Clinical trial NCT01332630
Conditions: Breast Cancer
Keywords: Breast cancer Brain metastases TPI 287 Computed Tomography CT Magnetic Resonance Imaging MRI
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-08-16; Completion date: 2017-04-14
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of the first part of this clinical research study is to find the highest tolerable dose of TPI-287 in patients with breast cancer that has spread to the brain.

The goal of the second part of this study is to learn if TPI-287 can control breast cancer that has spread to the brain. The safety of this drug will also be studied.

Detailed description:
The Study Drug:

TPI-287 is designed to prevent cancer cells from dividing, which may slow and/or stop the growth of cancer cell.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive, TPI 287 by vein over 60 minutes on Day 1 of every 21 day cycle.

Before you receive the study drug, you will receive dexamethasone by mouth, Benadryl (diphenhydramine HCL) by vein over 30-60 minutes, and ranitidine over 30-60 minutes to help prevent a potential serious allergic reaction.

Study Visits:

At all study visits, you will be asked about any side effects you may be having and about any other drugs you may be taking.

On Days 1, 8, and 15 of Cycle 1, blood (about 2-3 teaspoons) will be drawn for routine tests. If you are taking coumadin, blood (about 1-2 teaspoons) will be drawn to check how well your blood clots.

On Day 1 of Cycle 1, your performance status will be recorded and your vital signs will be measured.

Within 7 days of Day 1 of Cycles 2 and beyond:

* Blood (about 2-3 tablespoons) will be drawn for routine tests. If you are taking coumadin, blood (about 1-2 teaspoons) will be drawn to check how well your blood clots.
* You will have a physical exam, including measurement of your weight and vital signs.
* Your performance status will be recorded.
* You will have a neurological exam.

Every 6 weeks (that is, before each odd-numbered cycle):

* You may have CT scans or MRI scans of the chest, abdomen, and pelvis to check the status of the disease.
* You will have a MRI of your brain. The MRI will require a catheter to be inserted into one of your veins in order to inject the MRI contrast agent.

The study doctor and staff will review your imaging scans to check what stage of disease the tumors inside and/or outside your brain are.

Length of Study:

You may continue to receive TPI 287 for as long as the doctor thinks it is in your best interest. You will no longer be able to receive TPI 287 if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after you have completed the end-of-treatment and follow-up visits.

End-of Treatment Visit:

About 4 weeks after you stop taking TPI 287:

* You will have a physical exam, including measurement of your vital signs.
* You will have a neurological exam.
* Your performance status will be measured.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* You will have a CT and/or MRI to check the status of the disease. This may include a brain MRI. If your doctor thinks it is needed, you will have a bone scan.
* You will be asked about any side effects you may have had any drugs you may be taking.

Follow-Up Visits:

Once you are off-study, you will be contacted either in the clinic or by phone every 3 months for up to 1 year after you enrolled on the study to check on the status of your health. If you are called, it will take less than 5 minutes.

This is an investigational study. TPI 287 is not FDA approved or commercially available. At this time, TPI 287 is being used in research only.

Up to 69 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: TPI 287 administered at 160 mg/m2 by vein on Day 1 and repeated every three weeks. Day 1 of each subsequent cycle is equivalent of day 22 of the previous cycle; pre TPI 287: Dexamethasone 6 mg by mouth at 12 hours and 6 hours prior to treatment. As alternative and based on the treating physician discretion, Dexamethasone 10 mgby vein may be given 30-60 minutes prior to treatment with TPI 287, Benadryl 12.5-25 mg IV push over 30-60 minutes, and Ranitidine 1mg/kg IV over 30-60 minutes.
Interventions: intervention 1: TPI 287 intervention 2: Dexamethasone intervention 3: Benadryl intervention 4: Ranitidine
Intervention descriptions: intervention 1: Starting dose Phase I: 160 mg/m2 by vein over 60 minutes on Days 1, 8, and 15 of every 28 day cycle.

