or radiation is allowed as long as the metastatic lesion(s) to be 
targeted in this study has not previously been treated with radiation. 
  
 Ability to understand and the willingness to sign a written informed consent document. 
              
3.2 Exclusion Criteria 
 
 Patients who have had chemotherapy within 1 week (6 weeks for nitrosoureas or 
mitomycin C) or investigational therapies/monoclonal antibodies within 5 half-life of 
investigational compound or those who have not recovered from adverse events due to 
agents administered more than 1 week earlier. Bisphosphonates, endocrine therapy, and 
trastuzumab are permitted without restriction. 
 
 Patients who are receiving any other investigational agents. 
 
 Previous treatment of the target lesions with radiation therapy. 
 
 Patients who have previously been treated with whole brain radiation. 
 
 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to TPI 287. 
 
 Pregnant women are excluded from this study because TPI 287 is an agent with an 
unknown but potential risk for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with TPI 287, breastfeeding should be discontinued if the mother is treated 
with TPI 287. 
 
 Known contraindication to enhanced MRI and CT scan. 
 

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 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
uncontrolled seizure activity or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.3 Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. INFORMED CONSENT PROCESS 
 
Eligible patients will be evaluated by a multi-disciplinary team composed of radiation 
oncologists, neurosurgeons, and a medical oncologist. During their visit, either a physician or a 
research coordinator will explain the study to the patient. Informed consent form will be 
provided and if the patient agrees to participate, signed consent form will be obtained prior to 
participation. 
 
Following registration, patients should begin protocol treatment within 7 days. If a patient does 
not receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.   
 
 
 
5. TREATMENT PLAN 
 
5.1 Pre-Treatment Evaluation 
                   
Patients will be evaluated by a multi-disciplinary team composed of medical/neuro oncologists, 
radiation oncologists, and neurosurgeons to assess for their eligibility. Patient’s oncologic 
history, presenting symptoms, physical examination, pathology, extent of systemic disease, and 
imaging studies will be reviewed. 
 
5.2 Fractionated stereotactic radiotherapy (FSRT) 
 
Brain metastases will be delineated by gadolinium enhanced magnetic resonance imaging (MRI) 
(Siemens Sonata, Siemens Medical Systems, Erlangen, Germany) with 1 mm slices for treatment 
planning purposes performed within 2 weeks prior to the delivery of radiation (MRI Novalis 
protocol). If MRI Novalis is not possible, CT scan of the brain with contrast or other suitable 
MRI scan brain may be used for delineation of the brain metastases. Patient immobilization will 
be achieved by using a commercially available frameless head mask fixation system 
(BrainlabAG, Feldkirchen, Germany). The image planning data set will be co-registered and 
fused with 1-2mm slice thickness computed tomography (CT) imaging (General Electric 
Medical System, Milwaukee, WI) obtained at simulation. The gross tumor volume (GTV) will be 
designated by the edge of the tumor. The planning target volume (PTV) will include a 1 mm 

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expansion on the GTV. The prescription dose will be 25 Gy in 5 daily fractions delivered to the 
PTV. Planning will take place with the BrainLab treatment planning system and FSRT will be 
delivered via the Novalis linear accelerator with robotic table. Doses will be prescribed to ensure 
coverage of at least 95% of the PTV with the prescription dose. The maximum dose will not 
exceed 115% of the prescription dose. Treatments will be delivered using dynamic conformal 
arcs or intensity modulated radiotherapy (IMRT). 
 
5.3 Drug therapy 
 
TPI 287 will be administered on an outpatient basis. Reported adverse events and potential risks 
are described in Section 7. Appropriate dose modifications are described in Section 6.   
 
TPI 287 Administrations 
TPI 287 will be administered as an intravenous infusion over 60 minutes. A window of ± 15 
minutes will be permitted. 
 
Patients will receive the TPI 287 once per week, for total of 3 doses. Treatment with TPI 287 
will start the same day of starting FSRT treatment. 
On the day of FSRT, TPI 287 will be given 4 (+/-2) hours prior to FSRT. 
 
In order to prevent any potential hypersensitivity reactions, all subjects must be premedicated 
prior to TPI 287 administration. The following drugs and dosing regimens are provided as 
guidelines for premedication, which must include a corticosteroid, an antihistamine, and an H2 
blocker. The concomitant use of steroids in some subjects should be considered in determining 
the dose of an additional corticosteroid. Oral (PO) dosing as an alternative to IV dosing for 
premedication is acceptable where appropriate.  
 
Premedication Regimen 
Dexamethasone* 20 mg PO at 12 hours prior and 20 mg PO at 6 hours prior 
Diphenhydramine 50 mg IV push prior 
H2 blocker 
IV prior (e.g., Cimetidine 300 mg) 
*In the event that dexamethasone is not available, methylprednisolone may be 
substituted at an equivalent dose (4 mg methylprednisolone = 0.75 mg dexamethasone). 
 
Subjects will be closely monitored for signs and symptoms of a hypersensitivity reaction during 
the entire infusion of TPI 287, and 1 hour after completion of TPI 287 infusion. Vital signs will 
be measured every 30 minutes. If a mild-to-moderate (Grade 1 to 2) hypersensitivity reaction is 
observed, the TPI 287 infusion will be interrupted. Patient will receive intravenous 
diphenhydramine 50 mg, hydrocortisone IV 100 mg, and appropriate supportive care until the 
symptoms resolve. If the signs and symptoms resolve within 1 hour, the TPI 287 infusion will be 
restarted at a slower infusion rate (half that of the initial attempt), and this slower infusion rate 
will be used for the remainder of the trial. If the symptoms take longer to resolve, the infusion 
will not be restarted, and the next dose of TPI 287 will be administered 1 week after the 

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interrupted dose at a slower infusion rate (half of the rate at which hypersensitivity reaction 
occurred) pending all signs and symptoms of hypersensitivity have resolved. 
If a ≥ Grade 3 hypersensitivity reaction is observed, the TPI 287 infusion will be stopped and 
appropriate supportive care administered until the symptoms resolve. The subject will be 
discontinued from the trial. 
 
