Randomized Efficacy Study of TPI 287 to Treat Primary Refractory or Early Relapsed Neuroblastoma

A Randomized, Phase I/II Trial of Irinotecan and Temozolomide Compared to Irinotecan and Temozolomide in Combination With TPI 287 in Patients With Primary Refractory or Early Relapsed Neuroblastoma

The purpose of this research study is to evaluate a new investigational drug (TPI 287) for early relapsed neuroblastoma. 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, in combination with Irinotecan and Temozolomide versus the combination of Irinotecan and Temozolomide alone. This study will also evaluate the safety and tolerability of the study drug, TPI 287.

Inclusion Criteria:

• Subjects must have histologically proven Neuroblastoma and confirmation of primary refractory or recurrent disease with histologic confirmation at diagnosis or at the time of recurrence/progression. Subjects must have primary refractory or have early relapse disease (early relapse disease is defined as having received ≤ one or two relapse therapies).
• Subjects must be age >12 months and diagnosed before the age of 21 years
• Measurable disease, including at least one of the following:

Measurable tumor >10 mm 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 table
• 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 written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
• Subjects may have received microtubulin inhibitors during previous therapies.
• Subjects may have received any number of prior biological 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 may not have received more than 1 cycle of Irinotecan and Temozolomide as previous relapse therapy.
• Subjects who have received any myeloablative therapy within the previous 2 months.
• Subjects receiving 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 subject's ability to sign or the legal guardian's ability to sign the informed consent, and subject'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.
• Subjects who have previously been treated with TPI 287.