Tyrosine Kinase Inhibitor Of KIT Research Articles

Unusual presentation of gastrointestinal stromal tumor with early cerebral involvement

Gastrointestinal stromal tumor (GIST) is a rare tumor typically arising from gastrointestinal tract. GIST very rarely metastasizes beyond abdominal cavity. Metastatic spread to the brain is anecdotal. This is a case study describing metastatic GIST with early cerebral involvement and resistance to therapy with KIT tyrosine kinase inhibitor imatinib mesylate.

Survival and prognostic factors analysis in surgically resected gastrointestinal stromal tumor (GIST) patients. An Interdisciplinary GIST Group Study (432)

Background Gastrointestinal stromal tumor (GIST) is the most common type mesenchymal tumor of the digestive tract and is a recently recognized tumor. Predicting its clinical behavior and prognosis has still been a problem for both pathologists and clinicians. The aim of this study was to investigate the survival and prognostic factors of gastrointestinal stromal tumors after surgery. Methods Patients with resected primary GISTs operated on between 1997 and 2008 at the University of Padua were enrolled in the study. Hematoxylin and eosin (H&E) stained histopathological slides of tumors from patients with GISTs were reviewed. Immunohistochemical staining was performed to demonstrate CD117, CD34, platelet derived growth factor receptor (PDGFR-alpha) and desmin protein expression. Clinicopathologic features (age, sex, tumor location and size, cell type, mitotic count, risk category, and expression of CD117 and CD34 protein) were evaluated by univariate and multivariate analyses in order to identify independent prognostic factors. Results 110 consecutive patients (median age 63 years, range 24-89) with resected GISTs were enrolled with a median follow-up of 40 months. 57 (51.8 %) tumors were located in the stomach, 31 (28.1 %) in the small bowel, 13 (11.8 %) in the duodenum and 9 (8.1 %) in other sites including the rectum, esophagus and retroperitoneum. Metastasis was found in 10 patients (9 %). An R0 resection was achieved in 86 patients (78 %). The postoperative mortality was 1,8 % (2/110). Considering the remaining 108 patients, the overall diseasespecific survival was 100 % at 1 year and 84 % at 5 years. The positive rate for the KIT protein (CD117) in immunostaining was 91.8 %, while that for CD34 was 59.4 %. Univariate analysis revealed that higher mitotic index, advanced pathologic stage and epithelioid histologic type contributed to worse prognosis (p Conclusions Surgical resection is the gold standard of treatment for primary GIST. Accurate pathologic findings could provide evidence for postoperative adjuvant targeted therapy. Targeted therapy such as imatinib, a KIT tyrosine kinase inhibitor, may play an important role in the treatment of GIST.

Preliminary data of nilotinib in the first-line treatment of patients with metastatic or unresectable gastrointestinal stromal tumors (GIST).

TPS332^ Background: Nilotinib (N) is a novel tyrosine kinase inhibitor (TKI) of KIT, PDGFRA, and BCR-AbL that has been shown to inhibit the proliferation of imatinib (I)-resistant GIST cell lines. Preliminary studies with N have shown that it can provide clinical activity in patients (pts) who have failed first- and second-line therapies and is safe in pts with advanced GIST. This Phase II study was conducted to investigate the efficacy of N as first-line treatment. Methods: The multicenter, single-arm trial evaluated the efficacy of N in newly diagnosed pts with unresectable or metastatic GIST or with recurrent GIST post adjuvant treatment. Pts were given N 400 mg bid until disease progression, unacceptable toxicity, or discontinuation for another reason. Primary endpoint was PFS at 6 months determined by RECIST; secondary endpoints included objective tumor response (RECIST), time to overall response, duration of response, progression-free survival, overall survival, and safety. Results: As of December 2...

Phase I study of sunitinib with irinotecan/5-fluorouracil/ leucovorin (FOLFIRI) for advanced gastroesophageal cancers.