Dose Definition 
 
Dose Escalation Phase: 
 
The starting dose (i.e., dose level 1) will be 14 mg/m2 /dose. Provided that MTD has not been 
reached, the TPI 287 dose will be increased as follows: 
 
Table 1. Dose Escalation Schedule 
                                              Dose Escalation Schedule 
Dose Level 
Dose 
TPI 287 IV  
Radiotherapy 
Level -2 
5 mg/m2/dose 
5 Gy daily fraction 
Level -1 
7 mg/m2/dose 
5 Gy daily fraction 
Level 1 
14 mg/m2/dose
 
5 Gy daily fraction 
Level 2 
28 mg/m2/dose
 
5 Gy daily fraction 
Level 3 
56 mg/m2/dose
 
5 Gy daily fraction 
Level 4 
85 mg/m2/dose 
5 Gy daily fraction 
Level 5 
113 mg/m2/dose 
5 Gy daily fraction 
Level 6 
127.5 mg/m2/dose 
5 Gy daily fraction 
 
If dose level 1 is found to cause unacceptable toxicity, the dose will be de-escalated to 
levels -1 or -2.  
 
Dose Expansion Phase: 
 
The TPI 287 dose used in the dose expansion cohort will be MTD determined from the dose 
escalation phase. TPI 287 will be administered intravenously prior to treatment of brain 
metastasis with FSRT on day 1 and will be given for 2 more weekly doses. The prescription dose 
of FSRT will be 25 Gy in 5 daily fractions as described in section 5.2. 
 

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Definition of Maximum Tolerated Dose: 
 
The maximum tolerated dose (MTD) is the highest dose of TPI 287 that does not cause 
unacceptable toxicity in more than one of six patients at that dose level. The MTD is defined as 
one dose level below the highest toxic dose (i.e., the DLT dose). 
 
5.4 Definition of Dose-Limiting Toxicity 
 
Toxicities will be graded in severity according to the guidelines outlined in the NCI-CTCAE 
version 4.0. Dose limiting CNS and non-CNS (hematologic and non-hematologic) toxicities will 
be defined differently and will be based on events that occur during the study period. In order to 
be declared as dose-limiting toxicity, an adverse event must be related (definite, probable, or 
possible) to study treatment. 
 
A dose-limiting toxicity (DLT) will be defined as any one of the following adverse events 
occurring within 8 weeks from last dose of radiation therapy: 
 
     CNS toxicities: 
 
      Acute CNS toxicities (occurring ≤ 30 days after completing FSRT treatment):  
 Any grade 3 or higher central nervous adverse events including but not limited to 
headache, dizziness, vertigo, new onset seizures, cerebral edema, cerebral 
hemorrhage, and new onset neurologic deficit. 
 
      Delayed onset CNS toxicities (occurring >30 days after completing FSRT treatment): 
 Any grade 3 or 4 adverse event arising within the irradiated volume including but 
not limited to radiation necrosis or focal neurological deficits. 
 
 
      Non-CNS toxicities: 
 
      Non-hematologic toxicities: 
 
 Any grade 3 or higher non-hematologic adverse event with the exception of 
alopecia, fatigue, and anorexia. 
 
 Grade 3 or higher nausea and/or vomiting that persists ≥ 48 hours despite optimal 
medical management. 
 
       Hematologic toxicities:       
 Grade 4 neutropenia lasting for ≥ 7 days in duration 
 
 Grade ≥ 3 febrile neutropenia with/without infection 
 

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 Grade 4 thrombocytopenia 
 
 
Dose escalation will be determined based on the occurrence of DLTs. For the purposes of 
determining whether to advance the dose levels, DLTs will be counted by patient. In the event of 
the development of any grade 3 or 4 toxicity felt to be at least possibly related to study drug, TPI 
287 will be held until resolution to grade 1 or baseline assuming that occurs within 15 day 
window. 
 
Dose escalation will follow the standard 3+3 design. The enrollment to next higher dose level 
will be delayed for 8 weeks after the completion of FSRT by the last patient enrolled at the dose 
level. This period of 8 weeks will allow monitoring potential delayed toxicities. Management 
and dose modifications associated with the above adverse events are outlined in Section 6. Dose 
escalation will proceed according to the following scheme.  Dose-limiting toxicity (DLT) is 
defined above.   
 
     Table 2. Dose Escalation Rules  
 
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be entered 
at the next lowest dose level if only 3 patients were treated 
previously at that dose. 
1 out of 3 
or 
≥ 2 grade 2 CNS toxicities 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
 If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the dose to be used in the expanded cohort and will 
be considered recommended phase 2 dose. At least 6 
patients must be entered at this dose. 
 
If dose level 1 is found to cause unacceptable toxicity, the dose will be de-escalated to level -1 (7 
mg/m2). Three patients will be enrolled at dose level -1. If no DLT is observed, three additional 
patients will be enrolled at dose level -1 such that safety is established in at least 6 patients prior 
to entering dose expansion phase. 

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Any delayed CNS-toxicity arising within the radiation field but seen beyond the window for 
DLT registration (> 8weeks following completion of FSRT) will be recorded. Furthermore, 
occurrence of any delayed-onset treatment related grade 3 or higher central nervous toxicity at 
any time (during and after DLT period of 8 weeks) will lead to holding dose-escalation and 
adding 3 patients to the dose level at which toxicity has occurred. Occurrence of additional 
delayed-onset treatment related grade 3 or higher CNS- toxicity will be reviewed with Protocol 
Monitoring Committee and IRB to determine whether discontinuation or modification of trial is 
subsequently warranted. 
 
