bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose-specific clearance of TRC105 (anti-CD105 antibody) in advanced solid tumor patients.
Authors: Spencer Shawn D , Figg William Douglas , Rosen Lee S. , Gordon Michael S. , Hurwitz Herbert , Wong Michael K.K. , Goldman Jonathan Wade , Mendelson David S. , Adams Bonne J. , Alvarez Delia , Seon Ben K. , Theuer Charles P. , Leigh Bryan R.
Published: March 2020

3042^

Background: CD105 is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels. TRC105 is an anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with advanced solid tumors and normal organ function were treated with escalating doses of intravenously administered TRC105 and assessed for safety and pharmacokinetics (PK). PK parameters for determining dose-linearity were estimated following single doses on in 16 patients at 3, 10 and 15 mg/kg and correlated with safety. Results: TRC105 was tolerated at 10 mg/kg weekly and 15 mg/kg every 2 weeks, but hyproliferative anemia was dose-limiting at 15 mg/kg weekly and was associated with TRC105 accumulation in serum from target saturation. Preliminary evidence of activity was observed with 21 of 45 evaluable patients progression-free at 2 months, including two ongoing responders. The AUC-single dose relationship of TRC105 revealed supra-proportionality in serum exposure at 15 mg/kg compared to 3 and 10 mg/kg. Dose proportionality using a power model revealed a nonlinear pharmacokinetic process (log[AUC] = 0.125*Dose+2.67, r2 = 0.92, ANOVA p<0.0035). The steady state volume of distribution was low (≈ 5.40 L/70kg) indicating TRC105 was confined to the vasculature with a low capacity target (i.e., low relative abundance) making it susceptible to saturation. The post-infusion Cmax however was linearly related to dose (r = 0.85) which suggested the nonlinearity in clearance was attributed to target-mediated disposition. The nonlinear disposition in the presence of low distribution indicated TRC105 bound avidly to endothelial cells. Concentrations expected to saturate CD105 binding were achieved continuously at 15 mg/kg dosed every 2 weeks and 10 mg/kg/wk. TRC105 accumulated at 15 mg/kg/wk as the accumulation factor at 56 days was 1.77-fold over single doses on C1D1. Conclusions: TRC105 clearance decreased above the MTD resulting in drug accumulation and hypoproliferative anemia with weekly dosing. The nonlinearity in clearance was attributed to saturating target-mediated disposition, consistent with binding to proliferating endothelial cells.
A phase I study of TRC105 (Anti-CD105 [endoglin] antibody) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Karzai Fatima H , Apolo Andrea Borghese , Adelberg David , Madan Ravi A. , Gulley James L. , Arlen Philip M. , Parnes Howard L. , Pierpoint Ann , Kohler David R. , Trepel Jane B. , Price Douglas K. , Steinberg Seth M. , Figg William Douglas , Dahut William L.
Published: March 2020

3043

Background: Pre−clinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate (ORR) and overall survival (OS). Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Six cohorts of patients, on escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10, 15, or 20 mg/kg IV every 2 weeks (cohorts 1, 2, 3, 5, and 6) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with imaging studies every 2 months for the first four months and then every 3 months thereafter. Results: Sixteen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range 0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range 8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with measurable soft tissue disease achieved stable disease for at least two cycles. Conclusions: TRC105 is tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. An additional cohort (6), with dosage of 20 mg/kg, is currently under investigation. Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of this study.
SORAVE: Phase I study for the treatment of relapsed solid tumors with the combination of sorafenib and everolimus.
Authors: Nogova Lucia , Mattonet Christian , Scheffler Matthias , Bos Marc Christiaan Allardt , Gardizi Masyar , Papachristou Irini , Muthen Noemi , Rokitta Denis , Kinzig Martina , Soergel Fritz , Fuhr Uwe , Kahraman Deniz , Kobe Carsten , Rhiem Kerstin , Mallmann Peter , Schnell Roland , Katay Ildiko , Schlaak Max , Dietlein Markus , Wolf Juergen
Published: March 2020

3044

Background: Dual inhibition of signaling pathways interfering with angiogenesis and cell proliferation may increase anti-tumor efficacy. We evaluated the combination of the VEGFR inhibitor sorafenib (S) and the mTOR inhibitor everolimus (E) and used FDG-PET to assess pharmacodynamic (PD) activity of E. Methods: Patients with relapsed solid tumors were treated with escalating doses of E 2.5-10.0mg/d p.o. in a 14 days monotherapy run in phase followed by combination therapy with a fixed dose of S 400mg bid from day 15. The primary aim was to define a safe and feasible combination treatment regimen for a subsequent phase II trial. DLT was defined as any drug related toxicity of CTC IV° or toxicity requiring hospitalization or interruption of therapy for more than 2 weeks within the first 29 days of treatment. Pharmacokinetic (PK) analyses were performed on day 5, 14 and 29 combined with explorative PD assessment of E by FDG-PET on days 1, 5 and 14 of treatment. Results: Nineteen patients were treated with the combination of E and S. The DLT was not reached according to protocol definition. However, at a dose level of E 10mg/d p.o. the following adverse events (AE) occurred in the non-DLT interval: Pneumonia III°, treatment delay due to leucopoenia/thrombopenia III° and sudden cardiac death probably due to arrhythmia. Based on these observations, the dose level of 7.5mg/day E p.o. in combination with 400mg S bid was defined as the MTD. The steady state of E alone was reached after 5 days of treatment and did not change until day 14. However, on day 29 everolimus plasma concentrations (AUC and Cmax) showed a significant 30 % reduction when co-administered with S. A metabolic response of the hottest lesion in PET on day 5 defined as ≤ 80% of baseline was seen in 4 of 15 evaluable patients. Median PFS and OS were 4.2 and 5.4 months, respectively. A patient with neuroendocrine carcinoma reached the longest PFS of 16.6 months. Conclusions: Treatment of patients with relapsed solid tumors with a combination of E 7.5mg/day and 400mg S bid is safe and feasible. The extension phase for confirmation of safety data, further PK and PD modeling and preliminary exploration of efficacy in KRAS mutant cancer patients will be performed at this dose level.
A dose-escalation phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 28 days on/14 days off schedule.
Authors: Grilley-Olson Juneko E. , Weiss Glen J. , Rajagopalan Prabhu , Henderson David Andrew , Kornacker Martin , Govindan Ramaswamy
Published: March 2020