TPS201 Background: The incidence of gastroesophageal junction (GEJ) adenocarcinoma (AC) has dramatically increased in the Western world. Chemotherapy (CT) options have reached a plateau with median survival for advanced GEJ cancer rarely exceeding 12 months. VEGF and PDGF are strong angiogenic promoters in gastric cancer increasing proliferation, invasion and survival of the neoplastic cell. Disrupting this pathway may serve as a new therapeutic strategy in GEJ cancer. Sunitinib (S) is an oral receptor tyrosine kinase inhibitor of VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with CT, including 5FU in preclinical models (Mol Cancer Ther 2:471-478, 2003). We hypothesized that the addition of S to FOLFIRI in advanced GEJ AC would augment therapeutic efficacy. Methods: Primary aim is to determine the MTD of S in combination with FOLFIRI in advanced GEJ cancer. Secondary end-pts include response, overall and progression-free survival, and pharmacokinetics (PKs) of irinotecan (I), SN-38, and S (steady-state) to determine any interactions. Therapy-naïve advanced gastric and GEJ AC patients (pts) with adequate organ function, performance status (ECOG 0-1) are eligible. UGT1A1*28 7/7 homozygous polymorphism is an exclusion. Treatment consists of standard FOLFIRI (I 180 mg/m2, leucovorin 400 mg/m2, 5FU 400 mg/m2 followed by 46-hr infusion 5FU 2,400 mg/m2 q2w) with escalating doses of S given orally daily starting on day 2 (dose range 25 mg–67.5 mg, increments of 12.5 mg per cohort). Per prespecified design, initial intra- and inter-patient dose escalation was permitted, but then changed to a standard 3+3 design after observed toxicities. Initial experience also mandated amendments to an intermittent S dosing schedule of 14 days in a 28-day cycle, with decrease in I dose to 150 mg/m2, 5FU bolus to 320 mg/m2 and 5FU infusion to 2,000 mg/m2 q2w. Dose- limiting toxicities are assessed in the 1st 4 wks of treatment (febrile neutropenia, G4 neutropenia > 7d, G4 thrombocytopenia or anemia, ≥ G3 non- heme toxicity, dose delay > 14d). PKs for I/SN-38 assessed without and with S; PKs for S assessed on days 14 and 15 of cycle 1. Current accrual is at 12 pts. This study is supported by an IISP research grant from Pfizer, Inc. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer

An Exploratory Study of Sunitinib (SU) Plus Docetaxel (D) and Trastuzumab (T) for First-Line Therapy of HER2+ Advanced Breast Cancer (ABC).

Abstract Background: T + D is a standard 1st-line treatment (tx) for HER2+ ABC (locally recurrent or metastatic BC). SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3 with single-agent activity in previously treated ABC. In this study, a SU/D/T combination was investigated as 1st-line tx for pts with HER2+ ABC.Materials and methods: Female pts (≥18 yrs, ECOG PS ≤1) with HER2+ ABC were enrolled. Starting doses were D: 75 mg/m2, q3w, iv, day 1; T q1w: 4 mg/kg, day 1, followed by 2 mg/kg q1w, iv or q3w: 8 mg/kg, day 1, followed by 6 mg/kg q3w, iv; SU: 37.5 mg/d, Schedule 2/1, po, day 2. The primary objective was safety. Antitumor activity and pharmacokinetics were secondary endpoints. On discontinuation of D, responsive pts (PR or SD) could continue SU + T until disease progression.Results: As of Mar 2009, 25 pts were enrolled. 1 pt did not receive tx, 1 pt received a dose of D/T (pt died from multiorgan failure after T administration), and 23 pts received ≥1 dose of SU/D/T; data from the latter group are reported. 12 pts (52%) were chemo-naïve. 5 pts continue on study tx; 18 have discontinued (8 due to PD, 2 due to pt decision, 7 due to AEs, 1 due to global deterioration). Pts received 201/128/211 cycles of SU/D/T, respectively, with a median of 9/6/10 cycles/pt (range: 1–18/1–12/1–18). The 37.5 mg/d SU dose was reduced to 25 mg/d in 14/23 pts and interrupted in 17/23 pts. AEs led to SU dose reductions/interruptions in 17 pts, most frequently grade (G) 3/4 neutropenia (n=8) and G3 febrile neutropenia, G3 fatigue, and G3 diarrhea (each n=2). In 23 evaluable pts, the most frequent non-hematologic G3 AEs were fatigue/asthenia (26%), diarrhea (13%), and stomatitis, vomiting, and dyspnea (each 9%). G4 AEs were transaminase increase, accidental overdose of SU, and intestinal perforation (each n=1). 1 cardiac AE was reported (G3 supraventricular tachycardia) and transient G1/2 LVEF decline was seen in 2 pts (9%). G3/4 neutropenia was reported in 20 pts (91%); 5 pts (22%) had febrile neutropenia. 2 pts (9%) had G3 anemia and 1 pt (4%) had G3 thrombocytopenia. G-CSF was administered to 11 pts without complications. Preliminary median steady-state levels of SU and its metabolite: 40.6 and 15.6 ng/mL, respectively; end D infusion: 993 ng/mL; T levels: <20 µg/mL. In 19 evaluable pts, ORR was 79% (1 CR [5%], 14 confirmed PRs [74%], 2 SD [11%]). Preliminary median PFS was 10.5 months (95% CI: 8.1–13.6) and median DR was 9.0 months (95% CI: 7.3–12.3).Conclusions: The combination of SU/D/T, given as 1st-line tx to HER2+ pts with ABC, is feasible. AEs were manageable through dose delay/reduction, and no new, unexpected AEs occurred. SU and D levels were consistent with known single-agent levels; evaluation of T levels is ongoing. Preliminary evidence of antitumor activity is encouraging and warrants further evaluation. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6088.