 
5.5 General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of TPI 287 with other concomitantly administered 
drugs through the cytochrome P450 system, the use of drugs or herbal supplements that are 
known to be strong inhibitors/inducers of CYP3A4 and CYP2C8 are not permitted (Appendix 
B).  
Prophylactic use of corticosteroids is allowed during the study to limit symptoms from 
metastases or radiation.  
Non-enzyme inducing anti-epileptic drugs may be utilized to control or prevent seizures. 
Principal Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential to affect selected CYP450 isoenzymes.   
 
5.6 Duration of Therapy 
 
Patients will receive TPI 287 on days 1, 8, and 15 (total of 3 doses). On day 1, the TPI 287 will 
be administered 4 (+/- 2) hours prior to FSRT.  
 
 
5.7 Duration of Follow Up 
 
Patients will be seen in follow-up on the 3rd, 6
th, 9
th, 12
th, 15
th, and 18
th   month following the first 
day of treatment with TPI 287. Patients will be followed for 18 months after first treatment on 
study or until death, whichever occurs first.   
The following will be obtained at pre-treatment evaluation and at each follow up visit: 
Symptoms history, vital signs/ height and weight, physical examination, KPS/ECOG score, 
Mini-Mental State Examination, steroid use, quality of life questionnaire, and toxicity 
evaluation. 
Radiologic assessment, MRI brain with and without gadolinium, will be performed at pre-
treatment and every three months following the end of treatment until the patient is off-study or 
reaches the 18 month study completion date. 
Furthermore, the principal investigator will have close collaboration with oncologists treating the 
systemic malignancy. Information regarding the status of systemic malignancy such as results of 
standard imaging evaluations, serum biomarkers measurements, and systemic treatments will be 
collected and recorded at each visit. 

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5.8 Criteria for Removal from Study 
 
Patients will be removed from study when any of the below criteria applies: 
 
 Disease progression requiring therapy not allowed in the protocol, including whole brain 
radiation. 
 
 Intercurrent illness that prevents further administration of treatment: a condition, injury, 
or disease unrelated to cancer, that renders TPI 287 or radiation treatment unsafe  or 
regular study visits impossible, including, but not limited to, active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
pregnancy, or psychiatric illness that would limit compliance with study requirements. 
 
 Unacceptable adverse event(s) (see adverse events) 
 
 Patient decides to withdraw from the study 
 
 General or specific changes in the patient’s condition that render the patient ineligible for 
the study 
 
 Non-compliance with study treatment or protocol-required evaluations and study visits 
 
 Inability of subject to comply with study requirements 
 
 Determination by the investigator that it is no longer safe for the patient to continue 
therapy 
 
 Patient who inadvertently becomes pregnant (see reporting of pregnancy) 
  
Patients may withdraw at any time or be dropped from the study at the discretion of investigator 
should any untoward effects occur. In addition, a patient may be withdrawn by the investigator if 
he/she violates the study plan or for administrative and/or other safety reasons. The investigator 
or study coordinator must notify Cortice Biosciences immediately when a patient has been 
discontinued/withdrawn due to a serious adverse experience. All trial treatment-related toxicities 
and SAEs at the time of discontinuation/withdrawal should be followed until resolution or 
stabilization. Patients who are discontinued from the study will still be followed for disease 
progression. 
 
All deaths that occur within the trial period or within 30 days after administration of the last dose 
of trial drug must be reported to Cortice Biosciences for the purposes of serious adverse event 
(SAE) reporting; however, deaths due to progression are not SAEs. 
 
Patients who discontinue from the study for reasons unrelated to the study (e.g., personal 

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reasons, or adverse events after registration but prior to receiving study therapy) may be replaced 
as required for the study to meet its objective. The replacement will generally receive the same 
treatment or treatment sequence (as appropriate) as the allocation number replaced.  
 
5.9 Stopping Rules 
 
The expected rate of neurologic death with FSRT alone is 13-14%. 
24,25 The reported rate for 
symptomatic radiation necrosis is 7.7%. 24 A higher rate of neurologic death (> 14%) or 
symptomatic brain necrosis (> 10%) in this study would imply that the combination of FSRT and 
TPI 287 is excessively toxic and not suitable for further clinical development. In addition grade ≥ 
3 delayed-onset toxicity in this study would imply that the combination of FSRT and TPI 287 is 
excessively toxic and not suitable for further clinical development. In such condition, the results 
will be discussed with Cortice Bioscience, Protocol Monitoring Committee and IRB and study 
will be closed. In addition, occurrence of other delayed-onset treatment related grade 3 or higher 
CNS- toxicity will be monitored closely and reviewed with Protocol Monitoring Committee and 
IRB to determine whether discontinuation of trial is subsequently warranted. 
 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS/TREATMENT DISCONTINUATION 
 
  Table 3. Dose Levels for Dose Modification of TPI 287 
 
Dose Level 
TPI 287 Dose 
-2 
5 mg/m2/dose 
-1 
7 mg/m2/dose 
1 
14 mg/m2/dose 
2 
28 mg/m2/dose 
3 
56 mg/m2/dose 
4 
85 mg/m2/dose 
5 
113 mg/m2/dose 
6 
127.5 mg/m2/dose 
Below are dose modification tables for the following adverse events:  nausea, vomiting, diarrhea, 
neutropenia, and thrombocytopenia: 
 
   Table 4. Management of Nausea 
Nausea 
Management/Next Dose for TPI 287 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.* 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management:  antiemetics. 
 

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Table 5. Management of Vomiting 
Vomiting 
Management/Next Dose for TPI 287 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated. 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management:  antiemetics. 
 
     Table 6. Management of Diarrhea 
Diarrhea 
Management/Next Dose for TPI 287 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.* 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
     Table 7. Management of Neutropenia 
Neutropenia 
Management/Next Dose for TPI 287 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated. 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 Table 8. Management of Thrombocytopenia 
Thrombocytopenia 
Management/Next Dose for TPI 287 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.* 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
Infusion interruption is required if a subject experiences a hypersensitivity reaction. A ≥ Grade 3 
hypersensitivity reaction requires discontinuation. A mild-to-moderate hypersensitivity reaction 
requires that the infusion rate be slowed (half that of the initial attempt) for the remainder of the 
trial. The infusion is restarted within 1 hour if the mild-to-moderate signs and symptoms resolve 
or, if the symptoms take longer to resolve, the infusion is not restarted and the next dose is 1 
week at the slower rate. 
 

