Progressive Solid Tumors Research Articles

Ipilimumab: First results of a phase I trial in pediatric patients with advanced solid tumors.

9545 Background: Ipilimumab is a fully-human IgG1 monoclonal anti-CTLA-4 antibody which has been approved by the FDA for adult patients with metastatic melanoma . Although the approved dose is 3mg/kg every 21 days, the dose of 10mg/kg IV every 21 days for 4 doses in combination with chemotherapy was well tolerated in a phase III trial enrolling adult patients with melanoma. Methods: This pediatric phase I, dose escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of ipilimumab administered to patients <21yo with recurrent or progressive solid tumors. Ipilimumab was administered at 1, 3, 5, and 10mg/kg IV in a standard 3 + 3 design with 4 doses of induction therapy q3 weeks followed by maintenance q3 months until disease progression or unacceptable toxicity. Tumors were measured after 6 weeks, 12 weeks, and then every 3 months. Results: Twenty one patients (melanoma n=6, osteosarcoma n=6, soft tissue sarcomas n=7, neuroblastoma, and renal cell carcinoma) received a total of 57 doses of Ipilimumab to date. One of 6 patients treated at 5mg/kg developed a dose-limiting grade 3 pancreatitis. .At the highest dose level of 10mg/kg, two of three patients under 12yo developed DLT: grade 3 colitis and concurrent norovirus in one patient, and self-resolving grade 3 transaminitis in a second patient. Three of three patients between the ages of 12 and 21yo tolerated the 10mg/kg dosing schedule without DLT. Across all dose levels, grade 2 or 3 adverse events included colitis (n=1), transaminitis (n=3), pancreatitis (n=1), autoimmune thyroiditis (n=2), and hypophysitis (n=1) observed between C1D8 and C4D21. A single grade 1 rash was observed. Stable disease was the best response in 5 patients with a duration of 3 to 18 months. Conclusions: Ipilimumab can be safely administered to pediatric patients. Adolescents are able to tolerate the highest dose of 10mg/kg. Younger children (<12yo) had 2 DLTs in 3 patients at 10 mg/kg . Expansion of the 10 mg/kg cohort for adolescents and of the 5 mg/kg dose for the <12yo for further safety and pharmacokinetic information is underway. The spectrum of adverse events appears similar to those described in the adult trials, although there were no grade 2 or higher incidents of rash.

Phase I and pharmacokinetic (PK) study of pazopanib (P) in combination with two schedules of ifosfamide (I) in patients (pts) with advanced solid tumors (STs).

2593 Background: P is a tyrosine kinase inhibitor of PDGFR, VEGFR and KIT. This study aimed to determine the recommended phase II dose (RP2D) of P combined with I. To assess the impact of scheduling on tolerability, two I schedules were explored. Methods: Pts with progressive ST, no standard therapy available, PS 0-1 and good organ function were eligible. Pts received daily P with 3-weekly I, 9 g/m2/cycle, either continuously (Iciv) or as 3 hrs boluses (Ibolus) for 3 days. P was escalated in serial cohorts of 3-9 pts per I-schedule. If in 3-6 pts dose-limiting toxicity (DLT) of 33.3% within 1st cycle was seen 3 more pts at that dose level (DL) were enrolled. RP2D was exceeded if in > 1/3 pts, > 2/6 pts or ≥ 3/9 pts DLT occurred. P was maximized at 1000 mg/day. At RP2D, an expansion cohort of 6-9 pts was studied to confirm safety. PK samples of P and I were collected in all pts. Sampling allowed intra-individual comparison of I-PK with or without P and vice versa. Results: 47 pts were studied. For Iciv (25 pts), RP2D was the maximum dose of P (1000 mg), higher than the single agent RP2D. At RP2D 2 DLTs in 15 pts occurred: 1 febrile neutropenia (FN); 1 encephalopathy. With Ibolus (22 pts), P 400 mg with or without GCSF was not tolerated (5 DLTs in 10 pts: 3*FN, 1 encephalopathy; 1 proteinuria). At RP2D (P 200 mg + Ibolus + GCSF) 3 DLTs in 12 pts (FN; encephalopathy, renal insufficiency) were observed. Toxicity occurring in >30% of pts in Iciv (all grades/grade 3-4,%) were neutropenia (92/92) anemia (92/8); thrombocytopenia (35/12), elevated ASAT, ALAT, alkaline phosphatase (73/4; 73/0; 62/2), nausea (58/0), vomiting (73/0), diarrhea (54/0) and hypertension (31/12). 4/25 pts in Iciv evaluable for response had PR (2 sarcoma, 2 ovary) and 10 prolonged (≥3 mths) SD. In Ibolus, 6/20 pts had PR (2 urothelial, 1 sarcoma, 1 ovary, 1 CUP, 1 mesothelioma) and 3/20 prolonged SD. Preliminary PK analysis showed no effect of P on I-exposure, neither of Ibolus or Iciv on P. Conclusions: P is tolerated at a higher dose combined with Iciv compared to Ibolus (1000 vs 200 mg). PK cannot explain this difference. This study underlines the impact of scheduling on the tolerability of VEGFR-TKI and cytotoxic drug combinations.