Sunitinib (SU) in Combination with Trastuzumab (T) for the Treatment of Advanced Breast Cancer (ABC): Activity and Safety Results from a Phase II Study.

Abstract Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSF-1R, with single-agent activity in patients (pts) with heavily pretreated ABC (locally recurrent or metastatic breast cancer). T is approved for 2nd-line monotherapy and in combination with taxane-based therapies for 1st-line ABC. The combination of SU + T in HER2+ ABC pts was investigated.Materials and methods: Eligible pts with HER2+ ABC received a starting dose of oral SU 37.5 mg/d (continuous daily dosing [CDD]) and either T administered wkly (iv loading 4 mg/kg then wkly 2 mg/kg) or q3w (loading 8 mg/kg then q3w 6 mg/kg). Due to changing standard of care, the trial was amended to include pts having prior chemotherapy in the 1st-line setting. Previous treatment (tx) with T (± lapatinib) was permitted. The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), pharmacokinetics (PK) and quality of life (QoL).Results: As of April 2009, 60 pts were enrolled (6 on the original protocol and 54 under the amendment). Of 54 pts enrolled post-amendment, 6 pts continue on study and 48 have discontinued, 12 due to AEs. Most (n=31; 57%) pts received SU + T as 1st-line tx and 11/31 pts were completely tx-naïve. Pts received a median of 5 cycles (range: 1–16) of SU and 4 cycles (range: 1–15) of T. SU was dose reduced from 37.5 mg/d to 25 mg/d in 39% of pts. All pts were evaluable for safety and 52 pts were evaluable for efficacy. ORR was 34.6% and clinical benefit rate was 48% (2 CR; 16 PR; 7 SD ≥24 wks). Of the 18 responders, 5 pts were completely tx-naïve and 9 pts were 1st-line. Median PFS was 25.3 wks (95% CI, 19.3, 29.1). Most AEs were G1/2. G3 non-hematologic AEs in ≥10% pts were asthenia (17%) and hypertension (11%) and 3 G4 events occurred (LVEF decline, pulmonary embolism, and pancreatitis). Hematologic AEs (G3/4 in ≥10% pts) were neutropenia (22%) and thrombocytopenia (17%). One G5 event (cardiogenic shock) was reported. LVEF decline/LV dysfunction occurred in 21 pts (6 pts had ≥G3 AEs); 18/21 pts (86%) had received prior anthracycline and 12 pts (57%) prior T. There was no significant on-tx change from baseline in the QoL domain. Mean (SD) steady state level for SU was 46.1 (25.9) ng/mL in agreement with prior observations.Conclusions: The combination of SU (37.5 mg/d; CDD schedule) + T (wkly or q3w) showed acceptable tolerability and antitumor activity in HER2+ ABC pts without adversely affecting overall QoL. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 201.

KIT Inhibition Affects Heat Shock Protein (HSP) Activity: A Potential Rescue Mechanism towards KIT Tyrosine Kinase Inhibition and a Rationale for Dual KIT/HSP Inhibition.

Abstract 2753Poster Board II-729Activating mutations of the KIT class III receptor tyrosine kinases are associated with core binding factor leukemias (CBF AML), systemic mastocytosis (SM), gastrointestinal stromal tumors (GIST), melanomas, seminoma/dysgerminoma and sinonasal natural killer/T-cell non-Hodgkin lymphoma. Despite the encouraging therapeutic potential of KIT-tyrosine kinase inhibitors (TKI), resistance leading to disease progression occurs in many patients, specifically after TKI monotherapy. We hypothesized that resistance to therapy is promoted by activation of alternative signaling pathways which override TKI inhibition.To explore the downstream signaling pathways of class III receptor tyrosine kinases, we performed unbiased phoshoproteomic analyses of mutant FLT3 or KIT leukemia and mastocytosis cell lines before and after TKI treatment. Tantalizingly, immunoaffinity purification of phosphopeptides followed by tandem mass spectrometry following KIT-inhibition with Imatinib at IC90 (100nM) revealed a significant upregulation of phosphorylation levels of peptides identified as members of the heat shock protein (HSP) family. Of interest, mRNA GeneChip® Array analysis of hematopoietic Ba/F3 cells transfected with either a mutant KIT isoform (D816V) or a mutant FLT3 isoform (ITD) and treated with TKI revealed significant downregulation of HSP family members in the FLT3 model – but stable mRNA levels in the KIT model. Taken together, our phosphoproteome and mRNA data suggest a protective function of HSP in mutant-KIT tumors treated with TKI.Next we studied the antiproliferative and proapoptotic effects of the HSP90 inhibitor IPI-504, a 17-AGG-derivative, in mutant-KIT cell models. IPI-504 potently inhibited proliferation and induced apoptosis with an IC50 of 0.5 up to 5μM depending on the KIT isoform. Importantly, combination of IPI-504 with TKIs resulted in potentiation of the antiproliferative and proapoptotic effects achieved by either drug alone. Antitumor efficacy in combination therapy was observed even at HSP90 inhibitor concentrations that did not display antitumor activity if administered alone.In conclusion, our model suggests that inhibition of KIT affects heat shock protein activity serving to stabilize the functionality of targeted autoactivated receptor tyrosine kinases, which provides a potential mechanism for resistance to TKI therapy. Importantly, we provide a rationale to combine TKI with (low-dose) HSP-inhibitors such as IPI-504 to optimize TKI therapy. Disclosures:Normant:Infinity: Employment.

