C-kit Tyrosine Kinase Inhibitor Research Articles

Intratumoral concentrations of imatinib after oral administration in patients with glioblastoma multiforme

Imatinib, an orally administered tyrosine kinase inhibitor of PDGF receptor, c-abl and c-kit, is currently in clinical trials to assess its efficacy in malignant gliomas. Although imatinib does not readily penetrate an intact blood-brain barrier (BBB), the extent to which it distributes into regions of high grade gliomas where the BBB is compromised has not been determined. Patients with recurrent high-grade gliomas for whom repeat surgical tumor debulking was clinically indicated received imatinib mesylate 600 mg orally once a day for seven days prior to surgery. Tissue samples were collected from different regions of the tumor and the approximate location of these samples was determined using frameless stereotactic neuronavigation. Plasma samples were obtained immediately before and after the resection. The concentration of imatinib in the plasma and tumor samples was determined using high performance liquid chromatography with mass spectrometric detection. Eleven tumor samples were obtained from three patients with recurrent glioblastoma multiforme. The median concentration of imatinib in these 11 tumor specimens was 1.34 microg/g (range 0.21-4.31 microg/g) and the median tumor-to-plasma ratio was 0.71 (range 0.28-3.03). These findings suggest that imatinib can reach intratumoral concentrations similar to those or higher than in plasma in regions of glioblastoma where the BBB is disrupted as indicated by contrast enhancement on magnetic resonance imaging.

Phase II study of sunitinib malate in head and neck squamous cell carcinoma

Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor of RET, VEGFR, PDGFR, and c-KIT. We conducted a phase II trial to evaluate the tolerability and efficacy of sunitinib in metastatic and/or recurrent SCCHN patients. Patients who had received no more than two prior chemotherapy regimens were eligible and, depending on ECOG performance status (PS), were entered into either Cohort A (PS 0-1) or Cohort B (PS 2). Sunitinib was administered in 6-week cycles at 50 mg daily for 4 weeks followed by 2 weeks off. Primary endpoint for Cohort A was objective tumor response. A Simon two-stage design required twelve patients to be enrolled in the first stage and if 1 or fewer responses were observed, further study of this cohort would be terminated due to lack of treatment efficacy. Primary endpoint of Cohort B was to determine the feasibility of sunitinib in patients with ECOG performance status 2. Twenty-two patients were accrued (Cohort A - 15 patients, Cohort B - 7 patients). Median age in cohort A and B was 56 and 61 years, respectively. Grade 3 hematologic toxicities encountered were lymphopenia (18%), neutropenia (14%) and thrombocytopenia (5%). There was only one incidence of grade 4 hematologic toxicity which was thrombocytopenia. Fatigue and anorexia were the most common non-hematologic toxicities. Grade 3 fatigue occurred in 23% of patients. The only grade 4 non-hematologic toxicity was one incidence of gastrointestinal hemorrhage. Non-fatal hemorrhagic complications occurred in 8 patients: epistaxis (3 patients), pulmonary hemorrhage (2 patients), gastrointestinal hemorrhage (2 patients) and tumor hemorrhage (1 patient). Four patients were not evaluable for tumor response (Cohort A - 3patients, Cohort B - 1 pt). One partial response was observed in the entire study. Dose reduction was required in 5 patients (Cohort A - 3 patients for grd 3 fatigue, grd 3 mucositis and recurrent grd 3 neutropenia; Cohort B - 2 patients for grd 3 fatigue and grd 3 nausea). Median time to progression for cohort A and B were 8.4 and 10.5 weeks, respectively. Median overall survival for cohort A and B was 21 and 19 weeks, respectively. Sunitinib had low single agent activity in SCCHN necessitating early closure of cohort A at interim analysis. Sunitinib was well tolerated in PS 2 patients. Further evaluation of single agent sunitinib in head and neck is not supported by the results of this trial.