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For each patient, a maximum of one (1) dose reduction of TPI 287 will be allowed after which 
the patient will be discontinued from the study treatment. If, after interruption of treatment and 
resolution, treatment is resumed at the same dose and the same toxicity reoccurs with the same 
severity, next treatment re-initiation must resume at the next dose level irrespective of duration. 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease experienced 
by a study participant while in a clinical study, whether or not considered related to the 
investigational product.  Examples include:  reactions or side effects, a pre-existing condition 
that worsens in severity or frequency, a concurrent illness, an injury, or a clinically significant 
laboratory abnormality. 
 
7.1 Potential Adverse Events 
 
7.1.1 Radiation  
 
 
 Early (≤ 30 days from treatment): Expected adverse events include fatigue, 
headache, neck pain, nausea and vomiting, and lethargy. 
 
 Late (> 30 days from treatment): Possible adverse events include focal neurologic 
deficits, memory difficulties, dementia, radiation necrosis, and radiation induced 
neoplasms. 
 
7.1.2 TPI 287 
 
 
Adverse events (AEs) listed as possibly, probably, or definitely related to TPI 287 for the 
single agent trials irrespective of dose level and schedule are summarized below by 
system organ class: 
 
 Blood and Lymphatic System Disorders: anaemia, leukopenia, lymphopenia, 
neutropenia, thrombocytopenia  
 
 Cardiac Disorders: tachycardia  
 
 Gastrointestinal Disorders: abdominal pain, abdominal pain lower, abdominal pain 
upper,  ascites, constipation, diarrhoea, dyspepsia, dysphagia, flatulence, gastroenteritis, 
gastrointestinal bleed, 
mucositis, nausea, oral pain, stomach discomfort,                         
stomatitis, vomiting  
 
 General Disorders and Administration Site Conditions: asthenia, chest discomfort, 
chest pain, chills, clinical progression, difficulty in walking, disease  progression                         
with higher than expected speed of progression, face edema, fatigue, gait disturbance, 
mucosal inflammation, edema peripheral, pain, pyrexia 
 

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 Hepatobiliary Disorders: hepatic pain, hyperbilirubinaemia  
 
 Immune System Disorders: anaphylactic reaction, hypersensitivity  
 
 Infections and Infestations: bacterial sepsis, Candidiasis, enterococcal infection, eye 
infection, Herpes zoster, infection 
 
 Injury, Poisoning and Procedural Complications: Head injury  
 
 Investigations: ALT increased, AST increased, blood ALP increased, blood bilirubin  
increased, gamma-glutamyltransferase increased, granulocyte count decreased,  
haemoglobin decreased, neutrophil count decreased, protein urine, protein urine 
present, white blood cell count decreased  
 
 Metabolism and Nutrition Disorders: anorexia, decreased appetite, dehydration, failure 
to  thrive, hypokalaemia, hyponatraemia  
 
 Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain, bone pain, 
facial muscle weakness, muscle spasms, muscular weakness, musculoskeletal pain, 
myalgia, pain in extremity  
 
 Nervous System Disorders: amnesia, balance disorder, disturbance in attention, 
dizziness,  dysarthria, headache, hypoaesthesia, motor neuropathy, neuropathic pain,                          
neuropathy, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, peroneal 
nerve palsy  
 
 Psychiatric Disorders: anxiety, confusion, insomnia, sleep disorder  
 
 Renal and Urinary Disorders: dysuria, haematuria, nephrolithiasis, renal failure, 
urinary incontinence  
 
 Reproductive System and Breast Disorders: vaginal haemorrhage  
 
 Respiratory, Thoracic and Mediastinal Disorders: cough, dysphonia, dyspnoea,  
pharyngolaryngeal pain, pneumonia, pulmonary embolism, rhinorrhoea  
 
 Skin and Subcutaneous Tissue Disorders: acne, alopecia, dry skin, hyperhidrosis,   
hypotrichosis, night sweats, pigmentation disorder, rash, skin chapped, skin exfoliation  
 
 Vascular Disorders: deep vein thrombosis, flushing, hypotension, orthostatic 
hypotension 
     
In a phase I trial of TPI 287 administered weekly for 3 weeks, the most frequent AEs (≥10%)            
considered possibly, probably, or definitely related to TPI 287 were fatigue (40%), nausea 

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(29%), diarrhoea (21%), anaemia and neuropathy (19%), neuropathy peripheral (17%), vomiting 
and anorexia (15%), dyspnoea (13%), and dehydration, myalgia, and constipation (10%). 
             
7.2 Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  
http://ctep.cancer.gov/protocolDevelopment/electronicapplications/ctc.htm. 
 
 
 Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
For this study, adverse events that are considered by the Investigator to have a Possible, 
Probable, or Definite relationship to the investigational product are considered to be related to 
the investigational product. 
 
 
7.3 Recording & Reporting Adverse Events 
 
AEs will be listed by patient ID number.  Deaths and other SAEs will be listed and summarized 
by patient ID number and treatment duration.  Additionally, AEs leading to discontinuations will 
be listed separately.  Incidence of AEs will be summarized by preferred term, maximum grade 
reported, and relationship to study treatment. 
 
Adverse events should only be recorded by an investigator or by a health-care provider qualified 
by training and experience.  Patients should be asked in an open-ended manner about the 
occurrence of AEs.   
 
Adverse events will be captured starting from day 1 of receiving TPI 287. 
 
Grade 1 and 2 toxicities unrelated to study treatment will not be captured. 
 

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  7.4 Adverse Event Reporting Period 
Adverse events reporting period will start from day 1 of receiving TPI 287 until the last day of 
patient’s participation in study. 
 
