bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase IB study of an all-oral chemotherapy regimen, tesetaxel plus capecitabine, in patients with advanced solid tumors.
Authors: Martin Michael Gary , Fryar Beverly B. , Danesi Hassan , Schwartzberg Lee Steven
Published: March 2020

3085

Background: Tesetaxel is a novel oral taxane that is not a substrate for P-glycoprotein, does not cause hypersensitivity, and may cause less neurotoxicity. The anticancer activity of tesetaxel exceeds other taxanes in various cell lines and xenografts. Phase II studies showed overall response rates [ORRs] of 50% and 38% in patients (pts) treated for 1st- and 2nd-line breast cancer, respectively, and 20% in pts with 2nd-line gastric cancer. Neutropenia was dose-limiting, and the maximally tolerated dose (MTD) was 27 mg/m2 once every 3 weeks. Capecitabine, an oral fluoropyrimidine, is commonly used for treatment of breast and gastric cancer. While the approved capecitabine dose is 2500 mg/m2/day x 14 days, most pts are unable to sustain treatment at this dose due to hand-foot syndrome (HFS). A prior PK study suggested that short courses of tesetaxel could be combined with capecitabine at the recommended MTDs of both drugs with non-overlapping adverse events (AEs) (Cancer Chemother Pharmacol. 68:1565, 2011). We conducted a phase IB study of the tesetaxel/capecitabine regimen in pts using lower doses of capecitabine to confirm a tolerable combination dose for extended treatment. Methods: Eligibility included: solid tumor treated with ≤ 1 line of chemotherapy; no prior taxane exposure; adequate organ function; ECOG PS ≤ 1. Pts received tesetaxel 27 mg/m2 on Day 1 and capecitabine 1500-2000 mg/m2/day (in divided doses on Days 1-14) every 3 weeks. Results: To date, 10 pts have been treated. AEs were largely Grade 1-2 (83%) and consistent with those for each drug as a single agent. Grade 3-4 neutropenia occurred in 3 pts (30%) and HFS in 4 (40%). Tesetaxel dose reduction was required in 1 pt for neutropenia; capecitabine dose reduction was required in 3 pts (30%) (2 for hand-foot syndrome, 1 for diarrhea). Comprehensive toxicity data will be presented. Conclusions: This combination of all-oral chemotherapy is generally well-tolerated, although lower than maximally approved doses of capecitabine are required, similar to other regimens that employ this agent. AEs are largely non-overlapping, which suggests this combination may be clinically useful in pts with advanced breast and gastric cancer.
Phase l study assessing a two-consecutive-day (QD x 2) dosing schedule of the HSP90 inhibitor, AT13387, in patients with advanced solid tumors.
Authors: Do Khanh Tu , Speranza Giovanna , Chen Alice P. , Trepel Jane B. , Lee Min-Jung , Lee Sunmin , Phillips Larry , Collins Jerry M. , Weil Marcie K. , Kinders Robert J. , Khin Sonny , Allen Deborah , Parthasarathy Ramya , Doroshow James H. , Kummar Shivaani
Published: March 2020

