An Open-Label, Non-Randomized, Single-Center Study to Determine the Metabolism and Elimination of Carbon-14 labeled Eribulin Acetate (14C-Eribulin) in Patients with Advanced Solid Tumors

E7389 (eribulin) is a synthetic analogue of a natural product isolated from the
marine sponge Halichondria okadai. It has potent anticancer effects in
cell-based and animal models of cancer. Eribulin exerts its chemotherapeutic
effect by inhibiting microtubule dynamics, which differs from those of other
known tubulin targeted-agents. The maximum-tolerated dose and dosing schedule
has been determined in Phase 1 studies. Phase 2 studies investigating the
efficacy and toxicity profile of eribulin in advanced metastatic breast cancer,
non-small cell lung cancer and prostate cancer have been completed. In addition
further phase II studies in multiple other tumor types and two phase III
studies in advanced breast cancer are ongoing. Eribulin is a complex molecule
whose metabolism and route of elimination in man has not been fully evaluated.
By performing a mass balance study with radio-labeled drug information on the
metabolic pathway and elimination can be obtained.

The primary objective of this study is to determine the excretion balance and
to elucidate the metabolic pathway of eribulin in vivo after a single dose of
carbon-14 radio-labeled eribulin (14C-eribulin), inpatients with advanced solid
tumors.

Open Label, Single-Arm

At Cycle 1, Day 1 patients will receive a single 2 mg flat dose of 14C-eribulin
(approximately 80 - 90 µCi) as an intravenous infusion over 2 - 5 minutes.
Thereafter patients will be given 1.4 mg/m2 non-radiolabeld eribulin on Day 8
of Cycle 1 and then on Days 1 and 8 every 21 days.

Common (5% or more, may occur in more than one person in 20) side-effects from
eribulin are a temporary decrease of the body*s white and red blood cells.
• Decrease in the numbers of white blood cells (leukopenia and neutropenia) may
increase the risk of infections, including pneumonia and urinary tract
infections. Infections in patients with low numbers of white blood cells in
some circumstances can be life-threatening. Neutropenia has occurred in
patients treated with eribulin, and is associated with infection in some
patients.
• A decrease in the number of red blood cells (anaemia) may result in a feeling
of tiredness.
• Eribulin could also decrease the number of platelets (thrombocytopenia) and
this may result in an increased risk of bleeding and bruising.
Other common side-effects of eribulin might include:
• Gastrointestinal problems such as nausea, vomiting, diarrhoea, constipation,
indigestion, abdominal pain, a bad taste in the mouth and the development of
sensitive areas like an ulcer in the mouth and throat.
• Neuropathy
• Respiratory problems including difficulty breathing and cough
• Other common effects include dry mouth, eyes watering, joint pain, muscle
pain or weakness, fluid retention, weight loss, loss of appetite, dizziness,
fatigue, headache and hair loss
• Some patients experienced an elevated temperature, which may be associated
with an infection.
Other uncommon (less than 5%, less than one person in 20, but may be serious in
some patients) possible side-effects of eribulin might include:
• Increased heart rate
• Infections, including pneumonia (infection of the lungs or chest), cellulitis
(infection of the skin) and urinary tract infections (bladder infections)
• Confusion
• Kidney failure
• Seizure (like an epileptic fit)
• Dehydration
• Low blood pressure
• Deep vein thrombosis and pulmonary embolism (blood clots in the legs and
lungs)
• During prior clinical studies some patients have died. The cause of death is
often due to the patients known cancer, or a serious infection. In a few cases
the cause of death was not established.
• During prior clinical studies a few patients have experienced allergic
reactions during or after receiving this drug.
As these possible uncommon side effects have not occurred very often and are
often seen in patients with cancer it can be difficult to establish if these
are a true side effect of the drug.

The effects of eribulin on the unborn child are currently not known. However it
is likely that eribulin, like other anti-cancer medications, would harm an
unborn child.

The additional radiation burden due to administration of approximately 100 µCi
of 14 C-eribulin is approximately 0.187 mSv. This is about 11% of the average
annual environmental background radiation burden in the Netherlands. Patients
will not receive any additional tumor assessments involving exposure to
radiation than in routine care. Patients are required to stay in hospital for a
minimum of 8 days, during which time frequent blood samples will be taken and
full urine and faeces collection is required.
It is not possible to determine whether a patient will benefit from receiving
eribulin. Early indications of anticancer activity have been observed in phase
2 studies. Two phase 3 studies in patients with metastatic breast cancer are
ongoing.