Simultaneous Integrated Boost Radiation Therapy with concomitant Capecitabine and Mitomycin-C chemotherapy for locally advanced Anal Carcinoma

Until three decades ago, the treatment of anal cancer consisted of
abdominoperineal resection resulting in a permanent colostomy. This rather
inconvenient approach has been substituted now for a combined modality
treatment of radio- and chemotherapy. In general treatment nowadays consists of
radiotherapy of 45 - 50.4 Gy over 4 - 5 weeks (± boost), with a continuous
infusion of 1000 mg/m2 5-FU for 4 days or 750 mg/m2 for 5 days in the first and
last week of radiotherapy, with/without mitomycin-C 10 - 15 mg/m2 on day 1 on
the first and/or second course. This leads to a complete remission rate of
about 80% of the patients and the disease-free survival of 50% after 4 years.
Capecitabine is the oral prodrug of 5-FU and is approved for the first-line
treatment of metastatic colorectal carcinoma and for the treatment of advanced
breast cancer and gastric cancer.
Furthermore, several studies have shown that capecitabine is a convenient
treatment alternative for 5-FU in the treatment of rectal cancer, with
treatment consisting of the combination of radiotherapy and capecitabine (5 - 7
days a week), similar to the proposal in this study protocol. Therefore,
replacement of 5-FU by capecitabine seems also an attractive alternative in the
treatment of patients with locally advanced cancer of the anal canal, which
would make the treatment much more convenient for these patients rather than
the protracted venous infusion of 5-FU. It enables continuous administration
during the whole treatment period with radiotherapy.
Radiation dose and schedule are of importance for treatment outcome in anal
cancer. Dose-limiting toxicity is often skin and bone marrow toxicity. For this
reason, split dose radiation schedules have been developed, which have an
unfavourable influence on outcome. A promising approach is the use of newer
techniques such as SIBRT, which permits treatment of anal cancer without
interruption of radiotherapy.

Primary objective of the study is the assessment of the dose limiting toxicity
(DLT) and the maximal tolerated dose (MTD) of capecitabine and mitomycin-C with
concomitant SIBRT in patients with locally advanced anal carcinoma.

Secondary objectives are:
- To determine preliminary clinical activity (response rate, time to
progression) of SIBRT with concomitant capecitabine and mitomycin-C in patients
with locally advanced AC
- To determine the pharmacokinetics of capecitabine and mitomycin-C with
concomitant SIBRT
- To establish the effect of functional genetic polymorphisms of the drug
metabolizing gene DPYD and target gene TS on the pharmacokinetics and
pharmacodynamics of capecitabine and mitomycin-C with concomitant SIBRT
- To assess the prevalence of HPV in this patient population
- To determine the type of the HPV in HPV-positive patients

This is a non-randomized, multi-center, dose-escalating, phase I study, to
assess the safety, maximum tolerated dose and pharmacokinetics of capecitabine
and mitomycin-C with concomitant SIBRT in patients with locally advanced anal
carcinoma.
Patients who meet the eligibility criteria will be treated according to study
protocol, starting with the first 3 patients at the lowest dose level, i.e.
dose level 1. In total, 3 dose levels are defined. Entering of patients in
subsequent dose levels will proceed until DLT and MTD are assessed.
Additionally, the pharmacokinetics and - genetics will be assessed, and
tumormaterial will be analyzed to assess the prevalence and type of HPV in this
patient population.

Treatment consists of:
- SIBRT 5 days a week (Monday - Friday) for 6 * weeks, i.e. 33 x 1.8/1.5 Gy (±
3 x 1.8 Gy boost)
- Capecitabine po BID 5 days a week (Monday - Friday) for 6 * weeks
- Mitomycin-C 10 mg/m2 (with a maximum of 15 mg) as intravenous bolus injection
on day 1

Radiotherapy will start 2 ± 1 hours after the morning dose of capecitabine.

3 dose levels are defined. Only the dose of capecitabine will be escalated from
500 to 650 and 825 mg/m2 twice daily in dose levels 1, 2 and 3, respectively.
The dose of mitomycine-C is in all dose levels 10 mg/m2 (max 15 mg), and the
radiation dose is 33 x 1.8/1.5 Gy (± 3 x 1.8 Gy boost).

The first 3 patients will start in dose level 1. If no dose-limiting toxicity
is observed 2 weeks after end of treatment of these 3 patients at that dose
level, the next three patients may proceed to dose level 2. The same accounts
for the proceeding to dose level 3. No intrapatient dose escalation will be
applied.
If at any dose level one of the 3 patients develops dose-limiting toxicity, up
to an additional 3 patients (up to a total of 6) will be treated at the same
dose level. If 2 or more out of 6 exhibit DLT, the maximum tolerated dose (MTD)
will be considered to be the dose given at the previous lower dose level. This
will be the advised dose for capecitabine and mitomycin-C given with
concomitant SIBRT in patients with locally advanced AC. Finally, a total of 8
patients will be treated at the MTD.

Blood sampling procedures are planned on day 1, which is associated with a
minimal risk.