Abstract 5283: Autophagy regulation of angiogenesis in human neuroblastoma

Abstract Neuroblastoma is a progressive solid tumor in infants and children that originates from neural crest and it remains a clinical challenge to treat. It is a highly malignant tumor, in part, because angiogenesis is a key factor in tumor progression of neuroblastoma. We have previously identified that gastrin-releasing peptide (GRP)-receptor-mediated cell signaling is critical to its tumorigenicity. In this study, we hypothesized that increased autophagy via blockage of GRP receptor could potentially inhibit angiogenesis in human neuroblastomas. METHODS. Autophagic key molecular markers were detected with ATG5, Beclin-1 and LC3 antibodies. Phosphorylation of Akt, mTOR and S6R were detected by Western blotting. Angiogenesis were measured using tubule formation of human umbilical vein endothelial cells (HUVECs) grown on top of Matrigel Matrix Basement Membrane in vitro. They were also determined using a mouse model of the cornea pocket assay in vivo. Autophagy was determined by punctuate localization of GFP-LC3 fusion protein, and observed under a confocal fluorescence microscope in vitro. RESULTS. Levels of phospho-Akt, -mTOR and -S6R were increased in BE(2)-C cells treated with GRP in both time- as well as dose-dependent manner. However, the PI3K/Akt/mTOR pathway was inactivated in short-hairpin (sh) silenced targeted at GRP receptor in BE(2)-C cells when compared to control shLac cells, indicating that angiogenesis may be reduced. We also observed increased levels of ATG5, Beclin-1 and LC3 proteins, key autophagic mediators, in shGRP receptor-BE(2)-C cells when compared to controls (shLac cells). In particular, overexpression of ATG5 and Beclin-1 also significantly decreased tube formation on HUVECs when treated with exogenous GRP (100 nM). Consistent with the in vitro findings, treatment with GRP receptor antagonist (RC3095) showed a dramatically decrease in angiogenesis in a mouse model of the cornea pocket assay in vivo. CONCLUSIONS. Our results show that enhanced autophagy was associated with a downregulation of angiogenesis signaling pathways, and an increase in characteristic punctuate localization of GFP-LC3 as a marker for autophagy. A better understanding of how autophagic proteins can regulate the angiogenic process may lead to novel therapeutic strategies in the treatment of neuroblastomas or its vascular disorders. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5283. doi:1538-7445.AM2012-5283

Abstract A212: First in human phase I study of PRS-050 (Angiocal), a VEGF-A targeting anticalin, in patients with advanced solid tumors: Results of a dose escalation study.

Abstract Background: Anticalins are a new class of therapeutic small protein (20kDa) antibody mimetics based on human lipocalins which can be engineered to bind key molecules involved in tumor progression with high affinity and specificity. PRS-050 (40kDa PEGylated Anticalin) targets VEGF-A. The first clinical trial of this putative therapeutic drug is reported. Methods: This Phase I study is a dose-escalation trial in patients with solid tumors according to the 3+3 escalation scheme investigating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of PRS-050 given via a 5–20 min iv infusion/bolus on days 1, 22, 29, 36, and 43 and in 2-weeks intervals thereafter until toxicity or tumor progression. PK was assessed after the first administration. Anti-PRS-050 antibodies and PD markers including target engagement (PRS-050:VEGF-A complex), free plasma VEGF-A, serum MMP-2 levels, and DCE-MRI were assessed repetitively. Tumor response was evaluated at day 43 according to RECIST. Results: Twenty-six patients (pts) with progressive solid tumors were enrolled and treated with doses ranging from 0.1 to 10 mg/kg. Tumor types included CRC (46%), malignant melanoma (12%), and pancreatic cancer (8%). The median treatment duration was 43 days (min. 1, max. 251). Drug-related adverse events (AEs) of all grades reported in >20% of pts were chills (46%, G3 4%), fever (23%, G3 4%), hypertension (39%, G3 12%), which were responsive to pretreatment with steroids, antipyretics, and/or H1/H2 blockers, or antihypertensive medication. DLT's include 1 G3 hypertension at 1.5mg/kg and 1 G3 infusion reaction at 10mg/kg. As a result, infusion time was increased to 2 hrs in 4 pts and there was no further infusion reaction. There was one nonfatal intestinal perforation after dose 9. Anti-PRS-050 antibodies were not detected at day 43 (21 pts) or at day 71 (16 pts). PRS-050 showed a dose-dependent increase in exposure up to 10 mg/kg with a terminal half-life of 6 days. No patient achieved an objective response (PR/CR). Stable disease was observed in 9 pts with the longest duration, to date, of 8.5 months in a patient with melanoma. Free VEGF-A levels were detectable at baseline in 8/22 pts, becoming undetectable after 15 min subsequent to the infusion of PRS-050, and remained so for 21 days. PRS-050:VEGF-A complex formation was detectable for up to 3 weeks at all dose levels (22/22 pts) including pts with no detectable free VEGF-A at baseline. Furthermore, circulating MMP-2 levels and changes in the DCE-MRI response at day 2 suggest an anti-angiogenic effect. Conclusions: PRS-050 a small selective high affinity antibody mimetics is well-tolerated when administered with premedication as a 2 hour infusion at doses up to 10mg/kg. No formally defined MTD was reached. The recommended dose of PRS-050 for phase II is 6 mg/kg every 2 weeks, with premedication and 2 hour infusion time, based on results in preclinical xenograft models, preclinical and clinical PK/PD data of this phase I study. Most important, the drug demonstrates the intended PD effects and is ready for Phase II studies in patients with solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A212.

