Gastrointestinal Neuroendocrine Carcinomas Clinical Trial
Official title:
A Feasibility Study Of NAB-Paclitaxel In Combination With Carboplatin As First Line Treatment Of Gastrointestinal Neuroendocrine Carcinomas
Gastrointestinal Neuroendocrine Tumours (NETs) are gaining increasing recognition as a highly
prevalent disease, responsive to a number of therapies, some of which are proven in modern
randomised controlled trials, but many of which still require high quality clinical trial
evidence to confirm their effectiveness and guide their use in practice. This study is the
first prospective trial to evaluate modern combination chemotherapy. The study will determine
whether Carboplatin and Paclitaxel NAB is a suitable combination for comparison in a
subsequent randomised controlled phase III international trial.
Given the paucity of randomized studies in NETs, there are no clear evidence based
guidelines. Patients are treated according to guidelines established for small cell lung
cancer, incorporating platinum (cisplatin or carboplatin) based doublet treatment with
etoposide. Although these tumors are initially highly chemosensitive, the natural history of
this disease is such that relapses occur early, which ultimately leads to a very poor
prognosis. Almost all clinical trials investigating cytotoxic chemotherapy in NETs are small
single arm studies and guidelines are derived from expert opinion and from extrapolating
results from small cell lung cancer studies. Prospective clinical trials in this group of
patients needs to be conducted to establish an evidence based standard of care and to improve
the prognosis of this highly aggressive group of tumors.
Participants will receive albumin bound paclitaxel (ABRAXANE®) 100 mg/m2 administered as an
intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21 day cycle. Carboplatin
will be given at an Area Under the Curve (AUC) = 5 mg/min/mL on Day 1 only of each 21 day
cycle administered over 30 mins, beginning immediately after the completion of albumin bound
paclitaxel administration. Participants can continue treatment at the investigator's
discretion until disease progression, development of an unacceptable toxicity, or withdrawal
of consent.
Gastrointestinal Neuroendocrine Tumours (NETs) are gaining increasing international
recognition as a highly prevalent disease, responsive to a number of therapies, some of which
are proven, but many of which still require high quality clinical trial evidence to confirm
their effectiveness and guide their use in practice. This study is the first prospective
trial to evaluate modern combination chemotherapy. Given the paucity of randomized studies in
neuroendocrine carcinomas (NECs), there are no clear evidence based guidelines. Patients are
treated according to guidelines established for small cell lung cancer. Although these tumors
are initially highly chemosensitive, the natural history of this disease is such that
relapses occur early, which ultimately leads to a very poor prognosis. Prospective clinical
trials in this group of patients needs to be conducted to establish an evidence based
standard of care and to improve prognosis. NETs are a heterogeneous group of malignancies
originating from cells of the neural. They have a variable and often long natural history.
They commonly arise from the gastrointestinal tract (58%), pancreas or lung (27%), and low
grade NETs can be associated with symptoms resulting from the secretion of hormones or
vasoactive peptides. NETs used to be thought of as rare but recently have been shown to be
more common with rising incidence rates (3.3/100,000 in Australia 2000-2006). Prevalence
(35/100, 000) is much higher than incidence resulting from five year survivorship of ~ 60%
resulting in NETs being more prevalent than either gastric, pancreatic, oesophageal or
hepatobiliary adenocarcinomas, or any 2 of these cancers combined. They can present multiple
complex clinical challenges, thereby significantly contributing to cancer related morbidity
and health costs in the Australian population. More recently, international interest groups
such as the European Neuroendocrine Tumor Society have identified the need to establish a
framework promoting opportunities for research and ensuring that the available evidence is
incorporated into clinical practice guidelines.
Almost all clinical trials investigating cytotoxic chemotherapy in NECs are small single arm
studies with guidelines derived from expert opinion and from extrapolating results from small
cell lung cancer studies. Most guidelines recommend the combination of a platinum compound
with etoposide. This combination is an established standard of care for small cell lung
cancer, another tumour with neuroendocrine differentiation. However, the data are less clear
for non-pulmonary neuroendocrine neoplasms (NENs) and NECs.
It is striking that almost all published NEC chemotherapy studies are non randomized and
include relatively small numbers of patients often with heterogeneous pathology. Although
there are no prospective studies with carboplatin and etoposide for NECs, it is remarkable
that it is widely accepted as the standard chemotherapy for this disease.
A Phase 2 multi-center trial evaluating the efficacy of chemotherapy with paclitaxel,
carboplatin and etoposide in advanced poorly differentiated NECs showed after 4 cycles of
this combination treatment, patients who achieved an objective response or stable disease
went on to have 24 weeks of weekly paclitaxel as maintenance treatment. Of the 78 patients
treated, 15% had a complete response and the overall response rate was 53%. Five patients
remained disease free from 18 to 66 months after therapy. The median survival was 14.5
months. However, the authors concluded that the 3 drug combination was moderately toxic and
had no obvious efficacy advantage over the standard platinum/etoposide regimens.
This year (2013 ASCO) in an abstract a single European centre reported relative responses up
to 50% in a retrospective series of NECs using 3 weekly paclitaxel, carboplatin and
etoposide.
NAB paclitaxel is suggested to achieve a higher intracellular tumour paclitaxel concentration
via the albumin mediated transendothelial transport system.
Participants will receive albumin-bound paclitaxel (ABRAXANE®) 100 mg/m2 administered as an
intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Carboplatin
will be given at an Area Under the Curve (AUC) = 5 mg/min/mL on Day 1 only of each 21-day
cycle administered over 30 mins, beginning immediately after the completion of albumin-bound
paclitaxel administration. Participants can continue treatment at the investigator's
discretion until disease progression, development of an unacceptable toxicity, or withdrawal
of consent.
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