3046

Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting CDKs 1, 2, 4, 7, and 9 in the low nanomolar range. A phase I dose escalation multicenter study was initiated to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) in patients (pts) with advanced solid tumors. Methods: BAY was administered twice daily as an oral solution on a 28 days on / 14 days off schedule (cycle length 42 days, 3+3 design). PK was evaluated on cycle 1 day 1, 2, and 15. Response rate was assessed according to RECIST 1.1. Results: Ten pts were treated at doses of 0.6 (4 pts) and 1.0 (6 pts) mg per day. Tumor types included 3 non-small cell lung, 2 colorectal, 2 melanoma and 3 others. CTCAEv4 grade 1/2 drug related adverse events (AEs) occurring in more than 3 patients were nausea (5 pts), hot flashes (4), vomiting, diarrhea, dyspepsia, and fatigue (3). The median interval between start of treatment and occurrence of hot flashes was 23 days. Drug-related grade 3 AEs were hyponatremia (2 pts) and edema, lymphopenia, myalgia, fatigue, and hypokalemia in 1 pt each. Hyponatremia in one and hypokalemia in another patient were dose limiting toxicities in cohort 2. Enrollment has been stopped. BAY PK was dose proportional and T1/2 was 13 hours; major metabolite levels were low. One pt with metastatic malignant melanoma pretreated with interferon, talimogene laherparepvec, and ipilimumab (best prior response: progressive disease) achieved stable disease (SD) lasting for 5 months. Three pts had SD lasting for 2.5 - 3 months (thyroid, colorectal, squamous esophageal). Conclusions: BAY administered for 28 days on / 14 days off demonstrated a limited tolerability. This is in contrast to the ongoing 3 days on / 4 days off trial which is currently at a dose level of 20 mg per day. Hot flashes were an infrequent AE in the other dosing schedule but occurred in 4 of the 10 pts presented here. The long interval between start of treatment and occurrence of hot flashes suggests that the 28 days of continuous treatment contributed to the lower tolerability observed in this trial. The 3 days on / 4 days off schedule will be used in the further clinical development of BAY.
Safety and efficacy results from two randomized expansions of a phase I study of a tablet formulation of the PARP inhibitor, olaparib, in ovarian and breast cancer patients with BRCA1/2 mutations.
Authors: Molife L Rhoda , Mateo Joaquin , McGoldrick Trevor , Krebs Matthew , Drew Yvette , Banerjee Susana N. , Nicum Shibani , Ranson Malcolm , Rustin Gordon J. S. , Sessa Cristiana , Plummer Ruth , Leunen Karin , Friedlander Michael , Swaisland Helen , Burke Wendy , McCormack Peter , Pemberton Kristine , Tchakov Ilian , Kaye Stanley B. , Gourley Charlie
Published: March 2020

3048

Background: We previously reported the comparative bioavailability of the capsule (CAP) formulation of olaparib and the more convenient new tablet (TAB) formulation (Molife et al ASCO 2010). We subsequently performed two separate dose expansions (DE1 and DE2) to explore comparative safety and efficacy of the TAB (NCT00777582). Methods: Patients with breast or ovarian cancer and BRCA1/2 mutations, ECOG PS 0–2 and adequate organ function were randomized to receive: DE1: 200 TAB or 400 CAP; DE2: 300 TAB, 400 TAB or 400 CAP (all mg BID). Endpoints included safety, pharmacokinetics and exploratory analysis of efficacy (change in tumor size at 8 weeks by RECIST 1.0). Groups were compared using analysis of covariance, including baseline tumor size and treatment as covariates; results are presented using least square (LS) means. Results: 24 patients (ovarian n=15, breast n=9) entered DE1 and 53 patients (ovarian n=38, breast n=15) entered DE2. Baseline characteristics including age, BRCA mutation status and tumor histology were balanced. The table shows key toxicity-related information and change in tumor size at 8 weeks by cohort. Conclusions: These data suggest a dose-response effect for tolerability and, possibly, efficacy with the new TAB between 200 and 400 mg BID. Further studies will require dosing according to patient tolerability within this dose range. [Table: see text]
A phase I study of veliparib (ABT-888) in combination with carboplatin and paclitaxel in advanced solid malignancies.
Authors: Appleman Leonard Joseph , Beumer Jan Hendrik , Jiang Yixing , Puhalla Shannon , Lin Yan , Owonikoko Taofeek Kunle , Harvey R Donald , Stoller Ronald , Petro Daniel P. , Tawbi Hussein Abdul-Hassan , Argiris Athanassios , Strychor Sandra , Kiesel Brian , Chu Edward , Shepherd Stacie Peacock , Giranda Vincent L. , Chen Alice P. , Belani Chandra Prakash , Ramalingam Suresh S.
Published: March 2020