Targeting Angiogenesis for Controlling Neuroblastoma

Neuroblastoma, a progressive solid tumor in childhood, continues to be a clinical challenge. It is highly vascular, heterogeneous, and extracranial tumor that originates from neural crest. Angiogenesis, genetic abnormalities, and oncogene amplification are mainly responsible for malignant phenotype of this tumor. Survivability of malignant neuroblastoma patients remains poor despite the use of traditional therapeutic strategies. Angiogenesis is a very common and necessary pre-requisite for tumor progression and metastasis. Angiogenesis is also a major factor in making malignant neuroblastoma. Thus, prevention of angiogenesis can be a highly significant strategy in the treatment of malignant neuroblastoma. Here, we summarize our current understanding of angiogenesis in malignant neuroblstoma and describe the use of experimental anti-angiogenic agents either alone or in combination therapy. This review will clearly indicate the importance of angiogenesis in the pathogenesis of malignant neuroblastoma, its prevention as a promising therapy in preclinical models of malignant neuroblastoma, and prospective clinical trials.

A first-in-human phase I dose-escalation study of MK-1496, first-in-class orally available novel PLK1 inhibitor, in patients with advanced solid tumors.

3012 Background: Polo-like kinase 1 (PLK1) is a serine/threonine kinase involved in cell cycle control, especially has key roles in multiple steps of mitosis progression. Overexpression of PLK1 is frequently observed in a range of human tumors, suggesting PLK1 function is important for proliferation of cancer cells. MK-1496 is an orally available highly potent and selective inhibitor of PLK1 with demonstrated anti-proliferative activity in vitro and in vivo. Methods: Sequential cohorts of 3 to 6 patients (pts) with progressive advanced or metastatic solid tumors received an MK-1496 dosing regimen of days 1 and 3 of each treatment wk for 3 wks followed by 1 wk rest period, following a toxicity guided dose escalation design. A total of 17 pts were treated at doses from 20 to 120 mg. Results: Reversible hematotoxicity was the main side effect constituting DLTs observed at 100 mg and 120 mg. The most frequent G3/4 adverse events were leukopenia (35%), neutropenia (35%), thrombocytopenia (29%), febrile neutrop...

Combination of the immunocytokine F16-IL2 with doxorubicin or paclitaxel in patients with solid tumors: Results from two phase Ib trials.

2595 Background: F16-IL2 is a tumor-targeting immunocytokine composed of the antibody fragment F16 (specific to the tumor marker A1 domain of tenascin) and of human interleukin-2 (IL2). Thorough preclinical work showed that F16-IL2 localizes selectively at tumor tissues and enhances the activity of certain anticancer drugs. In these phase Ib studies, we investigated F16-IL2 in combination with doxorubicin or paclitaxel, defining the recommended dose (RD) and assessing safety, tolerability, and early signs of activity. Methods: Cohorts of pretreated patients with progressive solid tumors received weekly administrations of 6 escalating doses of doxorubicin (up to 25mg/m2) or 8 escalating doses of paclitaxel (up to 90mg/m2), combined with F16-IL2 (up to 25 MioIU of IL2 equivalent) for a maximum of 6 months. Safety and efficacy were evaluated using CTC v3.0 and RECIST criteria. Results: 18 and 28 patients, with a median age of 63 years (37-75) and 64 years (42-79), were treated in the doxorubicin and paclitaxel combination trials, respectively. Toxicity was manageable with only few reversible G4 events, no serious unexpected adverse reactions, and no treatment related deaths. The RD was defined as 25 MioIU of F16-IL2 given in combination with 25mg/m2 doxorubicin or 90mg/m2 paclitaxel weekly. Objective responses and long-lasting disease stabilizations were observed, including 4 partial responses, 2 of which in heavily pretreated NSCLC patients and 1 still ongoing after 17 months from beginning of treatment. Among the evaluable patients treated with the paclitaxel or doxorubicin combination respectively, PFS rate at 3 months is 50% and 44% (n=24 and n=16) and 1-year survival rate is 41% and 38% (n=17 and n=13). Conclusions: 25 Mio IU of F16-IL2 combined with full-dose doxorubicin or paclitaxel can be safely and repeatedly administered weekly to patients with solid tumors, and showed early signs of clinical activity. Based on preclinical evidence, these combination regimens are being administered to breast cancer patients in phase II trials. Moreover, starting from the observed promising signs of activity, a study of F16-IL2 in lung cancer patients is being planned.