Masitinib, a c‐kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid‐dependent asthmatics

Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c-kit) and platelet-derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c-kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma. The primary endpoint was the percent change from baseline in oral corticosteroids after 16 weeks of treatment. Change in asthma control (asthma control questionnaire), exacerbation rate, pulmonary function tests, rescue medication requirement and safety were secondary endpoints. A 16-week randomized, dose-ranging (3, 4.5, and 6 mg/kg/day), placebo-controlled study was undertaken in 44 patients with severe corticosteroid-dependent asthma who remained poorly controlled despite optimal asthma management. At 16 weeks of treatment, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo (median reduction of -78% and -57% in the masitinib and placebo arms, respectively). Despite this similar reduction, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 (P < 0.001) vs 0.43 unit in the placebo arm. Masitinib therapy was associated with more transient skin rash and edema. Masitinib, a c-kit and PDGF-receptor tyrosine kinase inhibitor, may represent an innovative avenue of treatment in corticosteroid-dependent asthma. These preliminary results warrant further long-term clinical studies in severe asthma

Phase II study of dasatinib in non-small cell lung cancer (NSCLC)

e19015 Background: Lung cancer is the leading cause of cancer-related deaths. Better systemic therapies are needed. One potential therapeutic target is c-Src which is expressed and activated in NSCLC patient tumors where it can mediate invasion, angiogenesis, and proliferation. Additionally, epidermal growth factor receptor (EGFR) and c-Src cooperate to promote NSCLC survival. We are conducting a phase II study of dasatinib, a tyrosine kinase inhibitor of c-Src, Abl, c-Kit, PDGFR, Btk, and EphA2. The primary objective is to determine the rate of progression free survival at 12 weeks in patients with metastatic NSCLC treated with dasatinib as front line therapy. Methods: Patients with metastatic NSCLC were treated with dasatinib (100 mg BID), with PET/CT scans every 6 weeks. KRAS and EGFR mutations, EGFR copy number, and pSrc expression were measured in pre-treatment biopsies. Blood was collected pretreatment and on day 21 to measure drug exposure (PK), pharmacodynamics (PD), and serum cytokine levels. Results: Twenty five patients have enrolled on study. Of the 16 patients evaluable for response: 1 had a partial response (PR) with no evidence of recurrence for at least 18 months (male smoker with adenocarcinoma and KRAS mutation); 6 patients had stable disease (SD) which includes 3 patients with prolonged stable disease for 4, 6, and 18 months; 9 had progressive disease (PD). Only 4 patients had a significant change in SUV (&gt;25%): decreased in 2 with PR and SD and increased in 2 with PD and SD. There is currently no clear association between EGFR and KRAS mutational analysis and response, although the sample number is small. Only 2 patients have activating EGFR mutations: one with SD and one with PD. PK, PD, and cytokine data will be presented. The most common grade 3/4 toxicity is dyspnea/pleural effusion that has led to a reduced dasatinib starting dose in subsequent patients. Conclusions: Dasatinib as a single agent has activity in a subset of patients with NSCLC. Planned correlative studies may lead to the discovery of biomarkers that predict response. Toxicities observed were consistent with prior dasatinib phase I studies in solid tumor patients. Supported by NCI/CTEP (NIH contract N01-CM-62202), The Commonwealth Foundation for Cancer Research and Bristol-Myers Squibb. [Table: see text]

A phase I study of pazopanib in combination with FOLFOX 6 or capeOx in subjects with colorectal cancer