3049

Background: Veliparib (ABT-888, NSC 737664) is an orally available inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and -2: enzymes that recruit base excision repair machinery to single-stranded DNA breaks. Expression of PARP-1 may be increased in cancer cells and confer resistance to DNA-damaging agents. The objectives of this phase I study included determination of the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of veliparib in combination with paclitaxel (P) and carboplatin (C). Methods: Eligibility criteria included advanced solid tumors, ≤ 3 prior chemotherapy regimens for advanced disease, ECOG performance status 0-2. Veliparib was given PO BID on days 1-7 of each 21 day cycle, and P and C were administered on day 3. In dose levels 1-7, veliparib was not given during cycle 1 to serve as intra-patient control for toxicity and PK assessment, and DLT was evaluated during cycle 2. A standard “3+3” dose escalation was utilized starting at veliparib 20 mg BID, P 150 mg/m2, C AUC 5. Plasma concentrations of veliparib, P and C were determined by LC-MS/MS and AAS during cycle 1 and 2. Results: To date, 68 patients have been enrolled. Tumor types included lung (15), breast (14), melanoma (10), squamous cell of head/neck (7), and urothelial (5). Toxicities observed were expected with C plus P chemotherapy, including neutropenia, thrombocytopenia, peripheral neuropathy. DLTs were seen in 2 out of 7 evaluable patients at the maximum administered dose: veliparib 120 mg BID, P 200 mg/m2, C AUC 6, (febrile neutropenia, hyponatremia). Veliparib 80 mg, P 200 mg/m2, C AUC 6 was well tolerated with 1 out of 9 DLT (febrile neutropenia). Median number of cycles was 5 (1-17). Partial response was seen in 11 (Lung-2, breast-2, melanoma-2, urothelial-2, head and neck, gastric, unknown primary) and complete response in 1 patient with breast cancer and 1 patient with urothelial cancer. Stable disease was observed in 35 patients. Veliparib did not affect the PK disposition of P or C. Conclusions: Veliparib in combination with P and C was well-tolerated with a safety profile similar to P and C alone. Promising anti-tumor activity was observed in several tumor types.
Phase I dose-escalation study to evaluate the safety, pharmacokinetics, and pharmacodynamics of CEP-9722 (a PARP1-2 inhibitor) as single‑agent and in combination with temozolomide in patients with advanced solid tumors (NCT00920595).
Authors: Campone Mario , Plummer Ruth , Stephens Peter , Brakchi Zahir , Aissat-Daudigny Louiza , Kasiborski Fabrice , Cambois Anne , Moachon Gilbert , Brown Peter D. , Kayitalire Louis
Published: March 2020

3052

Background: Poly-ADP-ribose (PAR) polymerases (PARPs) are essential in cellular processing of DNA damage via the base excision repair pathway. CEP-9722, an orally available PARP1-2 inhibitor, demonstrated single-agent antitumor activity and synergy with temozolomide (TMZ) in xenograft models. This phase I study evaluated the pharmacokinetics, pharmacodynamics, and the maximum tolerated dose (MTD) of CEP-9722 in monotherapy and combination with TMZ. Methods: Adult patients with advanced solid tumors were enrolled in cohorts of 3-6 patients to receive a 14-day cycle of CEP-9722 (days 1-5), followed by 28-day cycles of CEP-9722 (days 1-5) plus TMZ (150 mg/m2 days 1-5). The dose of CEP-9722 was 150 mg/day in the first cohort and was escalated depending on the occurrence of dose-limiting toxicities (DLTs) during cycles 1 and 2. The safety, pharmacokinetics, and pharmacodynamics (PAR levels in peripheral blood mononuclear cells) of CEP-9722 were analyzed. Results: Overall, 26 patients (18F,8 M) 18 to 71 years of age were enrolled in 5 cohorts of 3-9 patients and treated with CEP-9722 at 150-1000 mg/day. The MTD of CEP-9722 in combination with TMZ (150 mg/m2) was reached at 1000 mg/day. The recommended dose was 750 mg/day. A total of 9 patients were treated at the recommended dose. DLTs were observed in 2 patients during cycle 1 (1 grade 3 myositis at 750 mg/day and 1 grade 3 asthenia at 1000 mg/day) and 2 patients during cycle 2 (1 grade 3 asthenia at 300 mg/day and 1 persistent grade 2 weight loss at 1000 mg/day). Overall during this study, 4 grade 3 treatment-related adverse events were observed. The pharmacokinetics showed high intra- and inter-patient variability at all doses. The pharmacodynamic analysis demonstrated PARP inhibition at all doses, but the high inter- and intra-patient variability prevented any conclusion regarding a dose / PARP inhibition relationship. Conclusions: TheMTD of CEP-9722 when administered with TMZ was 1000 mg days 1-5 and the combination CEP-9722/TMZ was well tolerated. In addition, a clear signal of PARP inhibition was demonstrated.
High concordance for MammaPrint 70 genes by RNA next generation sequencing.
Authors: Mittempergher Lorenza , de Rink Iris , Nieuwland Marja , Kerkhoven Ron M , Glas Annuska , Bernards Rene' , van't Veer Laura
Published: March 2020

3065

Background: The development of new biomarkers often requires fresh frozen (FF) samples. Recently we showed that microarray gene expression data generated from FFPE material are comparable to data extracted from the FF counterpart, including known signatures such as the 70-gene prognosis signature (Mittempergher L et al., 2011). As described by Luo et al (2010) RNA profiling using next generation sequencing (RNA-Seq) is now applicable to archival FFPE specimens. Methods: Technical performance and the comparison between the RNA-Seq 70-gene read-out and the MammaPrint test (Glas et al., 2006) is evaluated in a series of 15 patients (11/15 with matched FFPE/FF material). RNA-Seq was carried out using minor adjustments of the Illumina TruSeq RNA preparation method. RNA sequencing libraries were prepared starting from 100ng of total RNA. Next, the DSN (Duplex-Specific Nuclease) normalization process was used to remove ribosomal RNA and other abundant transcripts (Luo et al, 2010). The libraries were paired-end sequenced on the Illumina HiSeq 2000 instrument with multiplexing of 4 libraries per lane. The resulting sequences were mapped to the human reference genome (build 37) using TopHat 1.3.1(Trapnell et al., 2009). The HTSeq-count tool was used to generate the total number of uniquely mapped reads for each gene. Results: Between 14% and 45% of the total number of reads were assigned to protein-coding genes. The minimum coverage per 1000bp of CDS was 38 reads. The 70 MammaPrint genes were successfully mapped to the RNA-Seq transcripts. We calculated the Pearson correlation coefficient between the centroids of the original good prognosis template (van’t Veer et al., 2002) and the 70-gene read count determined by RNA-Seq of each sample. Predictions based on the 70-gene RNA-Seq data showed a high agreement with the actual MammaPrint test predictions (>90%), irrespective of whether the RNA-seq was performed on FF or FFPE tissue. Conclusions: New generation RNA-sequencing is a feasible technology to assess diagnostic signatures.
Tumor drug distribution and target engagement of MLN9708, an investigational proteasome inhibitor, in patients with advanced solid tumors.
Authors: Di Bacco Alessandra , Berger Allison , Gupta Neeraj , Gao Feng , Blakemore Stephen , Qian Mark , Chen Susan , Stringer Bradley , Yang Yu , Liu Ray , Tirrell Stephen , Bowman Doug , Smith David C. , Sullivan Daniel , Infante Jeffrey R. , Kauh John S. , Siu Lillian L. , Vlahovic Gordana , Thompson John A. , Kalebic Thea
Published: March 2020

