Phase III Randomized Double-blind Cross-over trial of Supersaturated Calcium-phosphate rinse (Caphosol®) versus NaCl 0.9% in the relief of Oral Mucositis in patients receiving Targeted Therapy

Targeted therapies such as multi-targeted tyrosine kinase inhibitors (TKI) and
mammalian target of rapamycin inhibitors (mTORI) in renal cell carcinoma (RCC),
demonstrate a high level of efficacy with acceptable tolerability. Currently,
there are six EU approved targeted therapies available for treating RCC:
sunitinib (Sutent®), sorafenib (Nexavar®), pazopanib (Votrient®), temsirolimus
(Torisel®), everolimus (Afinitor®), and bevacizumab (Avastin®) plus interferon
alfa-2-a. Because bevacizumab combined with interferon alfa-2-a has a different
mechanism of action and side effect profile, patients with these agents will
not be included.
Although some of these targeted therapies share a common mode of action, it
should not be assumed that their adverse event (AE) profiles are similar.
Indeed, evidence indicates clinically relevant differences between the toxicity
profiles of targeted therapies - including between agents with similar
mechanism of action. It should also be noted that the AE profile for a targeted
agent may differ between tumor types.
Optimal antitumor activity requires maintaining the highest tolerable dose in
individual patients. In order to improve health related quality of life (HRQoL)
and patient adherence, adverse effects should be prevented, if possible avoided
and treated if necessary. Current oral formulations consist of various
schedules (continuous administration or 4 weeks on, 2 weeks off) to optimize
the benefit-risk profile. Adherence to anti-cancer treatment is particularly
important when prescribing oral therapies as adherence to the protocol can have
a significant impact on efficacy and the severity of treatment-related AEs. As
sorafenib, sunitinib, pazopanib, and everolimus are taken in the outpatient
setting, patient education on the correct treatment dosing, usage and the
nature, recognition, and severity of AEs is essential.
Since these agents have dermatological AEs in common, with oral
mucositis/stomatitis (OM/S), hand-foot skin reaction (HFSR) and papulopustular
eruption (PPE) as the most disabling AE, we require evidence based management
options to prevent and treat these complications.
OM with mucosal change, associated pain, and taste change - are clinically
relevant toxicities of TKI*s and mTORI*s presently in use. The incidence of
OM/S of any grade is for sunitinib 38%, sorafenib 28%, pazopanib 4%,
temsirolimus 41%, and for everolimus 44%.
An analysis of the appearance, clinical course, and toxicity profiles
demonstrated that TKI and mTORI associated OM is distinct from conventional
chemotherapy related OM, and more closely resembles aphthous
stomatitis/aphthous like ulcerations. There is no consensus about the
nomenclature yet, but in most studies these ulcerations are described as OM.
TKI/mTORI related OM/S may represent a dose-limiting toxicity for this new
class of agents, especially considering the fact that even lower grades of OM/S
with chronic daily dosing may be cumbersome to the patient and lead to dose
reductions. Studies of management strategies may therefore be important for the
dose adherence of TKI and mTORI and for the overall acceptance of this therapy
for patients.
Recently, supersaturated calcium-phosphate rinse (Caphosol®), a Ca2+/PO43-
mouth rinse, became available to prevent or treat OM. Caphosol rinse is
registered on the basis that it met the medical need to manage clinical
sequelae of OM in cytotoxic therapies. Caphosol is registered in the United
States and in Europe as an adjunct to standard oral care in treating CM caused
by radiation or (high-dose) chemotherapy. Relief of dryness of the oral mucosa
in these conditions is associated with amelioration of pain. Caphosol has been
shown to decrease the incidence, severity and duration of OM and pain and use
of opioids of patients given a hematopoietic stem cell transplantation (HSCT).
The present multicenter randomized crossover study is aimed to assess the oral
symptom burden (OM/S (aphthous-like), oral pain, taste change (dysgeusia),
difficulty swallowing (dysphagia), difficulty oral intake, and dry mouth)
originating from their targeted anticancer therapy, and to determine whether
Caphosol® reduces these oral AEs.

To assess the effect of Caphosol® oral rinse on clinical outcomes of selected
oral symptom burden (oral mucositis/stomatitis (aphthous-like), oral pain,
taste change (dysgeusia), difficulty swallowing (dysphagia), difficulty oral
intake, and dry mouth) associated with incidence of grade >= 1 oral adverse
events and the anticancer therapy cessation in patients treated with selected
targeted anticancer therapy in selected tumors.

Multicenter, prospective, two-arm randomized, double blind, parallel-group,
cross-over design, phase III study

The study will follow a cross-over design to maximize statistical power and
decrease biases inherent to small samples as patients will become their own
controls.
After a baseline assessment, patients will be randomly allocated to receive
either Caphosol® or NaCl 0.9% rinse for the first rinse period (14 days). For
rinse period 2 all patients will switch to the opposite treatment arm (NaCl
0.9% or Caphosol®).
The first 14 day oral rinse period will start within 2 days after the initial
work-up. Because of the two week off treatment period within sunitinib
treatment, this patients will start the oral rinse period between day 1-14 of a
treatment cycle to last them a 14 day rinse period during active anticancer
treatment. When selected AEs reappear, oral rinse period 2 will start. When
selected adverse events are not resolved at the end of rinse period 1, patients
start immediately with rinse period 2 without the wash-out period (sunitinib
patients have to wait till start of next sunitinib cycle). During the wash out
period patients rinse with self-prepared NaCl 0.9% rinse solution (one tea
spoon of salt per 500 ml of water 4 times a day).
Duration and severity of OM/S (aphthous-like), oral pain, difficulty swallowing
(dysphagia), difficulty oral intake, dry mouth, taste change (dysgeusia),
changes in saliva consistency, and talking problems will be recorded three
times a week by the patient and assessed weekly by the oncology staff.
Patients will be stratified by targeted anticancer agent and per tumor type in
pre-defined cohorts.
A DNA blood sample will be taken at baseline for exploratory analysis of
polymorphisms in Matrix metalloproteinases (MMPs) and in genes encoding for
pharmacokinetic and pharmacodynamic variables related to the targeted
anticancer agents.

The burden is to fill out 14 times a questionnaire (10 minutes each time) and
optional a biopsy of the ulcer.