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Phase I Study of Aerosolized SLIT Cisplatin in the Treatment of Patients with Carcinoma of the Lung

Authors' Affiliations: Departments of ¹ Pulmonary Diseases and ² Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands; ³ Transave, Inc., Monmouth Junction, NJ; and ⁴ Department of Medical Oncology, Montefiore Medical Center, Bronx, New York

Requests for reprints: Pieter E. Postmus, Department of Pulmonary Diseases, VU University Medical Center, De Boelelaan 1117, 1007 MB Amsterdam, the Netherlands. Phone: 31-20-444-4782; Fax: 31-20-444-4328; E-mail: pe.postmus{at}vumc.nl.

	Abstract

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Purpose: To investigate the safety and pharmacokinetics of aerosolized Sustained Release Lipid Inhalation Targeting (SLIT) Cisplatin in patients with lung carcinoma.

Experimental Design: Phase I, dose-escalating study of SLIT Cisplatin given in two sessions daily. Safety data, including laboratory variables, adverse events, pulmonary function tests, and radiographic imaging, were collected and analyzed for all patients to determine toxicity. Pharmacokinetic monitoring was done during the first course.

Results: Seventeen patients and one tracheostomy patient on compassionate use received treatment. Aerosolized cisplatin was well tolerated. No dose-limiting toxicity was observed at the maximum delivered dose. Safety data showed no hematologic toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Most common adverse events were nausea (64.7%), vomiting (47.1%), dyspnea (64.7%), fatigue (64.7%), and hoarseness (47.1%). Pharmacokinetic data showed very low plasma platinum levels only with the longest repeated inhalations. Common Toxicity Criteria grade 2 decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide after one course occurred both in two patients and grade one decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide in six and five patients, respectively. Direct airway deposition via the tracheostomy resulted in clinical deterioration after two cycles best described as bronchitis, completely reversible within days. Overall response: stable disease in 12 patients and progressive disease in 4 patients (one patient received one cycle).

Conclusions: Aerosolized liposomal cisplatin was found to be feasible and safe.

In addition to potentially lowering the systemic toxicity, encapsulation of the agent in microscopic phospholipid spheres provides prolonged release at the tumor site. The lipid nature of the spheres can also promote mononuclear phagocyte uptake and absorption into lymphatic vessels, a common site of tumor metastasis.

Cisplatin (cis-diaminedichloroplatinum) is one of the most frequently used antineoplastic agents. It is administered i.v., usually in combination with other antineoplastic agents. Most first-line chemotherapeutic regimens in advanced stages of non–small cell lung cancer contain cisplatin. A major dose-limiting toxicity (DLT) associated with i.v. cisplatin therapy is nephrotoxicity. Other commonly observed toxicities that may lead to dose reduction are peripheral neuropathy, ototoxicity, myelosuppression, and hypersensitivity reactions or even nausea and vomiting. For this reason, research in the past was aimed at the development of new platinum compounds with less systemic side effects. Previous investigation of liposomal encapsulation of cisplatin was for i.v. use only (23, 24). To date, no studies have been done to investigate the effect of cisplatin, encapsulated in liposomes, by inhalation.

Preclinical study data show that liposomal entrapment of cisplatin does not render the drug inactive. Free cisplatin and Sustained Release Lipid Inhalation Targeting (SLIT) Cisplatin tested in vitro in a human lung tumor cell line (NCI-H460) showed that encapsulation did not alter the cytotoxic properties of the nebulized drug; IC₅₀ values for SLIT Cisplatin and cisplatin were found to be 0.55 ± 0.05 and 0.49 ± 0.04 µg/mL, respectively.⁵ Intratracheal instillation of SLIT Cisplatin versus i.v. cisplatin in Sprague-Dawley rats led to much higher ratios of lung/kidney levels for SLIT Cisplatin, indicating that it may be possible to achieve therapeutic levels with reduced exposure to kidneys, thus minimizing the potential for nephrotoxicity compared with i.v. cisplatin (25). In terms of localized toxicity, for beagle dogs administered a single dose of SLIT Cisplatin (2 mg/kg body weight = total deposited dose in the lungs) by inhalation and evaluated 14 days later, there were no histopathologic changes noted in the lungs, kidneys, or bone marrow.⁵