3087

Background: AT13387, a synthetic, non-ansamycin, small molecule inhibitor of HSP90 (Kd 0.71 nM), binds to the N-terminal ATP-binding site resulting in down-regulation of key oncoproteins (HER2 and ERK). In xenograft models AT13387 produced tumor growth inhibition on a QD x 2 dosing schedule. Objectives: To determine toxicity, MTD, PK, and pharmacodynamic (PD) effect of AT13387 given IV QD x 2, 3 weeks out of 4. Methods: Adult patients (pts) with advanced cancers progressing following standard therapy; ECOG ≤ 2; adequate organ function. One pt cohorts for first three dose levels (DLs, 20, 40, 80 mg/m2), planned 3+3 design at DL 4 (120 mg/m2). PK evaluations on C1D1 and C1D15. Mandatory tumor biopsies in expansion cohort at MTD for HER2+ tumors (baseline, C1D17) to evaluate HSP70 and HSP27 mRNA by RT-PCR; and client protein by IHC and immunoassay. HSP70 in PBMCs as a PD marker (pre-dose, D2, D15, D16) assessed by Western blot; serum markers of cell death, M30 and M65 (baseline and pre-dose C1D16), assessed by ELISA. Results: 12 pts treated up to DL 5 (160 mg/m2). Median age, 59; median # prior therapies, 3; diagnosis (# pts): colorectal (7); esophageal (2), liposarcoma (1); head and neck (1); synovial sarcoma (1). Drug-related toxicities (gr ≤ 2; # pts) in 9 evaluable pts: fatigue (5), rash (2), nausea (5), diarrhea (7), QTc prolongation (2), thrombocytopenia (5), AST (3) and ALT (2). Vision disorder (2 pts): gr 1, reversible, no objective findings on eye exams. DLT (1 pt, with liver metastases): DL 5, gr 3 AST/ALT. PK was dose proportional; T1/2 8 hrs. In one paired tumor biopsy (DL 3) an increase in HSP70 (> 1.5 fold) and HSP27 (2 fold) mRNA and a decrease in pERK was observed. M30 and M65 increased in 5/6 pts (p-value n.s.). Induction of HSP70 (1.48 - 5.01 fold) in PBMCs was noted at all time points following first dose (≥ DL 2). 3/9 pts had SD after 2 cycles. Conclusions: Preliminary data indicate that AT13387 QD x 2 is well tolerated and produces a sustained induction of HSP70 in PBMCs. Accrual is ongoing to establish the MTD and obtain further tumor biopsies for assessment of drug effect. Optional Indium-labeled trastuzumab scan will be used to evaluate drug effect on HER2 levels in pts with HER2 expressing tumors.
BI 836845, a fully human IGF ligand neutralizing antibody, to improve the efficacy of rapamycin by blocking rapamycin-induced AKT activation.
Authors: Adam Paul J. , Friedbichler Katrin , Hofmann Marco H. , Bogenrieder Thomas , Borges Eric , Adolf Guenther R.
Published: March 2020

3092

Background: Analogs of rapamycin (rapalogs) targeting mammalian target of rapamycin complex 1 (mTORC1) have shown clinical activity in several cancers. Nonetheless, preclinical and clinical data suggest that there may be intrinsic resistance to rapalogs through a feedback loop which activates upstream signaling when mTORC1 is blocked. BI 836845 is a fully human antibody, currently in phase I clinical trials, which potently neutralizes both IGF-1 and IGF-2. We tested whether BI 836845 is able to improve the efficacy of rapamycin by inhibiting upstream signaling in preclinical models. Methods: Cancer cell lines were profiled in vitro and in vivo for sensitivity to BI 836845 and rapamycin, alone or in combination. Mitogenic signaling was examined by measuring levels of phosphorylated AKT (pAKT) using Western blot analysis. IGF bioactivity was determined using a cellular IGF-1R phosphorylation ELISA. Results: The combination of BI 836845 and rapamycin was more effective than either agent alone at inhibiting the proliferation of Ewing’s sarcoma cells cultured in vitro as well as in a nude mouse xenograft model in vivo. Analysis of cell signaling upstream of mTOR demonstrated that treatment with rapamycin alone resulted in elevated pAKT, indicating feedback loop activation. BI 836845 treatment alone or in combination with rapamycin inhibited AKT phosphorylation, demonstrating that the rapamycin-induced increase in pAKT was due to elevated IGF bioactivity. Consistent with this we demonstrated that rapamycin increased IGF bioactivity in mice and that this could be inhibited by BI 836845. We extended these studies to include other cancer cell lines and profiled the correlation between improved efficacy of the combination with BI 836845 inhibition of rapamycin-induced feedback. A correlation has been observed for cancer cells derived from several indications. Conclusions: Rapamycin treatment increases AKT activation via elevated IGF ligand bioactivity. This effect can be inhibited by BI 836845, thus explaining the improved pre-clinical efficacy seen when both agents are combined. These data provide a rationale for the clinical combination of rapalogs and BI 836845.
Phase I dose-finding and pharmacokinetic study of a combination of elisidepsin (E) and erlotinib (T) in patients (pts) with advanced solid tumors.
Authors: Goel Sanjay , Moran Teresa , Coronado Cinthya , Viteri Ramirez Santiago , Chaudhary Imran , Ghalib Mohammad Haroon , Swami Umang , Hou Yijuan , Carcereny Enric , Alcantara Jose , Iglesias Dios Jorge Luis , De Miguel Bernardo , Buges Cristina , Rosell Rafael
Published: March 2020