Abstract 1276: A novel targeted oral insulin-like growth factor 1 (IGF-1) receptor inhibitor and its implications for patients with squamous cell lung carcinoma

Abstract Background The incidence of lung cancer has increased throughout the twentieth century and is today the most common cancer in the Western World. Lung cancer is divided into two major histological subtypes, non-small cell lung cancer (NSCLC) accounting for approximately 80% of all lung cancer cases and small cell lung cancer (SCLC) accounting for approximately 20 % of all lung cancer cases. The median age at diagnosis is 68 years for patients with non-small cell lung cancer (NSCLC) and 20% of lung cancer deaths occur in patients aged 80 or more. The overall objective of the present abstract is to identify a novel compound targeting the Insulin-Like Growth Factor 1 receptor (IGF-1R) without influencing the closely related Insulin receptor and its impact in patients with especially NSCLC. Methods AXL1717 is a compound that has been optimized to inhibit the IGF-1R without inhibiting closely related receptors including IR. AXL1717 is presently studied in a Phase I/II clinical trial on advanced-stage cancer patients with progressive solid tumors and no remaining treatment options. The primary objective of the study is to identify and confirm a recommended Phase II dose. AXL1717 has been administered every third week as a single-day BID oral treatment in consecutively increasing doses as the only treatment with anti-tumor efficacy. Doses have been increased both within and between patients. The single-day oral dosing part of the ongoing Phase I/II clinical trial on cancer patients with AXL1717 has successfully been concluded. The results show that AXL1717 can be administered as a single-day BID treatment in very high doses with excellent tolerability. Dose-limiting toxicity has not been reported. The second part of the study is ongoing where consecutive cohorts of advanced-stage cancer patients are given 7-28 days of increasing BID doses of AXL1717. Results In the present abstract we describe our experience with the four patients with progressive squamous non-small cell lung cancer (NSCLC) that have received treatment with AXL 1717. Despite the fact that at inclusion these patients had already received third or fourth line treatment, treatment with AXL1717 resulted in more than seven months of treatment response within the study protocol and the reported patients did not develop any additional metastases. Furthermore, these patients demonstrated large central necrotic areas, which may suggest tumor response. Conclusion This first clinical study of AXL1717 has shown that the agent can be administrated safely orally to advanced stage cancer patients resulting in good bioavailability and tolerability. Encouraging signs of tumor response were seen in patients with NSCLC. Further update of these patients as well as a compilation of all included patients with NSCLC, as well as their toxicity, will be reported at the meeting Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1276. doi:10.1158/1538-7445.AM2011-1276

Cyclophilin A release as a biomarker of necrotic cell death

Necroptosis is a form of programmed necrotic cell death mediated by the activity of receptor-interacting protein 1 (RIP1) kinase (1). This type of cell death is caspase-independent and marked by early membrane permeabilization and does not exhibit any other hallmarks of apoptotic cell death such as phosphatidylserine externalization or DNA strand breaks (1). Thus, the markers available to characterize apoptotic cell death cannot be used to analyze necroptosis. Only one marker of necrosis has been identified, and that is the release of the chromatin protein high mobility group B1 (HMGB1) (2). However, we have found the release of HMGB1 to occur at a late stage of death. In this study we have found that cyclophilin A (CypA), a cytosolic peptidyl-prolyl cis-trans isomerase, is released early in necroptosis. We propose that the release of CypA may be used as a biomarker for necroptosis and other cell death processes when the integrity of the plasma membrane is compromised. Since necroptotic cells exhibit early permeabilization of the plasma membrane (1), we hypothesized that the release of intracellular protein(s) may be used as a biomarker for necroptosis. Treatment of L929 cells with zVAD.fmk induces necroptosis, which can be inhibited by treatment with the RIP1 kinase inhibitor, necrostatin-1 (Nec-1) (1). We observed the appearance of a strong band around 17 kD by SDS-PAGE in the supernatant of zVAD-treated L929 cells at an early stage of cell death (Supplemental Figure 1, top panel). Mass spectrometry analysis identified this band as cyclophilin A (CypA), a soluble cytosolic protein that catalyzes the cis-trans isomerization of proline bonds. The release of CypA was further confirmed by western blot (Supplemental Figure 1, bottom panel). In contrast to the necrosis marker HMGB1, the timing of CypA release precedes or occurs around the same time as that of HMGB1 (Figure 1A). Nec-1 blocks the release of CypA into the supernatant (Figure 1B). Figure 1 Cyclophilin A is released from necroptotic cells as a result of cytoplasmic membrane permeabilization. A, L929 cells were treated with 100μM zVAD.fmk for indicated hrs. The supernatants were collected, concentrated, and analyzed by SDS-PAGE followed ... To determine if the release of CypA from the cells was specific to necroptosis, we tested the supernatant of apoptotic cells. We were unable to detect CypA released from Jurkat cells treated with TNFα and CHX to induce apoptosis, even though intracellular CypA appears to be degraded at 24h when cell death was completed (Figure 1C). However, FADD-deficient Jurkat cells, which undergo necroptosis in response to TNFα, did release CypA (Figure 1C). We also tested different inducers of apoptosis for the ability to release CypA. Treatment of doxorubicin and staurosporine caused a small amount of CypA release at later stages of cell death, hours after caspase-3 activation (Supplemental Figures 2-3). Thus, CypA may also be released after permeabilization of the plasma membrane in late phase of apoptotic cell death. However, since apoptotic cells are efficiently engulfed in vivo, the release of CypA by apoptotic cells may not occur in vivo. To examine if CypA could be released by permeabilization of the cells, we treated cells with the detergent digitonin, which led to cell membrane permeabilization. We found that digitonin permeabilized cells also release CypA (Supplemental Figure 4). This may explain why CypA is released during necroptosis, which exhibit early permeabilization of the plasma membrane (1). Elevated serum CypA levels have been found in inflammatory diseases such as rheumatoid arthritis and CypA is secreted in vivo by progressive solid tumors (3, 4). CypA release from necrotic cells may play a role in the effects of necrosis on surrounding tissue. Necrosis is typically associated with inflammation. Necroptosis occurs in models of neuronal ischemia and traumatic brain injury (1, 5). Treatment with Nec-1 significantly reduces cell death and inhibits the recruitment of neutrophils to the injured area (5). Extracellular CypA has been shown to induce a rapid inflammatory response upon injection in vivo and to recruit neutrophils. This recruitment is dependent on the CypA receptor, CD147 (EMMPRIN) (3). Signaling of CypA through CD147 is proposed to contribute to the migration of neutrophils into the joints in rheumatoid arthritis and possibly in the destruction of bone and cartilage in the disease (6). We propose that CypA may be used as a biomarker for necroptosis. The release of CypA, in combination with Nec-1, a specific inhibitor of necroptosis, may be used as an assay for the activation of necroptosis, both in vitro and in vivo.

