TPI 287 in Patients With Refractory or Recurrent Neuroblastoma or Medulloblastoma
Condition: Neuroblastoma; Medulloblastoma; Relapse
MeSH terms: Neuroblastoma; Medulloblastoma
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      Neuroblastoma:

      Neuroblastoma is the most common pediatric extracranial solid tumor and accounts for 7% to
      10% of childhood cancers (American Cancer Society 2008; Bernstein et al. 1992). Whereas the
      prognosis for infants with neuroblastoma is generally good, currently only 30% of children
      diagnosed after 12-15 months of age survive despite aggressive multimodal therapies (Brodeur
      et al 1993; Park et al 2008). High-dose chemotherapy (HDC) followed by hematopoietic stem
      cell transplantation (HSCT) and maintenance therapy with retinoic acid improves survival by
      35% in children presenting with metastatic NB, but the 5-year event-free survival remains
      below 50% (Matthay et al, 1999; Hartmann, et al, 1999). Consequently, the evaluation of new
      drugs is strongly needed in this disease.

      1.2

      Medulloblastoma:

      Medulloblastoma is the most common malignant brain tumor in children and accounts for 16% of
      all brain tumors in children 0-14 years old and 6% in adolescents 15-19 years old (CBTRUS
      2008). Current therapies for children with disseminated disease are associated with severe
      long-term toxicities, and lead to cure in only a minority of cases. (Partap et al, 2007).
      Thus, the development of new therapies-especially ones with more favorable toxicity
      profiles-would represent a significant improvement in the treatment of this disease. Although
      there have been reports that the survival rate of children with chemosensitive relapsed
      medulloblastoma can approach 40% following intensive chemotherapy combined with autologous
      stem cell support, more recent data looking at survival of all patients relapsing after
      modern combination chemotherapy and radiation is also on the order of 10-15%. (Rood, et al,
      2004) As such, new therapeutic approaches are needed to treat these children.

      1.3 The Investigational Product TPI 287 1.3.1

      Preclinical Studies:

      Tapestry Pharmaceuticals, Inc. developed a novel anti-microtubule agent, TPI 287, for which
      Archer Biosciences, Inc. is now the sponsor. TPI 287 is synthetically manufactured from
      naturally occurring taxanes extracted from yew starting material. The synthesis involves
      modifications of the side chain to make the drug more lipophilic, and modification of the
      baccatin ring structure with the intent of circumventing MDR-based resistance and allowing
      for binding to mutant tubulin. Selection of TPI 287 was also made on the basis of the very
      high potency of this drug against several neuroblastoma cell lines and xenograft models (see
      below).

      In vitro, TPI 287 was shown to have comparable cytotoxicity to paclitaxel in several MDR-
      cell lines, but was 5 - 3900-fold more active than several comparator compounds in MDR+ cells
      lines. In MCF-7-AR breast cancer cells, which display MDR-based resistance, TPI 287 was
      20-times more active than paclitaxel. Similar findings were observed in MDR+ cells derived
      from colorectal, breast and prostate cancers, as well as from neuroblastoma, as noted.TPI 287
      was also evaluated in a variety of xenograft models. As in vitro, TPI 287 was superior to
      paclitaxel in vivo in the MCF-7-AR xenograft. TPI 287 also had superior activity when
      compared to SN-38 in the HCT-15 and HCT-116 colon cancer xenografts; when compared to
      docetaxel in the PC3 prostate cancer xenograft; and when compared to docetaxel and
      doxorubicin in the MV522 NSCLC xenograft.

      Activity against glioblastoma was shown in transplanted xenografts, and efficacy was
      demonstrable using both IV and oral administration. In addition, in an orthotopic xenograft
      using U251 cells implanted in the brains of nude mice, treatment with either TPI 287,
      temozolomide, or combinations were compared to control animals, evaluating median survival
      (10 animals per group) as well as animals whose survival extended beyond 110 days. The
      results of this study, repeated for corroboration at an outside facility, are shown in Table
      4. Significant synergy and improvement in long term survival can be seen with the combination
      of temozolomide (TMZ) plus TPI 287.Potent activity had also been shown against neuroblastoma
      cell lines as previously noted, and this was also demonstratable in transplanted xenografts,
      showing greater activity than paclitaxel, docetaxel or nab-paclitaxel. Studies recently
      completed (Sholler, et al, personal communication) show TPI 287 has activity against
      additional neuroblastoma cell lines as well as medulloblastoma cell lines and increased
      efficacy when TPI 287 is combined with TMZ in neuroblastoma.Toxicology studies demonstrated
      that TPI 287 was generally well tolerated. The MTD in the rat was 48 mg/kg and in the dog,
      12.5 mg/kg. Toxicity was primarily characterized by bone marrow suppression and mucositis.
    

Intervention name(s): TPI 287
Intervention type(s): Drug
Intervention description(s): 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.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Relapsed Neuroblastoma; Refractory Neuroblastoma; Relapsed Medulloblastoma; Refractory Medulloblastoma