3077

Background: MLN9708 is a potent investigational proteasome inhibitor, which upon intravenous (IV) administration immediately hydrolyzes to the active form MLN2238. MLN9708 is currently being evaluated in a phase 1 trial in solid tumors (NCT00830869). This trial has a dose-escalation arm and five expansion cohorts: non-small cell lung cancer (NSCLC), soft tissue sarcoma, head and neck cancer, prostate cancer, and a tumor biopsy cohort of mixed histology. The purpose of the tumor biopsy cohort was to obtain pre- and post-dose biopsies to determine drug distribution and target engagement in post-dose tumor samples. The latter was measured by the increase in levels of ATF-3, a marker of unfolded protein response/endoplasmic reticulum stress, which is upregulated in response to proteasome inhibition. Methods: The tumor biopsy cohort included 20 patients dosed at the maximum tolerated dose who consented to core needle biopsies during screening and after either the first or second dose of MLN9708 (IV 1.76 mg/m2; 4–20 hours post-dose). Tumor biopsies were individually weighed, homogenized, and analyzed for the presence of MLN2238 using a quantified LC/MS/MS methodology. ATF-3 levels in tumors were determined by an immunohistochemical assay (IHC) on six sections for each tumor biopsy. Tumor area was identified using Aperio Genie, a machine learning program for pattern recognition, and the percentage of ATF-3 positive area in the tumor was measured. Results: Biopsies from 20 patients were collected for assessment of drug distribution and target engagement. Ten patients with paired pre- and post-dose biopsies of sufficient size were considered evaluable for PK analysis; MLN2238 was present in all 10 (100%) post-dose biopsies analyzed. Tumor pairs from 7 patients passed quality control by H&E staining for tumor content and were evaluable for ATF-3 IHC. Six of 7 paired samples (86%) showed a statistically significant (p<0.05) increase in post-dose ATF-3 levels. Conclusions: Overall, emerging data from MLN9708 phase 1 solid tumor analysis show that MLN2238 is present in tumors and demonstrates target engagement upon inhibition of the proteasome in tumor tissue biopsies.
A phase I study of ombrabulin (O) combined with bevacizumab (B) in patients with advanced solid tumors (NCT01193595).
Authors: Del Conte Gianluca , Bahleda Rastilav , Moreno Victor , Damian Silvia , Perotti Antonella , Lassau Nathalie , Farace Françoise , Ong Michael , Stimpson Sarah Jane , Tunariu Nina , Micallef Sandrine , Demers Brigitte , Oprea Corina , Capri Giuseppe , Soria Jean-Charles , Sessa Cristiana , Molife L Rhoda
Published: March 2020

3080

Background: O is a vascular-disrupting agent derived from combretastatin A4-phosphate that induces rapid but transient tumor vascular shutdown. In experimental models, the combination of O with VEGF-blockade induced more regressions than O alone. This phase I study was performed to determine the maximum tolerated dose (MTD), and assess the overall safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O plus B. Trial is funded by sanofi. Methods: Patients (pt) with advanced solid tumors, ECOG PS ≤1, and adequate organ function were eligible. Increasing doses of O (mg/m²) was administered intravenously (IV) on day (d) 1; B (5 or 10mg/kg) was administered IV on d2, in 21d cycles (C). A Bayesian design was applied to determine dose escalation steps and MTD. PK sampling was performed in C1 and C2. PD sampling for circulating endothelial cells (CEC) and progenitors (CEP) were performed throughout. Dynamic contrast-enhanced ultrasound (DCE-US) to assess tumor perfusion was performed before and after C1 and C2 dosing. Results: 25 pts (M:F 6:19; median age 49 years [range 27-75]) have been treated at 8 dose levels of O/B: 8/5 (3), 11.5/5 (4), 11.5/10 (3), 15.5/10 (3), 20/10 (3), 25/10 (3); 35/10 (3) and 42/10 (3). Ovarian cancer was the most frequent tumor type (n=11). Median Cs received was 3 (1 to 14). No DLTs were observed during C1. Drug-related grade (g) 3-4 adverse events (AE) included hypertension in 2 pts (8/5; 11.5/5) and ileal perforation in 1 pt with peritoneal carcinomatosis at laparotomy (11.5/10). A case of duodenal perforation was unlikely related (25/10). Two pts with ovarian cancer (11.5/5; 20/10) had confirmed partial responses (4.4 months (mo) and 7+ mo). 13/23 (57%) pts with ≥ 1 tumor assessment had stable disease (n=8; median 4.3 mo [1.8-9.5]; 5 ongoing). Data from cohorts 1 and 2 demonstrated no evidence of a PK interaction.17/25 patients demonstrated a peak in CEC, and 7/9 patients a peak in CEP. 4/7 DCE-US evaluable pts had >50% drop in tumor perfusion (AUC) at Day 8 of C1. Conclusions: O combined with B is well tolerated with early evidence of clinical activity. The MTD has not been reached (current dose level 50/10); cohorts of O combined with B at 15 mg/kg will be tested.
A phase I dose-escalation study of the HSP90 inhibitor AUY922 and erlotinib for patients with EGFR-mutant lung cancer with acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).
Authors: Johnson Melissa Lynne , Yu Helena Alexandra , Hart Eric M , Worden Rebekah , Rademaker Alfred , Gupta Rajesh , Miller Claire , Patel Jyoti D. , Kris Mark G. , Miller Vincent A. , Riely Gregory J.
Published: March 2020