4133 Background: Pazopanib (paz) is a tyrosine kinase inhibitor of VEGFR-1, -2, -3, PDGF-α, -β, and c-kit. Inhibition of angiogenic pathways in combination with chemotherapy has been shown to benefit patients (pts) with colorectal cancer (CRC). Methods: Pts with previously untreated advanced or metastatic CRC and adequate organ function were assigned to paz with FOLFOX6 (FO) or capeOx (CO) by their physician. Doses of paz were escalated with full strength chemotherapy, starting at 400mg daily. The optimally tolerated regimen (OTR) was the combination dose at which &lt;1/6 pts experienced dose-limiting toxicity (DLT). Results: Fifty pts were enrolled in FO (paz 400 mg, n=6; 800, 15), CO (400, 12; 800, 9) and reduced capecitabine (rc) CO (800, 8) cohorts: median age = 55.5, M/F = 37/13. Pts have remained on therapy for a median of 3 (range 0–17) months. Three pts remain on study. Safety data is available on 41. The most common AEs are summarized in the table below. The OTR was exceeded with CO in combination with 800 mg and 400 mg of pazopanib, but was not exceeded with 800 mg pazopanib when capecitabine was reduced to 850 mg/m2 twice daily or with FO with 800 mg pazopanib. Efficacy and pharmacokinetic analyses are ongoing. Conclusions: The OTRs were achieved at 800 mg paz with full-dose FO, and at 800mg paz with rcCO. [Table: see text] [Table: see text]

Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study

IntroductionSince current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.MethodsThis was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12.ResultsImprovement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends.ConclusionsTreatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation.Trial registrationClinicalTrials.gov NCT00831922.

3D-QSAR Studies of Various Diaryl Urea Derivatives of Multi-targeted Receptor Tyrosine Kinase Inhibitors: Molecular Field Analysis Approach

3D-QSAR analysis has been performed on a series of diaryl urea derivatives of multi-targeted receptor tyrosine kinase inhibitors. Models were developed using the most widely used computational approach molecular field analysis (MFA) from our dataset for the KDR, cKit and FLT3 inhibitors using genetic partial least square (G/PLS) method. These models showed excellent internal predictability and consistency and validation using test set compounds yielded a good predictive power for the activity values of three set of inhibitors. These models would offer utility in guiding the rational design of multi-targeted KDR, cKit and FLT3 receptor tyrosine kinase inhibitors for therapeutic applications. Keywords: QSAR, Receptor tyrosine kinase, MFA, Molecular field analysis, Genetic partial least squares (G/PLS) method

A pediatric phase I trial and pharmacokinetic (PK) study of sunitinib: A Children’s Oncology Group Phase I Consortium study

3561 Background: Sunitinib is an oral multitargeted tyrosine kinase inhibitor of VEGF, PDGF, c-KIT, and flt-3 receptors. This study was conducted to define the dose limiting toxicities (DLT) and to determine the maximum tolerated dose (MTD) of sunitinib in children with relapsed or refractory solid tumors. Methods: Sunitinib was administered orally once daily in 6 week cycles (4 weeks on / 2 weeks off). Cohorts of 3–6 pts (≥ 2 to ≤ 21 yr) were enrolled at a starting dose level of 20 mg/m2/d, based on the adult recommended dose of 50 mg/d. Weekly 24-hour trough plasma concentrations of sunitinib and the active metabolite, SU12662, were determined. Results: 12 pts (8 male), median age 14.6 (range 10.6–20.6) yrs, were enrolled. 3/6 pts at the initial dose level of 20 mg/m2/d had DLT: grade 2 systolic dysfunction, grade 3 anorexia, and grade 4 neutropenia. Two pts developed grade 2 hypothyroidism. 2/6 pts at dose level -1 (15 mg/m2/d) had DLTs: grade 3 systolic dysfunction and grade 3 ALT. Of the 2 pts with cardiotoxicity, one required treatment with digoxin and lisinopril for symptom control; both improved several weeks following sunitinib discontinuation. No objective responses were observed. The median d21 steady-state trough sunitinib plasma concentrations were 24.6 (range 6.0–37.7) and 37.4 (24.2–62.9) ng/mL at the 15 and 20 mg/m2 dose levels, respectively. Conclusions: Sunitinib at a dose of 20 mg/m2/d exceeded the MTD in pediatric patients included in this study. The steady-state PK profile of sunitinib in children appears comparable to that observed in adults. Due to the observed and emerging concerns of cardiotoxicity, further pediatric evaluation of sunitinib is being undertaken in pts not previously treated with anthracyclines or radiation fields involving the heart. No significant financial relationships to disclose.