SLIT Cisplatin administered by inhalation has shown significant antitumor activity in an animal model of metastatic disease (25). Briefly, in vivo antitumor activity was studied in a murine Lewis lung tumor metastasis model (C57Bl/6) where mice were i.v. inoculated with 2 x 10⁶ tumor cells and then received 1.2 mg/m² SLIT Cisplatin or saline on days 5, 8, and 11 or an i.v. bolus of cisplatin solution of 18 mg/m² on day 5. For lungs that were excised 2 weeks later, the tumor burden was significantly reduced in case of treatment with SLIT cisplatin (P = 0.03) but not for the treatment with the bolus of cisplatin (P = 0.22) when both groups were compared with the animals that had inhaled saline. From these studies in animals, it seems that inhaled SLIT Cisplatin may be well tolerated and provides antitumor activity with little systemic exposure and toxicity. Therefore, further development of this inhalation therapy seemed warranted.

This phase I study was done in our hospital to evaluate the maximum tolerated dose within an acceptable and convenient time, the safety profile, and the pharmacokinetics of aerosolized SLIT Cisplatin in patients with primary or metastatic carcinoma of the lung.

	Patients and Methods

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Patient eligibility. This study was conducted in accordance with the ICH Harmonized Tripartite Good Clinical Practice Guidelines issued by the International Conference on Harmonization (ICH-GCP) and the principles of the Declaration of Helsinki. Written informed consent was obtained from each patient before study enrollment. Patients eligible for the study were between 18 and 75 years of age. They had an Eastern Cooperative Oncology Group performance status between 0 and 2 and a life expectancy of at least 12 weeks. They had primary cancer of the lung or metastatic cancer to the lungs deemed by their physicians to be unresponsive to, or to which no other standard treatment was available. The subjects had to be recovered from all acute adverse effects of prior therapies, excluding alopecia. An adequate pulmonary reserve as defined by a measured forced expiratory volume in one second (FEV₁), determined according to a joint statement based on the previous statements from the American Thorax Society and European Respiratory Society (26), not <50% of the age/height predicted value, was mandatory, as were adequate renal function (defined by a serum creatinine of 1.5 mg mL^–1), hepatic enzymes (bilirubin of 1.5 mg·dL^–1 and aspartate aminotransferase and alanine aminotransferase of <2.5x the institution's upper normal limit), and hematologic function (absolute neutrophil count of 1.5 x 10³ mm^–3 and platelet count of 1.0 x 10⁵ mm^–3).

Criteria for exclusion: more than three prior chemotherapy regimens, painful neuropathy persisting after a prior platinum containing regimen, pregnancy or child-bearing potential without using methods to avoid pregnancy, concurrent serious infections (i.e., requiring an i.v. antibiotic), an unstable or serious concurrent medical condition (e.g., recent myocardial infarction and superior vena cava syndrome), recent major surgery, or large-field radiation therapy or chemotherapy in the month before entry. Patients were not allowed to receive any concurrent chemotherapy, radiotherapy to the lungs, immunotherapy, or investigational agents while on study.

Study drug. SLIT Cisplatin was supplied by Transave, Inc. (Monmouth Junction, NJ) as a dispersion of cisplatin encapsulated in lipid vesicles, which are dispersed throughout the aqueous phase. NaCl solution (0.9%) is present to render the product iso-osmotic as well as to enhance the stability of the cisplatin. The concentration of cisplatin in the product was 1.0 mg mL^–1 as determined by high-performance liquid chromatography. Liposome composition was dipalmitoyl phosphatidylcholine (16.0 mg mL^–1) and cholesterol (7.5 mg mL^–1), both determined by spectrophotometry. For nebulized SLIT Cisplatin droplet size, mass median aerodynamic diameter was 3.7 microns with geometric SD of 1.9 microns and was measured by cascade impaction using a next generation pharmaceutical impactor that operated at 5°C and a 15 L·min^–1 flow rate. During nebulization, SLIT Cisplatin releases 40% to 50% of total cisplatin from cisplatin-lipid for immediate availability. The rest of total cisplatin (50-60%) remains in the liposome for a prolonged period for sustained release.

