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Purpose Liquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor ( EGFR) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non–small-cell lung cancer treated with rociletinib. Methods Tissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples. Results Positive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) than tissue alone (83%) among matched samples (n = 177). The ability to identify mutations in plasma was strongly associated with M stage ( P < .001); rate of T790M detection for patients with M1a/M0 disease increased from 54% for plasma alone to 85% when urine and plasma were both examined. Objective response rates of patients who were T790M positive were comparable between tumor (34%), plasma (32%), and urine (37%). Conclusion Clinical response to rociletinib was comparable irrespective of whether T790M status was identified by liquid or tissue biopsy. Combined, urine and plasma identified a higher percentage of patients who were T790M positive than tumor genotyping alone and improved detection of T790M, particularly in the absence of distant metastases. These findings support the noninvasive analysis of urine and plasma before tumor rebiopsy when assessing T790M status.

BACKGROUND: Lucitanib is a potent, oral antiangiogenic tyrosine kinase inhibitor of Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3), Platelet-Derived Growth Factor Receptors alpha and beta (PDGFRα/β), and Fibroblast Growth Factor Receptors 1-3 (FGFR1-3). FGF aberrancies (amplification of FGFR1,or 11q[amplicon containing FGF ligands 3, 4, and 19]), are genomic alterations observed in over 20% of breast cancer pts and promote cancer proliferation and survival. METHODS: MBC pts who had received at least 1 metastatic line of therapy were randomized 1:1 to 10 or 15 mg QD of lucitanib. Stratification was based on local assessment of FGF aberrancy; pts with both FGFR1 and 11q-amplified tumors were stratified as FGFR1 amplified. Central confirmation of FGFR1 or 11q amplification was done using Abbott FISH probes (FGFR1 or 11q copy number ≥ 6 and a ratio of FGFR1 or 11q to centromere ≥ 2). Investigator-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints included objective response rate (ORR) per RECIST 1.1, disease control rate (DCR), duration of response (DR), and incidence of treatment-emergent adverse events (TEAE). RESULTS: Enrollment completed in 3/2016; 178 pts that received at least 1 dose of lucitanib are included in this analysis (baseline characteristics in Table 1). Due to grade 3 hypertension in the 15 mg group (46% vs 37% in 10 mg group), enrollment to the 15 mg group was halted. Overall, most pts (97%) experienced at least 1 TEAE, with the most frequently (≥ 30%) occurring events being hypertension (73%), fatigue (48%), nausea (43%), hypothyroidism (40%), and headache (33%). Grade ≥ 3 TEAEs occurred in 66% of pts, with hypertension as the most frequent event (40%) followed by proteinuria and hyponatremia (both 6%). AEs were manageable with dose interruption or reduction, with approximately 8% of pts ending treatment due to an AE. Current median PFS is 3.5 mos (95% CI 2.8-4.6; range 0.62-12.95) and 2.6 mos (95% CI 1.8-2.9; range 0.82-18.87) respectively for the 10 mg and 15 mg treatment groups. No differences in clinical activity were observed by treatment group, FGF aberrancy, hormone receptor or HER2 status. Of the 168 evaluable pts, confirmed ORR was 3%; overall DCR was 27% (32% for pts in the 10 mg group compared to 20% for the 15 mg group); overall mean (standard deviation) DR of 3.3 (1.8) mos. Baseline Characteristics 10 mg QD15 mg QD N=109N=69Age (years)Median5653Range27-8227-80SexFemale109 (100%)67 (97%)Male02 (3%)ECOG PSmissing5 (5%)2 (3%)051 (47%)30 (43%)153 (49%)37 (54%)Number of prior anticancer therapies in the metastatic setting> 332 (29%)21 (30%)3-648 (44%)32 (46%)> 629 (27%)16 (23%)Endocrine/HER2 statusmissing7 (6%)1 (1%)ER+ or PR+74 (68%)50 (73%)HER2+12 (11%)7 (10%)TNBC16 (15%)11 (16%)FGFR aberrancyFGFR1 amplified54 (49%)29 (42%)11q amplified31 (28%)24 (35%)FGFR1 and 11q amplified13 (12%)9 (13%)FGFR1 and 11q non-amplified11 (10%)7 (10%) CONCLUSION: At 10 mg QD, lucitanib has modest activity with manageable toxicity in this heavily pretreated pt population. Future clinical development for lucitanib may focus on alternative biomarkers to identify sensitive tumors and rational combinations with other anti-cancer drugs. Citation Format: Mayer IA, Arteaga CL, Nanda R, Miller KD, Jhaveri K, Brufsky AM, Rugo H, Yardley DA, Vahdat LT, Sadeghi S, Audeh MW, Rolfe L, Litten J, Knox A, Raponi M, Tankersley C, Isaacson J, Wride K, Morganstern DE, Vogel C, Connolly RM, Gradishar WJ, Patel R, Pusztai L, Abu-Khalaf M. A phase 2 open-label study of lucitanib in patients (pts) with FGF aberrant metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-03.