Midostaurin (PKC412) inhibits immunoglobulin E‐dependent activation and mediator release in human blood basophils and mast cells

KIT tyrosine kinase inhibitors (TKI), such as nilotinib or midostaurin (PKC412), are increasingly used in clinical trials to counteract neoplastic cell growth in patients with aggressive mast cell (MC) disorders. However, these patients suffer not only from MC infiltration and consecutive organ damage but also from MC mediator-related symptoms. We examined the effects of three KIT TKI, imatinib, nilotinib, and midostaurin, on IgE-dependent mediator release in normal human blood basophils and cultured cord blood cell-derived MC, and on spontaneous histamine secretion in the MC leukaemia cell line HMC-1 and the basophil cell line KU812. The multi-kinase inhibitor midostaurin that interacts with KIT and protein kinase C was found to counteract anti-IgE-induced mediator release in blood basophils and cultured cord blood cell-derived MC in all samples examined. By contrast, no effects of imatinib or nilotinib on histamine secretion in basophils or MC were found. The effects of midostaurin on histamine release were dose-dependent and occurred at pharmacologic concentrations (IC(50) 10-100 nm). Midostaurin was also found to inhibit the IgE-dependent up-regulation of CD63 on cultured cord blood cell-derived human MC, but did not inhibit IgE-dependent up-regulation of CD63 or CD203c in human blood basophils. Midostaurin may be a beneficial drug in aggressive systemic mastocytosis not only because of its growth-inhibitory effects but also because of its additional effects on activation and mediator release in MC and basophils.

Evaluating and Reporting Gastrointestinal Stromal Tumors after Imatinib Mesylate Treatment

Malignant and advanced gastrointestinal stromal tumors (GIST) are currently treated with imatinib mesylate, an inhibitor of KIT and PDGFRA receptor tyrosine kinase. Pathologic evaluation of residual disease is the gold standard in these cases, as clinical and radiologic assessments of treatment response do not always correlate with the pathologic response. Phenotypic and genotypic changes may also occur which may have an impact on treatment decisions. This review will focus on the role of the pathologist in ordering appropriate testing for the primary tumor, the morphologic, phenotypic and genotypic changes seen following imatinib therapy in cases of advanced GIST, and essential components of the pathology reports.

Decreased toxicity schedule of suitinib in renal cell cancer: 2 weeks on/1 week off

e16113 Background: Sunitinib (SU) is an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET approved for treatment of metastatic renal cell cancer (mRCC). Pharmacokinetics and pharmacodynamics suggest that dose reduction might decrease the plasma concentration of SU and its major metabolite to an ineffective level. Methods: Pts with mRCC, measurable disease, ECOG PS 0–2 received SU 50 mg po daily 4 weeks on/2 weeks off. Results: Of 36 pts, median age 59.5 yrs (range 42–83), M/F (26:10), ECOG: 0 (21); 1 (9); 2 (6); prior nephrectomy (35),prior radiation therapy (28), prior cytokine therapy: IFNα (25), IL-2+IFNα (9) none (2); pts with 1 metastatic organ (24); 2 metastatic sites (7); ≥ 3 sites (5); Sites of metastases: Lung (27), Bone (11), Liver (3); MSCC risk factors: 0 (20), 1–2 (14); ≥3 (2). Objective response occurred: PR (13) 42%; CR (2) 5%; SD (9) 25%. Number of cycles (6 weeks cycles) given was: 162 (2–15).Main side effects were: fatigue 42% (Gr≥3: 17%), diarrhoea 42% (Gr≥3: 25%), nausea 31% (Gr≥3: 6%), stomatitis 10%, anorexia 10%, weight-loss 20% (Gr≥3: 11%), hand-foot syndrome 39% (Gr≥3: 17%), hypertension 28%, anemia 25%, neutropenia 8%, thrombopenia 11%, hypothyroidism 11%. Five cases of dose reduction and two cases of treatment discontinuation occurred due to toxicity. During the second part of the study if serious toxicity had been reported, instead of dose reduction, two weeks on and one week off schedule (50mg daily) had been offered to pts. 14 pts (79 cycles) were treated according to the schedule. Short term side effects decreased significantly: fatigue 28%, diarrhea 14%, nausea 14%, stomatitis 7%, anorexia 7%, weight-loss 7%, hand-foot syndrome 14%, hypertension 7%, anemia 14%, hypothyroidism 11%. Conclusions: Further prospective studies are needed to confirm the better tolerance of the SU, without decreasing the dose intensity of the treatment. No significant financial relationships to disclose.