3093

Background: E is a new marine compound that has shown synergism with T in vitro even in T-resistant non-small-cell lung cancer (NSCLC) cell lines. Based on these findings, a phase I clinical trial was undertaken to identify the maximum tolerated dose (MTD) and recommended dose (RD) of E (3-h iv, days 1, 8 and 15) followed by T (once daily) in 3-week cycles. Secondary objectives were evaluation of safety and feasibility, PK and preliminary efficacy results. Methods: Patients (pts) with advanced solid tumors with no standard therapeutic option were recruited. Cohorts of 3-6 pts were included at each dose level (DL), with escalating doses of E in increments of 25-50% according to toxicities, and 2 different T doses (100 and 150 mg/day). Results: Thirty pts (median age, 57 years; 19 females) were evaluable. Main tumor types included NSCLC, colorectal, melanoma, and ovarian cancer. Six DLs were assessed. Starting DL was E 0.33 mg + T 100mg. One dose-limiting toxicity (DLT) out of 6 pts (grade 3 bilirubin increase) was observed at DL3 (E 0.75 mg + T 150 mg). Another DLT (dose omissions due to ALT increase) was found at DL6 (E 2.25 mg + T 100 mg). Frequent toxicities were diarrhea (53%), nausea (23%), vomiting (33%), rash (47%), pruritus (43%), dry skin (27%) and acneiform dermatitis (17%). Grade 3/4 toxicities included diarrhea (2 pts), rash (2 pts) and pruritus (1 pts). Main biochemical abnormalities were ALT (grade 3/4 in 4 pts) and total bilirubin increase (grade 3 in 2 pts). No severe hematological abnormalities were observed. Most toxicities were related to T; therefore, T dose was reduced to 100 mg/day. No PK interaction between E and T was observed. No objective responses were reported. Six pts attained stable disease >3 months (3 NSCLC; 1 ovarian cancer, 1 colorectal cancer, 1 invasive thymoma). Conclusions: E + T was a manageable combination; however, the difficulty of combining E with the standard dose of T (150mg) and the lack of activity made this combination unattractive for further development in the current schedule. Possibly, other schedules may demonstrate more efficacy.
The PI3K/mTOR inhibitor BEZ235 given twice daily for the treatment of patients (pts) with advanced solid tumors.
Authors: Arkenau Hendrik-Tobias , Jones Suzanne Fields , Kurkjian Carla , Infante Jeffrey R. , Pant Shubham , Burris Howard A. , Moore Kathleen N. , McMeekin D. Scott , Greco Frank A. , Ramsey Sara , Bendell Johanna C.
Published: March 2020