Objective To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Methods In this open-label phase 1b study, patients received trebananib 10mg/kg or 15mg/kg IV QW plus PLD 50mg/m 2 (cohorts A1 and A3, respectively) or topotecan 4mg/m 2 (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). Results 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug–drug interactions were apparent. Conclusions Trebananib 10mg/kg and 15mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.

This study examined the effects of panitumumab, a human monoclonal antibody against epidermal growth factor receptor (EGFR), on irinotecan pharmacokinetics. This phase I, open-label, multicenter, single-arm study enrolled patients with metastatic colorectal cancer (mCRC) without prior exposu

Healthcare providers use recombinant biologics such as monoclonal antibodies to treat a variety of serious illnesses. Manufacturing of approved biotechnology products is complex, and the quality of the resulting biologic is dependent on careful control of process inputs and operating conditions. Biosimilars, which are similar but not identical to innovator biologics, are entering regulatory evaluation, approval, and marketing in regions with biosimilar approval pathways.This article describes the evaluation and potential impact of manufacturing process changes and biosimilar product development, and explores the similarities and distinctions between the two. Regulatory agencies generally require a comparability exercise following a manufacturing process change. This comparability is focused primarily on analytical characterization of the approved product before and after the manufacturing process change, with non-clinical and clinical confirmation required when determined necessary. When developing a biosimilar, the manufacturer does not have access to key information including the innovator manufacturer's cell line, cell culture conditions, purification procedures, and fill and finish processes. Further, the biosimilar manufacturer does not have access to information about the innovator manufacturer's product development history, including knowledge about the quality attributes of lots used in non-clinical and clinical development. We define the biosimilar manufacturer's lack of information as the knowledge gap. As a result, a biosimilarity exercise to compare a biosimilar to an approved innovator biologic requires a rigorous evaluation to ensure the safety and efficacy of the biosimilar.Given the knowledge gap under which biosimilars are developed, data to establish biosimilarity should go beyond a simple comparability exercise.

A previously healthy 4-year-old boy was admitted because of acute liver failure. He was icteric, lethargic, had elevated ammonia and abnormal liver function tests. Serology was negative for viral hepatitis. There was no history of hepatotoxic drugs. Family history was unremarkable. The child was taken to the operating room for a living-related hepatic transplant. Frozen section showed massive hepatic leukemic infiltration and hepatocellular necrosis. Bone marrow aspiration confirmed the diagnosis of acute lymphoblastic leukemia (ALL). Transplant was withheld and chemotherapy was attempted. He died the following day due to systemic leukemic infiltration, cerebral edema, and severe anoxic ischemic encephalopathy.

Lessons Learned Trebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC). In support of previously reported high Ang-2 levels’ association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2. Background Ang-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC). Methods Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2. Results Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts. Conclusion There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

Background Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and β (PGFRα/β), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. Methods This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). Results Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31–40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. Conclusion Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.