Phase I safety and pharmacokinetic (PK) study of sunitinib (S) in combination with ifosfamide (I) in patients (pts) with advanced solid tumors (STs)

e13520 Background: S is a tyrosine kinase inhibitor (TKI) of PDGFR, VEGFR and KIT. As combinations of VEGFR-TKI with cytotoxic therapy are promising, this phase I study aimed to determine the recommended phase II dose (RP2D) of S in combination with 2 different I schedules. Methods: Pts with progressive STs, good PS, organ function, and no standard therapy available, were eligible. I (3 g/m2/day, 72h CIV (I*3), every 3 wks) was combined with continuous S. S was started at 12.5 mg/day and to be escalated in serial cohorts of 3–6 pts. RP2D was exceeded if ≥ 1/3 pts experienced dose-limiting toxicity (DLT) within the 1st cycle. After establishing the RP2D of S with I*3, feasibility of this S dose with I at 1.2 g/m2/day for 5 days CIV (I*5) every 3 wks was assessed without further scheduled dose-escalation. At RP2D, additional patients were enrolled to assess PK. Circulating endothelial cells (CECs) were measured prior to the 1st, 3rd and 6th cycle. Results: 26 pts (36–68 yrs) were accrued. 12.5 mg S was not feasible with I*3 due to neutropenia > 7 days in 2/6 pts. After protocol amendment, pegfilgrastim 6 mg (P) was given to all subsequent patients after each I-cycle. Using P, the RP2D was I*3 plus 12.5 mg S (in 1/9 pts DLT: febrile neutropenia), while I*3 plus 25 mg S was not feasible due to febrile neutropenia in 2/5 pts and hypertension & cardiac chest pain in 1/5 pts. 12.5 mg S was also feasible using I*5 as 1/6 pts had a DLT: encephalopathy. Most frequent drug related adverse events (all grades/grade 3–4) were: neutropenia (77%/62%), thrombocytopenia (73%/31%), elevated transaminases (65%/0%), renal (42%/4%), nausea (77%/0%), vomiting (58%/0%) and alopecia (62%/0%). 4/22 pts evaluable for response had PR: 1 CUP, 1 small cell carcinoma (SCC) and 2 sarcoma pts. 7 pts had SD for ≥ 3 months: 1 CUP, 1 uveal melanoma, 1 SCC, and 4 sarcoma pts. The AUC ratio of I and its metabolites in cycles I*3 without versus with S ranged from 0.72 to 1.36. No consistent change in the number of CECs during treatment was observed. Conclusions: S at 12.5 mg/day with I*3 or I*5 every 3 weeks supported by P is tolerable in pts with advanced STs. S does not affect I-PK. Antitumor activity was observed in pts with diverse tumor entities including sarcoma. No significant financial relationships to disclose.

An open-label study of sunitinib (SU) plus exemestane (E) in the first-line treatment of hormone receptor (HR)-positive metastatic breast cancer (MBC)

e12019 Background: SU, an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET has activity in heavily pretreated pts with MBC. The aromatase inhibitor (AI), E, has proven 1st-line activity that compares favorably with tamoxifen in pts with HR+ BC in the adjuvant setting (Jones et al. 2008). Combining agents that target different signaling pathways may have additive/synergistic activity; combining the AI letrozole with the anti-VEGF agent bevacizumab prolonged progression-free survival to >14 mos as 1st-line therapy for HR+ MBC (Dickler et al. 2008). An open-label, phase I, dose-finding study of first-line SU + E was conducted in HR+ MBC pts. Methods: Eligible pts (postmenopausal; female; ≥18 yrs) had an ECOG PS ≤1, LVEF ≥50% and locally recurrent (unresectable) or MBC. Exclusion criteria included HER2+ BC (unless pt had progressed after trastuzumab) and prior treatment in the metastatic setting. Pts received SU 37.5 mg/d + E 25 mg/d on a continuous daily dosing regimen; if dose-limiting toxicities (DLTs) were experienced by >1/6 pts in the first 8 wks then further pts would be enrolled at SU 25 mg/d + E 25 mg/d. Pharmacokinetic (PK) analyses were performed for each drug and the active SU metabolite SU12662. Results: As of December 2008, enrollment was completed (N=6; mean age 59 ± 11 yrs; 50% of pts had ≥3 metastatic sites). No DLTs were observed and no dose reductions were required throughout the treatment period. An overview of key data is shown below. One death occurred on study (non treatment-related Enterobacter sepsis). No treatment-related G4/5 AEs occurred. PK parameter values determined for SU and E suggested increases in the systemic exposure of both drugs when administered concurrently. Conclusions: These data indicate that SU + E was tolerable with manageable toxicities, with increases in PK parameters and a similar AE profile to that of either single agent alone. This combination should be considered in future clinical trials. [Table: see text] [Table: see text]