3097

Background: The PI3 kinase (PI3K) pathway is the most deregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is an oral highly specific and selective inhibitor of the PI3K and TORC1/2. The MTD (1200 mg) and toxicity profile of BEZ235 once daily dosing has been established. This study was designed to evaluate twice daily dosing of BEZ235 and its effect on treatment tolerability, PK, PD, and preliminary efficacy. Methods: Pts with advanced disease were enrolled in a 3+3 dose escalation schedule starting at 200 mg PO BID in 28 day cycles. For intrapatient PK comparison the first week pts received the total dose in a QD schedule. DLT assessment was in Cycle 1. Efficacy evaluations were every 2 cycles, and PK and PD were assessed. Results: 12 pts were enrolled at the following dose levels: 200 mg (n=3), 400 mg (n=3), 600 mg (n=3), and 600 mg (BID only, no QD lead-in) (n=3). No G4 AEs were reported. G3 related AEs were mucositis (n=2), AST/ALT elevation (n=2), anorexia (n=1) and diarrhea (n=1). The most common related G1/2 adverse events (AEs) were anorexia (n=6), diarrhea (n=3), fatigue (n=2), and headache (n=2). DLTs of G3 mucositis were observed in 2 patients at the 600 mg BID dose level with 1 week 1200 mg QD lead-in, which were attributed to the QD lead-in dosing during the first week. 3 pts then enrolled at 600 mg BID without lead in and had no further DLT. PK shows consistent increase in PK parameters with dose level. Of 10 evaluable, 3 pts had stable disease (13+ to 21+ weeks, 2 colorectal, 1 endometrial). Of 9 evaluable, 4 pts at various dose levels had decreased PET SUV uptake by greater than 25%. Conclusions: BEZ235 is tolerable at a dose of 600 mg BID, with less toxicity than has been seen with equivalent QD dosing. Preliminary signs of clinical and PD activity are noted.
Validation of two gene-expression risk scores in a large colon cancer cohort and contribution to an improved prognostic method.
Authors: Roth Arnaud , Di Narzo Antonio Fabio , Tejpar Sabine , Bosman Fred , Popovici Vlad Calin , Wirapati Pratyaksha , Xie Tao , Estrella Heather , Pavlicek Adam , Mao Mao , Martin Eric , Weinrich Scott , Hodgson John Graeme , Van Cutsem Eric , Delorenzi Mauro
Published: March 2020

3509

Background: Prognosis prediction for resected primary colon cancer is currently based on the tumor, nodes, metastasis (TNM) staging system. Gene expression based risk scores have been proposed, but need to be validated and integrated with clinical and TNM variables. We performed an independent assessment of the individual recurrence signatures developed for commercial use by Veridex and Genomic Health. Methods: The Veridex (aVDS) and Genomic Health (aGHS) risk scores were applied to existing gene expression data of 580 stage III and 108 stage II tumors from the PETACC-3 trial. Association of the scores with relapse-free (RFS) and overall survival (OS) of the patients was assessed singularly, and in a combination with TNM and other clinico-pathological variables, by univariate and multivariate Cox regression models and logrank methods. Results: Both risk scores were significantly associated with RFS in univariate and multivariate models (Table) for the stage III cohort. The scores contributed different and additive prognostic information, and reached highest effect sizes (approximate p-value 0.001 and HR per interquartile range 1.4 each) in a combined model (Table) that includes both scores as well as T-stage, N-stage and MSI status as significant factors. Analysis in the stage II cohort gave similar effect estimates. Conclusions: This study confirms in an independent colon cancer patient cohort that gene expression based risk scores improve current prognostic models. The best prognostic model was obtained by using clinico-pathological variables and both gene-expression risk-scores. [Table: see text]
Epiregulin (EREG) and amphiregulin (AREG) gene expression to predict response to cetuximab therapy in combination with oxaliplatin (Ox) and 5FU in first-line treatment of advanced colorectal cancer (aCRC).
Authors: Adams Richard A. , Fisher David , Farragher Susan , Scott Alastair , Smith Christopher G , James Michelle D , Cheadle Jeremy , Nichols Laura L , Meade Angela M. , Kaplan Richard S. , Wilson Richard H. , Wasan Harpreet S , Maughan Tim
Published: March 2020