Experimental setup. Due to the cytotoxic properties of cisplatin, minimizing exposure to the drug is mandatory. For this reason, the healthcare workers and patients were dressed in full barrier protection clothing [safety glasses, respirator face mask (3M 1873V Health Care Respirator), gown, gloves, cap, and sleeves]. Treatment was done in a negative pressure room, and the drug was administered to the patients inside a demistifier tent (Demistifier Canopy model 2000, Peace Medical, Inc., Orange, NJ). The tent, industry standard for healthcare worker protection, meets all requirements for high-risk procedures according to Centers for Disease Control and Prevention and Occupational Safety and Health Administration regulation. It isolates the patient in a vinyl enclosure similar to an oxygen tent. Air is drawn upward from the area inside the canopy and flows through a High-Efficiency Particulate Air system at a rate of 240 to 360 air changes per hour. Previous studies with aerosolized toxic agents, such as ribavirin and pentamidine, as well as a study with SLIT Cisplatin showed the effectiveness of the system in limiting occupational exposure (27–30). The PARI LC Star nebulizer with PARI filter set containing a filter pad that collects the exhaled aerosols was used for aerosol delivery. The pressure generated by the compressor enables nebulization of 0.2 to 0.3 mL of drug per minute. To determine whether patients continue to exhale platinum following dosing, one patient was asked to breathe through a nebulizer for 20 min, 1 h, and 18 h after the last inhalation. The exhalation filters of these nebulizers and the one used during the last 20-min inhalation session were washed with 100 mL buffer and this fluid was assayed for platinum. The concentration of total platinum amounted to 126.5 µmol/L in the filter taken directly after an inhalation session. However, in the assayed filters, 1 and 18 h after treatment, no platinum was measurable at all. This suggests that exhaled air of the patient after 1 h seems to contain very low up until no concentrations of total platinum, and so the environment seems to be safe for other persons.

Dose escalation. SLIT Cisplatin was administered by inhalation during 1 to 4 consecutive days in 21-day treatment cycles. The dose was based on body surface area as calculated from actual body weight and height before each cycle. The nebulizations were administered over 20 min with no more than three nebulizations given per session and a maximum of two sessions daily with at least 2 h of rest between each session. Cycles were repeated every 3 weeks. The initial dose was 1.5 mg·m^–2. Subsequently, doses were doubled until Common Toxicity Criteria (CTC) grade 1 or greater toxicity was seen, excluding nausea, vomiting, and alopecia. At that point, further dose increases were by 25% until grade 2 treatment-related toxicity was observed. Thereafter, doses would be increased by 20% until DLT was reached.

Monitoring. Baseline diagnostic procedures included clinical examination, standard blood and urinary tests, pregnancy test, pulmonary function tests (PFT), a histamine provocation test, chest X-ray, and computed tomography (CT) of the thorax. A histology report with the initial diagnosis was mandatory for inclusion. Patients visited the outpatient clinic on a weekly basis between the courses for examination and blood and urinary tests. Before every course, blood and urinary tests, chest X-ray, and PFT were done. After every two courses, a CT of the thorax was made for the assessment of safety and efficacy. DLT was defined as, during cycle 1, drug related: grade 3 pulmonary toxicity, grade 4 hematologic toxicity, which lasted at least 5 days, grade 3 or greater nonhematologic toxicities (including grade 3 or greater diarrhea, nausea, and vomiting despite adequate treatment), and grade 2 hemorrhage using the National Cancer Institute-CTC (version 2.0, April 30, 1999).

