Vol 51, No 7 (2023)

Background: Ras oncogene mutations leading to hyperactivation of the MAPK/ERK signaling pathway occur in 25% of all human tumors, and for gastrointestinal tumors, the frequency of Ras mutations amounts to 60%. The introduction of a Ras-GTPase inhibitor into clinical practice would increase the effectiveness of the treatment of socially significant diseases such as stomach and intestinal cancer.

Aim: To select the optimal dose with a subsequent assessment of the safety of iRAS when administered to patients with gastrointestinal tract tumors, including those with peritoneal carcinomatosis.

Materials and methods: This was a prospective open-label non-randomized phase I study for the assessment of safety and tolerability, with an adaptive design and determination of the maximally tolerated dose of the iRAS. Three dose levels were used (0.45 mg/kg, 0.9 mg/kg, 1.8 mg/kg) according to the "3 + 3" scheme. The study included 11 patients after surgery for stomach or colorectal cancer. The patients were administered PIPAC therapy with iRAS twice with a 7-days interval. The study duration was 28 ± 1 days. During the study, the patient monitoring included physical examination, assessment of vital signs, electrocardiography and echocardiography, laboratory parameters (hematology, clinical chemistry, coagulation tests, and urine analysis).

Results: The anti-tumor iRAS agent demonstrated satisfactory tolerability of all doses studied, including the maximal 1.8 mg/kg dose. Vital sign and laboratory abnormalities were clinically non-significant and did not require additional therapeutic interventions. Statistically significant abnormalities were registered for total protein (p = 0.00028), white blood cell counts (p = 0.007), lymphocyte counts (p = 0.0008), and a number of other blood parameters; however, most of these abnormalities were within the physiological normal ranges. Vital signs such as electrocardiography and echocardiography parameters remained stable throughout the entire follow-up period (28 days after administration of the drug). There were short-term rises in body temperature, minor pains in the postoperative scar area.

Conclusion: This trial of safety and tolerability of iRAS showed that no cases of dose-limiting toxicity in the studied dose range. The 1.8 mg/kg dose can be recommended for further clinical studies.

Tyrosine kinase inhibitor imatinib is a standard agent for treatment of gastrointestinal stromal tumors (GIST). Treatment courses are quite long and are usually well tolerated. However, skin rash can occur on treatment, with a prevalence of 7 to 88.9%. We describe a clinical case of a patient with GIST, who has been on treatment with imatinib at daily dose of 400 mg for one year. Several weeks from the treatment initiation, she had facial edema, and 4 months thereafter psoriasiform rash appeared which was initially considered to be psoriatic. After 8 months, the patient had lichenoid rash on the inguinal skin and oral, tongue and vulvar mucosae. Clinically, the lichenoid rash was similar with lichen ruber planus. To confirm the diagnosis, we performed biopsy of psoriasiform and lichenoid foci. Histological examination verified the drug-induced rash. Topical treatment of psoriasiform rash with glucocorticosteroids resulted in regression of some plaques, although a proportion of them persisted. Inguinal and vulvar lichenoid rashes completely regressed and numbers of oral and tongue foci decreased after a 6-week daily application of the 0.1% tacrolimus cream. Treatment with imatinib 400 mg daily was not interrupted. The clinical observation illustrates the possibility of skin and mucosal lichenoid and psoriasiform rash simultaneously during treatment with imatinib and demonstrates the first successful experience in the treatment of lichenoid rashes with 0.1% tacrolimus cream.