A phase Ib/II study on the addition of Nab-paclitaxel (Abraxane) to capecitabine and oxaliplatin in the first-line treatment of metastastasized oesophagogastric carcinoma

Background
Esophagogastric cancer is a major cause of cancer related mortality, with an
overall 5-year survival rate of 10% worldwide. The incidence of tumours of the
oesophagus and cardia is rapidly increasing, mainly as the result of a marked
increase in the incidence of adenocarcinoma. It ranks second of overall cancer
incidence and mortality, and patients are often diagnosed with locally advanced
or metastasized disease at first presentation. This group of patients has a
dismal prognosis, with a median survival of less than a year, despite several
extensive chemo- and chemoradiotherapy treatments.

Although oesophageal and gastric carcinomas may be regarded as two distinct
entities with different etiologies (e.g. Barrett dysplasia due to acid reflux
in oeosophageal cancer and chronic inflammation due to Helicobacter pylori
infection) in gastric cancer - patients with metastasized adenocarcinoma of the
esophagus, gastro-esophageal junction (GEJ) and stomach are often studied
collectively, because the dysregulation of oncogenic pathways and the standard
treatment do overlap.

For advanced oesophagogastric cancer fluoropyrimidines are the backbone of
palliative chemotherapy and is commonly used in 2- or 3-drug combinations. The
oral 5-FU analogues and prodrugs S1 and capecitabine have been shown to be (at
least) equipotent to i.v. 5-FU.

In the western world, several fluoropyrimidine containing triplets have been
used, such as 5- FU + doxorubicin + mitomycin (FAM), 5FU + doxorubicin +
methotrexate (FAMTX), 5-FU + leucovorin + etoposide (ELF), 5-FU +
epirubicin+cisplatin (ECF), 5-FU + mitomycin + cisplatin (MCF), and etoposide +
doxorubicin + cisplatin (EAP). ECF was found to be superior compared with FAMTX
in terms of survival and quality of life, although it should be noted that in
this trial the control arm FAMTX performed poorly compared to other trials.
Nevertheless, ECF has been regarded standard chemotherapy for advanced
oesophagogastric cancer in different parts of the western world.

Currently, several new drugs have shown activity in oesophagogastric cancer,
including docetaxel, irinotecan and oxaliplatin. The REAL-2 trial, aphase III
trial testing oxaliplatin and capecitabine in a 2 × 2 design, has shown that
the overall survival was non-inferior in patients treated with oxaliplatin
combinations compared with cisplatin combinations in advanced oesophago-gastric
cancer. The EOX regimen was superior to the ECF regimen in terms of overall
survival (median 11.2 versus 9.9 months, HR 0.8 95% CI 0.65-0.97).3 A
randomized phase III trial comparing docetaxel + cisplatin + 5-FU (DCF) versus
5-FU + cisplatin (FP) (11), confirmed a significant advantage for DCF compared
to FP in terms of overall survival (9.2 months versus 8.6 months). However, the
addition of docetaxel has led to increased toxicity, with more neutropenia and
diarrhoea seen in patients treated with DCF compared to FP, although quality of
life was reported better in the DCF arm.
In general, triplets have lead to modestly increased response rates and
survival, but at the cost of increased toxicity. In fact, sequential use of
doublets and singlets may achieve a better therapeutic index than first-line
use of three drugs. However, in clinical practice after progression on first
line therapy, a substantial number of oesophagogastric cancer patients may not
be able to start second line chemotherapy due to rapid clinical deterioration.
Therefore, new triplets with high anti-tumor activity and low toxicity are
urgently needed.