Pharmacokinetics. Blood samples were obtained at various time points: baseline (i.e., before the first session), 5, 10, 30, and 60 min after every session and finally 18 h after the last session. Blood samples were collected and put on ice for immediate preparation. Afterwards, plasma samples were stored at –20°C until assay by flameless atomic absorption spectrometry (Varian Spectra AA-300 Zeeman, Houten, the Netherlands) was done as described previously (31).

Statistical analysis. Demographic data are displayed, and summary statistics (mean and SD) were used to describe the study population. GraphPad Prism 4.0 software was used to create the figures and to do statistical analysis. Pulmonary function data at baseline were compared with the data after the first cycle and off study using the repeated measure ANOVA with a post-hoc Bonferroni multiple comparison test.

	Results

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Patient characteristics
The trial was conducted in our hospital from May 2003 to January 2005. A total of 17 eligible patients were enrolled to receive treatment, mean age 56.6 years (41.8-70.7 years), 61% of the participants were male. Eastern Cooperative Oncology Group performance score of all patients was 0 to 2. Sixteen patients had histologically proven non–small cell carcinoma (seven adeno, five squamous cell, two bronchoalveolar, and two large cell undifferentiated). One patient had small cell carcinoma.

Dose escalation
Data are presented in Table 1 . Up to 24 mg·m^–2, the dose was doubled. However, due to the magnitude of doubling doses, the dose was escalated by 50% afterwards, up to a maximal deliverable dose of 48 mg·m^–2. At this dose, DLT was not reached and inhalation time became the limiting factor for further escalation. Consequently, the cycle duration was decreased from 3 to 2 weeks (patients 07-09) and subsequently to 1 week (patient 10). Beginning with patient 11, the 1-h treatment sessions were increased from two times to three times daily, with a minimum 3-h interval, between every session, in a 2-week schedule. To increase the amount nebulized in 20 min, the compressor output was changed from 0.2 to 0.3 mg·mL^–1 (patients 12-18). Finally, patients 17 and 18 received therapy in a 1-week schedule. Every time a variable was changed to adjust the schedule, one or two steps back were made in the dosage scheme based on the amount of drug per week.

Table 2 displays the documented adverse events during the study. Besides nausea and vomiting, most side effects observed during the study affected the respiratory system. Eleven patients experienced dyspnea. Productive and irritative cough were observed in five patients. Hoarseness was observed in eight patients and more often at the higher dose levels just like irritative and productive cough. Blood eosinophil counts were collected starting from patient 08 to 18. Eosinophilia was observed in 4 of 11 (36.4%) patients.

View larger version (14K): [in this window] [in a new window]   Fig. 1. Total platinum concentration in plasma during the first course of the patients in whom platinum (Pt) was detectable. *, blood sample collection the next morning.

View larger version (5K): [in this window] [in a new window]   Fig. 2. FEV1 of patient 14 during the study shows substantial decrease in FEV1 after inhalation of the study drug during course III and IV. Extra PFT were done 1 d and 1 wk after the last inhalation during the third course and 1 h, 4 h, and 1 d after the first inhalation (3 mg) of the fourth course. Patient refused a PFT for an off study value. B, baseline.

Case report. Patient 14, a 62-year-old male, was included on compassionate basis. His medical history reveals excision of a low-grade chondrosarcoma of the cricoid in 1990 and 1995 (recurrence). A second recurrence with involvement of the larynx and gradual progression resulted in total laryngectomy and a tracheostomy. During the period 2002 to 2004, multiple wedge excisions for pulmonary metastases of the chondrosarcoma were done in three sessions. Due to gradual worsening of pulmonary function after multiple surgical interventions, renewed metastasectomy for new metastases was not possible anymore. In a multidisciplinary setting, the patient was proposed to receive treatment with inhalation cisplatin.

