Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung

Abstract

7131 Background: Investigate the safety and pharmacokinetics of aerosolized SLIT (Sustained release Lipid Inhalation Targeting) cisplatin in patients with carcinoma of the lung. Methods: In this single-center, dose-escalating study patients received SLIT cisplatin for a maximum of 6 cycles. The dose level defines the cycle duration and number of inhalations per day. Safety data, including laboratory parameters, adverse events, pulmonary function tests, bronchial responsiveness, and radiographic imaging were collected and analyzed for all patients in order to determine toxicity. Pharmacokinetic data was collected during the first treatment course. Results: 17 patients and 1 patient on compassionate use received treatment. SLIT cisplatin was well tolerated. No dose limiting toxicity was observed. The maximum delivered dose was 60 mg/m2 in a 2 week schedule and 40 mg/m2 on a weekly schedule. Safety data showed no hematological toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Common side effects were nausea (66.7%), vomiting (44.4%), dyspnea (66.7%), hoarseness (27.8%), and fatigue (66.7%). Pharmacokinetic data showed very low systemic concentrations only at the higher doses. CTC grade-2 decrease in FEV1 and DLCO occurred both in 2 patients after 1 course, and grade-1 decrease in FEV1 and DLCO in 6 and 4 patients respectively. Best overall response was stable disease in 13 patients, while 4 had progressive disease (1 patient received only one course). These results indicate that high doses of aerosolized SLIT cisplatin can be inhaled safely. The therapeutic effect of the formulation will be tested in a phase II study. Conclusions: Inhaled SLIT cisplatin was found to be feasible and safe in patients with lung cancer. [Table: see text]

Inhaled chemotherapy adverse effects: mechanisms and protection methods

“…Regarding human trials, the administration was performed with jet-nebulizers as a production system and under strict protection measures such as the high efficiency particulate air (HEPA) filter. In the animal studies, the aerosol was administered while the animals were inside a plastic cage or a plexi-glass chamber [28,64,[67][68][69][70][71]. A number of evaluation examinations were utilized in order to check the safety and efficiency of the treatment.…”

Nanomedicine-Based Inhalation Treatments for Lung Cancer

“…With nebulization, the administration procedure to delivering therapeutic doses is long. For example, it took up to 6 h in the case of cisplatin liposomes delivered using an air jet nebulizer [13]. It is also often inefficient in terms of lung deposition.…”

“…It is also often inefficient in terms of lung deposition. A low fraction of the nominal dose is deposited, usually 10% e15% [13,14], although up to 43% was deposited in the lungs in a trial with gemcitabine by means of a vibrating mesh nebulizer [15]. This second drawback leads to contamination of the device and the environment, which is difficult to manage.…”

“…In phase I, no systemic limiting toxicities were reached for cisplatin at the highest delivered dose (60 mg/m 2 ). This dose was delivered in a total nebulization time of more than 6 h within two cycles of three consecutive inhalation days (cycle interval of 2 weeks) [13].…”

“…Cisplatin is one of the most potent and frequently used anticancer drugs despite severe toxicities following its systemic administration. These toxicities include cumulative nephrotoxicity (the main DLT), peripheral neuropathy, myelosuppression, and ototoxicity [13]. Cisplatin is therefore a potential candidate in aerosol chemotherapy for the reduction of systemic toxicities through use of this route of administration.…”