Rationale for the study
Given the activity of capecitabine and oxaliplatin containing regimens and the
potential of taxanes in oesophagogastric cancer, we propose a phase I study
combining capecitabine and oxliplatin with Nab-paclitaxel. Solvent-based
taxanes (paclitaxel, docetaxel) can cause severe toxicities not only by the
active agents itself but also by the solvents like cremophor. Nab-paclitaxel
(Abraxane) is a solvent-free formulation of paclitaxel encapsulated in albumin.
It does not require premedication with corticosteroids or antihistamines to
prevent the risk of solvent-mediated hypersensitivity reactions. This new
formulation improves safety profile, allows higher dosing with shorter infusion
duration, and produces higher tumor drug concentration. It has proven activity
in breast cancer, non small lung cancer and pancreatic cancer, as well as in
gastric cancer models.

Primary objective
Phase 1: To assess the safety and tolerability of Nab-paclitaxel added to
oxaliplatin and capecitabine at their currently optimal doses.

Phase 2: To determine the anti-tumor activity of Nab-paclitaxel when
co-administered with oxaliplatin and capecitabine in patients with irresectable
or metastasized oesophagogastric cancer in terms of progression free survival.

Secondary objectives
Phase 1: 1. To assess the number of complete cycles of Nab-paclitaxel,
oxaliplatin and capecitabine delivered.
2. To assess response rate, progression free survival, overall
survival.
3. To assess self-reported neurotoxicity.

Phase 2: 1. To assess the number of complete cycles of Nab-paclitaxel,
oxaliplatin and capecitabine delivered.
2. To assess response rate, overall survival.
3. To assess self-reported neurotoxicity.

This is a single-center, open label, dose finding, phase I/II study.

In the phase I part of the study, the dose of nab-paclitaxel in combination of
capecitabine and oxaliplatin will be escalated in fixed increments according to
the dose escalation scheme outlined below

doselevel nab-paclitaxel day 1and 8 capecitabine twice daily for
14 days oxaliplatin day 1 and 8 minimal number of patients
-1 40 mg/m2 1000
mg/m2 65
mg/m2 -
1 (start) 60 mg/m2 1000
mg/m2 65
mg/m2 3
2 80 mg/m2 1000
mg/m2 65
mg/m2 3
3 100 mg/m2 1000
mg/m2 65
mg/m2 3
4 120 mg/m2 1000
mg/m2 65
mg/m2 3

Once the maximum tolerated dose (MTD) for the combination therapy has been
determined, 6 up to 14 additional patients will be enrolled in this part of the
study to further evaluate safety and tolerability (i.e. in total 20 patients
will be treated at the recommended phase 2 dose before proceeding to phase II,
in case of unacceptable toxicity the investiagator can decide to lower the
doselevel and re-determine the MTD)

In the phase II part of the study the maximum tolerated dose from the phase I
part of the study will be used in combination with fixed dosages of
capecitabine and oxaliplatin; nab-paclitaxel day 1 and 8 according to the MTD
of the phase 1 part of the study combined with capecitabine for 14 days at
1000mg/m2 twice daily and oxaliplatin day 1 and 8 65mg/m2.

By participating in this study, additional research on tumor material available
in the pathology archives at the AMC will be done. If this material is not
(sufficiently) present, an additional biopsy will have to be taken.
Before conducting any additional biopsy, the patient will have to come to the
hospital. Before the biopsy is taken, the skin is numbed. The taking of
biopsies is then virtually painless and safe. However, there is a slightly
increased risk of the occurrence of bleeding.

Subsequently, nab-pacitaxel is administered intravenously in combination with
oxaliplatin on day 1 and day 8 of a three-weekly cycle, and during day 1-14,
capecitabine tablets will be taken. Prior to treatment, during treatment and
after treatment additional blood is collected.
We will also ask to complete the quality of life questionnaire before
initiation of treatment, after three weeks, after nine weeks, and then every
nine weeks.

Several side effects of nab-paclitaxel have preiously been reported, first
important to mention is neurotoxicity. Other possible side effects are nausea /
vomiting, and diarrhea, mouth sores, loss of appetite, muscle pain, joint pain,
hair loss, rash, acute hypersensitivity reactions during the running of the
medication through the IV and bone marrow suppression.

The occurrence of other or serious side effects as a result of the combined
administration of the three medications nothing is known because this has never
been done before.