The tumour-targeting human L19-IL2 immunocytokine: Preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma

BackgroundL19-IL2, a tumour-targeting immunocytokine composed of the recombinant human antibody fragment L19 (specific to the alternatively-spliced EDB domain of fibronectin, a well characterised marker of tumour neo-vasculature) and of human IL2, has demonstrated strong therapeutic activity in animal cancer models. This phase I/II trial was performed to evaluate safety, tolerability, recommended phase II dose (RD) and early signs of activity of L19-IL2. Patients and methodsFive cohorts of patients with progressive solid tumours (n=21) received an intravenous infusion of L19-IL2 (from 5 to 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 3weeks. This treatment cycle was repeated up to six times. In the following expansion phase, patients with metastatic renal cell carcinoma (RCC) (n=12) were treated at the RD of L19-IL2. Clinical data and laboratory findings were analysed for safety, tolerability and activity. ResultsPreclinical studies in rats and monkeys did not raise any safety concerns. The RD was defined to be 22.5 Mio IU IL2 equivalent. Pharmacokinetics of L19-IL2 was dose proportional over the tested range, with a terminal half-life of 2–3h. Toxicities were manageable and reversible with no treatment-related deaths. We observed stable disease in 17/33 patients (51%) and 15/18 with mRCC (83%) after two cycles. Median progression-free survival of RCC patients in the expansion phase of the study was 8months (1.5–30.5). ConclusionsL19-IL2 can be safely and repeatedly administered at the RD of 22.5 Mio IU IL2 equivalent in advanced solid tumours. Preliminary evaluation suggests clinical activity of L19-IL2 in patients with mRCC.

Lexatumumab: Results of a phase I trial in pediatric patients with advanced solid tumors.

9500 Background: Lexatumumab is an agonist, fully-human monoclonal antibody against TNF-Related Apoptosis Inducing Ligand Receptor 2 (TRAIL-R2) with preclinical evidence of activity in several pediatric solids tumors. A phase I trial in adult patients with solid tumors revealed a maximum tolerated dose of 10mg/kg IV every 14 days. Methods: This pediatric phase I, dose escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab administered every 2 weeks to patients 21 years old and younger with recurrent or progressive solid tumors. Patient received increasing doses of lexatumumab (3, 5, 8, 10mg/m2) in a 3 + 3 design. Tumors were measured after 4 weeks, then every 2 months. Treatment was continued until disease progression or unacceptable toxicity. The expanded cohort at the maximum tolerated dose included 6 children (2-12yo) and 6 adolescents (13-21yo). Results: Twenty four patients received a total of 57 cycles of lexatumumab to date over 4 dose levels (3, 5, 8, and 10mg/kg q14days; 1 cycle = 28days). Stable disease occurred in 5 patients for 3 to 17 cycles. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed a grade 3 pneumonia with hypoxia during the second cycle of study drug. One patient with unresectable osteosarcoma pulmonary metastases continues on Lexatumumab 10mg/kg at 35+ doses (17+ cycles) with stable disease and marked clinical improvement. Transient clinical activity was observed in a patient with hepatoblastoma and Ewing sarcoma. Conclusions: Lexatumumab is well tolerated and can be safely administered every 14 days in pediatric patients. Pediatric patients tolerate 10 mg/kg, the maximum tolerated dose identified in adults. No significant financial relationships to disclose.