Biosimilars are biologic medicines that are highly similar to approved biologics, notwithstanding minor differences in clinically inactive components. Since 2007, biosimilars have been approved for use in patients in the European Union (EU) and other regions. European experience provides several lessons as the United States (US) healthcare system prepares for biosimilar approvals. These lessons emphasize the need for adequate efficacy and safety studies, post-marketing surveys and a robust pharmacovigilance system that can accurately track and trace biologics, including biosimilars and their reference products, from the patient to the manufacturer.We review the EU experience with biosimilar pharmacovigilance and discuss the implications for biosimilar pharmacovigilance in the USA. Furthermore, we review several aspects of biosimilar pharmacovigilance, including cohort event monitoring, traceability, biosimilar interchangeability, pharmacovigilance system development, nomenclature and counterfeit tracking.The availability of biosimilars as lower-cost biologics must carefully consider issues of safety, efficacy and traceability. Stringent pharmacovigilance procedures are required to detect potential differences in safety signals between biosimilars and their reference products. Pharmacovigilance of biologics should include processes that are easily used by prescribing practitioners to ensure that data are consistent and new safety signals are properly reported and assigned to the correct product.

Hepatoblastoma is a pediatric malignancy characterized by the uncontrolled proliferation of immature hepatocytes (hepatoblasts). This disease is diagnosed primarily in children younger than 5 years and is disproportionately observed in former premature infants. Cytogenetically, hepatoblastoma is characterized by numerical aberrations, as well as unbalanced translocations involving the proximal region of chromosome 1q. The NOTCH2 gene has been mapped to this locus, and it is well established that the NOTCH gene family is an important regulator of several developmental pathways. Specifically, the NOTCH2 protein is known to delay hepatoblast maturation during early hepatic organogenesis, and the reduction of NOTCH2 expression correlates with the differentiation of hepatoblasts into hepatocytes and biliary cells in the developing liver. We hypothesized that NOTCH2 is involved in the pathogenesis of hepatoblastoma by maintaining a population of undifferentiated hepatoblasts. We studied the immunohistochemical expression of NOTCH2 and its isoforms NOTCH1, NOTCH3, and NOTCH4 and the NOTCH2 primary ligand JAGGED1 in hepatoblastomas. Compared with the normal liver, an increasedlevelofNOTCH2expressionwasseenin22of 24 (92%) hepatoblastomas. There was no significant staining for other NOTCH isoforms and JAGGED1 in hepatoblastomas. Therefore, we suggest that NOTCH2 expression and activation, independent of JAGGED1 expression, may contribute to the pathogenesis of hepatoblastoma. In the hepatoblastoma sinusoidal vasculature, we saw NOTCH3 and NOTCH1 expression. These observations have potential implications with regard to therapeutic targeting of the NOTCH signaling pathway in hepatoblastomas.

Learning ObjectivesAfter completing this course, the reader should be able to: Describe the current epidemiologic trends in hepatoblastoma.Identify the genetic syndromes that are seen in a subset of liver tumors.Assess the need for complete tumor resection in the treatment of liver tumors in children as well as the increasingly important option of liver transplantation for those patients with unresectable tumors.Discuss the impact of the hepatitis vaccine in reducing the incidence of hepatocellular carcinoma.Explain the prognostic impact of different histologic subtypes of hepatoblastoma.Promote the need for future clinical trials in testing new agents for hepatocellular carcinoma in children.Employ the different staging systems used in liver tumors, including the traditional North American postsurgical staging system and the European presurgical staging system using imaging.CME This article is available for continuing medical education credit at CME.TheOncologist.com.Malignant liver tumors account for slightly >1% of all pediatric malignancies, with roughly 150 new cases of liver tumors diagnosed in the U.S. annually. The embryonal tumor, hepatoblastoma, accounts for two thirds of malignant liver tumors in children. Other liver malignancies in children include hepatocellular carcinoma, sarcomas, germ cell tumors, and rhabdoid tumors. Benign tumors of the liver in children include vascular tumors, hamartomas, and adenomas. There is an apparent increase in the incidence of hepatoblastoma with perinatal exposures and decreased premature infant mortality as postulated causes for this increased risk. The known causes and associations of liver tumors in children as well as the approaches to diagnosis and treatment of children are discussed in this review article.

TPS8108 Background: Activating EGFR mutations including exon 21 L858R and exon 19 deletions (del19) are key drivers of NSCLC in 10%–15% of patients (pts) of European and 30%–35% of Asian descent.1 ...

