Know Cancer

or
forgot password

Phase I/II Adaptive Randomized Trial of Bevacizumab Versus Bevacizumab Plus TPI 287 in Adults With Recurrent Glioblastoma


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Brain Neoplasms, Central Nervous System Neoplasms

Thank you

Trial Information

Phase I/II Adaptive Randomized Trial of Bevacizumab Versus Bevacizumab Plus TPI 287 in Adults With Recurrent Glioblastoma


Part I and Part II of the Study:

If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you joined this study. Up to 3 groups of 3-6 participants will be
enrolled in Part I of the study. After that, up to 90 participants will be enrolled in Part
II.

If you are in Part I, you will be assigned to receive 1 of 4 dose levels of TPI 287 based on
when you join this study. The first 3-6 participants will receive a starting dose level.
The next 3-6 participants will receive a higher dose if no intolerable side effects were
seen or a lower dose if intolerable side effects were seen. Your dose may be lowered if you
have side effects.

All participants will receive bevacizumab at the same dose level for the entire study.

If you are in Part II, you will be randomly assigned (as in the flip of a coin) to 1 of 2
groups. If you are one of the first 20 participants in Part II, you will be randomly
assigned to a group. If you are enrolled after the first 20 participants, you will be more
likely to be enrolled in the group that is showing better results.

- If you are in Group 1, you will receive bevacizumab.

- If you are in Group 2, you will receive bevacizumab and TPI 287.

If the disease gets worse at any time during the treatment with bevacizumab alone, you may
enroll in the Crossover Group to receive TPI 287 and bevacizumab.

Other Drugs:

If you are taking TPI 287, you will be given standard drugs such as Benadryl®
(diphenhydramine) and cimetidine to help decrease the risk of side effects. You may ask the
study staff for information about how the drugs are given and their risks.

Study Drug Administration:

There are 42 days in each study cycle.

Part I:

- On Days 1 and 22 of every cycle, you will receive TPI 287 by vein over 1 hour.

- On Days 1, 15, and 29 of every cycle, you will receive bevacizumab by vein over 30-90
minutes.

Part II:

If you are in Group 1:

-On Days 1,15, and 29 of every cycle, you will receive bevacizumab by vein over 30-90
minutes.

If you are in Group 2 or the Crossover Group:

- On Days 1 and 22 of every cycle, you will receive TPI 287 by vein over 1 hour.

- On Days 1, 15, and 29 of every cycle, you will receive bevacizumab by vein over 30-90
minutes.

Study Visits for Part I, Group 2, or Crossover Group of Part II:

Every time you receive the study drug(s), your vital signs will be recorded before and at
the end of the infusion.

On Days 1, 15, 22, and 29 of Cycle 1, blood (about 1- 2 teaspoons) will be collected for
routine tests.

On Days 1, 15, and 29 of Cycle 1, urine will be collected for kidney function tests.

On Day 1 of Cycles 2 and beyond:

- Your medical history and performance status will be recorded.

- You will be asked about any drugs you may be taking and if you have had any side
effects.

- You will have a complete physical exam, including measurement of your weight.

- You will have a neurological exam.

- Blood (about 1-2 teaspoons) will be collected for routine tests.

- Urine will be collected for kidney function tests.

- You will have an MRI scan of the brain to check the status of the disease.

On Days 15, 22, and 29 of Cycles 2 and beyond, blood (about 1-2 teaspoons) will be drawn for
routine tests.

Study Visits for Group 1 of Part II:

Every time you receive the study drug(s), your vital signs will be recorded before and after
the infusion.

On Days 1, 15, and 29 of Cycle 1:

- Blood (about 1-2 teaspoons) will be drawn for routine tests.

- Urine will be collected for kidney function tests.

On Day 1 of Cycle 2 and beyond:

- Your medical history and performance status will be recorded.

- You will be asked about any drugs you may be taking and if you have had any side
effects.

- You will have a complete physical exam, including measurement of your weight.

- You will have a neurological exam.

- Blood (about 2 teaspoons) will be collected for routine tests.

- Urine will be collected for kidney function tests.

- You will have an MRI scan of the brain to check the status of the disease.

On Day 15 and 29 of Cycles 2 and beyond, blood (about 1-2 teaspoons) will be drawn for
routine tests.

At any time during the study, extra tests may be performed if the doctor thinks they are
needed for your safety. The study doctor will tell you more about any extra tests.

Length of Treatment:

You may continue taking the study drug(s) for as long as the doctor thinks it is in your
best interest. If you enroll in the Crossover Group, you may continue taking the study
drugs for up to 6 additional cycles in the Crossover Group.

You may no longer be able to receive the study drug(s) 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 once you have completed the end-of-treatment
and follow-up visits.