Combinations of the immunocytokine F16-IL2 with doxorubicin or with paclitaxel investigated in phase Ib studies in patients with advanced solid tumors.

e13017 Background: F16-IL2 is a recombinant fusion protein composed of the antibody fragment scFv(F16) (specific to the alternatively spliced domain A1 of tenascin-C) and of human interleukin-2 (IL-2). Extensive preclinical studies have shown that F16- IL2 is capable of selectively and efficiently localizing in the tumor stroma in vivo. Furthermore, F16-IL2 strongly potentiates the therapeutic action of many anticancer agents. We have been performing two phase Ib studies to evaluate safety, tolerability, recommended dose (RD), and early signs of activity of F16-IL2 combined with either doxorubicin or paclitaxel. Methods: Cohorts of chemotherapy-pretreated patients with progressive solid tumors received weekly administrations of 6 escalating doses of doxorubicin (up to 25 mg/m2) or 8 escalating doses of paclitaxel (up to 90 mg/m2), combined with F16-IL2 (up to 25 million International Units of IL-2) for a maximum of 6 months. Results: 14 and 20 patients were treated in the doxorubicin and paclitaxel combination study, respectively. Phase Ib studies are planned to be completed by end of March 2010. Treatment was very well tolerated, no DLTs were observed. Toxicities were mainly G1 (fever, nausea, fatigue) and only few G2 toxicities were observed (anemia). Only one reversible G3 toxicity (hand-foot syndrome) was observed (paclitaxel trial). Pharmacokinetic (PK) analyses for both the immunocytokine and the drugs showed that the F16-IL2 blood concentration drops rapidly (half-life < 1 hour), while the immunocytokine was showed in preclinical studies to remain on the lesions for several days. Importantly, F16-IL2 PK profiles did not change significantly after multiple rounds of treatment. Objective responses and long-lasting disease stabilizations were observed, including 2 PR in heavily pretreated patients with advanced NSCLC and melanoma (paclitaxel trial). Conclusions: F16-IL2 combined with full dose of either doxorubicin (25 mg/m2) or paclitaxel (90 mg/m2), can be safely administered to chemotherapy-pretreated cancer patients. Early signs of activity in heavily pretreated patients warrant future developments in randomized phase II clinical trials. No significant financial relationships to disclose.

Pharmacokinetic and pharmacodynamic investigation of irinotecan hydrochloride in pediatric patients with recurrent or progressive solid tumors

A multicenter Phase I/II study of Irinotecan hydrochloride (CPT-11; 40-45 mg/m(2)/dose) was conducted for the treatment of refractory pediatric solid tumors. The pharmacokinetics of CPT-11 and its metabolites were characterized using both traditional noncompartmental analysis and population pharmacokinetics using NONMEM VI; pharmacokinetic pharmacodynamic relationships of SN-38 with indices of toxicity were also evaluated. 11 patients between 3 and 18 years were enrolled. Pharmacokinetic parameters and consideration of relevant covariates (performance status (PS), BSA, corrected body weight (CBW), exponent of 3/4 on weight, etc.) were evaluated. Relationships between pharmacokinetic parameters of SN-38 and percentage change from baseline in patient biochemical response data were investigated via regression analysis. CPT-11 exhibited a mean clearance (CL) of 15.31 +/- 5.95 (l/h) (13.06 +/- 3.58 (l/hr/m(2))) and AUC(0-inf) of 3547.0 +/- 1406.5 (ng x h/ml); the AUC ratio of parent CPT-11 to SN-38 was 5.0%. Based on the population pharmacokinetic analysis, decreasing PS was significantly dependent on reduction in CL of CPT-11 (p < 0.001). The final model for CPT-11 are as follows: CL (l/h) = 1.31 x CBW(0.75) (omegaCL = 21.7%), Vss (l) = 2.66 x CBW (omegaVss = 21.2%), Vc (l) = 1.13 x CBW, inter-compartment CL (l/h) = 0.257 x CBW(0.75). Percentage changes of leucocyte and neutrophil count within a first month treatment were significantly correlated with Cmax of SN-38 (r = 0.78 and r = 0.74) and AUC0-2 of SN-38 (r = 0.73 and r = 0.73). Pharmacokinetic parameters were similar to results published in several past reports. An allometric scaling of CBW(0.75) would seem to provide a good index of dosage requirement of CPT-11 in pediatric patients.

Bilaterale Augenbrauentumoren

We report about a 5-year-old boy who presented in our clinic with bilateral, slowly progressive solid tumors of the eyebrows. Histological examination of the excised tumors revealed the typical diversified picture of pilomatrixoma with basophilic and shadow cells. The bilateral or multiple manifestation of pilomatrixoma is uncommon and can be associated with myotonic dystrophy, sarcoidosis or Gardner's syndrome.

