TPI 287 in Patients With Refractory or Recurrent Neuroblastoma or Medulloblastoma

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.

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