TPI 287 in Patients With Refractory or Recurrent Neuroblastoma or Medulloblastoma
Condition: Neuroblastoma; Medulloblastoma; Relapse
MeSH terms: Neuroblastoma; Medulloblastoma
Intervention: TPI 287
Intervention description: Three patients will be enrolled to receive single agent TPI 287 IV administered on Days 1, 8 and 15 of the first and second 28-day cycle. The starting dose of 90 mg/m2 (Dose Level 1) is 75% of the established adult MTD for this schedule in adults, which is 125 mg/m2. Dose escalation will take place in a standard 3+3 design, in which doses will increase by approximately 20 to 25% in successive 3-patient cohorts.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 12 Months
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Relapsed Neuroblastoma; Refractory Neuroblastoma; Relapsed Medulloblastoma; Refractory Medulloblastoma

Summary:

      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.

      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. All of
      these subjects that have received TPI 287 have been adults. TPI 287 has not been tested in a
      pediatric population before this study.

      Temozolomide was tested in recurrent neuroblastoma and showed activity in a recently
      published study. Preclinical studies of TPI in combination with temozolomide have shown at
      minimum an additive effect. The ability of temozolomide and TPI 287 to be effective in
      combination is suggested by these two drugs showing even greater activity when used together.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically proven neuroblastoma and confirmation of refractory
             or recurrent disease or medulloblastoma with histologic confirmation at diagnosis or
             at the time of recurrence/progression

          -  Patients must be age >12 months and diagnosed before the age of 21

          -  Life expectancy must be more than 3 months

          -  If measurable disease, this must be demonstrated by residual abnormal tissue at a
             primary or metastatic site measuring more than 1 cm in any dimension by standardized
             imaging (CT or MRI). For patients with neuroblastoma who only have skeletal disease,
             there must be at least two persisting skeletal foci on meta-iodobenzylguanidine (MIBG)
             follow-up scans

          -  Current disease state must be one for which there is currently no known curative
             therapy

          -  Lansky Play Score must be more than 30 and/or ECOG performance status must be 0 to 2

          -  For patients with medulloblastoma receiving steroids, the dose must be stable (i.e.
             not increasing) for at least one week before starting study

          -  Patients without bone marrow metastases must have an ANC > 750/μl and platelet count
             >50,000/μl

          -  Adequate liver function must be demonstrated, defined as:

               -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND

               -  SGPT (ALT) < 10 x 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 version 3 (NCI-CTCAE V3.0
             (http://ctep.cancer.gov/forms/CTCAEv3.pdf))

          -  A negative urine pregnancy test is required for female participants of child bearing
             potential (≥13 years of age or after the 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 can not
             be used, contraceptive foam with a condom is recommended

          -  Informed Consent: All patients and/or legal guardians must sign informed written
             consent. Assent, when appropriate, will be obtained according to institutional
             guidelines

          -  Patients may have received microtubulin inhibitors and/or temozolomide during previous
             therapies

        Exclusion Criteria:

          -  Patients who have received any chemotherapy administered within the last 21 days

          -  Patients who have received radiotherapy within the last 30 days

          -  Patients who have received myeloablative therapy within the previous 3 months

          -  Patients receiving anti-tumor therapy for their disease or any investigational drug
             concurrently

          -  Patients with serious infection or a life-threatening illness (unrelated to tumor)
             that is > Grade 2 (NCI CTCAE V3.0), or active, serious infections requiring parenteral
             antibiotic therapy within 4 weeks prior to screening

          -  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

          -  Patients with known hypersensitivity to any of the components of the drugs to be
             administered on study

          -  Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study