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors

Eighteen patients with refractory and progressive solid tumors were treated with a single round of triple modified oncolytic adenovirus (Ad5/3-Cox2L-D24). Ad5/3-Cox2L-D24 is the first non-Coxsackie-adenovirus receptor-binding oncolytic adenovirus used in humans. Grades 1-2 flu-like symptoms, fever, and fatigue were seen in most patients, whereas transaminitis or thrombocytopenia were seen in some. Non-hematological grades 3-5 side effects were seen in one patient with grade 3 ileus. Treatment resulted in high neutralizing antibody titers within 3 weeks. Virus appeared in serum 2-4 days after treatment in 83% of patients and persisted for up to 5 weeks. One out of five radiologically evaluable patients had partial response (PR), one had minor response (MR), and three had progressive disease (PD). Two patients scored as PD had a decrease in tumor density. Tumor reductions not measurable with Response Evaluation Criteria In Solid Tumors (RECIST) were seen in a further four patients. PR, MR, stable disease, and PD were seen in 12, 23.5, 35, and 29.5% of tumor markers analyzed, respectively (N=17). Ad5/3-Cox2L-D24 appears safe for treatment of cancer in humans and extended virus circulation results from a single treatment. Objective evidence of anti-tumor activity was seen in 11/18 (61%) of patients. Clinical trials are needed to extend these findings.

Abstract B256: A novel targeted oral insulin-like growth factor 1 (IGF-1) receptor inhibitor in clinical phase I/II testing

Abstract The overall objective was to identify a novel compound targeting the Insulin-Like Growth Factor 1 receptor (IGF-1R) without influencing the closely related insulin receptor and to test such a compound in cancer patients with solid tumors. IGF-1R belongs to a family of related receptors also including the insulin receptor (IR). The IGF-1R signaling pathway is crucial for the survival and growth of most types of cancer cells, but not of normal cells. The concept has general applicability with respect to many different cancers. AXL1717 is a compound that has been optimized to inhibit the IGF-1R without inhibiting closely related receptors including IR. AXL1717 demonstrates strong and unique anti-tumor efficacy, including complete regression of established tumors in animals xenografted with human malignant cells, including breast cancer, prostate cancer, glioblastoma (intracerebral implants), malignant melanoma, sarcoma and multiple myeloma. AXL1717 did not show any effect in animals with IGF-1R negative xenografts. Preclinical testing showed excellent tolerability together with good oral bioavailability. AXL1717 is presently studied in a Phase I/II clinical trial on advanced-stage cancer patients with progressive solid tumors and no remaining treatment options. The primary objective of the study is to identify and confirm a recommended Phase II dose. AXL1717 has been administered every third week as a single-day BID oral treatment in consecutively increasing doses as the only treatment with anti-tumor efficacy. Doses have been increased both within and between patients. The single-day oral dosing part of the ongoing Phase I/II clinical trial on cancer patients with AXL1717 has successfully been concluded. The results show that AXL1717 can be administered as a single-day BID treatment in very high doses with excellent tolerability. Dose-limiting toxicity has not been reported. The second part of the study is ongoing where consecutive cohorts of advanced-stage cancer patients are given 7–28 days of increasing BID doses of AXL1717. The preliminary results as of September 3rd 2009 have identified possible Phase II dosages. Even though the study was not designed to evaluate tumor or biomarker response, 4 out of 6 patients have shown decreased density of IGF-1R on granulocytes. Two patients, with progressive non-small cell lung cancer, treated with AXL1717 as 3rd and 4th line treatment, respectively, were reported to have documented tumor necrosis. The preliminary results from the Phase I/II clinical trial indicate a recommended phase II dose with good tolerability and with an oral bioavailability resulting in an exposure several fold higher than the exposure resulting in complete regression of tumors in animals. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B256.

Abstract B55: Phase I/II study of the tumor-targeting human L19TNF-monoclonal antibody-cytokine fusion protein in patients with advanced solid tumors

