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Medulloblastoma

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Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

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Temozolomide

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.

TPI 287

Giselle Sholler, MD

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.

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.

TPI 287 in Patients With Refractory or Recurrent Neuroblastoma or Medulloblastoma

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

To determine the safety, tolerability and maximum tolerated dose (MTD) of TPI 287 as a single agent and collect exploratory data on the safety and tolerability of TPI 287 in combination with temozolomide (TMZ) in pediatric and young adult patients with refractory or recurrent neuroblastoma or medulloblastoma

Per 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.

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

Cortice Biosciences, Inc.

Giselle Sholler

Study Chair

TPI 287: 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.

One subject, age 25, was allowed to enroll on study, but was censored from endpoints due to age.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Number of Participants With Adverse Events as a Measure of Safety and Tolerability

Six patients at the MTD dose of 125mg/m2/dose

Tmax of TPI 287in Pediatrics Using Pharmacokinetic (PK) Testing.

18 subjects enrolled, one subject censored due to age, 5 subjects not evaluable. Analysis population= 12 patients.

Spots Global Cancer Trial Database for relapsed medulloblastoma