Starting Dose Phase II: Maximum tolerated dose from Phase I. intervention 2: 6 mg by mouth at 12 hours and 6 hours prior to treatment. As alternative and based on the treating physician discretion, dexamethasone 10 mg by vein may be given 30-60 minutes prior to treatment with TPI 287. intervention 3: 12.5-25 mg intravenous (IV) push 30-60 minutes prior intervention 4: As H2 blocker 1mg/kg IV 30-60 minutes prior

Protocol documents:
Prot_SAP_000.pdf: 
2010-0198
June 17,  2015
Abstract - Page 1
Protocol Abstract Page
A Phase 1/2 Open-Label Study of TPI 287 in Patients with Breast Cancer 
Metastatic to the Brain
2010-0198
Core Protocol Information
Study Chairman: 
Nuhad K. Ibrahim
Department:
Breast Medical Oncology
Phone:
713-792-2817
Unit:
1354
Full Title: 
A Phase 1/2 Open-Label Study of TPI 287 in Patients with Breast Cancer Metastatic to the 
Brain
Protocol Phase:
Phase II
Version Status:
Terminated 04/18/2017
Version:
11
Document Status:
Final
Abstract
Objectives:
Primary objective (Phase 1)
To evaluate the maximum tolerated dose (MTD)  and safety of TPI 287 administered 
once every three weeks in patients with refractory or recurrent breast cancer metastatic 
to the brain
Primary objective (Phase 2):  
To estimate the efficacy of TPI 287 by assessing the overall response rate [ORR (CR + 
PR)] of recurrent brain metastases using the McDonald Criteria.
Secondary objectives (Phase 1 and 2):
a.
To evaluate response duration of breast brain metastases on  TPI 287
b.
To evaluate rate and duration of the clinical benefit (CR+PR+SD)
c.
To assess activity of TPI 287 on extracranial metastatic disease
d.
To measure median progression free and overall survival of patients with metastatic
breast cancer treated with TPI 287
Rationale: (Be as concise as possible)
The current study proposes to examine a novel microtubule inhibitor TPI 287 that has 
shown potency and efficacy in a number of taxane sensitive and resistant tumors in 


2010-0198
June 17,  2015
Abstract - Page 2
both preclinical and clinical studies.  TPI 287 has also been shown to be very well 
tolerated and exhibits limited myelosuppression at the currently employed doses.  It has 
also been shown that IV TPI 287 can penetrate the brain parenchyma to reach 
pharmacologically and clinically relevant levels, which suggests that breast cancers 
metastatic to the brain would be an appropriate target for therapy.  There is a significant 
amount of human safety data for TPI 287 with over 100 adult patients and now 5 
pediatric patients who have received drug in prior clinical trials to adequately assess the 
safety of the clinical trial and the dosing regimen for TPI 287 planned. 
A brain-tropic derivative of the MDA-MB-231 “triple negative” breast cancer cell line, 
231-BR, has been used to test the efficacy of drugs administered systemically to mice 
with nascent and established brain tumors.  In this assay, paclitaxel, ixabepilone and 
abraxane (all microtubule inhibitors) did not have significant inhibitory activity. TPI-287 
at 18 mg/kg delivered on days 3, 7 and 11  significantly reduced the outgrowth of brain 
metastases (55% reduction, p=0.028), and reduced proliferation in brain metastases 
(16% reduction, p=0.008).  Based on the results of this preclinical model, the utility of 
TPI 287 for the treatment of breast cancer metastatic to the brain is being explored in 
the clinical setting in this current protocol. 
In a recent clinical pilot study in glioma patients at MD Anderson Cancer Center dosing 
at 185 mg/m2 once every three weeks in combination with Avastin showed no dose 
limiting toxicity. In the initial version of this study, TPI 287 administered at a dose of 
125 mg/m2 showed no evidence of any toxicity when administered weekly for three out 
of every four weeks.  However, since it was also suggested by other Phase 2 studies 
that higher concentrations administered once every three weeks may provide greater 
efficacy, this amendment provides for a higher starting dose to explore the MTD on this 
schedule and then to evaluate efficacy.
Eligibility: (List All Criteria)
Inclusion:
1)
Patients must have histologically proven breast cancer with metastatic disease to the brain.
2)
Patients must have measurable disease on MRI that has progressed after prior therapy. PD will be 
defined as a>/= 25% increase in the sum of the products of greatest perpendicular diameters of all 
measurable disease over the smallest sum observed (since treatment started) on Gd-MRI, the 
appearance of new lesions on scan, or clinical or neurologic worsening despite stable disease on the last 
2 scans.
3)
Patients may have had any number of prior surgeries, radiation and/or chemotherapy regimens as 
adjuvant, neoadjuvant or palliative therapy for the treatment of their disease
4)
Patients must be >/=18 years of age.
5)
Patients must have an ECOG performance status of 0,1 or 2.
6)
Patients must have adequate bone marrow function as evidenced by an absolute neutrophil count 
>/=1,500/microliters and a platelet count >/=100,000/microliter, adequate renal function as evidenced by 