End-of-Treatment Visit:

Within 28 days after you stop the study drugs:

- Your medical history and performance status will be recorded.

- You will be asked about any drugs you may be taking and if you have had any side
effects.

- You will have a complete physical exam, including measurement of your weight and vital
signs.

- You will have a neurological exam.

- Blood (about 2 teaspoons) will be collected for routine tests.

- Urine will be collected for kidney function tests.

- You may have an MRI scan of the brain to check the status of the disease.

Long-Term Follow-Up:

Every 3 months after the end-of-treatment visit for up to 1 year, you will be called and
asked how you are feeling. This call will take about 5-10 minutes.

This is an investigational study. TPI 287 is not FDA approved or commercially available.
It is currently being used for research purposes only. Bevacizumab is FDA approved and
commercially available for the treatment of brain tumors, including glioblastoma. The
combination of TPI 287 and bevacizumab in glioblastoma is investigational.

Up to 108 patients will take part in this study. All will be enrolled at MD Anderson.


Inclusion Criteria:



1. Patients must have histologically proven glioblastoma or gliosarcoma to be eligible
for this protocol. Patients will be eligible if the original histology was low-grade
glioma or anaplastic glioma (WHO II or III) and a subsequent histological diagnosis
of glioblastoma or gliosarcoma is made. Only patients with histologically proven or
imaging proven recurrent glioblastoma or gliosarcoma will be eligible for this
protocol.

2. Patients must have shown unequivocal evidence for tumor recurrence or progression by
MRI scan and should have failed radiation and temozolomide therapy. The scan done
prior to study entry documenting progression will be reviewed by the treating
physician to document changes in tumor dimension to confirm recurrence. Patients with
prior therapy that included interstitial brachytherapy or stereotactic radiosurgery
must have confirmation of true progressive disease rather than radiation necrosis.

3. For this study, patients may have had up to 2 prior relapses provided the functional
status and other eligibility criteria for enrollment are met.

4. All patients must sign an informed consent indicating their awareness of the
investigational nature of this study in keeping with the policies of this hospital.

5. The baseline on-study MRI should be performed within 14 days (+/- 3 working days)
prior to registration and on a steroid dosage that has been stable or decreasing for
at least 5 days. If the steroid dose is increased between the date of imaging and the
initiation of therapy (or at that time), a new baseline MRI is required. The same
type of scan, i.e., MRI, must be used throughout the period of protocol treatment for
tumor measurement.

6. Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply: a) At least 4 weeks have
elapsed from the date of surgery and the patients have recovered from the effects of
surgery. b) Evaluable or measurable disease following resection of recurrent tumor is
not mandated for eligibility into the study. c) To best assess the extent of residual
measurable disease post-operatively, a MRI should be done no later than 96 hours in
the immediate post-operative period.

7. Patients must be 18 years old or older.

8. Patients must have a Karnofsky performance status (KPS) equal or greater than 60.

9. Patients must have recovered from the toxic effects of prior therapy to < grade 2
toxicity per CTC version 4 (except deep vein thrombosis) prior to Day 1 of Cycle 1:
a) at least 12 weeks from completion of radiation therapy except if there is
unequivocal evidence for tumor recurrence (such as histological confirmation or
advanced imaging data such as PET scan) in which case at least 4 weeks from
completion of radiation therapy will suffice (Note: for patients who have undergone
surgery to confirm recurrence after radiation therapy, guidelines in 5.2.6a should be
followed). b) 4 weeks from prior cytotoxic therapy. c) 4 weeks from prior
experimental drug. d) 2 weeks from vincristine.

10. 9) (continued) e) 6 weeks from nitrosoureas. f) 3 weeks from procarbazine
administration. g) 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen,
cis-retinoic acid, etc. (radiosensitizer does not count). h) Patients who receive
anticancer agents for non-therapeutic purposes unrelated to this study (such as
presurgically for obtaining pharmacology data for the agent) will be eligible to
enter the study provided they have recovered from the toxic effects of the agent if
any. i) Any questions related to the definition of non-cytotoxic agents should be
directed to the Study Chair.

11. Patients must have adequate bone marrow function (ANC> 1,500/mm3 and platelet count
of > 100,000/mm3), adequate liver function (SGPT < 3 times upper limit normal and
alkaline phosphatase < 2 times upper limit normal, total bilirubin <1.5 mg/dl), and
adequate renal function (BUN and creatinine <1.5 times institutional normal) prior to
starting therapy.