Phase II study of sunitinib as second-line therapy in malignant pleural mesothelioma (MPM)

8063 Background: There is no standard second-line therapy for progressive MPM following first line chemotherapy. Sunitinib is a multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, c-Kit and Flt-3. VEGFR and PDGFR are potential targets in MPM. We examined the safety and efficacy of sunitinib as second line treatment in MPM. Methods: Eligible patients had progressive MPM during or after first-line chemotherapy with platinum and antimetabolite, ECOG PS 0–1, adequate organ function, measurable disease, and gave informed consent. Treatment: sunitinib 50 mg/day x28d q6 weeks. Primary endpoint was objective response defined by either a). Modified RECIST Criteria (MRC) on CT scan or b) metabolic response on FDG-PET in patients without prior talc pleuradesis (Francis et al, J Nuc Med (48) 1449–58; 2007). Imaging was performed at baseline and after cycles 1, 2, and every 2 cycles thereafter. Simon’s 2 stage design required 2 responses in 23 patients (stage I) to give α = 0.05, β = 0.1 assuming a true RR of 20% to be of interest. Stage I is reported here. Results: From May 2006 to October 2007 23 patients were accrued: 22 radiologically assessable for response. Demographics: M/F (18:5); median age 65 (range 49–81); histology epithelial/sarcomatoid/mixed/unknown (11:0:2:10). ECOG PS 0/1 (4:19). Prior platinum/pemetrexed 57%, prior platinum gemcitabine 43%. Best MRC response: CR 0; PR 3 (15%); SD 11 (55%); PD 6 (30%). Metabolic response on PET: 3 of 10 assessable (30%), 1 also with MRC response. Total protocol-defined response 5/22 (23%, 95% CI 5%-40%). Median follow up is 9.5 months (range 1.2–18.5 months). Median OS was 5.9 months (95% CI 2.4–9.4). Median TTP was 3.5 months (95% CI 2.8–4.2). Total cycles given is 51. Adverse events (% of all cycles): Grade 4, thrombocytopenia 1%; Grade 3, fatigue 17%, anorexia 3%, diarrhea 3%. 5/23 required dose reduction. There was one possible treatment-related death from pulmonary infiltrates and respiratory failure. Three patients developed increasing pleural effusions or ascites without other radiologic evidence of PD. Treatment was otherwise well tolerated. Conclusions: Sunitinib has activity in previously treated MPM. Stage II will continue to accrue to 51 patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology

Prognostic analysis of previously unidentified GISTs treated before the advent of c-kit immunostaining and tyrosine kinase inhibitors.

Prognostic analysis of previously unidentified GISTs treated before the advent of c-kit immunostaining and tyrosine kinase inhibitors.

Phase I study of the safety and pharmacokinetics (PK) of paclitaxel or paclitaxel with carboplatin administered in combination with pazopanib (GW786034)

