Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00867568 |
| Other study ID # |
TPI-287 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
March 2009 |
| Est. completion date |
February 2016 |
Study information
| Verified date |
April 2024 |
| Source |
Milton S. Hershey Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