2010-0198
June 17,  2015
Abstract - Page 3
serum creatinine </=2.0 mg/dL, adequate hepatic function as evidenced by serum total bilirubin </=2.0 
mg/dL, AST/SGOT and ALT/SGPT </= 3X the ULN.
7)
Patients must have recovered and healed from the effects of any prior surgery, must have received 
prior chemotherapy at least 2 weeks prior to dosing with adequate recovery of WBC and platelet counts, 
and at least 12 weeks must have elapsed from the completion of radiotherapy, unless there are new 
lesions appearing on imaging within this 12 weeks frame.
8)
Women of child-bearing potential (i.e. </= 50 years of age or has had menstrual cycle within the 
past 12 months, if > 50 years of age. If in doubt, check FSH, LH and estradiol level) must have a negative 
urine or serum pregnancy test at screening.
9)
Sexually active patients must agree to use adequate contraception (abstinence or barrier 
contraceptives must be used throughout the trial and one month after end of treatment) for the duration of 
the study .
10)
Patients or their legal representative must be able to read, understand and sign an informed 
consent form (ICF).
11)
TPI 287 may interfere with coumadin dosing and patients who are taking this combination will 
require monitoring of their PT, PTT and INR.
Exclusion:
1)
Patients who are receiving concurrent enzyme-inducing anti-epileptic drugs (EIAEDs) (e.g., 
carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital and primidone) or who received 
EIAEDs within 2 weeks prior to the first dose of study drug.
2)
Patients with uncontrolled intracranial hypertension syndrome (defined as: persistence of 
headache, transient visual obscurations, and/or diplopia despite optimal clinical management) or 
uncontrolled seizure activity (i.e. recorded despite optimal medical management).
3)
Patients who are not on a stable or decreasing steroid dose for the previous week prior to the first 
dose of study enrollment
4)
Patients who are taking bevacizumab or have taken bevacizumab within the past 2 weeks for 
treatment of their brain metastases
5)
Patients with an active infection (i.e., clinical signs or symptoms, including, but not limited to: 
bleeding/pustulent skin infections; productive cough associated with fever) on antibiotics or with a fever 
>/=38.5°C within 3 days prior to registration (i.e. date when the patient signs the consent and/or the 
patient is registered in CORE).
6)
Patients with NYHA Class 3 or 4 congestive heart failure.
7)
Patients with known HIV or Hepatitis B or C
8)
Patients who are pregnant or lactating or not practicing adequate contraception
9)
Patients with any other medical condition, including mental illness or substance abuse, deemed by 
the Investigator to be likely to interfere with the patient’s ability to sign the ICF or his/her ability to 
cooperate and participate in the study, or to interfere with the interpretation of the results.
10)
Patients who are receiving concomitant systemic therapy for breast cancer.
11)
Patients with leptomeningeal disease (LMD) or with a history of LMD will be excluded.