3083

Background: AUY922 is a highly potent, non-geldanamycin analog, HSP90 inhibitor that degrades mutated EGFR and MET. Preclinical studies demonstrate that HSP90 inhibitors have anti-tumor activity in EGFR mutant, EGFR TKI-sensitive and TKI-resistant lung cancer xenograft models. To prevent disease flare after stopping EGFR TKIs in patients (pts) with EGFR mutated lung cancer, erlotinib (E) is often continued with subsequent lines of treatment for AR. This phase I study will determine the maximally tolerated dose (MTD) of AUY922 and E for pts with mutated EGFR and RECIST progression on EGFR TKIs. Methods: All pts have EGFR mutant lung cancer, with development of AR (per Jackman, JCO 2010) after treatment with an EGFR TKI. Pts underwent repeat tumor biopsies after development of AR and prior to study entry. Pts receive AUY922 IV weekly and E oral daily in 28-day cycles, with dose escalation using standard 3+3 design. Pharmacokinetics, serial ophthalmology evaluations and weekly assessment for toxicity are required. Tumor tissue from re-biopsy at study entry is analyzed for EGFR T790M and MET. Results: Since April 2011, 11 pts have been enrolled, in 4 of 5 planned cohorts (AUY922 25 mg/m2 + E 75 mg; AUY922 25 mg/m2+ E 150 mg; AUY922 37.5 mg/m2+ E 150 mg; AUY922 55 mg/m2+E 150 mg). Prior to developing AR, pts were treated with EGFR TKIs for a median of 9 months (range 8-32). Of 9 pts with tissue analyzed thus far, 6 had EGFR T790M. Pts have received a median of two cycles (range 1-7), and 5 remain on study. There have been no dose-limiting toxicities. Adverse events reported in ≥ 20% of pts were diarrhea, nausea, vomiting, fatigue, and rash, all graded 1 or 2. No cardiovascular, renal or hepatic toxicities have been observed. Three pts have reported “flashing lights” and 2 pts transient night blindness, all grade 1. Dose escalation continues. No partial responses have been seen in 6 evaluable pts, 4 patients have confirmed stable disease at 8 wks. Conclusions: AUY922 and E is a well-tolerated combination at dose levels up to AUY922 55 mg/m2+ E 150 mg. Further dose-escalation, MTD, and correlation with markers of AR will be reported. Supported by Novartis, Inc.
A phase I study of dovitinib (TKI258) in Japanese patients with advanced solid tumors.
Authors: Takiuchi Hiroya , Gotoh Masahiro , Yoshida Motoki , Kii Takayuki , Yamashita Keishi , Sunakawa Yu , Kaneta Toshikado , Robson Matthew , Kakizume Tomoyuki , Sasaki Yasutsuna
Published: March 2020

3088^

Background: Dovitinib is a tyrosine kinase inhibitor with demonstrated inhibitory activity against FGFRs, VEGFRs, and PDGFRs in vivo. Based on responses observed in renal cell carcinoma, breast cancer, AML, melanoma, and multiple myeloma in clinical studies in the West, we investigated dovitinib in Japanese patients (pts). Methods: This multicenter phase I study determined the maximum tolerated dose (MTD) of dovitinib based on the occurrence of dose-limiting toxicity (DLT) in Japanese pts with advanced solid tumors. Following a 2-day pharmacokinetic (PK) run-in period, dovitinib was administered orally once daily on a 5-days-on/2-days-off schedule in 28-day cycles until disease progression or withdrawal. The planned dose range was 100-600 mg/day. A 2-parameter Bayesian logistic regression model based on the principle of escalation with overdose control was used to estimate the MTD. Results: In total, 28 pts received dovitinib: 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 7), 400 mg (n = 9), and 500 mg (n = 6). The median age was 58.5 years (range, 30-76); 16 of 28 pts (57%) were male. All pts had stage IV disease, with an ECOG performance status of 0 or 1. Pts completed a median of 3 cycles. One pt is currently ongoing in the study (peritoneal adenocarcinoma, 400-mg cohort, cycle 19), 23 discontinued due to disease progression, and 4 discontinued due to adverse events (AEs). All DLTs were grade 3: anorexia (n = 1; 300 mg), nausea/vomiting (n = 1; 400 mg), liver function disorder (n = 1; 400 mg), and increased alanine transaminase (n = 1; 500 mg). The most common grade 3/4 AEs (occurring in >10% of pts) suspected to be related to study drug were lymphopenia (18%), neutropenia (14%), abnormal hepatic function (14%), decreased white blood cell count (14%), decreased appetite (14%), and hypertension (14%). Best responses were confirmed partial response in 1 pt (4%; peritoneal adenocarcinoma, 400-mg cohort), stable disease in 9 pts (32%), and progressive disease in 10 pts (36%). No treatment-related deaths have been reported. Safety and PK parameters were comparable to those of non-Japanese pts in the global study. Conclusions: The study has completed enrollment. Dovitinib was found to be tolerable at doses up to 500 mg, which was declared as the MTD in Japanese pts.
A phase I and pharmacokinetic study of multiple schedules of ganetespib (STA-9090), a heat shock protein 90 inhibitor, in combination with docetaxel for subjects with advanced solid tumor malignancies.
Authors: Kauh John S. , Harvey R Donald , Owonikoko Taofeek Kunle , El-Rayes Bassel F. , Shin Dong Moon , Murali Sujatha , Lewis Colleen Margaret , Karol Michael D. , Teofilovici Florentina , Du Yuhong , Fu Haian , Khuri Fadlo Raja , Ramalingam Suresh S.
Published: March 2020

