A Phase 1 Trial of TPI 287 as a Single Agent and in Combination with Temozolomide in Patients with Refractory or Recurrent Neuroblastoma or Medulloblastoma

Principle Investigator
Giselle Sholler, M.D.
Pediatric Hematology-Oncology
Vermont Cancer Center at UVM College of Medicine
Vermont Children's Hospital

This study is currently recruiting patients.

Rationale
This Phase I trial is designed to evaluate the safety of TPI 287 in children with neuroblastoma and medulloblastoma.

Purpose
The purpose of this research study is to evaluate a new investigational drug (TPI 287) for neuroblastoma and medulloblastoma both alone and in combination with temozolomide (a currently approved drug). An investigational drug is one that has not yet been approved by the Food and Drug Administration. This investigational drug is called TPI 287. This study will look at the safety and tolerability of TPI 287 both alone and in combination with temozolomide, and look to establish a safe dose of this agent. The study will also look at the tumor's response to these drugs, but this is not the primary objective of this study.

Targeted Patients
Relapsed and Refractory Neuroblastoma and Medulloblastoma

Eligibility

   Inclusion Criteria:

1. Disease Status: Refractory or first or multiple relapsed neuroblastoma, or medulloblastoma that has relapsed after, or is refractory to, a chemotherapy-containing treatment regimen.
2. Measurable disease, including at least one of the following: Measurable tumor by CT or MRI.
3. Patients must be age >12 months and diagnosed before the age of 21;
4. Life expectancy must be more than 3 months
5. Current disease state must be one for which there is currently no known curative therapy
6. Lansky Play Score must be more than 30 and/or ECOG performance status must be 0 to 2
7. For patients with medulloblastoma receiving steroids, the dose must be stable (i.e. not increasing) for at least one week before starting study
8. Patients without bone marrow metastases must have an ANC > 750/μl and platelet count >50,000/μl
9. Adequate liver function must be demonstrated, defined as:
       a. Total bilirubin <= 1.5 x upper limit of normal (ULN) for age AND
       b. SGPT (ALT) < 10 x upper limit of normal (ULN) for age
10. A negative urine pregnancy test is required for female participants of child bearing potential (>=13 years of age or after the onset of menses)
11. Patients may have received microtubulin inhibitors and/or temozolomide during previous therapies.

   Exclusion Criteria:

1. Patients who have received any chemotherapy administered within the last 21 days
2. Patients who have received radiotherapy within the last 30 days.
3. Patients who have received myeloablative therapy within the previous 3 months
4. Patients receiving anti-tumor therapy for their disease or any investigational drug concurrently
5. Patients with serious infection or a life-threatening illness (unrelated to tumor), or active, serious infections requiring IV antibiotic therapy within 4 weeks prior to screening
6. Any other medical condition, including malabsorption syndromes, mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the interpretation of the results or which would interfere with a patient's ability to sign or the legal guardian's ability to sign the informed consent, and patient's ability to cooperate and participate in the study

Summary of Treatment Plan
You will be given an oral steroid (may also be given by IV) 12 hours and 6 hours prior to the first TPI 287 dose. TPI 287 will be started in clinic on Day 1 and given through a vein. The medicine will be given on Day 1, Day 8, and Day 15 of each 28 day cycle, for as long as you are on this study, unless you have side effects from the medicine or your tumor gets worse after adding in the temozolomide.

TPI 287 will be given to you in six individual cycles of therapy. Each cycle of therapy lasts about 28 days. During the first two cycles, you will receive TPI 287 by itself, on Day 1, Day 8 and Day 15 of the cycles. At the end of these cycles, you will undergo testing [laboratory tests, bone marrow test, and radiologic evaluations (MIBG scan {if done at screening}, CT scans and/or MRI) which were done at screening] to assess the response of the tumor.

You will then start cycle 3. During cycle 3 you will receive the TPI 287 the same as in cycle 1 and 2, but in cycle 3 you will also receive Temozolomide orally (by mouth) on Days 1 through 5 of the 28 day cycle.

You may receive up to 4 cycles in total of TPI 287 + Temozolomide plus the two cycles of TPI 287 alone, which equals a total of six cycles.

You must to be seen at the study institution clinic, Fletcher Allen Health Care, during all TPI-287 administration times. All required radiology scans (MIBG's and MRI/CT's), must be done at the study institution, Fletcher Allen Health Care. If Fletcher Allen Health Care is not your home institution, all other care (excluding the previously mentioned) can be done at your home institution.

Contact
For information about enrolling in the study, contact:
Genevieve Bergendahl, R.N.
Senior Research Nurse Coordinator
Vermont Cancer Center
HSRF 326C
149 Beaumont Avenue
Burlington, VT 05401
Phone: (802) 656-4511
Fax: (802) 656-2140
Genevieve.Bergendahl@uvm.edu