12. Male patients on treatment with TPI 287 must agree to use an adequate method of
contraception for the duration of the study, and for 30 days after the last dose of
study medication. Women of childbearing potential must not be pregnant (as evidenced
by a negative pregnancy test prior to study entry), must not be breast-feeding and
must practice adequate contraception for the duration of the study, and for 30 days
after the last dose of study medication. An adequate method of contraception is one
highly effective method or more than one additional methods. Highly effective methods
include intrauterine device (IUD), hormonal (birth control pills, injections,
implants), tubal ligation and partner's vasectomy. Additional effective methods
include latex condom, diaphragm and cervical cap.

13. Patient must be able to tolerate the procedures required in this study including
periodic blood sampling, study related assessments, and management at the treating
institution for the duration of the study.

14. Exploratory, Cross-Over Trial Arm: Patients with evidence of clinical or radiographic
progression on the bevacizumab alone arm are eligible for cross-over into the
exploratory arm of the trial if KPS is 50 or greater and all other criteria for
initial enrollment in the trial are still met at time of progression. Patients will
be excluded if the investigators feel the patient will not tolerate TPI 287 or if an
alternative treatment approach is deemed necessary by the treating physician.

Exclusion Criteria:

1. Inability to comply with protocol or study procedures.

2. Prior treatment with bevacizumab or TPI 287.

3. 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.

4. Patients who have received more than one course of radiation therapy or more than a
total dose of 65 Gy. Patients may have received radiosurgery as part of the initial
therapy (i.e., in addition to one course of radiation therapy); however, the dose
used for the radiosurgery counts against the total dose limit listed above.

5. Patient who have received prior taxane chemotherapy for treatment of GBM or other
malignancy. GliadelTM as part of the initial therapy is permitted. Patients who have
received prior biologic therapy other than bevacizumab will be eligible.

6. Any condition, including the presence of clinically significant laboratory
abnormalities, which places the patient at unacceptable risk if he/she were to
participate in the study or confounds the ability to interpret data from the study.
These would include: a) Active infection including known AIDS or Hepatitis C or with
a fever >/= 38.5┬░C within 3 days prior to the study enrollment. b) Diseases or
conditions that obscure toxicity or dangerously alter drug metabolism. c) Serious
intercurrent medical illness (e.g. symptomatic congestive heart failure).

7. Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from providing informed consent.

8. Inadequately controlled hypertension (defined as systolic blood pressure >140 mmHg
and/or diastolic blood pressure > 90 mmHg)

9. Prior history of hypertensive crisis or hypertensive encephalopathy

10. New York Heart Association (NYHA) Grade II or greater congestive heart failure.

11. History of myocardial infarction or unstable angina within 6 months prior to Day 1

12. History of stroke or transient ischemic attack within 6 months prior to Day1

13. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1

14. History of hemoptysis (>/= 1/2 teaspoon of bright red blood per episode) within 1
month prior to Day 1

15. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)

16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1 or anticipation of need for major surgical procedure during the course
of the study.

17. Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to Day 1

18. History of abdominal fistula or gastrointestinal perforation within 6 months prior to
Day 1

19. Serious, non-healing wound, active ulcer, or untreated bone fracture.

20. Proteinuria as demonstrated by: (1) Urine protein:creatinine (UPC) ratio >/= 1.0 at
screening; OR (2) Urine dipstick for proteinuria >/= 2+ (patients discovered to have
>/= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine
collection and must demonstrate
21. Known hypersensitivity to any component of bevacizumab

22. Pregnancy (positive pregnancy test) or lactation. Not able to use of effective means
of contraception (men and women) in subjects of child-bearing potential.

23. Patients with Grade 2 or higher peripheral neuropathy.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression Free Survival (PFS)

Outcome Description:

Progression of disease assessed by utilizing the RANO criteria to interpret repeat Gd-MRI, neurological status and steroid dosing. Progression free survival (PFS) measured from time of registration until date of progression or death (whichever is earlier) (event time) or last date patient was known to be alive without progression (censoring time). Kaplan-Meier estimates of overall survival (OS) and PFS will be calculated. The exploratory arm will also look at the 3-month and 6-month progression free survival rate after bevacizumab failure.

Outcome Time Frame:

6 months

Safety Issue:

No

Principal Investigator

Charles A. Conrad, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2011-0705

NCT ID:

NCT01582152

Start Date:

July 2012

Completion Date:

Related Keywords:

  • Brain Neoplasms
  • Central Nervous System Neoplasms
  • Brain Neoplasms
  • Central Nervous System Neoplasms
  • Recurrent Glioblastoma
  • Glioblastoma multiforme
  • GBM
  • Gliosarcoma
  • TPI287
  • Bevacizumab
  • Avastin
  • Anti-VEGF Monoclonal Antibody
  • rhuMAb-VEGF
  • Brain Neoplasms
  • Neoplasms
  • Glioblastoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

UT MD Anderson Cancer Center Houston, Texas  77030