14118 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit. Pazopanib also is a moderate inhibitor of CYP2C8 and CYP3A4 in vitro. Paclitaxel (T), a substrate for CYP2C8 and CYP3A4, administered alone and in combination with carboplatin (Cb) is highly active in breast, NSCLC, and ovarian cancers. The additive benefit of the anti-VEGF agent bevacizumab with T or T-Cb in breast and NSCLC provides strong rationale for use of a multi-targeted TKI with T or T-Cb. Methods: Pts with advanced cancer (ECOG PS 0–1) were eligible. Dose escalation was split into Part 1 [T (15–80 mg/m2) days 1, 8, 15 q 28 days plus pazopanib (400–800 mg) QD starting on day 2 of cycle 1] and Part 2 [T (80- 225 mg/m2) plus Cb AUC 6 q 21 days plus pazopanib 800 mg QD starting on day 2 of cycle 1]. Safety, PK, and clinical response were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicities (DLTs) and PK. Results: 12 pts in Part 1 received the following pazopanib/T doses (n = pts): 400 mg/15 mg/m2 (3), 800 mg/15 mg/m2 (3), 800mg /50 mg/m2 (3), 800mg /80 mg/m2 (3). Preliminary data were available from 9 pts in Part 1. Selected mean PK results for T are shown. 4 pts in Part 2 received 800mg /175 mg/m2/AUC 6 of pazopanib/T/Cb (data not yet available). Most common AEs (&gt;20%) in Part 1 were Gr 1/2 and consisted of fatigue, diarrhea, anorexia, nausea, vomiting, dysgeusia, AST elevation, rash, hypertension, and cough; Gr 3 diarrhea was reported in 1 pt. The 800mg pazopanib/80 mg/m2 T cohort in Part 1 is being expanded to 6 pts due to a DLT (dose delay of &gt; 2 wks due to an abscess). Best response (n=6 pts) in Part 1 was SD (83%) (range 1–5 cycles). Conclusions: Concomitant administration of pazopanib increased paclitaxel mean Cmax and AUC(0–8) approximately 20–35%. Determination of the MTR in Parts 1 and 2 is ongoing. These findings warrant further studies at therapeutic doses of pazopanib, paclitaxel, and carboplatin. [Table: see text] No significant financial relationships to disclose.

Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT)

5031 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth &amp; inhibits angiogenesis. This Phase II RDT determined effects of pazopanib on tumor growth in patients with adv/met RCC after 12 wks of treatment. Methods: Cytokine naïve and refractory (failed 1 prior cytokine or bevacizumab-containing regimen) patients with adv/met RCC, ECOG 1–2, were enrolled. Pazopanib 800 mg po qd was administered. Response (RECIST) assessed at wk 12: SD patients randomized to continue pazopanib or placebo (blinded); PR/CR patients continued pazopanib. Interim analysis (first 60 patients) endpoints: % randomized (SD) and % CR/PR at wk 12. Futility boundary was based on a randomization rate of &lt;40%. Safety was analyzed in enrolled patients (n=161) at the time of interim analysis. Results: In the first 60 patients, response at wk 12 by independent review: PR in 24 (40%); SD in 25 (42%); PD in 5 (8%); unknown response in 2 (3%); and withdrawal prior to wk 12 (reasons other than PD/AE) in 4 (7%). 27 (45%) patients were randomized based on investigator review at wk 12. Total disease control rate was 82% (PR + SD). 67% of patients were treatment naïve, 33% had failed one prior treatment regimen (23% cytokine, 8% bevacizumab, 2% both). Most common AEs/lab abnormalities in all patients (n=161; 71% M, 29% F; mean 60.3 yrs; 81% Caucasian) were ALT/AST elevations, diarrhea, fatigue, nausea, hair depigmentation, &amp; hypertension. Gr 3/4 AEs occurred in 26% of patients; most common were hypertension (8%) &amp; ALT elevation (8%). One patient had Gr 5 AE due to large intestinal perforation. AEs led to discontinuation in 5% of patients. Conclusions: Interim analysis of this Ph II study demonstrated that pazopanib treatment resulted in a PR rate at wk 12 of 40% among patients with adv/met RCC and an acceptable toxicity profile. Based on these results, the Independent Data Monitoring Committee recommended discontinuation of randomization to placebo. Patients without PD were offered continued treatment with pazopanib beyond wk 12. At the time of publication, efficacy and safety data will be available for all 225 patients. [Table: see text]

Pazopanib (GW786034) is active in women with advanced epithelial ovarian, fallopian tube and peritoneal cancers: Initial results of a phase II study