BACKGROUND: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B). Aberrant FGF signaling, as defined as FGFR1 and/or 11q amplification, is a hallmark genomic alteration in breast cancer, observed at a combined frequency of up to 25% of patients. Breast cancer patients with measurable disease and aberrant FGF signaling treated in the ongoing Phase 1/2 clinical trial of lucitanib monotherapy experienced an ORR of 50% and a DCR of 100%. This compelling clinical activity has led to the initiation of a global clinical development program for lucitanib in breast cancer. TRIAL DESIGN: The current study is comparing PFS for doses of lucitanib (10 or 15 mg daily) in patients with FGF-aberrant metastatic breast cancer after failure of currently available standard therapies. Approximately 160 patients will be randomized 1:1 to the 10 mg and 15 mg daily dosing groups and stratified by FGF pathway alteration (FGFR1 or 11q amplification) and prior anti-VEGF therapy (yes or no). FGFR1 and 11q (containing the FGF ligands 3, 4, and 19) amplification is determined locally for patient enrolment and confirmed by central laboratory fluorescent in situ hybridization (FISH) testing. A total of 130 PFS events provides 80% power at a 2-sided significance level of 0.05 to detect a hazard ratio of 0.60 for comparing the 10 mg and 15 mg dose groups. Secondary objectives are ORR, DoR, DCR, OS, PROs, safety and population PK. Exploratory endpoints include tissue and blood-based biomarkers that may be predictive of response or primary resistance to treatment with lucitanib. ELIGIBILITY CRITERIA: Histologically or cytologically confirmed FGF-aberrant metastatic breast cancer relapsed or refractory to approved standard available treatment. ECOG 0 or 1. Normal organ function. Patients with uncontrolled hypertension are excluded. Citation Format: Maysa Abu-Khalaf, Ingrid Mayer, Jason B Litten, Mitch Raponi, Andrew R Allen, Lajos Pusztai, Carlos L Arteaga. A Phase 2, randomized, open-label, multicenter, safety and efficacy study of oral lucitanib in patients with metastatic breast cancer with alterations in the FGF pathway [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-13.

Aim: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of FGFR1/2, VEGFR1-3 and PDGFRa/b. These well-described signaling pathways are essential for tumor growth, survival, migration, and angiogenesis. Considering the highly vascular nature and the expression of FGFR in thyroid cancer, targeting these pathways is particularly relevant in metastatic setting. Methods: The first in human phase I/II study is currently evaluating oral lucitanib as monotherapy. The escalation phase used a 3 + 3 design in pts with advanced solid tumors to establish a recommended dose for further study. Safety and efficacy were further evaluated in pts with FGF aberrant or angiogenesis sensitive tumors, using continuous or intermittent dosing schedules. Results: Among 32 pts treated in Vall d'Hebron Institute of Oncology (VHIO), 3 had medullary thyroid cancer and 6 differentiated thyroid cancer. Median age was 56 yrs [range 38-68]. All pts were treated at 15mg, 5 on continuous and 4 on intermittent schedules (21 days on / 7 days off). 4 pts (45%) received lucitanib after progression on at least one previous multikinase inhibitor (MKI). In this population, the most common adverse events related to lucitanib (all grades, continuous and intermittent dosing schedules) were hypertension, asthenia and proteinuria. For all these AEs, the highest grade observed was G2. All pts on continuous schedule had a dose decrease to 10mg due to drug-related toxicities. 2/4 pts on intermittent schedule maintained on their initial 15mg dosing. The anti-tumor activity was recorded in 8 of the 9 pts evaluable according to RECISTv1.1. One pt achieved CR (12%), 2 pts had PR (25%) including 1 MKI pretreated, and 4 pts had SD (50%) lasting at least 6 months, including 2 pts MKI pretreated. Moreover, 1 pt had a prolonged CR (30 months), evaluable on non-target lesions only. Median PFS was 15.0 months, and 3 pts are still ongoing for more than 28 cycles. Conclusions: Lucitanib demonstrated promising clinical activity and a torelable side-effect profile in pts with metastatic thyroid cancer even in those already pretreated with multikinase inhibitors. Disclosure: R. Cereda: Full employment at EOS Spa; J. Litten: Full employment at Clovis; J. Collin, F. Legrand, R. Robert and C. Saba: full employment at Servier. All other authors have declared no conflicts of interest.