Abstract Background: L19TNF-α is a tumor targeted immunocytokine composed of a single chain variable fragment (scFv) directed against the ED-B domain of fibronectin and the human recombinant cytokine tumor necrosis factor-α. It was created to selectively localize TNF-α to tumor tissues and to minimize systemic toxicity. We evaluated safety, early signs of clinical activity and pharmacokinetic properties of L19TNF-α in patients with refractory solid tumors. Patients and Methods: Six cohorts of patients with refractory solid tumors were planned to receive escalating doses of L19TNF-α (60 minute-intravenous infusion of 1.3, 2.6, 5.2, 7.8, 10.4, e 13 g/kg) on days 1, 3 and 5 of a 21-days treatment cycle (maximum 6 cycles). Serum samples were taken for pharmacokinetic assessment and the analysis of 5-hydroxyindoleacetic acid (5-HIAA; surrogate marker of vascular disruption) during the first treatment cycle. Immunophenotyping (marker panels: CD71/CD8/CD3/CD4 for T-cell; CD71/CD19/CD3/CD56 for NK/B; CD25/CD122/CD3/CD4 for IL-2 expression on T-cell) on blood mononuclear cells was performed on days 1, 5, and 15 of each cycle for the first consecutive patients. The formation of human antifusion protein antibodies to L19 (HAFA) was analyzed at screening and on day 1 of each cycle. Data on safety and activity were collected. Results: Eightheen patients with solid tumors were recruited into the trial between January 2008 and September 2009. Patient's median age was 59 years (range 35–74), 8 were male and 9 female. Eight patients had colorectal cancer, 3 cholangiocarcinoma, 2 thymoma, 1 gastric carcinoma, 1 papilla Vater adenocarcinoma, and 1 parotid adenoidocystic carcinoma. A maximum tolerated dose was not yet reached. At the highest dose level achieved so far (10.4 g/kg) severe lumbar pain occurred in one patient during the L19TNF-infusion constituting a DLT. Most common (&amp;gt; 20%) toxicities included G1 Chills (100%), G2 Chills (41%), febricula (47%), G1 fever (70%), G1 asthenia (41%), headache (41%), G1 Nausea (52%), G1 vomiting (52%), G1 constipation (30%), herpes simplex recurrence (30%), G1 pain (58%), G2 pain (30%). Eight of the 18 patients achieved confirmed disease stabilization, lasting for 5 months (range: 1.5 to 8 months). All other patients progressed. Baseline and post-treatment 5′HIAA values were measured in patients of the first two cohorts (6 patients). A significant increase of 5′-HIAA levels on day 1 of the treatment (within 12 hours after end of infusion) as compared to baseline was found in most patients. Immunophenotyping, pharmacokinetic, HAFA and 5′HIAA analyses will be presented at the meeting. Conclusions: L19TNF- up to a dose of 10.4 g/kg was found safe when intravenously administered to patients with advanced progressive solid tumors in an outpatient setting. The observed toxicity profile was mild and reversible. Encouraging long-lasting disease stabilization was found in a larger fraction of patients, in particular in patients suffering from upper tract gastrointestinal adenocarcinomas. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B55.

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 &gt; 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 &amp; 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.

Phase I trial of molecularly targeted, radiolabeled somatostatin analog in children and young adults with recurrent or progressive solid tumors

10029 Background: Somatostatin receptors are highly expressed in several pediatric solid tumors, including neuroblastoma, medulloblastoma and neuroendocrine tumors. We hypothesize that molecularly targeted somatostatin analog, 90Y-DOTA- tyr3-Octreotide which binds with high affinity to somatostatin receptor type 2 (sst2), will be an effective therapy for pediatric malignancies that express sst2. Methods: A Phase I, dose/toxicity trial of 90Y-DOTA-tyr3-Octreotide was conducted at 30 (cohort 1), 40 (cohort2), and 50 (cohort 3) mCi/m2 with concomitant Aminosyn II infusion. Subjects received 3 cycles of treatment, 6 weeks apart. Eligibility criteria included: recurrent or progressive malignancy with at least one Octreoscan positive lesion; age 2–25 yrs; bone marrow cellularity >40%; GFR >80 ml/min/m2; no radiation therapy for 3 months; no chemotherapy for 30 days. Escalation was based on 3/3 or 4/6 subjects with no dose limiting toxicity. Additionally, subjects were limited to <21Gy calculated radiation dose to kidneys, including any previous external beam radiotherapy received prior to 90Y-DOTA-tyr3- Octreotide dosing. Results: Twelve subjects completed 3 cycles (5, 3 and 4 subjects in cohorts 1,2, 3, respectively). Diagnoses included gastrinoma (3), foregut carcinoid (3), neuroblastoma (2), paraganglioma (2), MENIIb, and anaplastic astrocytoma. Five subjects (38%) had a PR (>50% decrease in target lesion); four subjects had a positive response (>25%<50% decrease in target lesion); three subjects had stable disease for > 4 months; seven subjects remain alive without progression 2 months to 3.5 years after completion of therapy. Four subjects withdrew from the study after one cycle and had progressive disease within 6 weeks. No dose limiting toxicities were observed; specifically, no Grade III or greater renal or hematologic toxicity was observed. Conclusions: Based on intent to treat, 53% of children and young adults with recurrent, sst2 positive tumor had a positive response to 90Y-DOTA-tyr3- Octreotide. PR was obtained in at least one subject at each dose level. No dose limiting toxicities were observed with 50 mCi/m2, the recommended dose for Phase II studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Molecular Insight Pharmaceuticals Milecular Insight Pharmaceuticals, Novartis Pharmaceuticals, Inc. Molecular Insight Pharmaceuticals

Oral metronomic cyclophosphamide (OMC) versus megestrol acetate (MA) among patients with advanced, refractory and progressive solid tumours: A randomized phase II study

20603 Background: OMC has antiangiogenic properties and MA is an orexigen that may maintain the general condition in critically ill patients (pts). Anecdotal responses have been reported with both ...