2010-0198
June 17,  2015
Abstract - Page 4
Are patients <18 years of age eligible to participate in this study?  
Yes
No
Studies that include children must meet the criteria for inclusion.
http://www.fda.gov/ohrms/dockets/AC/04/briefing/4028B1_05_NIH-Inclusion%20of%20Children.doc
http://www.hhs.gov/ohrp/policy/populations/children.html
Studies that exclude children must have appropriate justification.  Please select all that 
apply:
Phase I or Phase II study targeting cancer that is very unusual in pediatrics (e.g., prostate, lung, 
breast, chronic lymphocytic leukemia, etc.)
Are participants >65 years of age eligible to participate in this study?  
Yes
No
Are pregnant women eligible to participate in this study?
Yes
No
Will the recruitment population at M. D. Anderson include persons who are incarcerated at time of 
enrollment (e.g., prisoners) or likely to become incarcerated during the study?
Yes
No
Disease Group:
Breast
Treatment Agents/Devices/Interventions:
TPI 287
Proposed Treatment/Study Plan:
Is treatment assignment randomized?
Yes
No
Is this a blinded or double-blinded study?
Yes
No
This is an open label, Phase 1/2, exploratory trial evaluating the efficacy and safety of 
TPI 287 in patients with refractory or recurrent brain metastases from breast cancer.
During Phase 1, the dose of TPI 287 will be escalated in sequential dose cohorts 
(inter-cohort dose escalation).  TPI 287 will be administered at an initial dose of 160 
mg/m^2 as a 60-minute (± 10 minutes) intravenous (IV) infusion once every three weeks 
(i.e., 1 cycle = 21 days).  If patients enrolled at this dose have no dose limiting toxicities 
(DLTs) within 21 days of receiving the first dose of study drug, additional patients will be 
enrolled in subsequent cohorts of 3 patients at 20 mg/m2 increments (180 mg/m^2, 200 
mg/m^2, 220 mg/m^2, etc.) to explore a maximum tolerated dose (MTD) on this 
schedule for this patient population.  If patients experience DLT at the starting dose, one 
dose level below (Level -1) is also proposed.
If 1 out of 3 patients experiences a DLT within 21 days of receiving the first dose of 
study drug, an additional 3 patients will be enrolled in that cohort.  If >/= 2 patients at 


2010-0198
June 17,  2015
Abstract - Page 5
any dose level experience DLT within 21 days of receiving the first dose of study drug, 
the MTD will be the previous dose level tested.  
The MTD determination will be based on the number of patients that experience DLTs 
within 21 days of receiving the first dose of study drug.  DLTs will be considered to be 
any hematologic toxicity >/= Grade 3 within 21 days of receiving the first dose of study 
drug that does not recover within 3 weeks or any non-hematological toxicity >/= Grade 3 
within 21 days of receiving the first dose of study drug that does not improve to Grade 1 
or baseline within 3 weeks
Patients on the Phase 2 portion of the study will be enrolled at the MTD determined 
during Phase 1.  Initially, 25 patients will be enrolled in the Phase 2 portion of the trial; if 
at least 5 patients are shown to have an objective response, an additional 26 patients 
will be enrolled.
Patients may continue treatment in the study at any dose until intracranial disease 
progression or death, unacceptable toxicity, withdrawal of consent, or discontinuation 
based on Investigator discretion.  Patients will be followed for survival for up to 1 year 
after enrollment on the study.
Intra-patient dose escalation will be allowed for patients with extracranial progressive 
disease as long as the response of intracranial disease is stable or better and there is 
no unacceptable toxicity.  Only one dose escalation will be allowed per patient.  The 
dose will be escalated to the next higher dose level (20 mg/m^2 increase); under the 
condition that this higher dose level was previously shown to be safe per the 
inter-cohort dose escalation criteria.
Table of Procedures and Assessments:


2010-0198
June 17,  2015
Abstract - Page 6
  
Dose Levels:
CTCAE version 4 will be utilized in this protocol.
Study Enrollment:
The study population for this research will consist of participants from:
Only at MDACC
Estimated Accrual:
Total Accrual at MDACC:
69
Estimated monthly accrual at MDACC:
0-1


2010-0198
June 17,  2015
Abstract - Page 7
Accrual Comments:
All patients will be accrued MD Anderson Cancer Center
Is this an NCI-Cancer Therapy Evaluation Protocol (CTEP)?
No
Is this an NCI-Division of Cancer Prevention Protocol (DCP)?
No
Statistical Considerations:
This is an open label, Phase 1/2, exploratory trial evaluating the efficacy and safety of 
TPI 287 in patients with refractory or recurrent brain metastases from breast cancer.
The primary objective of the Phase 1 portion of the study is to determine the 
MTD of TPI 287 and in the Phase 2 portion of the study whether TPI 287 can 
provide clinical benefit for patients with metastatic breast cancer to the brain 
following failure of prior therapy, as measured by overall response rate. 
TPI 287 will be administered intravenously at an initial dose of 160 mg/m2 once 
every three weeks.  Dose escalation will continue in cohorts of 3 patients who will 
receive increasing doses until 1 out of 3 experience a dose limiting toxicity (DLT) 
at which time an additional 3 patients will be added at that dose.  If >/=2 patients 
experience a DLT, the MTD will be considered the prior dose level.  Dose levels 
will be 160 mg/m2, 180 mg/m2, 200 mg/m2 and then increased in 20 mg/m2 
increments until the MTD is reached.  
Once the MTD has been reached an initial cohort of 25 patients will be enrolled; 
if at least 5 patients are shown to have an objective response, an additional 26 
patients will be enrolled.
The following data sets will be used in this study:
•
All enrolled and eligible subjects (ITT) population: All eligible subjects who 
signed the informed consent form.
•
All treated and eligible patients (Safety and Efficacy evaluable) population: All 
patients who received at least one dose of study drug
Efficacy analyses will be performed on the Safety and Efficacy evaluable 
population in the patients on Phase 2. Safety analysis will be performed on the 
Safety and Efficacy evaluable population in both portions of the study.
The primary outcome measure will be response rate in the Phase 2 portion of the 
study. A  two-stage patient accrual plan is used for this portion. Based on 
historical data, responses to chemotherapy in this disease ranged from 
approximately 30 to 55%; however in most cases these were combined with 
whole brain radiation therapy. Therefore, a 15% response rate to single agent 