5561 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth &amp; inhibits angiogenesis. Clinical studies have demonstrated activity of anti-angiogenesis agents in ovarian carcinoma. Methods: Pts with epithelial ovarian, fallopian tube or primary peritoneal carcinoma; ECOG PS 0–1 with complete CA-125 response to initial platinum-based chemotherapy with subsequent rise to = 42 U/mL; no disease on CT; or non-bulky disease (masses ≤ 4 cm) were eligible. All pts must have received 1–2 prior regimens. Treatment consisted of pazopanib 800mg QD until PD, withdrawal due to AEs, or withdrawal of consent. Two-stage Green-Dahlberg design was employed requiring 2 CA-125 responses in Stage I (20 pts) to proceed to Stage II (15 pts). Primary endpoint was CA-125 response (= 50% decrease from 2 baseline samples, confirmed ≥ 21 d after initial response sample). Results: Data were available from 15/17 pts enrolled. Median age was 60 yrs (46–79). Majority of pts had platinum-sensitive disease to first line therapy (74%) and had 1 prior line of therapy (60%). 40% of pts relapsed &lt; 6 mos, 27% relapsed 6–12 mos; 27% relapsed &gt; 12 mos. CA-125 responses were seen in 7 pts (47%) with a median time to response of 29 d (5 pts have continuing response of 56–140 d and 2 pts had response duration of 56 &amp; 112 d). SD was observed in 4 pts (27%) and PD in 4 pts (27%). Most common AEs were fatigue, diarrhea, nausea, vomiting, and headache. Most common Gr 3/4 AEs were diarrhea (n=2) and ALT elevation (n=2). Five pts (33%) withdrew due to an AE; 1pt (7%) withdrew due to a potentially disease-related AE (Gr 3 ascites) and 4 pts (26%) withdrew due to toxicity (Gr 3 fatigue, Gr 2 vomiting, Gr 3 double vision, Gr 3 AST/ALT elevations). Conclusions: Preliminary review of Stage I suggests that pazopanib monotherapy demonstrates biologic activity in pts with ovarian cancer with biochemical relapse following prior platinum chemotherapy. The study has met the response criteria to proceed to stage II of enrollment. No significant financial relationships to disclose.

Interferon-γ is produced by another player of innate immune responses: The interferon-producing killer dendritic cell (IKDC)

Interferon-γ is a key cytokine in tumor immunosurveillance. The recently described interferon-producing killer dendritic cell (IKDC), can be distinguished from other innate effectors by its ability to kill a large variety of tumor cells and to produce high amounts of interferon-γ after encountering tumors in the absence of exogenous cytokines. The cytotoxic activity of IKDC was unraveled during an efficient immunotherapy combining c-kit tyrosine kinase inhibitors and interleukin-2, and is mediated through tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon type IIR.

Results of a multicenter phase II trial for older patients with c‐Kit‐positive acute myeloid leukemia (AML) and high‐risk myelodysplastic syndrome (HR‐MDS) using low‐dose Ara‐C and Imatinib

Imatinib (IM) is a potent tyrosine kinase inhibitor of c-Kit. c-Kit is expressed in the majority of patients with acute myeloid leukemia (AML). Whereas clinical trials evaluating monotherapy with IM in AML revealed low response rates, Ara-C and IM showed synergistic effects in vitro. This suggested evaluation of a combination treatment. Low-dose Ara-C (LDAC) combined with IM was tested to determine the efficacy and safety of this regimen. Forty patients from 4 centers with c-Kit-positive AML (n = 34) and high-risk myelodysplastic syndrome (HR-MDS) (n = 6) with a median age of 73 years were enrolled. They were either not eligible for myelosuppressive therapy and/or had recurring/refractory disease. Thirty-eight patients were evaluable for analysis. In 6 of 38 patients a blast response was observed. Eight of 38 patients showed stable disease for more than 2 months. The objective hematologic response rate was low (11%), with 2 patients showing hematologic improvement and 1 each with a partial response (PR) or complete response (CR). Median overall survival was 138 days, with 20% of patients alive after an observation period of 600 days. Study medication was applied in an ambulatory setting with minimal hospitalization time, an early mortality rate of only 18.9%, and a low toxicity rate. LDAC plus IM does not appear to be inferior in older AML patients incomparison with historic controls receiving myelosuppressive therapy. However, this trial also shows that LDAC/IM does not appear to be more effective than LDAC monotherapy in a patient population not selected for appropriate molecular markers.