3516

Background: Previous data suggest the EGF ligands EREG/AREG may predict outcome of KRAS wt patients (pts) in the chemo-refractory setting but has not been previously reported from first line randomised trials. Methods: FFPE samples from primary tumors of pts in Arms A&B of the COIN trial of Ox fluoropyrimidine (Fp) +/- cet were analysed for EGFR IHC, KRAS/NRAS/BRAF mutation and EREG/AREG expression by RT-PCR. Ligand levels were assessed against baseline data, prognostic markers as uni/multivariate analyses and as predictive markers in wild type (wt) and mutant (mt) cohorts and separately by Fp backbone [capecitabine (CapOx) or 5FU (FOLFOX)]. Tests for interaction were performed with EREG/AREG continuous, using Flexible Parametric survival analysis. Optimal cutoffs for predictive effects were defined using point at which 95% CI first excluded zero. Results: 952/1630 (57%) of pts were evaluable for all parameters. EREG/AREG were highly correlated Pearson’s rho (ρ) = 0.74; p<0.0001. High EREG/AREG levels were associated with KRAS wt (p<0.005) and with primary tumor in left colon/rectum, presence of liver metastases and high CEA (p<0.05). In the control arm, high EREG/AREG conferred a better prognosis among KRAS wt pts in multivariate. EREG superseded AREG in a combined model. High EREG predicted for OS benefit in KRAS wt pts treated with FOLFOX +cet, with optimal cut-off 80th centile. OS HR for ±cet ≥80th centile =0.33, 95% CI 0.14-0.78, p=0.011; <80% centile HR=0.99, 95% CI 0.67-1.47, p=0.96; interaction p=0.059; ≥50th centile HR=0.66, 95% CI 0.40-1.09, p=0.11; <50% centile HR=1.09, 95% CI 0.66-1.81, p=0.73; interaction p=0.17. Similar results were seen for PFS, with optimal cut-off 50th centile. There was no predictive effect for pts treated with CapOx. Conclusions: The data suggest a prognostic effect of EREG/AREG in aCRC. The original hypothesis, that KRAS wt patients with high EREG expression have improved outcome with cet, seems to be limited to patients treated with FOLFOX in the first-line setting.
A novel interaction of genotype, gender, and adjuvant treatment in survival after resection of stage III colon cancer: Results of CALGB 89803.
Authors: Warren Robert S. , Atreya Chloe Evelyn , Niedzwiecki Donna , Mayer Robert J. , Goldberg Richard M. , Compton Carolyn C. , Weinberg Vivian K. , Bertagnolli Monica M.
Published: March 2020

3517

Background: The p53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival is remains undefined. We investigated whether domain-specific mutations in p53 are predictive of survival in stage III colon cancer. Methods: p53 was evaluated in an intergroup trial (CALGB 89803) of patients with stage III colon cancer who were randomized to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL) Tissue was collected to allow correlation of molecular markers with outcomes. p53 was genotyped in 607 patient tumors. Results: p53 mutations were identified in 274 tumors, divided ~ equally between zinc binding and non-zinc binding regions of the DNA binding domain. Overall, p53 status was not predictive of benefit from either adjuvant regimen. Unexpectedly, the 5 year overall survival (OS) of women with tumors harboring non-zinc binding mutations treated with 5FU/LV was 97% compared to OS of 72% for women with p53 wild-type (wt) tumors (p =0.004). Adding irinotecan to 5FU/LV negated this survival benefit (5 year OS of 81% vs. 72%). Conversely, 5 year OS of women harboring tumors with zinc binding mutations who received 5FU/LV was 50% compared to 72% for women with p53 wt tumors (p=0.04). Adding irinotecan to 5FU/LV reversed the poor survival of women with tumors harboring zinc binding mutations and improved 5 year OS (50% vs. 73%; p=0.1). No difference in OS was observed for men on either treatment arm or when genotype was considered. Conclusions: CALGB 89803 demonstrated a lack of survival benefit for stage III colon cancer patients when irinotecan was added to 5FU/LV (IFL). We now show that in the setting of a large clinical trial, refined stratification of women, based upon domain- specific mutations of p53 identifies subsets of patients likely to benefit from, or respond poorly to, adjuvant 5FU/LV. The interaction of p53 genotype, gender, and adjuvant therapy regimen has the potential to be paradigm changing in the treatment of colon cancer, and possibly other malignancies. These data, if validated, suggest that evaluation of p53 genotype and gender may guide clinicians to make rational choices of adjuvant therapy.
Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal carcinoma (CRC).
Authors: Speranza Giovanna , Kinders Robert J. , Khin Sonny , Weil Marcie K. , Do Khanh Tu , Horneffer Yvonne , Juwara Lamin , Allen Deborah , Williams P. Mickey , Lih Chih Jian , Rubinstein Larry , Doyle Laurence A , Doroshow James H. , Kummar Shivaani
Published: March 2020