3094

Background: Ganetespib is a next-generation Hsp90 inhibitor unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has superior activity to these agents in preclinical studies. Ganetespib is well tolerated with promising antitumor activity. Based on synergy between ganetespib (G) and docetaxel (D), a phase I study evaluating preclinical dosing models was performed. Methods: Patients (pts) with advanced solid tumor malignancies and ECOG performance status (PS) 0-2 were eligible. Sequential cohorts of pts were treated (3+3 design) with increasing doses of D (day 1) and G (days 1, 8) (A) Q 21 days. Following MTD determination, safety and exploratory cohorts of D day 1 with G days 1, 15 (B); or G days 1, 4, 15 (C) were completed. PK sampling was performed during schedule A. The primary endpoint was determination of optimal doses and schedule of the two agents for combination therapy. Results: Twenty-seven patients were enrolled in schedules A (n=12), B (n=8), and C (n=7). Median age-64 (44-75); 11-M, 16-F; ECOG PS: 0 (n=5), 1 (n=21), 2 (n=1). Most pts had NSCLC (n=9), others were head/neck (n=4), and SCLC (n=3). The defined MTD was level 2 (D-75 mg/m2, G-150 mg/m2), as 2 of 4 pts at level 3 (D-75 mg/m2, G-200 mg/m2) had DLTs (febrile neutropenia and one g4 neutropenia of > 7 days), requiring expansion of level 2. The median number of cycles received is 2 (1-11), with 3 pts in schedule C still on study. Among 22 pts evaluable for response, 1 had a PR (head/neck), 12 had SD following 6 weeks evaluation, 10 pts for 12 weeks and 6 pts for 18 weeks. Common AEs included neutropenia, diarrhea, anemia, fatigue, nausea, and febrile neutropenia. Prophylactic filgrastim/pegfilgrastim was not used at any time. PK data indicates similar G exposure alone compared to G administered prior to D. No accumulation was observed following once-weekly dosing, consistent with studies of G alone. Conclusions: The combination is well tolerated at the recommended doses of D 75 mg/m2 and G 150 mg/m2. Promising anti-cancer activity was noted, and a randomized phase 2b/3 study with D day 1 and G days 1, 15 regimen is ongoing in advanced NSCLC (NCT01348126).
A phase Ib trial of FOLFIRINOX plus saridegib, an oral hedgehog (Hh) inhibitor, in pts with advanced pancreatic cancer (PDAC).
Authors: Ko Andrew H. , LoConte Noelle K. , Kantoff Emily , Ross Robert W. , Trehu Elizabeth G. , Tempero Margaret A. , Kelley Robin Katie , Venook Alan Paul , Wu Timothy , Kindler Hedy Lee
Published: March 2020

3105

Background: FOLFIRINOX has emerged as the optimal 1st-line treatment option for pts with advanced PDAC and good performance status; whether it can serve as the backbone upon which to add targeted agents in clinical trial design remains uncertain. The goal of this multicenter phase Ib study is to evaluate FOLFIRINOX in combination with saridegib, a novel oral agent that inhibits the Hh signaling pathway. In preclinical models of PDAC, saridegib increases chemotherapy delivery by depleting peritumoral stroma and increasing vascularity. Methods: Pts with previously untreated metastatic or locally advanced PDAC and ECOG PS 0-1 were eligible. Treatment consists of once-daily saridegib with concurrent administration of biweekly FOLFIRINOX (omitting the 5-FU bolus). A 3+3 dose escalation design was used (see dose levels below). Prophylactic WBC growth factor support is mandated.  DLT definitions include ALT/AST ≥10x ULN, grade 4 plts or ANC ≥5 d, or grade 3-4 nonheme toxicity. CT scans are obtained every 4 cycles. Limited PK analyses are performed. Results: Seven pts have been enrolled at the first 2 dose levels. Grade 1-2 AEs include GI (N/V/D), dehydration, fatigue, and LFT abnormalities. There was one DLT (grade 3 ALT elevation) at DL2. Other serious toxicities seen include grade 3 nausea (DL1) and grade 3 diarrhea (DL2). Tumor shrinkage has been observed in all 4 pts at DL1, ranging from 17-54%, with 2 unconfirmed PRs. Final MTD determination and updated safety and efficacy data will be presented at the meeting. Conclusions: A modified FOLFIRINOX regimen can be safely administered in combination with novel agents in clinical trials of PDAC. While saridegib was not beneficial when added to gemcitabine in a separate randomized phase II study, early evidence of significant responses on the current trial suggests that a more intensive chemotherapy platform may represent a preferable strategy in PDAC trial design. [Table: see text]
First-in-human phase I dose-escalation study of the oral selective C-met inhibitor EMD 1204831 in patients with advanced solid tumors.
Authors: Amin Hesham M. , Falchook Gerald Steven , Fu Siqing , Hong David S. , Tsimberidou Apostolia Maria , Naing Aung , Wheler Jennifer J. , Piha-Paul Sarina Anne , Janku Filip , Klevesath Manfred B , Jego Virginie , Johne Andreas , Kurzrock Razelle
Published: March 2020