Sunitinib in combination with paclitaxel and carboplatin in patients with advanced solid tumors: Updated phase I study results

e14509 Background: Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, and RET, approved for the treatment of advanced RCC and imatinib-resistant/intolerant GIST. Safety and antitumor activity of SU in combination with paclitaxel (P) and carboplatin (C) were evaluated. Methods: Successive pt cohorts with advanced solid tumors (STs) received oral SU at 25, 37.5, or 50 mg for 2 wks during 3-wk cycles (Schedule 2/1) or for continuous 3 wk cycles (CDD schedule) with P (175–200 mg/m2) plus C (AUC=6 mg·min/mL) on day 1 of each of 4 cycles. Dose limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the maximum tolerated dose (MTD). Response was evaluated for pts with measurable disease. Pts with clinical benefit continued on SU after 4 cycles under a continuation protocol. Results: Forty-three pts were enrolled (25 in Schedule 2/1 and 18 in CDD schedule). Median age was 58 yrs (range: 32–76), and 74% of pts had ECOG PS of 1. Tumor types included NSCLC (n=10), SCLC, esophageal, and pancreatic (n=4 of each), and other (n=21). In initial dose escalation cohorts, 4 DLTs were observed out of 23 pts (Heath et al. ASCO 2008). Based on overall tolerability, additional pts were enrolled on both schedules at SU 37.5 mg with P 175 mg/m2 plus C. In these expanded cohorts, 2 more DLTs were observed in Schedule 2/1 (Gr 4 thrombocytopenia) out of 7 pts; dose escalation and further enrollment was stopped (Table). Gr 3/4 AEs (all cohorts) included neutropenia (63%), thrombocytopenia (47%), and leukopenia (35%). Of 35 pts evaluable for response, there were 4 confirmed partial responses and 3 additional patients with unconfirmed PRs. Conclusions: SU in combination with P/C may represent a clinically useful treatment option in pts with advanced STs. The determination of MTD based on observed DLTs/tolerability is ongoing. [Table: see text] [Table: see text]

Growth-inhibitory effects of four tyrosine kinase inhibitors on neoplastic feline mast cells exhibiting a Kit exon 8 ITD mutation

Systemic mastocytosis (SM) in felines is a rare neoplasm defined by increased growth and accumulation of immature mast cells (MC) in various organs including the spleen. Although in many cases splenectomy is an effective approach, relapses may occur. In these patients, treatment options are limited. Recent data suggest that various Kit tyrosine kinase inhibitors (TKI) interfere with growth of neoplastic MC in humans. In the current study, we examined the effects of four TKI, imatinib, midostaurin, nilotinib, and dasatinib, on growth of spleen-derived feline neoplastic MC in three SM patients. Expression of Kit in neoplastic MC was confirmed by flow cytometry and/or Western blotting. In all three cases, a 12-bp internal tandem duplication in exon 8, resulting in a four amino acid-insertion between residues Thr418 and His419 in Kit, was detectable. As assessed by 3H-thymidine incorporation experiments, all four TKI were found to inhibit the growth of feline neoplastic MC in a dose-dependent manner. The growth-inhibitory TKI effects were found to be associated with morphologic signs of apoptosis in MC. In conclusion, various Kit-targeting TKI can inhibit the in vitro growth and survival of feline neoplastic MC in SM.

Soft Tissue Sarcoma Trials: One Size No Longer Fits All

Soft Tissue Sarcoma Trials: One Size No Longer Fits All

Activity and safety of sunitinib in combination with trastuzumab for the treatment of metastatic breast cancer: initial results from a phase II study.

