The REPEAT trial: Regorafenib in combination with Paclitaxel in advanced oesophagogastric carcinoma, a phase 1b study

Background on disease: advanced oesophagogastric cancer
Oesophagogastric cancer (OGC) is a highly lethal disease. In 2008, 989.600 new
cases and 738.000 deaths occurred worldwide, accounting for 10% of total cancer
deaths. OGC is the third most common cause of cancer-related death in males and
the fifth most common cause in females. The overall 5-year survival rate for
OGC is approximately 26%, as the majority of patients are diagnosed when they
already have advanced disease. This group of patients has a dismal prognosis,
with a median survival of less than a year, despite several extensive chemo-
and chemoradiotherapy treatments.

For these patients, the benefit of palliative chemotherapy compared with best
supportive care has been established both in terms of overall survival (OS) and
quality of life.
Although oesophageal and gastric carcinomas may be regarded as two distinct
entities with different etiologies (e.g. Barrett dysplasia due to acid reflux
in oesophageal cancer and chronic inflammation due to Helicobacter pylori
infection) in gastric cancer * patients with metastasized adenocarcinoma of the
oesophagus, gastro-oesophageal junction (GEJ) and stomach are often studied
collectively, because the dysregulation of oncogenic pathways and the standard
treatment do overlap.

Chemotherapy for advanced oesophagogastric cancer
For advanced oesophagogastric cancer fluoropyrimidines are the backbone of
palliative chemotherapy and is commonly used in 2- or 3-drug combinations . In
general, first line treatment with triplets have led 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.

More than half of patients with OGC who received first line chemotherapy did
not achieve response, and even in responders, the duration of response only
lasts few months. In recent years the benefit of second line chemotherapy
versus best supportive care in OGC has been shown in several large trials. In a
Korean study of 202 patients with advanced gastric cancer pre-treated with
fluoropyrimidines, patients were randomized to receive best supportive care vs
supportive care plus chemotherapy. Patients who received this regimen
(docetaxel 60mg/m2 every 2 weeks or irinotecan 150mg/m2 every two weeks) as
second line therapy had a significant better overall survival than the control
group (5.3 vs 3.8 months. HR 0.657, 95%CI 0.485-0.891).
The COUGAR-02 trial randomized patients that had received first line treatment
with a combination of a fluoropyrimidine and a platinum component between
docetaxel 75mg/m2 and supportive care vs supportive care alone. Median overall
survival improved significantly in the docetaxel and supportive care group (5.2
months vs 3.2 months. HR 0.67, 95% CI 0.49-0.92, P=0.01)
These trials have provided the evidence for second line chemotherapeutic
treatment versus best supportive care. Importantly, the COUGAR-02 trial showed
that global health related quality of life was similar in both groups and
disease specific quality of life measures showed that therapy reduced dysphagia
and abdominal pain. However, considering the median overall survival of less
than 6 months, improvement of outcome is still urgently needed.


Anti VEGF therapy in advanced oesophageal/gastric cancer
Angiogenesis plays a crucial role in tumor growth and progression.
Antiangiogenic treatment is based on the theory that tumor growth will be
stopped or slowed down if formation of new blood vessels is blocked. The
clinical applicability of the antiangiogenic concept has been shown by
successful phase III trials with antiangiogenic drugs which have subsequently
led to FDA approval. Efficacy of monotherapy with angiogenesis-inhibition in
second-line in metastatic oesophagogastric cancer has been shown, as well as
combination treatment with paclitaxel, making angiogenesis a relevant target in
this tumor type. To improve treatment efficacy, anti-angiogenic drugs have been
combined with other cytotoxic or targeted drugs.

Based on very recent data from the so-called RAINBOW study, second line
treatment of patients with metastasized oesophagogastric cancer could consist
of a combination of the vascular endothelial growth factor receptor 2 (VEGFR2)
inhibitor ramucirumab combined with paclitaxel. This combination regimen
improved overall survival from median 7.4 to 9.6 months compared to paclitaxel
monotherapy. Several biological rationales for the combination of
anti-angiogenic (i.e. anti-VEGF) treatment with other systemic treatments were
postulated in different studies, one of which being the so-called vascular
normalization hypothesis. Anti-angiogenic drugs targeting VEGF normalize tumor
vessels that in turn may improve blood flow and drug delivery. However,
evidence is accumulating that despite the induction of vascular normalization,
anti-angiogenic treatment does not lead to increased tumor drug uptake. In
fact, anti-angiogenic treatment may hamper drug delivery. It has been
postulated that smart dosing schedules with proper timing of the different
agents may (partially) overcome this issue. However, clinical evidence
supporting this approach is still lacking.