3529

Background: The RAF/MEK/ERK and PI3K/AKT signaling pathways are commonly deregulated in CRC. Each can serve as a compensatory mechanism mediating resistance to single pathway blockade. Combined inhibition with MK-2206 and selumetinib (AZD6244) could enhance antitumor activity. Tolerable doses for the combination in solid tumors (ASCO 2011, abstr 3004) are less than single agent MTDs. We conducted a biomarker driven trial of MK-2206 and selumetinib at the established combination doses to determine extent of pERK and pAKT inhibition in tumor biopsies (bx), using new, clinically validated immunoassays for pERK and pAKT. Methods: Patients (pts) with advanced CRC, refractory to standard therapy, ECOG ≤ 2, adequate organ function, and disease amenable to bx were treated with oral MK-2206, 90 mg QW and selumetinib, 75 mg daily, stratified for KRAS mutation status (+ or WT). For each strata, pAKT and pERK levels from paired tumor bx, baseline and 3-6 hrs post-dose in 3 pts each on C1D1 or C1D22, were measured using a quantitative, chemiluminescence immunoassay (dilution linearity R2 = 0.985 pERK, 0.995 pAKT; % CV at 0 < 6). 70% inhibition was considered biologically significant based on levels observed in preclinical models that demonstrated antitumor activity. Results: 11 pts enrolled to date (KRAS +, 6 pts; WT, 5 pts). 2/9 pts had SD after 2 cycles. Gr 1/ 2 toxicities: rash, reversible retinal detachment, liver abnormalities, hypoalbuminemia, lymphopenia. Target protein inhibition data are available for 8 paired bx samples (Table). Conclusions: Although 4/8 pts demonstrated biologically significant inhibition in one marker, at the MTD for this combination no pt had ≥ 70% inhibition of both targets. If repeated dosing does not produce the desired inhibition of pERK and pAKT, we will conclude that the dose reductions for each agent necessitated by the toxicity of the agents used in combination preclude the possibility of providing adequate dual pathway inhibition. Loss of PTEN and DNA mutation analyses (KRAS, BRAF, PIK3Ca, AKT) are planned. [Table: see text]
Overall survival (OS) of advanced colorectal cancer (aCRC) patients (pts) treated with the multipeptide vaccine IMA910: Results of a matched-pair analysis with arm C pts from COIN.
Authors: Maughan Tim , Adams Richard A. , Mayer-Mokler Andrea , Nowara Elzbieta , Torday Laszlo , Cseh Jozsef , Hoehler Thomas , Hitre Erika , Folprecht Gunnar , Fisher David , Ludwig Joerg , Roessler Bernhard , Kuttruff Sabrina , Walter Steffen , Hilf Norbert , Schoor Oliver , Weinschenk Toni , Singh Harpreet , Reinhardt Carsten , Mayer Frank
Published: March 2020