Abstract Abstract #4115 Background: Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSF-1R, with proven single-agent activity in pts with advanced BC. Trastuzumab (T) is indicated as both monotherapy for second-line treatment and in combination with taxane-based therapies for first-line treatment of metastatic BC. This study investigates the activity and safety/tolerability of SU administered in combination with T in pts with advanced, HER2+ BC.
 Materials and methods: Eligible pts have unresectable, locally recurrent or metastatic HER2+ BC. Pts received SU at a starting dose of 37.5 mg/d po continuous daily dosing (CDD). T was administered iv wkly (loading 4 mg/kg then wkly 2 mg/kg) or q3w (loading 8 mg/kg then 6 mg/kg q3w). Due to changes in standard of care, the trial was amended from a randomized, placebo controlled design, to a single-arm study, and eligibility criteria were changed to allow inclusion of pts who had previously received CT in the first-line setting. Previous treatment with T (± lapatinib) was also permitted. The planned sample size is 53 pts and the primary endpoint is ORR.
 Results: In this ongoing trial, a total of 49 pts have been enrolled to date (6 pts under the original protocol and 43 under the amendment). All 43 pts enrolled under the amendment were evaluable for safety/tolerability, and antitumor activity, measured by RECIST. As of May 2008, 25 pts continue on study and 18 have discontinued, 4 due to AEs. Pts started a total of 167 cycles of treatment with a median of 4 cycles/pt (range: 1–8). The planned dose of SU (37.5 mg/d) was maintained in 31/43 pts (72%). It was reduced to 25 mg/d in 12/43 pts (28%). One pt achieved a CR and 10 a PR. SD occurred in 20 pts and PD in 6 pts. This translated into an ORR of 26% (95% CI, 13.5–41.2) and a clinical benefit rate of 35% (95% CI, 21.0–50.9). Median PFS was 25.3 wks (95% CI, 19.3–32.0). The most common treatment-related AEs were diarrhea (55.8%), asthenia (48.8%) and hypertension (37.2%) of which most were G1 or 2. The most frequent G3 AEs were neutropenia (14%) and asthenia (11.6%). There were 2 treatment-related G4 events: thrombocytopenia (2.3%) and LVEF decline (2.3%). There was 1 treatment-related G5 AE (cardiogenic shock).
 Conclusions: SU 37.5 mg/d on a CDD schedule in combination with T (wkly or q3w) appears to have a manageable safety profile and antitumor activity in pts previously treated for advanced HER2+ BC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4115.

Tolerability of sunitinib in combination with docetaxel and trastuzumab as first-line therapy for HER2+ advanced breast cancer.

Abstract Abstract #4120 Background: Trastuzumab (T) combined with docetaxel (D) is approved for the first-line treatment of HER2+ advanced BC (ABC). Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3 with single-agent activity in pts with previously treated ABC. The tolerability and preliminary antitumor activity of SU combined with D and T was investigated in this exploratory study as a first-line regimen for ABC.
 Materials and methods: A target of 25 female pts (≥18 yrs, ECOG PS 0 or 1) with unresectable, locally recurrent or metastatic HER2+ BC are being enrolled. Starting doses for the 3 treatments are listed in the table below. The primary objective is safety. Secondary endpoints are PK and preliminary tumor activity according to RECIST. After discontinuation of D, responsive pts (PR or SD) can continue SU and T until PD.
 
 Results: As of May 2008, 18 pts were enrolled; 11 pts continue on study therapy and 7 have discontinued (5 due to PD; 1 due to pt decision; 1 due to G3 fatigue). Of the 18 pts enrolled, 16 are evaluable for safety and 11 for activity. Pts completed 75/96/98 cycles of D/SU/T, respectively, with a median of 5 cycles/pt for each drug (range: 1-13/1-12/1-13). The planned dose of SU (37.5 mg/d) was reduced to 25 mg/d in 6/16 pts due to G4 neutropenia (1); G3 febrile neutropenia (1); G3 fatigue (1); G2 hyperbilirubinemia (1); G2 hypertension (1); and G2 diarrhea (1). D was reduced in 4 pts due to febrile neutropenia (2) and G4 neutropenia (2). T was given q3w in 12 pts and wkly in 4 pts. T dosing was delayed by ≥4 days in 6 pts, 4 due to D dose delay and 2 due to AEs when D was already discontinued (G2 neutropenia and G3 fatigue). Overall, the most frequent AEs were fatigue (68.8%) and neutropenia (43.8%), consistent with the most common toxicities of D. No GI perforation or bleeding were reported. The most frequently reported severe AEs were neutropenia (1 G3 and 6 G4) and febrile neutropenia (5 G3). G-CSF was administered to 8 pts. Of the 11 pts evaluable for antitumor activity, 1 showed a confirmed CR, 7 a confirmed PR, 2 had PD and 1 was not evaluable.
 Conclusions: The combination of SU 37.5 mg/d (Schedule 2/1) with D 75 mg/m2 q3w and T wkly/3-wkly, given as first-line treatment to HER2+ pts with ABC, shows manageable toxicities. The use of G-CSF appears beneficial. Preliminary antitumor activity is encouraging. Enrollment is ongoing. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4120.