Although the results of the RAINBOW study are promising, it should be noted
that the absolute improvement in survival was only 2.2 months, which could in
part also be caused by limited drug delivery. It has been postulated that
targeting of tumor stroma may improve tumor blood flow and thereby chemotherapy
delivery.Thus, a combination of anti-angiogenic treatment and stroma targeting
may be beneficial.


Rationale for the study
Regorafenib is a new oral multikinase inhibitor of angiogenic, stromal and
oncogenic receptor tyrosine kinases. Regorafenib demonstrated to increase the
overall survival of patients with metastatic colorectal cancer and has been
approved by the U.S. Food and Drug Administration (FDA), as well as by The
European Medicines Agency (EMA). In a recent phase IB study the combination of
regorafenib with FOLFOX or FOLFIRI was shown to be a tolerable treatment
regimen as first- or second-line treatment of colorectal cancer. Unfortunately,
no data are available showing the effect of regorafenib on chemotherapy uptake
in metastases. Here we propose a phase IB study in advanced OGC with cytotoxic
treatment consisting of paclitaxel together with regorafenib, to assess the
tolerability of the combination as second line therapy for metastasized OGC and
to assess the effect of regorafinib on paclitaxel uptake in OGC metastases.

Primary objectives
* To assess the tolerability of regorafenib combined with paclitaxel.

Secondary objectives
* To assess the effect of regorafenib on uptake of paclitaxel in OGC metastases.
* To assess the effect of regorafenib on regorafenib targets in OGC metastases
and blood samples.
* To assess the effect of regorafenib on paclitaxel pharmacokinetics.
* To obtain exploratory data on the efficacy of the combination of regorafenib
with paclitaxel.

We will perform a phase 1b dose finding study (phase I) and then expand the
cohort for evaluating the uptake of paclitaxel in OCG metastasis. Paclitaxel
will be tested as cytotoxic backbone for combination with regorafenib in
advanced OGC.
Paclitaxel will be dosed 80 mg/m2 I.V. infusion on Days 1, 8, and 15 of every
4-week cycle as has been reported previously and has been used in the recent
RAINBOW study (NCT01170663).1
Patients will receive regorafenib daily from day 1-21 of a 28-day cycle. The
first cycle starting on day 2 after the first administration of chemotherapy
for pharmacodynamics/kinetic purposes (see section 7.2.5). From the second
cycle onwards, regorafenib will be dosed from day 1-21.
Four different dose levels will be asessed. Dose limiting toxicity will
determined and the maximum tolerated dose (MTD) based on the DLT. After MTD
has been defined, the corresponding patient cohort will be expanded to 33
patients (see section 9 for statistical considerations) to assess the effect of
regorafenib on uptake of paclitaxel in OGC metastases on day 1 and 15of the
first cycle (phase II). see protocol chapter 4, p 13-15

Regorafenib tolerability will be tested in a dose escalation scheme with a
cytotoxic backbone of paclitaxel 80mg/m2. The dose of regorafenib will be
escalated in fixed increments according to the scheme outlined below. When the
maximum tolerated dose (MTD) is defined, uptake of paclitaxel in OCG metastasis
will be evaluated in an expansion cohort.

Dose level Paclitaxel dose
Day 1 and 8 and 15 Regorafenib dose day 1-21 Minimum
number of patients
-1 80mg/m3 i.v 40 mg p.o.
qd -
1 (starting) 80mg/m3 i.v 80 mg p.o.
qd 3
2 80mg/m3 i.v 120 mg p.o.
qd 3
3 80mg/m3 i.v 160 mg p.o.
qd 3

Paclitaxal will be given intravenously on dag 1,8 and 15 of a 4-week cycle.
from dag 1-21 of this cycle the patient will tabek tablets of regorafenib.
Before the start and during the treatment extra bloodsamples will be taken.

The main adverse reactions for Regorafenib are Neutropenia/Trombocytopenia,
hand-foot-skin reaction, hepatotoxicity, but also alopecia, anemia, decreased
appetite and food intake,diarrhea, dysphonia, fatigue/asthenia, fever,
hand-foot skin reaction, headache,hemorrhage, hyperbilirubinemia, hypertension,
infection, mucosal inflammation, nausea, pain, rash, stomatitis,
thrombocytopenia, vomiting and weight loss are common reactions.

Several side effects of nab-paclitaxel have preiously been reported, first
important to mention is neurotoxicity. Other possible side effects are nausea I
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.

When participating in this study in the expansion cohort, two additional
biopsies will have to be taken.
Before conducting the biopsies, 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.