Emerging targets and novel strategies in the treatment of AIDS‐related Kaposi's sarcoma: Bidirectional translational science

Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research-not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are "pirated" by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed.

Imatinib mesylate in the treatment of patients with recurrent high grade gliomas expressing PDGF-R

1526 Background: Despite noticeable progress in the treatment of high-grade gliomas (HGG), most patients experience tumor recurrence after standard treatment consisting of surgery, radiotherapy and concomitant chemotherapy. Imatinib mesylate, a tyrosine kinase inhibitor of PDGFR-α, -β, c-kit, abl and arg, has been shown to produce tumor response in patients with recurrent gliomas (Raymond ProcASCO 2004, Dresemann ProcASCO 2004&amp;2005, Reardon Proc ASCO 2005). We treated 34 patients with recurrent HGGs showing immunohistochemical expression of “imatinib targets” in the tumor tissue with imatinib. Methods: 34 patients, 16 women, 18 men, aged from 27 to 72 years, in median 49 years with recurrent HGG (GBM n= 23, AA n=11) were treated with imatinib 400 mg/day as continuous daily oral dosing. MRI was performed every three months or at clinical suspicion of progression. The median interval from diagnosis to the start of imatinib was 12.6 months (range 4.3 to 143 months). Imatinib was the 2nd line therapy in 15 patients, 3rd line in 13 and 4th line in 6 patients. ECOG performance score at start of imatinib was 1 in 9, 2 in 21 and 3 in 4 patients, respectively.Immunohistochemical analysis was performed on formalin fixed and paraffin embedded tumor tissue with antibodies against PDGFR-α, and -β. Results: The median treatment period with imatinib was 4 months (3 weeks to 17 months). The best response achieved was major response in 2 patients, partial remission in 6, stable disease in 12 and progressive disease in 14 patients. Eleven patients were free from tumor progression after 6 months (PFS-6 32,4%). The two patients with major response improved clinically and showed no more evidence of increased metabolism as well in MRI spectroscopy as in C11-methionine PET for 13 and 17 months, respectively. One of them showed widespread PDGF-R-α expression in the tumor tissue. In all patients with objective response to imatinib, a clinical benefit was noted within the first month of treatment. Conclusions: Compared to the results of Raymond et al, we observed a higher percentage of patients with progression free survival at 6 months. Detailed analysis of imatinib targets in tumor tissue of patients treated with imatinib will be helpful to explore the potential of imatinib as treatment option for patients with HGG. No significant financial relationships to disclose.

A phase I, open-label study of the safety and pharmacokinetics (PK) of pazopanib (P) and lapatinib (L) administered concurrently

3088 Background: P is a potent tyrosine kinase inhibitor of VEGF-R1, -R2, and R3, PDGF-α/β, and c-Kit. L is a potent inhibitor of ErbB1 and ErbB2 tyrosine kinases. Several lines of evidence support combined inhibition of VEGFR and Erb in the treatment of malignancies. Methods: Patients (pts) with solid tumors received P and L daily. Safety, limited PK, biomarkers, and clinical activity were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on DLT. Results: Thirty-three pts received L/P doses of 750/250 (n=4), 750/500 (n=6), 1000/250 (n=3), 1000/400 (n=2), 1000/500 (n=4), 1250/250 (n=6), 1250/400 (n=5) and 1500/200 (n=3) mg once daily (qd). Preliminary mean plasma P concentrations 24 h after administration (C24) on Day 22 were ∼19 μg/mL and 23 μg/mL after administration of 250 mg and 500 mg, respectively. These values are similar to mean C24 values observed after administration of 800 mg P alone (23.1 μg/mL). Plasma L concentrations at 750 - 1500 mg qd were similar to those observed after monotherapy. The most frequent AE’s were diarrhea (Grade (G)1 n=10, G2 n=2, G3 n=3), fatigue (G1: n=7, G2 n=5, G4 n=1), nausea (G1 n=9, G2 n=2), anorexia (G1 n=8, G2 n=3), vomiting (G1 n=9), hair depigmentation (n=7), rash (G1 n=6, G2 n=1) and abdominal cramps (G1 n=3, G2 n=2, G3 n=1). Prolonged disease stabilization of &gt; 16 wks (median 21.5 wks) occurred in 10 pts (RCC n=3, CRC n=3, GIST n=1, mesothelioma n=1, adenocarcinoma GE junction n=1, aggressive fibromatosis n=1). 3 pts (renal cancer n=2, and giant cell tumor of the bone n=1) demonstrated tumor shrinkage of &lt; 30% (i.e. SD by RECIST). Conclusions: Concurrent administration of pazopanib and lapatinib was generally well tolerated. Coadministration of lapatinib may alter the PK of pazopanib. [Table: see text]