3530

Background: IMA910 is a novel cancer vaccine consisting of 10 class I and 3 class II tumor-associated peptides (TUMAPs), naturally presented on HLA molecules of CRC. Vaccine-induced immune responses are associated with prolonged OS of renal cell carcinoma pts treated with IMA901, a multi-peptide vaccine identified by the same antigen discovery platform. Methods: 92 HLA-A*02+ aCRC pts with stable or responding disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase I/II trial. After immunomodulation with cyclophosphamide (300 mg/m2) to reduce regulatory T cells, pts were immunized intradermally (up to 16 vaccinations) with IMA910 in combination with GM-CSF without (cohort 1; n=66) or with (cohort 2; n=26) topically applied imiquimod. Safety and PFS data was recently presented [Mayer et al., ASCO-GI 2012]. OS of IMA910 pts was compared to matched pts from arm C (intermittent chemotherapy) of the COIN trial [Adams et al., Lancet Oncology 2011]. Matching was performed in a prospectively defined, fully blinded fashion based on a propensity score involving all available prognostic factors. T-cell responses to individual IMA910 peptides were analyzed by HLA multimer and intracellular cytokine assays. Results: At a median follow up of 1.7 yrs, OS of IMA910 vaccinated pts was significantly longer in comparison to 1:1 matched HLA-A*02+ COIN pts (HR 0.675, 95% CI 0.458-0.995, p=0.047; 1 yr OS: 69% vs 55%; 2 yr OS: 40% vs 24%). Multi-TUMAP responders (≥2 CD8+ and ≥2 CD4+ vaccine-induced T cells) had a significantly longer OS (HR 0.45, p=0.04) compared to matched COIN pts while non-multi-TUMAP responders showed similar OS compared to matched COIN pts (HR 0.76, p=0.22). Conclusions: OS of IMA910 pts was significantly longer in comparison to matched COIN pts with separation of survival curves at ~9 months and increasing OS difference over time. Multi-TUMAP immune responders had a significantly longer OS compared to non-multi-TUMAP responders and compared to matched COIN pts. These clinical and immune response data strongly suggest clinical activity of IMA910 in 1st line CRC pts and warrant further development.
Molecular analysis of the randomized phase II/III study of the anti-IGF-1R antibody dalotuzumab (MK-0646) in combination with cetuximab (Cx) and irinotecan (Ir) in the treatment of chemorefractory KRAS wild-type metastatic colorectal cancer (mCRC).
Authors: Watkins David J. , Ayers Mark , Cunningham David , Tabernero Josep , Tejpar Sabine , Kim Tae-You , Kim Tae Won , Kim Sun Young , Roh Jae Kyung , Beale Philip James , Park Young Suk , Guren Tormod Kyrre , Loboda Andrey , Nebozhyn Michael , Mogg Robin , Lunceford Jared , Schmidt Emmett V. , Brown Holly M. , Sathyanarayanan Sriram , Mauro David J.
Published: March 2020

3531

Background: Previously reported results of this randomized study demonstrated that the addition of dalotuzumab (Dz) worsened the PFS and OS of chemofractory mCRC patients receiving Cx and Ir (Watkins et al; ASCO 2011). Comprehensive molecular analysis has been undertaken retrospectively to identify possible predictors of Cx resistance and Dz response. Methods: Quantitative RT-PCR for IGF-1, IGF-2, immunohistochemistry for IGF-1R and microarray expression profiling was conducted on archival tumor tissue. All patients had received Cx and Ir with either placebo (n=107), weekly Dz (n=112), or 2 weekly Dz (n=110). Results: Data from 292 and 206 patients was successfully obtained by RT-PCR or microarray respectively. Within the placebo arm, high IGF-1 expression was found to be associated with resistance to Cx (IGF-1-/IGF-1+; PFS 6.7/3.7 months, OS 15.5/9.6 months). High IGF-1 expression was associated with benefit from the addition of weekly Dz (placebo/weekly Dz; PFS 3.7/5.7 months, OS 9.6/18.2 months). By contrast the addition of Dz was not effective in tumors with high IGF-2 expression (placebo/weekly Dz; PFS 8.4/2.7 months). Microarray analysis revealed distinct populations that differentially correlated with Cx and Dz response. An epithelial phenotype appeared more associated with Cx response, whereas a mesenchymal phenotype more associated with Dz response. Rectal cancers showed greater association with increased IGF-1 expression, EMT gene signature and Dz response. Conclusions: These data support IGF-1 and IGF-2 as potential biomarkers for response to Dz therapy and high IGF-1 as a marker of resistance to Cx therapy. Based on these data Dz is being further evaluated in a molecularly selected population of mCRC. [Table: see text]
Final results of study 20050181: A randomized phase III study of FOLFIRI with our without panitumumab (pmab) for the second‑line treatment (tx) of metastatic colorectal cancer (mCRC).
Authors: Sobrero Alberto F. , Peeters Marc , Price Timothy Jay , Hotko Yevhen , Cervantes-Ruiperez Andres , Ducreux Michel , Andre Thierry , Chan Emily , Lordick Florian , Tian Ying , Sidhu Roger
Published: March 2020

