Safety and Efficacy Study of TPI-287 in Neuroblastoma and Medulloblastoma

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate a new investigational drug (TPI 287) for neuroblastoma and medulloblastoma. 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 tumor's response to the study drug, TPI 287, as well as the safety and tolerability of the drug. TPI 287 was shown to be effective in stopping tumor growth and was also shown to be safe in three different animal species. TPI 287 has been tested in humans in four clinical trials, and approximately 100 subjects with various types of cancers have received the drug, including a pediatric population in our previous Phase I trial.

Official Title
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A Phase I/II Trial of TPI-287 in Patients With Refractory or Recurrent Neuroblastoma and Medulloblastoma

Conditions
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Medulloblastoma, Neuroblastoma

Intervention / Treatment
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* Drug: TPI 287


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have histologically proven neuroblastoma or medulloblastoma and confirmation of refractory or recurrent disease with histologic confirmation at diagnosis or at the time of recurrence/progression Subjects must be age >12 months and diagnosed before the age of 21 Measurable disease, including at least one of the following: Measurable tumor >10mm by CT or MRI Positive bone marrow biopsy/aspirate. Positive MIBG Current disease state must be one for which there is currently no known curative therapy Lansky Play Score or Karnofsky scale must be more than 30 Subjects without bone marrow metastases must have an ANC > 750/μl and platelet count >50,000/μl Adequate Renal Function Defined As Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or A serum creatinine based on age/gender Adequate liver function must be demonstrated, defined as: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age SGPT (ALT) < 10 x upper limit of normal (ULN) for age SGOT (AST) < 10x upper limit of normal (ULN) for age No other significant organ toxicity defined as > Grade 2 by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE V4.0- http://ctep.cancer.gov/forms/CTCAEv4.pdf) A negative urine pregnancy test is required for female participants of child bearing potential (≥13 years of age or after onset of menses) Both male and female post-pubertal study subjects need to agree to use one of the more effective birth control methods during treatment and for six months after treatment is stopped. These methods include total abstinence (no sex), oral contraceptives (the pill), an intrauterine device (IUD), levonorgestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive foam with a condom is recommended. Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines Subjects may have received microtubulin inhibitors during previous therapies. Exclusion Criteria: Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the effects of prior chemotherapy (hematological and bone marrow suppression effects), generally at least 3 weeks from the most recent administration (6 weeks for nitrosoureas). Subjects who have received any myeloablative therapy within the previous 2 months. Subjects receiving anti-tumor therapy for their disease or any investigational drug concurrently Subjects with serious infection or a life-threatening illness (unrelated to tumor) that is > Grade 2 (NCI CTCAE V4.0), or active, serious infections requiring parenteral antibiotic therapy. Subjects with 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 Subjects with known hypersensitivity to any of the components of the drugs to be administered on study

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPI 287<br>Subjects will receive six cycles of intravenous (IV) TPI 287 at a dose of 125 mg/m2 on Days 1, 8 and 15 of a 21-day cycle. | Drug: TPI 287<br>* Subjects will receive six cycles of intravenous (IV) TPI 287 at a dose of 125 mg/m2 on Days 1, 8 and 15 of a 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Phase I portion of trial- To determine the safety and tolerability of TPI 287 as a single agent in pediatric and young adult patients with refractory or recurrent neuroblastoma or medulloblastoma. Adverse events collected from time of first dose to 30 days past last dose and until all related events resolved, average of one year. | length of study +30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Response Assessed Using RECIST Criteria | Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 6 months | 
| Number of Days Participants Experienced Progression Free Survival (PFS) | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 3 years | 
| Median Overall Survival (OS) of Participants | Overall Survival (OS) and clinical benefit (ORR + stable disease, SD) | 3 years | 
| Quality of Life of Children Receiving TPI287 Using PedsQL Questionnaires | To evaluate the impact of QOL of children receiving TPI287 using PedsQL questionnaires | 3 years | 
| To Evaluate the Drug Levels and Pharmacokinetics (PK) of TPI 287 From Blood Samples at Multiple Time Points Within the First 24 Hours on Study. | To evaluate the pharmacokinetics (PK) of TPI 287 in the Phase I population of this trial. | 1 year |