 
7.5 Immediate Reporting of Serious Adverse Event  
 
Any serious adverse event including, death due to any cause, pregnancy, which occurs to any 
patient treated on study or within 30 days following cessation of treatment, whether or not 
related to the investigational product, must be reported to Cortice Biosciences within 24 hours.  
 
It is the Investigator’s responsibility to report serious adverse events to the regulatory agencies 
and Institutional Review Board (IRB) according to the requirements of the IRB/IEC. 
 
Additionally, any serious adverse event considered by an investigator to be possibly, probably, or 
definitely related to the study treatment that is brought up to the attention of the investigator at 
any time outside of the time period specified in Table.9 must be reported immediately to Cortice 
Biosciences. 
 
All patients with serious adverse events must be followed up for outcome. 
 
Serious Adverse Events (SAE) are: 
 
Any untoward medical occurrences that at any dose: 
 
 Results in death 
 Is life threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity, or,  
 Is a congenital anomaly/birth defect 
 
The onset date of an SAE is defined as the date on which it met the criteria for an SAE; e.g., the 
date of admission to a hospital.  The end date is the date on which it no longer met the criteria for 
an SAE, e.g., the date that the patient was discharged from a hospital. 
 
 
Expedited Reporting Guidelines 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below. Attribution to treatment or other cause must be provided. 
 
    Table 9. Expedited Reporting Requirements for Adverse Events that Occur within 30    

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                   Days of the Last Administration of TPI 287
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR 
Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention 
(21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to 
the Cortice bioscience within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of 
the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE. 
Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 

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 Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
7.6 Second Malignancy 
 
Second malignancies require routine reporting to Cortice Bioscience. 
 
7.7 Pregnancy 
 
If a patient inadvertently becomes pregnant while on treatment with TPI 287, the patient will 
immediately be removed from the study. The site will contact the patient at least monthly and 
document the patient’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to Cortice Biosciences without delay and within 24 
hours if the outcome is a serious adverse event (e.g., death, abortion, congenital anomaly, or 
other disabling or life threatening complication to the mother or newborn). If a male patient’s 
partner becomes pregnant on study, the pregnancy must be reported to Cortice Biosciences. The 
study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or new born to Cortice Biosciences. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with TPI 287 administered in this study 
can be found in Section 7.1.2. 
 
Metabolism 
In vitro studies have shown that TPI 287 is rapidly metabolized by pooled human S-9 liver 
fractions with an elimination half-life (t1/2) of 58.5 minutes. Seven putative phase 1 
(modification) metabolites were detected. Structures of the two main metabolites (TPI 511 and 
TPI 513) were confirmed to be dihydroxyl and epoxy derivatives. Based on this and the well-
established metabolism of other taxanes by cytochrome P450 3A4 (CYP3A4) and cytochrome 
P450 2C8 (CYP2C8), the use of drugs or herbal supplements that are known to be strong 
inhibitors/inducers of CYP3A4 and CYP2C8 are not permitted (Investigator’s Brochure). 
 
Supply/Storage 
TPI 287 Injection should be stored in the provided packaging (vial) in the upright position, at 
room temperature (between 68-77°F; 20-25°C) away from direct sunlight. TPI 287 Injection 
must be diluted prior to administration.  TPI 287 injection, 10 mg/mL that has been diluted in the 
IV bag of 0.9% Sodium Chloride, should be stored at room temperature. The diluted   TPI 287 
must be prepared within 12 hours of use. 
 
9. CORRELATIVE  STUDIES 
 

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9.1 Laboratory Correlative Studies  
 
PK studies are optional. However, efforts will be made to obtain PK analysis from at least one  
patient per dose level. 
 
Cerebrospinal Fluid (CSF) PK 
CSF samples will be collected 2-3 hours after completion of TP 287 infusion on day 8 of 
treatment given there is no contraindication for lumbar puncture. 
Patient will undergo lumbar puncture in department of interventional radiology. Procedure will  
be performed under fluoroscopy.  
PK analysis will be performed at Moffitt Cancer Center. 
Serum PK 
Blood will be collected at the same time as lumbar puncture (2-3 hours post-infusion of TPI 287) 
on day 8 of treatment. 
The blood samples will be processed to plasma and the concentration of TPI 287 will be  
determined using a validated liquid chromatography/tandem mass spectrometry (LC/MS-MS)  
method at Moffitt Cancer Center. 
 
CSF/Plasma TPI concentration ratio will be calculated. 
 

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10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  MRI 
scans must be done <2 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
a  Radiotherapy will be delivered once daily Monday through Friday, D1-5 for a total of 5 treatments. 
b  Baseline symptoms include symptoms occurring on D1 prior to receiving TPI 287 and within 1 week prior. 
c Blood will include CBC and differential, sodium, potassium, chloride, creatinine, AST, ALT, bilirubin, ALP, 
albumin, calcium, magnesium, phosphate. 
d Radiologic assessment, MRI brain with and without gadolinium, will be performed at pre-treatment and every 
three months following the end of treatment until the patient is off-study or reaches the 18 month study completion 
date. 
e PK samples (blood and CSF) will be collected on D8. 
fA final visit will be performed approximately 30 days following completion of treatment  with FSRT and/or TPI-
287 (whichever treatment occurs last). 
g Information pertaining to survival and long term assessment of the subject’s disease status and adverse events will 
be collected approximately every 12 weeks beginning after the final visit for period of up to 18 months.
  