TPS8119^ Background: Lucitanib, a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1/2 (FGFR1/2), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR...

286 Background: Trebananib is a first-in-class antiangiogenic therapy that sequesters Ang1 and Ang 2, preventing their interaction with the Tie 2 receptor. A previous study of the combination of trebananib with sorafenib in renal cell carcinoma showed an acceptable toxicity profile. Elevated Ang 2 levels have been associated with a poor prognosis in HCC. We thus evaluated the safety and efficacy of trebananib plus sorafenib in HCC. Methods: Patients with HCC, ECOG ≤ 2, Childs-Pugh A, and adequate organ function received IV trebananib at 10mg/kg weekly (cohort 1) or 15 mg/kg weekly (cohort 2) plus sorafenib 400 mg PO twice daily. Thirty patients were accrued to each cohort to provide a power of 80% with the 1-sided exact test for single proportion at α = 0.20 to show a ≥ 78% PFS rate at 4 months relative to 62% reported in the sorafenib historical control. Secondary endpoints included safety and tolerability, progression free survival, objective response rate, disease control rate, time to progression, and overall survival. Results: See table. Conclusions: Trebananib at 10 mg/kg and 15 mg/kg plus sorafenib were well tolerated in patients with advanced HCC. When compared with historical controls, study results did not show an improvement in PFS rate at four months. Clinical trial information: NCT00872014. [Table: see text]

Background: Pmab, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFR), is indicated for treatment of EGFR-expressing, chemorefractory, metastatic colorectal cancer (mCRC). This study examined effects of Pmab on Iri PK when used as combination therapy in patients (pts) with mCRC. Methods: This phase 1, open-label, multicenter, single-arm study enrolled pts with mCRC without prior exposure to an EGFR inhibitor. Pts could not have CYP3A4 inhibiting or inducing medications ≥ 2 weeks before enrollment or UGT1A1*28 TA7/7, TA7/8, and TA8/8 polymorphisms. Pts received Iri (180 mg/m2, 90-min IV infusion) on day 1 cycle 1 followed by Pmab (6 mg/kg, 60-min IV infusion) on day 4 cycle 1. After 2 weeks (day 1 cycle 2), pts received Pmab followed immediately by Iri. Pmab and Iri were administered thereafter every 2 weeks until disease progression or intolerability. Plasma samples for Iri and its active metabolite SN-38 were collected pre-dose and up to 72 hours after Iri infusion in cycles 1 and 2. Primary endpoints were Cmax and AUC of Iri (PK subset), and secondary endpoints included rates of adverse events (AEs). Results: 28 pts enrolled; 19 of 27 pts who received treatment met PK evaluability criteria (dosed per protocol for 2 cycles with no reductions/delays). PK profiles of Iri with or without Pmab were nearly superimposable. 90% confidence intervals for the ratios of geometric means for Iri Cmax and AUC with or without Pmab were within a prespecified 0.70 to 1.43 interval, suggesting that Pmab had no impact on Iri PK. Similar results were seen for SN-38 PK. AEs were as expected for Iri plus Pmab combination therapy. Conclusions: Pmab in combination with Iri was generally well tolerated by pts with mCRC. Pmab had no significant effects on Iri PK.PK Profiles of Iri and SN-38 Ratio of Geometric Means Point Estimate Cycle (N = 19)Geometric Mean(Cycle 2 vs Cycle 1)90% CIIri Cmax (ng/mL)115400.9800.894 - 1.074 21510 AUC0-inf (ng·hr/mL)1112000.8980.819-0.985 210100 SN-38 Cmax (ng/mL)125.90.8230.731-0.926 221.3 AUC0-inf (ng·hr/mL)1a3260.8650.773 - 0.968 2b282 aN = 17; bN = 16; CI, Confidence interval; Iri, Irinotecan Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-75.