Effects of imatinib mesylate (Glivec®) as a c‐kit tyrosine kinase inhibitor in the guinea‐pig urinary bladder

In the gastrointestinal tract, slow wave activity in smooth muscle is generated by the interstitial cells of Cajal (ICC). Detrusor smooth muscle strips of most species show spontaneous contractions which are triggered by action potential bursts, however, the pacemaker mechanisms for the detrusor are still unknown. Recently, ICC-like cells have been found in guinea-pig bladder, using antibodies to the c-kit receptor. We have investigated the effects of Glivec, a c-kit tyrosine kinase inhibitor, on spontaneous action potentials in guinea-pig detrusor and intravesical pressure of isolated guinea-pig bladders. Changes in the membrane potential were measured in guinea-pig detrusor smooth muscle using conventional microelectrode techniques. Pressure changes in the bladder were recorded using whole organ bath techniques. Smooth muscle cells in detrusor muscle bundles exhibited spontaneous action potentials, and spontaneous pressure rises occurred in isolated bladders. Glivec (10 microM) converted action potential bursts into continuous firing with no effects on the shape of individual action potentials. Glivec (>50 microM) reduced the amplitude of spontaneous pressure rises in the whole bladder in a dose dependent manner and abolished spontaneous action potentials in detrusor smooth muscle cells. The results suggest that ICC-like cells may be responsible for generating bursts of action potentials and contractions in detrusor smooth muscle. Drugs inhibiting the c-kit receptor may prove useful for treating the overactive bladder.

Pharmacokinetic and Clinical Phase II Trial of Imatinib in Patients with Impaired Liver Function and Advanced Hepatocellular Carcinoma

Objectives: No effective chemotherapy for advanced hepatocellular carcinoma (HCC) exists. Expression of the platelet-derived growth factor receptor (PDGFR) has been demonstrated in HCC, which may derive from hepatic stem cells that express c-kit. The aim of this trial was to evaluate imatinib, a tyrosine kinase inhibitor of PDGFR and c-kit, in patients with advanced HCC and impaired liver function. Patients and Methods: Patients were treated with 400–600 mg imatinib daily. Immunohistochemical staining was performed for PDGFR and c-kit. Response was assessed by CT scans every 8 weeks. For pharmacokinetics studies, 74 plasma samples were assessed. Results: Of the 17 patients enrolled in the study, 15 were evaluable for response. Only 1 tumor was positive for PDGFR and none was positive for c-kit. Grade 3/4 neutropenia occurred in 2 patients (1 had neutropenic fever). There was no objective response, and 5 (33%) patients had stable disease. Median time to treatment failure was 1.8 months in the whole study cohort and 3.7 months in the patients with stable disease. Patients treated with 400 mg imatinib did not significantly differ in pharmacokinetics from patients with chronic myelogenous leukemia (CML). Conclusion: In this small group of patients with advanced, mostly PDGFR- and c-kit-negative HCC, imatinib showed no therapeutic effect. In contrast to CML patients, the pharmacokinetics of imatinib were not significantly affected by impaired liver function.