3107^

Background: The cell surface receptor tyrosine kinase c-Met and its ligand, the hepatocyte growth factor, are implicated in tumor cell migration, invasion, survival, and proliferation. EMD 1204831 is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor. Methods: This is a phase I, first-in-human clinical trial with escalating doses of EMD 1204831 (NCT01110083). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (Pd), and preliminary anti-tumor activity. Eligible patients had advanced solid tumors not amenable to standard therapies. Following a classical 3+3 dose-escalation scheme, successive cohorts of patients were treated with twice daily (BID) oral EMD 1204831 in 21-day cycles. Pd markers were evaluated in paired tumor biopsies (phospho-c-Met). Results: Until 31 December 2011, 30 patients were enrolled and treated. The dose was escalated in successive cohorts starting from 50 mg BID up to 1400 mg BID. After first (single) administration, median Cmax and AUC0–12 values increased with dose. At higher doses, a decrease in exposure of EMD 1204831 was noted after multiple dosing, potentially caused by autoinduction of the compound’s metabolism. Further dose escalation was discontinued, and no further patients were enrolled. One dose-limiting toxicity (DLT) of grade (G) 3 pancreatitis, considered as a serious adverse event (AE), was observed at 400 mg BID. No other DLTs or treatment-related serious AEs were observed. The remaining treatment-related AEs of G2 or higher included G3 and G2 lipase elevation (n=1 for each grade), G2 upper abdominal pain (n=2), G2 gastroesophageal reflux disease (n=2), and G2 constipation (n=1). Twenty-five patients (83%) had no drug-related toxicity greater than G1. Of 29 patients evaluable for anti-tumor activity, 3 had stable disease lasting for at least 4 months. Conclusions: Due to potential autoinduction of the compound’s metabolism, dose escalation was discontinued before an MTD was reached. Final safety, PK, and clinical tumor response results will be presented.
Phase I trials of PS-341 (bortezomib, B) in combination with topotecan (T) in advanced solid tumors: A potential pharmacokinetic (PK) interaction.
Authors: Morgan Robert , Valdes Frances , Synold Timothy W. , Frankel Paul Henry , Ruel Christopher , Carroll Mary I. , Lim Dean , Cristea Mihaela C. , Koczywas Marianna , Leong Lucille A. , Chung Vincent M. , Reckamp Karen L. , Shibata Stephen , Portnow Jana , Chow Warren Allen , Twardowski Przemyslaw , Luu Thehang H. , Somlo George
Published: March 2020

3108

Background: Preclinical data has demonstrated that B when combined with camptothecins enhances apoptotic effects which may be independent of NF-κB status and dependent on the sequence of exposure to the proteasome inhibitor. Other data suggests PK interactions of B with some chemotherapeutic agents. It is hypothesized that B will act synergistically with T and enhance the apoptotic effects of T. Conflicting data exists regarding schedule dependent synergistic cytotoxicity of the combination. This study examined both sequences of administration and determined the PK of each sequence. Methods: A standard 3 + 3 schedule was used in both sequences (S). The dose of B was fixed with escalating doses of T. S1: B 1.3 mg/m2 on days 1, 4, 8, and 11. T 2 to 3.5 mg/m2 on days 1 and 8 was given 6 h before B. S2: B 1.3 mg/m2 on days 1, 4, 8, 11 followed by T 2 to 3 mg/m2 given 6 h after B. Cycle length was q28 days. PK sampling for both sequences was performed. Results: 54 pts (S1: 27, S2: 27) received a median of 2 cycles (range 1-7) of therapy. Pts were heavily pre-treated. For S1, the maximum tolerated dose (MTD) of B and T were 1.3 and 3 mg/m2 respectively. For S2, the MTD of B and T were 1.3 and 2.5 mg/m2 respectively. Dose-limiting toxicities (2 pt in each sequence) were gr 3 thrombocytopenia in S1, and gr 4 thrombocytopenia in S2. Stable disease was seen in 6/27 pts in S1, and 6/27 in S2. PK results for S2 show no significant difference between the day 1 and day 8 PKs. However, the mean AUC (454±150 mg/Lxhr) and Cmax (123±51 mg/L) at the MTD of 2.5 mg/m2 reached on this trial is similar to those reported with single agent doses of 4 mg/m2 given over 30 minutes weekly x 3. As a result, the estimated topotecan clearance (11.3±5 L/hr) when given following bortezomib is approximately one half of the reported clearance for the single agent. (Curtis et al, J Clin Pharmacol, 50:268, 2010). Conclusions: The tolerability and toxicity of both sequences was similar. MTD differs with S2 having a lower tolerated dose of T. PK results suggest a possible drug-drug interaction with decreased clearance of T with S2. PK results for S1 are pending. Supported by CCSG CA62505.
Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU+Ox).
Authors: O'Connell Michael , Lee Mark , Lopatin Margarita , Yothers Greg , Clark-Langone Kim , Millward Carl , Paik Soonmyung , Sharif Saima , Shak Steven , Wolmark Norman
Published: March 2020