 
Baseline 
Concurrent 
phase 
Single agent 
phase 
Final 
f 
 
Follow up g 
D1 
D8 
D15 
TPI-287 infusion 
 
X 
X 
X 
 
 
XRT a 
 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
History and  Con-meds 
X 
X 
X 
X 
X 
X 
Baseline Symptoms b 
X 
 
 
 
 
 
Performance status (Karnofsky 
performance status/ECOG) 
X 
X 
X 
X 
X 
X 
Physical Examination (including 
neurological assessment) 
X 
X 
X 
X 
X 
X 
Vital signs and Height/Weight 
X 
X 
X 
X 
X 
X 
Documenting status of systemic 
disease 
X 
X 
X 
X 
X 
X 
Adverse event evaluation 
 
X 
X 
X 
X 
X 
Quality of life assessment 
( QLQ-BN20 and QLQ-C15-PAL  ) 
X 
X 
X 
X 
X 
X 
Steroid use assessment 
X 
X 
X 
X 
X 
X 
Blood 
 c 
X 
X 
X 
X 
X 
 
B-HCG  
X 
 
 
 
 
 
Radiological assessment 
 d 
X 
 
 
 
 
X 
PK samples
 e 
 
 
X 
 
 
 
Mini-Mental State Examination 
X 
X 
X 
X 
X 
X 
Lumbar puncture 
 
 
X 
 
 
 

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11. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria.  For the purposes of this study, patients should be re-evaluated 
every 3 months.  The serial MRI scans shall be examined at the institution by an independent 
reviewer, a neuroradiologist. The evaluation of scans will be compared to and corrected with the 
patient’s clinical course. In addition to a baseline brain MRI, confirmatory MRIs will also be 
obtained 4 weeks following initial documentation of an objective response. 
 
11.1 Antitumor Effect  
 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with TPI 287. 
 
Evaluable for objective response.  Only those patients who have received at least one 
dose of TPI 287 concurrent with FSRT, and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.   
 
Methods for Evaluation 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 2 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  
 
Evaluation of Target Lesions 
 
Complete Response (CR):  The tumor is no longer seen on two sequential MRI scans, 
and the patient is on no steroids or only adrenal-maintenance dose of steroids.  
 
Partial Response (PR):  ≥ 50% decrease in the product of two diameters of target 
lesions on two sequential MRIs, taking as reference the baseline product of two 
diameters, provided that the patient has not had his/her dose of steroids increased 
since the last evaluation period. 
 
Minor Response (MR): Decrease in diameter products of < 50% on two sequential 
MRI scans provided that the patient has not had his/her dose of steroids increased 
since the last evaluation. 

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Stable Disease (SD):  The scan shows no change, taking as reference the smallest 
product of diameters while on study. Patient should be receiving stable or decreasing 
doses of steroids. 
 
Progressive Disease (PD):  > 25% increase in the product of two diameters of target 
lesions; taking as reference the smallest product on study (this includes the baseline 
product if that is the smallest on study), provided that the patient has not had his/her 
dose of steroids decreased since the last evaluation period. A concomitant decrease in 
steroid dose will rule out a progression designation at this point. The appearance of 
one or more new lesions is also considered progressions. 
 
Furthermore, the response will be also measured with RANO working group criteria 
for metastatic brain tumors when this guideline is published. 
 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.2 Criteria for Evaluation of Therapy Effectiveness 
 
            Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
            Quality of life 
 
Quality of life will be measured using the EORTC QLQ-BN20+2 and QLQ-C15-PAL 
questionnaires. These questionnaires will be given to the patient at the same time points 
as MMSE during the follow up visits. 
 
 

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12. ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 Protocol and Regulatory Compliance 
The Investigator must conduct the study according to this protocol. 
 
The study must be conducted by all Investigators in compliance with Good Clinical Practices 
(GCP) as defined as described in the U.S. FDA Code of Federal Regulations 21 CFR 312 
(Investigational New Drug Application), 21 CFR 50 (Protection of Human Subjects), 21 CFR 54 
(Financial Disclosure by Clinical Investigators), 21 CFR 56 (Institutional Review Boards) and 
ICH guidelines (Guideline to Good Clinical Practice). 
 
The PI of this study is ultimately responsible for every aspect of the design, conduct and actions 
of all members of the research team. This includes the final analysis of the protocol. 
All protocols include a Data Safety Monitoring Plan (DSMP) and procedures for its 
implementation commensurate with the risk and complexity of the study. The DSMP must 
include a structured adverse event determination, monitoring and reporting system, including 
standardized forms and procedures for referring and/or treating subjects experiencing adverse 
events. The plan must include data and safety-monitoring procedures for subjects enrolled who 
may be receiving a part of their protocol-required treatment at community sites. 
The PI of this study will have primary responsibility for ensuring that the protocol is conducted 
as approved by the SRC and IRB. The PI will ensure that the monitoring plan is followed, that all 
data required for oversight of monitoring are accurately reported to a DSMP and/or to the 
Protocol Monitoring Committee (PMC) and IRB as required, that all adverse events are reported 
according to protocol guidelines, and that any adverse actions reflecting patient safety concerns 
are appropriately reported. 
 
12.2 Document Audits and Monitoring 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies.  Monitoring will be performed regularly to verify data is accurate, complete, and 
verifiable from source documents; and the conduct of the trial is in compliance with the currently 
approved protocol/amendments, Good Clinical Practice (GCP), and applicable regulatory 
requirements. 
 
The PMC monitors its assigned ongoing research protocols monthly for: adverse event reporting, 
data and safety monitoring, and internal audit findings. The PMC upon review of any agenda 
item may approve the study for continuation, require revisions, suspend or close a protocol. 
 
Investigators of studies which are designed to be reviewed by the PMC for data and safety 
monitoring, shall provide a statistical report of the study’s progress and summary of adverse 
events and deviations based on the phase of the study and the associated risk of the study or more 
often if applicable. The external DSMP (if applicable) shall forward its report for high-risk 
studies designated for external review at least annually or more often if applicable. 

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12.3 Protocol Amendments 
Any changes to this protocol will be initiated by the investigators or by the Regulatory Sponsor 
(Moffitt cancer Center) as a protocol amendment.  The Investigator must submit the amendment 
to the IRB, with a revised Informed Consent Document if applicable.  The Investigator must 
receive written approval from the IRB before the amendment may take effect. 
 