2010-0198
June 17,  2015
Abstract - Page 8
chemotherapy will be targeted as a reasonable outcome for this patient 
population.  We target this response rate of 15% because our experience in this 
heavily pre-treated patient population indicates that almost none of the patients 
of the patients will respond under the current best-supportive care/hospice care 
regimen.  We used trial and error to get a two-stage design with reasonable 
operating characteristics for p0 = 15%.  One such design would have 25 patients 
in the first stage and 26 patients in the second stage.  It would continue onto the 
second stage if more than 4 patients had response in the first stage.  The trial 
would be considered a success if 11 or more out of the total 51 patients had 
response.  This trial has a false positive (alpha) rate of 11% (under p0 = 15%) 
and a false negative (beta) rate of 12% (under p1 = 30%).  The trial also has a 
probability of early termination under p0 (i.e., if the true response probability is p0 
= 15%) of 68%.
Data Safety Monitoring Board / DSMB at MDACC:
Select the name of the data safety monitoring board (DSMB) monitoring this protocol:
Not Applicable
Please explain:
This study open label and not randomized.
Protocol Monitoring:
Does this protocol have a schedule for interim and final analysis?
No
Provide a rationale for no interim analysis.
This is not a randomized study.
Protocol Monitoring Plan:
The protocol will be monitored by MDACC IND office
Intellectual Property:
1.
Does this study include any agents, devices, or radioactive compound (or 
drug) manufactured at  MD Anderson Cancer Center or by a contract 
manufacturer?
No
Investigational New Drugs (IND):
Does this protocol require an IND?
Yes
Who is the IND Holder/Regulatory Sponsor?
MDACC
IND Number:
106,771
Please "Compose" an Investigator’s Brochure Cover Letter.  For technical assistance, contact the PDOL 


2010-0198
June 17,  2015
Abstract - Page 9
Help Desk, 713-745-7365.
Investigational Device (IDE):
Does this study utilize an Investigational Device?
No
Sponsorship and Support Information:
Does the Study have a Sponsor, Supporter or Granting Agency?
Yes
Sponsor Name:
Cortice Biosciences Inc. 
Support Type:
Industry Funding
Agent Name(s): TPI 287
This Sponsor/Supporter/Granting Agency will receive data.
Radioactive Material:
Does this study involve the administration of radioisotopes or a
radioisotope labeled agent?
Click here  for help
N/A
Biosafety:
Does this study involve the use of Recombinant DNA Technology? 
No
Does this study involve the use of organisms that are infectious to humans?
No
Does this study involve human/animal tissue other than blood derived 
hematopoietic stem cells?
No
Questions should be addressed to the Transfusion Medicine Tissue Coordinator at 713-792-8630.
Laboratory Tests:
Is there any biomarker testing in this study being used to determine patient/participant eligibility, 
treatment assignment, or management of patient/participant care?
Yes
No
Not Applicable For This Protocol
Manufacturing:
Will you manufacture in full or in part (split manufacturing) a drug or biological 
product at the M. D. Anderson Cancer Center for the proposed clinical study?
No


2010-0198
June 17,  2015
Abstract - Page 10
Student/Trainee Information:
Is this research being conducted as a partial fulfillment for completion of a degree?
No