3512

Background: Standardized clinical tools which accurately quantify recurrence risk are needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been validated in stage II colon cancer pts from QUASAR and CALGB 9581. We conducted a large prospectively-designed clinical validation study of RS, w/ pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer pts randomized to FU or FU+Ox in NSABP C-07. Methods: 50% of C-07 pts w/ tissue were randomly selected, stratified on stage (AJCC 6th) and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed colon tumor tissue. Data were analyzed by Cox regression controlling for stage and treatment (TRT). Results: RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence (HR/25 units=1.96, 95% CI 1.50-2.55 p<.001). RS also predicted disease-free survival (p<.001) and overall survival (p<.001). RS predicted recurrence (p=.001) independent of T and N stage, MMR, nodes examined, grade, and TRT. Predefined high RS group (26% of pts) had higher recurrence risk than low RS group (39% of pts): HR=2.11, p<.001. Cox model 5 yr recurrence risk (95%CI) in FU treated pts by RS group (low, int, high): st II 9% (6-13%), 13% (8-17%), 18% (12-25%); st IIIA/B 21% (16-26%), 29% (24-34%), 38% (30-46%); st IIIC 40% (32-48%), 51% (43-59%), 64% (55-74%). RS did not have significant interaction w/ stage (p=0.90) or age (p=0.76). Relative benefit of Ox was similar across range of RS (interaction p=0.48); accordingly, in Cox model and Kaplan-Meier analyses, absolute benefit of Ox increased w/ higher RS. Conclusions: RS predicts recurrence risk in stage II and III colon cancer, capturing underlying biology and providing risk information beyond conventional factors. RS is not predictive of relative benefit of Ox added to adjuvant FU but enables better discrimination of absolute Ox benefit as a function of risk. Incorporating RS into the clinical context may better inform adjuvant therapy decisions for pts w/ stage III as well as stage II colon cancer.
Prospective evaluation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI plus bevacizumab (BV).
Authors: Cremolini Chiara , Loupakis Fotios , Yang Dongyun , Salvatore Lisa , Zhang Wu , Wakatsuki Takeru , Schirripa Marta , Lonardi Sara , Antoniotti Carlotta , Aprile Giuseppe , Masi Gianluca , Graziano Francesco , Ruzzo Annamaria , Lucchesi Sara , Ronzoni Monica , Maus Martin Karl Herbert , Bocci Guido , Tonini Giuseppe , Falcone Alfredo , Lenz Heinz-Josef
Published: March 2020

3518

Background: Despite several attempts, no predictors of benefit from BV have been so far identified. We reported the association of VEGF rs833061 T/T to a worse outcome in mCRC pts treated with first-line FOLFIRI+BV, but not in a historical cohort treated with FOLFIRI. Recent post-hoc analyses on randomized trials suggested the potential prognostic and/or predictive role of other VEGF and VEGFR1/2 SNPs. Methods: Moving from our retrospective finding, we designed a prospective validation trial in mCRC pts treated with first-line FOLFIRI+ BV to detect a HR for PFS of 1.7 for VEGF rs833061 T/T compared to C- variants. With two-sided a=0.05 and b=0.20, 199 events were required. Accrual was faster than expected and in the meanwhile promising results about other SNPs were reported and we therefore included a confirmatory analysis of VEGF rs699946 A/G, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS rs4145836 A/G SNPs. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing. Results: Four-hundred-twenty-four pts were included. At a median follow up of 24 months, median PFS was 10.5 months. At the univariate analysis, no differences in PFS according to VEGF rs833061 C/T variants were observed (p=0.38). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants (n=118) were associated to shorter PFS compared to TT (n=306) (HR: 1.40 [95%CI: 1.07-1.84], p=0.015). In the multivariate model, this association retained significance (HR: 1.402 [95%CI:1.079-1.822], p=0.012), that was lost by applying multiple testing correction. Conclusions: This prospective experience failed to validate the hypothesized predictive impact of VEGF rs833061 variants. Also other previous retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic rather than predictive impact was previously reported, correlated with PFS. We suggest that future studies on biomarkers of benefit from BV should look at the complexity of tumoral angiogenesis at different levels and not only from the genetic perspective.
Ligand expression of the EGFR ligands amphiregulin, epiregulin, and amplification of the EGFR gene to predict for treatment efficacy in KRAS wild-type mCRC patients treated with cetuximab plus CAPIRI and CAPOX: Analysis of the randomized AIO CRC-0104 trial.
Authors: Stintzing Sebastian , Jung Andreas , Kapaun Christine , Reiche Jana , Modest Dominik Paul , Giessen Clemens Albrecht , Vehling-Kaiser Ursula , Stauch Martina , Hass Holger , Fischer von Weikersthal Ludwig , Kirchner Thomas , Heinemann Volker
Published: March 2020

3519^

Background: We investigated the expression of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) as well as the amplification of the EGFR-gene in tumor specimens of mCRC patients (pts) treated first-line with anti-EGFR targeted cetuximab together with CAPOX or CAPIRI. Expression levels were correlated with overall response rate (ORR), progression free survival (PFS) and overall survival (OS) to determine their relationship with effectiveness in this setting. Methods: A total of 185 mCRC pts were randomized to cetuximab (400mg/m² day 1, followed by 250mg/m² weekly) plus CAPIRI (irinotecan 200mg/m², day 1; capecitabine 800mg/m² twice daily days 1-14, every 3 weeks; 20% dose reduction of both agents for pts older than 65 years) or plus CAPOX (oxaliplatin 130mg/m² day 1; capecitabine 1000mg/m² twice daily days 1-14, every three weeks). The primary study endpoint was ORR. KRAS mutational status did not correlate with treatment outcome. The cut-offs for EGFR-amplification using FISH, AREG and EREG levels determined by RT-qPCR were calculated using ROC analysis for ORR. Results: Within the subgroup of KRAS wildtype tumors, analysis of EREG- and AREG-expression was possible in 99 pts and of EGFR-amplification in 63 pts. Higher AREG levels correlated significantly with higher ORR (83% vs 46%, p=0.006, OR 0.31), longer PFS (9.6mo vs 4.9, p<0.001, HR 0.35) and longer OS (39.9mo vs 17.2mo, p<0.001, HR 0.36). Higher EREG levels showed a significant correlation with ORR (74% vs 47%, p=0.036, OR 0.54), longer PFS (7.9mo vs 4.9mo, p=0.026, HR 0.57) and OS (33.0mo vs 20.2mo, p=0.041, HR 0.57). EGFR-amplification correlated significantly with higher ORR (71% vs 33%, p=0.004, OR 0.49), longer PFS (8.4mo vs 4.6mo, p=0.004, HR 0.50) and longer OS (30.5mo vs 15.2mo, p=0.001, HR 0.44). Conclusions: In the treatment setting of cetuximab combined with CAIPIRI or CAPOX, AREG, EREG and EGFR-amplification predicted treatment efficacy. Within the subgroup of pts with KRAS wildtype tumors, EGFR-FISH and AREG expression have the strongest relationship with treatment efficacy.