Because the tracheostomy bypasses the oral cavity and upper part of the trachea, we assumed that virtually all the inhaled dose is deposited in the central and peripheral parts of the lungs with the exception of the exhaled part and the residue in the nebulizer. Once the particles are inhaled, sites of deposition are determined by the breathing pattern, airway geometry, and the mass median aerodynamic diameter. This direct administration of the drug into the airways through the tracheostoma makes this patient ideal for studying direct effects of the inhaled drugs on airways and parenchyma. Approximately 10% to 15% of the inhaled drug will be deposited in the lower airways with oral inhalation by a jet nebulizer (17, 34). It was decided that the patient would receive 12.5% of the prior dose step. A total of 9 mg was administered in three 10-min inhalations (dose step 13 divided by eight) The patient at dose step 13 effectively received the same dose in a period of 4 h. This means that the amount given per unit of time was approximately eight times that of the amount given to the phase I patients due to the direct entrance to the trachea and lower airways. Baseline PFT revealed 1.51 L (46%) FEV₁ and 8.2 mmol kPa^–1 min^–1 (87%) DLCO. First adverse events occurred 1 day after the second cycle and existed of dyspnea, abundant mucus production with productive cough, vomiting, fever, and cold chills. On examination, patient was slightly short of breath, had a regular elevated pulse of 101/min, temperature of 38.5°C, 92% saturation, and normal pulmonary sounds on auscultation. Chest X-ray was unchanged; laboratory tests revealed 92 mg·L^–1 C-reactive protein, 10.2 x 10⁹ L^–1 leucocytes (90% neutrophils), and 0.03 x 10⁹ L^–1 eosinophils. PFT were not done. All symptoms resolved within 2 days after appearance. During the third course, a similar pattern occurred, however, this time immediately after the last inhalation. Laboratory tests revealed 153 mg·L^–1 C-reactive protein, 10.9 x 10⁹ L^–1 leucocytes (87% neutrophils), and 0.29 x 10⁹ L^–1 eosinophils. High-resolution CT did not show any changes suggestive of pulmonary toxicity. Codeine and oxygen support, together with salbutamol and ipratropiumbromide nebulizations, were given, which led to subjective improvement. PFT 24 h after the third course revealed a 33% decrease in FEV₁ (from the pretreatment value) that resolved within a week after the event started (Fig. 3 ). The length between successive inhalations during the fourth cycle was increased for safety reasons. Four hours after the first inhalation (only 3 mg were received), the same adverse events appeared. Again, a substantial decline in FEV₁ (49% decrease from pretreatment value) was present, whereas the DLCO remained stable. Laboratory tests revealed <2.5 mg·L^–1 C-reactive protein 1 and 7 h after; 5.5 x 10⁹ L^–1 and 9.1 x 10⁹ L^–1 leucocytes at 1 and 7 h (61% neutrophils at 1 h and 88% at 7 h), respectively; and 0.26 and 0.12 x 10⁹ L^–1 eosinophils after 1 and 7 h, respectively. The next day, all adverse events had disappeared almost completely and PFT were improving. Yet again, high-resolution CT slices of the thorax, made during the occurrence of the adverse events, did not indicate damage of the lung parenchyma.

View larger version (50K): [in this window] [in a new window]   Fig. 3. Thickening of bronchial walls after treatment in patient 08 at baseline (A), after two courses (B), after the last session of the third course (C), and 1 mo off study (D).

	Discussion

Top Abstract Patients and Methods Results Discussion References

Most adverse events documented in this study, besides nausea and vomiting, were due to effects of the inhaled compound on the local environment (i.e., the respiratory tract), whereas the effects of cisplatin during systemic administration (hematologic toxicity, nephrotoxicity, ototoxicity, or neurotoxicity) did not appear. CTC grade 2 decrease in FEV₁ and DLCO after one course was both observed in two patients and grade one decrease in FEV₁ and DLCO in six and five patients, respectively. Decrease in FEV₁ was reversible in all cases but one. This was the patient with the chemical bronchitis. Moreover, CTC grade 2 decrease in FEV₁ as well as DLCO during the study was observed in three and five patients, consecutively. Whenever necessary, adverse events, such as nausea, irritative cough, or bronchial irritation, ameliorated with medical treatment.