ATRA and KL promote differentiation toward the meiotic program of male germ cells.

While it is known that Retinoic Acid (RA) induces meiosis in mouse female fetal gonads, the mechanisms which regulate this process during spermatogenesis are poorly understood. We show that the All trans RA derivative (ATRA) and Kit Ligand (KL) increase meiotic entry of postnatal mouse spermatogonia in vitro without synergism. Competence to enter meiosis is reached by spermatogonia only at the stage in which they undergo Kit-dependent divisions. Besides increasing Kit expression in spermatogonia, ATRA also upregulates KL expression in Sertoli cells. Both ATRA and KL increase the expression of Stimulated by Retinoic Acid Gene 8 and Dmc1, an early meiotic marker. A specific Kit tyrosine kinase inhibitor prevents the increase in the number of meiotic cells induced by both the two factors, suggesting that they converge on common Kit-dependent signalling pathways. Meiotic entry induced by ATRA and KL is independent from their ability to affect germ cell viability, and is mediated by the activation of PI3K and MAPK pathways through Kit autophosphorylation. ATRA-induced phosphorylation of the two downstream kinases is mediated by a non-genomic mechanism.These data suggest that RA may control the timing of meiosis by influencing both the somatic and the germ cell compartment of the postnatal testis through the activation of the KL/Kit system.

Sunitinib-Induced Myeloid Lineage Redistribution in Renal Cell Cancer Patients: CD1c+ Dendritic Cell Frequency Predicts Progression-Free Survival

A disturbed myeloid lineage development with abnormally abundant neutrophils and impaired dendritic cell (DC) differentiation may contribute to tumor immune escape. We investigated the effect of sunitinib, a tyrosine kinase inhibitor of fms-like tyrosine kinase-3, KIT, and vascular endothelial growth factor receptors, on myeloid differentiation in renal cell cancer (RCC) patients. Twenty-six advanced RCC patients were treated with sunitinib in a 4-week on/2-week off schedule. Enumeration and extensive phenotyping of myeloid subsets in the blood was done at baseline and at weeks 4 and 6 of the first treatment cycle. Baseline patient data were compared with sex- and age-matched healthy donor data. Baseline frequencies of DC subsets were lower in RCC patients than in healthy donors. After 4 weeks of sunitinib treatment, a generalized decrease in myeloid frequencies was observed. Whereas neutrophils and monocytes, which were both abnormally high at baseline, remained low during the 2-week off period, DC rates recovered, resulting in a normalized myeloid lineage distribution. Subsequent to sunitinib treatment, an increase to high levels of myeloid DC (MDC) subset frequencies relative to other myeloid subsets, was specifically observed in patients experiencing tumor regression. Moreover, high CD1c/BDCA-1(+) MDC frequencies were predictive for tumor regression and improved progression-free survival. The sunitinib-induced myeloid lineage redistribution observed in advanced RCC patients is consistent with an improved immune status. Immunologic recovery may contribute to clinical efficacy as suggested by the finding of highly increased MDC frequencies relative to other myeloid subsets in patients with tumor regression.

Efficacy and safety profile of imatinib mesylate (ST1571) in Japanese patients with advanced gastrointestinal stromal tumors: a phase II study (STI571B1202)

Imatinib mesylate, an inhibitor of KIT, ABL protein, and platelet-derived growth factor receptor alpha (PDGFRalpha) tyrosine kinase, has recently been found to have a dramatic antitumor effect on gastrointestinal stromal tumor (GIST). The aim of this study was to assess the efficacy and safety of imatinib mesylate in Japanese patients with advanced GIST. Patients with measurable lesions were enrolled between April 1, 2002, and September 20, 2002, using a design based on previous phase II studies in the United States and the European Union. The diagnosis of GIST was proven histologically with positive immunostaining for KIT (CD117). Imatinib mesylate was administered at a dose of either 400 mg or 600 mg once a day. Pharmacokinetic parameters and mutation analysis of c-kit were also assessed in a subgroup of patients. A total of 74 patients (28 receiving imatinib mesylate at 400 mg/day; 46 receiving 600 mg/day); median age, 56.0 years, were enrolled. No patient had a complete response, 51 patients (69%) had a partial response, and 19 patients (26%) had stable disease. The median progression-free survival time was 96 weeks. The estimated 3-year overall survival (Kaplan-Meier) rate for all patients was 73.6%. The most frequent adverse effects related to the drug were nausea (78%), diarrhea (70%), dermatitis (62%), facial edema (61%), edema of the lower limbs (58%), vomiting (54%), and eyelid edema (51%). Most of the adverse effects were mild and manageable. Imatinib mesylate is generally safe and has significant activity in the treatment of advanced GIST in Japanese patients.