12.4 Regulatory Binder 
To be in compliance with GCPs, the Investigator must maintain accurate, complete, and 
organized documentation supporting the conduct of the study.  This documentation includes, but 
is not limited to, the following:  study personnel’s qualifications and training, IRB approvals and 
communications, communications with the Regulatory Sponsor, Site Signature & Responsibility 
Log, laboratory accreditations and reference ranges, Form FDA 1572s, and Informed Consent 
Documents (copies of IRB approved versions, signed/dated originals, or copies for all enrolled 
patients). 
 
12.5 Informed Consent 
Prior to the performance of any protocol-specific procedures, informed consent must be obtained 
and documented by the use of a written Informed Consent Document approved by the 
Regulatory Sponsor and the IRB.  The Informed Consent Document must be signed and dated by 
the patient or by the patient’s legally authorized representative and by the person conducting the 
informed consent discussion.  The Informed Consent Document must fulfill the requirements as 
contained in the U.S. Code of Federal Regulations (21 CFR 50.25), the ICH guidelines, and the 
Declaration of Helsinki.    The Informed Consent Document must be written in a language 
understandable to the patient or to the representative. 
 
A signed and dated copy of the Informed Consent Document must be given to the person signing 
the document.  The original must be retained by the Investigator with the study documentation 
and be available for inspection by persons conducting an audit of the study. 
 
Modifications to this template may be made by study site personnel to be in compliance with 
national, regional (e.g., state) or local laws and/or institutional requirements.   
 
12.6 Institutional Review Boards 
The protocol, Informed Consent Document, patient recruitment procedures (e.g., 
advertisements), information about payments and compensation available to patients, and any 
amendments must be approved by a properly constituted IRB in compliance with current 
regulations of the U.S. FDA, ICH guidelines, and any country-specific regulations.     

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12.7 Institutional Review Board/Independent Ethics Committee  
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials/process (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
sponsor should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling, information to be provided to subjects and any updates. The investigator or sponsor 
should provide the IRB/IEC with reports, updates and other information (eg, expedited safety 
reports, amendments and administrative letters) according to regulatory requirements or 
institution procedures. 
 
12.8 Curriculum Vitae and Medical Licenses 
The Principal Investigator is responsible for ensuring that the study is being conducted by 
qualified personnel.  Documentation of these qualifications must be maintained within the 
Regulatory Binder, and includes the following: 
 
Curriculum Vitae (CV):  CVs for the Principal Investigator and all Sub-investigators listed on 
the Form FDA 1572 must be signed and dated.  These CVs must show affiliation with the 
institution conducting the study and be current within two years of the personnel initiating their 
participation in the study. 
 
Medical Licenses:  Medical licenses (physicians, physician assistants, nurses) listed on the Form 
FDA 1572 must be kept current, and copies must be maintained in the Regulatory binder during 
the entire period of the person’s participation in the study. 
 
12.9 Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  Patient medical 
information obtained for the purposes of this study is confidential, and disclosure to third parties, 
other than those noted below, is prohibited.  Patients should be identified only by their initials 
and protocol-assigned patient ID number. For those patients whose surgical specimen is 
processed and read by the central pathology laboratory, the patient’s billing information will be 
requested by this laboratory and will not be shared with the sponsor or any of its affiliates or 
representatives.  
Study personnel should follow the requirements of the Health Insurance Portability and 
Accountability Act (HIPAA). 
 
All clinical information is confidential, but data generated for this study must be available for 
inspection on request to representatives of the U.S. FDA, other national or local regulatory or 
health authorities, Endo Pharmaceuticals representatives, and the associated IRB. 
 
All records must be kept in a secured area. 
 

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12.10 Financial Disclosure 
Documentation of each Investigator’s proprietary or financial interest is required by the U.S. 
Code of Federal Regulations (21 CFR 54).  A financial disclosure form provided by the Sponsor 
must be completed, signed, and dated by the Principal Investigator and each Sub-investigator 
listed on the Form FDA 1572.  This form must be executed prior to the personnel’s participation 
in the study.  The original form will be retained by the Sponsor.  Each Investigator must inform 
the Sponsor of any change in his/her financial interest in the Sponsor for up to one year after the 
end of the study. 
 
13. DATA MANAGEMENT AND RECORD KEEPING 
Data will be maintained by the Moffitt Cancer Center. 
14. STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design/Endpoints 
 
This is a standard 3+3 design and will include 2 cohorts: 1) dose escalation cohort, and 2) dose 
expansion cohort. 
 
                              Endpoints          
 Primary endpoints 
 
   To determine the maximum tolerated dose (MTD) of TPI 287 
given concurrently with FSRT to treat brain metastases from 
advanced breast and  non-small cell lung cancer 
 
   To determine the safety and toxicity of TPI 287 given 
concurrently with FSRT to treat brain metastases from advanced 
breast and  non-small cell lung cancer 
 
 Secondary endpoints 
 
   To determine the local control rate  
   To determine the distant intra-cranial control rate 
   To determine the short-term (≤ 30 days post-treatment) and long-
term (> 30 days post treatment) adverse effects 
   To determine the PFS  
   To evaluate the effect of concurrent therapy with TPI 287 and 
FSRT on measures of quality of life 
 
 

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14.2   
Sample Size/Accrual Rate 
The number of patients needed for doe escalation phase will depend on the number of dose levels 
reached. The maximum size for the dose escalation phase will be 36 patients. In the dose 
expansion phase, a total of 10 patients (including patients treated at the MTD from dose 
escalation phase) will be enrolled to confirm the safety and to assess radiologic response. 
 