The primary objective of this study was to assess the DLT for aerosolized SLIT Cisplatin after one treatment cycle. No DLT has been reached when using liposomal encapsulated cisplatin in a 1.0 mg mL^–1 concentration. During the study, doses were escalated by (a) increasing the dose level, (b) reducing the cycle interval (i.e., treatment was repeated after 21, 14, or 7 days), (c) increasing the number of nebulizations that can be administered in a day (from two treatment sessions up to three treatment sessions daily, one session lasting no more than 1 h), and (d) increasing the amount of drug per inhalation by increasing the flow rate of the compressor (0.2-0.3 mL min^–1) while expanding the maximum fill of the nebulizer from 5 to 7 mL. At the end of the study, the number of inhalation sessions daily in combination with the number of days on which the drug was administered was considered as the limiting factor that made further increase of the dose, with this concentration of SLIT Cisplatin administered with this inhalation device, practical impossible.

Although DLT during the first cycle of administration did not occur, most of the observed side effects were related to the respiratory tract. This varied from local irritation of the mucosa to shortness of breath. However, based on observations in some patients during the subsequent administrations, one might expect that toxicity in the respiratory tract might become more severe as cumulative higher total doses will be administered. For one patient, persistent dyspnea with considerable thickening of the bronchial wall on CT images was the reason to stop further treatment (Fig. 3).

A disadvantage of inhalation therapy remains the low deposition efficiency of the drug in the target area. As mentioned earlier, only 10% to 15% of the dose will reach the site of action during jet nebulization. For this reason, it is important that this percentage is deposited at the site of action. Droplets with a mass median aerodynamic diameter between 1 to 5 µm preferably deposit in the central and peripheral airways by mechanisms of inertial impaction and gravitational sedimentation. Larger particles will deposit in the upper airways and oropharynx by inertial impaction and smaller particles will be exhaled. Nebulized SLIT Cisplatin droplet size is 3.7 µm mass median aerodynamic diameter with 1.9 geometric SD. This means that the formulation is supposed to deposit at the site of action, in particular the peripheral airways.

Best overall response observed in this study was stable disease in 12 patients. Four patients had progressive disease.

Based on the effects seen in the patient on compassionate use (case report), the exposure of the mucosa of the airways to higher concentrations of cisplatin will probably result in local toxic effects of the mucosa (e.g., increased production of mucus due to a chemically induced "bronchitis" and secondary shortness of breath).

If a higher concentration will also affect the alveolar area remains uncertain. In the patients with the apparently highest absorption according to the pharmacokinetic data, probably coming from the deeper parts of the lung, no signs of alveolar damage were seen.

What would be the subsequent step in the development of administration of SLIT Cisplatin by inhalation is uncertain. Potentially, there are two ways to improve delivery, the easiest probably is increasing the concentration of SLIT Cisplatin in the inhalation fluid. A more complicated way is increasing the tidal volume per breath. This is possible for instance by forced respiration due to higher concentrations of CO₂ (36) in the inhaled air.

As mentioned previously, a subsequent study has started using a new concentration (i.e., 3.0 mg mL^–1). Using a higher concentration results in two major differences compared with the described phase I: per unit of time there is a three times higher deposition of drug in the respiratory tract and consequently the cumulative dose will increase much faster. From the observations in the tracheostomy patient delivering more drug per unit of time could be a reason for the observed side effects after the first cycle and also higher cumulative doses might result in toxicity during later cycles. Therefore, the design of this study is different with dose escalation based on toxicity seen during two cycles with a cycle length of 2 weeks. This study has started and still recruits patients.

This current study has proven that treatment with aerosolized liposomal cisplatin is feasible and safe. However, a dose and schedule recommendation for a phase II study with this concentration of SLIT Cisplatin cannot be made currently because the DLT has not been reached yet.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ Unpublished data.

Received 6/19/06; revised 10/27/06; accepted 2/ 2/07.

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