     
     14.3          Data Analysis  
 
Data will be summarized overall using descriptive statistics. Continuous data will be summarized 
with number of patients (n), mean, median, minimum, maximum, standard deviation, coefficient 
of variation, and geometric mean (where applicable). Categorical data will be summarized using 
frequency counts and percentages. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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REFERENCES 
 
1.  
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2.  
Kaal EC, Niel CG, Vecht CJ. Therapeutic management of brain metastasis. Lancet 
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3.  
Patchell RA. The management of brain metastases. Cancer treatment reviews. Dec 
2003;29(6):533-540. 
4.  
Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent 
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Nieder C, Berberich W, Schnabel K. Tumor-related prognostic factors for remission of 
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Fokas E, Henzel M, Surber G, Kleinert G, Hamm K, Engenhart-Cabillic R. Stereotactic 
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7.  
Oermann EK, Kress MA, Todd JV, et al. The impact of radiosurgery fractionation and 
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9.  
Fitzgerald DP, Emerson DL, Qian Y, et al. TPI-287, a new taxane family member, 
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therapeutics. Sep 2012;11(9):1959-1967. 
10.  Zhang H, Hyrien O, Pandya KJ, Keng PC, Chen Y. Tumor response kinetics after 
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lung cancer: a model for low-dose chemotherapy radiosensitization. Journal of thoracic 
oncology : official publication of the International Association for the Study of Lung 
Cancer. Jun 2008;3(6):563-568. 
11.  Yoshida T, Tokashiki R, Itoh H, et al. A phase I-II study of bi-weekly docetaxel 
combined with radiation therapy for patients with cancer of the larynx/hypopharynx. 
Japanese journal of clinical oncology. Sep 2007;37(9):641-646. 
12.  
Milas L, Milas MM, Mason KA. Combination of taxanes with radiation: preclinical 
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13.  Bearz A, Minatel E, Rumeileh IA, et al. Concurrent chemoradiotherapy with tomotherapy 
in locally advanced Non-Small Cell Lung Cancer: a phase I, docetaxel dose-escalation 
study, with hypofractionated radiation regimen. BMC cancer. 2013;13:513. 
14.  Lee TS, Kang SB, Kim YT, et al. Chemoradiation with paclitaxel and carboplatin in 
high-risk cervical cancer patients after radical hysterectomy: a Korean Gynecologic 

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Oncology Group study. International journal of radiation oncology, biology, physics. Jun 
1 2013;86(2):304-310. 
15.  Takayama K, Inoue K, Tokunaga S, et al. Phase II study of concurrent thoracic 
radiotherapy in combination with weekly paclitaxel plus carboplatin in locally advanced 
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2013;72(6):1353-1359. 
16.  
Mitin T, Hunt D, Shipley WU, et al. Transurethral surgery and twice-daily radiation plus 
paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and 
adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a 
randomised multicentre phase 2 trial. The lancet oncology. Aug 2013;14(9):863-872. 
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International journal of radiation oncology, biology, physics. Jul 15 2013;86(4):671-677. 
18.  Jhingran A, Ramondetta LM, Bodurka DC, et al. A prospective phase II study of 
chemoradiation followed by adjuvant chemotherapy for FIGO stage I-IIIA (1988) uterine 
papillary serous carcinoma of the endometrium. Gynecologic oncology. May 
2013;129(2):304-309. 
19.  Hirsh V, Soulieres D, Duclos M, et al. Phase II multicenter trial with carboplatin and 
gemcitabine induction chemotherapy followed by radiotherapy concomitantly with low-
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20.  Baykara M, Buyukberber S, Ozturk B, et al. Efficacy and safety of concurrent 
chemoradiotherapy with cisplatin and docetaxel in patients with locally advanced 
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21.  Bradley JD, Paulus R, Graham MV, et al. Phase II trial of postoperative adjuvant 
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Clinical Oncology. May 20 2005;23(15):3480-3487. 
22.  Feigenberg SJ, Hanlon AL, Langer C, et al. A phase II study of concurrent carboplatin 
and paclitaxel and thoracic radiotherapy for completely resected stage II and IIIA non-
small cell lung cancer. Journal of thoracic oncology : official publication of the 
International Association for the Study of Lung Cancer. Apr 2007;2(4):287-292. 
23.  Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and 
adjuvant temozolomide for glioblastoma. The New England journal of medicine. Mar 10 
2005;352(10):987-996.                                                                                                     
24.    Ammirati M, Kshettry VR, Lamki T, et al. A prospective phase II trial of fractionated 
stereotactic intensity modulated radiotherapy with or without surgery in the treatment of 
patients with 1 to 3  newly diagnosed symptomatic brain metastases. Neurosurgery. Jun 
2014; 74(6):586-594. 
25.    Murai T, Ogino H, Manabe Y, et al. Fractionated stereotactic radiotherapy using cyberknife 
for the treatment of large brain metastases: a dose escalation study. Clinical Oncology 
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  APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 

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APPENDIX B  
LIST OF PROHIBITED DRUGS 
1) Strong CYP3A inhibitors: Boceprevir, clarithromycin, cobicistat, conivaptan, 
elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, 
troleandomycin, voriconazole 
 
2) Strong CYP3A inducers: Avasimibe, carbamazepine, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin), St. John’s wort (hypericum perforatum) 
 
3) CYP3A substrates with narrow therapeutic index: Alfentanil, astemizole, cisapride, 
cyclosporine, diergotamine (dihydroergotamine), ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, terfenadine 
 
4) Sensitive CYP3A substrates: Alpha-dihydroergocryptine, aplaviroc, aprepitant, 
atorvastatin, brecanavir, brotizolam, budesonide, buspirone, capravirine, casopitant, 
conivaptan, darifenacin, darunavir, dasatinib, dronedarone, ebastine, eletriptan, 
eplerenone, everolimus, felodipine, fluticasone, indinavir, levomethadyl, lopinavir, 
lovastatin, lumefantrine, lurasidone, maraviroc, midazolam, neratinib, nisoldipine, 
perospirone, quetiapine, ridaforolimus, saquinavir, sildenafil, simvastatin, ticagrelor, 
tipranavir, tolvaptan, triazolam, vardenafil, vicriviroc 
 
5) Other investigational and antineoplastic therapies 
 
6) Herbal medications: Herbal medications should be stopped at least 7 days prior to first 
dose of study drug. 
 
7) Warfarin and coumarin derivatives: Therapeutic anticoagulation may be accomplished 
using low-molecular weight heparin.