3535

Background: The primary analysis of study 20050181 showed that in patients (pts) with wild-type (WT) KRAS mCRC, pmab plus FOLFIRI given as second-line therapy significantly improved progression-free survival (PFS) vs FOLFIRI alone. Here, we report on a prespecified descriptive analysis planned for 30 months (mos) after the last pt was enrolled. Methods: Pts with mCRC, ECOG 0-2, who had one prior fluoropyrimidine-based chemotherapy regimen were randomized 1:1 to pmab 6.0 mg/kg Q2W+FOLFIRI (Arm 1) vs FOLFIRI (Arm 2). Co-primary endpoints were OS and PFS (central assessment). Secondary endpoints included objective response rate (ORR) and safety. Tumor KRAS status was determined by a blinded central lab. Results: 1186 pts were randomised and received tx: 591 in Arm 1, 595 In Arm 2. 1083 pts (91%) had KRAS results. Adverse event rates were consistent with the primary analysis. Results are shown below. Conclusions: In pts with WT KRAS mCRC receiving pmab+FOLFIRI vs FOLFIRI, PFS and ORR were significantly improved, and there was a trend toward improved OS. Post-progression anti-EGFR tx may have attenuated any significant difference in OS between tx arms. In pts with MT KRAS mCRC, no difference in efficacy was observed between tx arms. KRAS testing is critical to select appropriate pts for tx with pmab. [Table: see text]
Patterns of chemotherapy (CT) use in a U.S.-wide population-based cohort of patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Abrams Thomas Adam , Meyer Gary , Moloney Julie , Meyerhardt Jeffrey A. , Schrag Deborah , Fuchs Charles S.
Published: March 2020

3537

Background: Few population studies have examined treatment regimens and duration in mCRC since the introduction of biologic therapies in 2004. Methods: We assessed 4,877 consecutive mCRC pts who received CT between Jan 2004 and Mar 2011 at academic, private, and community hospital-based practices participating in a US-wide CT order entry (COE) system that captures patient demographics, stage and treatment data. Multivariate analyses of prospectively recorded patient and provider characteristics identified significant predictors of specific therapeutic approaches. Results: Among all pts, median age was 64; 55% male; (ECOG PS 0/1/2+) (56%/33%/11%). In first-line CT, 17% of pts received fluoropyrimidine (FU) only, while 16% received FU and irinotecan and 65% received FU and oxaliplatin. Older pts, those with poorer ECOG PS, and those treated in private practices were significantly more likely to receive FU only (all p ≤0.05). 53% of all pts received treatment in line 2, 28% in line 3, and 13% in line 4. Mean duration of treatment was 170 days (line 1), 139 (line 2), 135 (line 3) and 126 (line 4). Bevacizumab (bev) was administered to 65% of pts at some point in their treatment. Among the 51% who received bev in line 1, 33% continued bev beyond progression (BBP) in line 2. Pts treated at academic centers, pts who received longer duration of line 1 therapy, and pts whose providers had greater CRC pt volume were significantly more likely to continue BBP. Overall, 23% of pts received cetuximab (cet) (4% of all line 1 pts, 17% of line 2, 31% of line 3, and 29% of line 4). Mean duration of cet use was 168 days (line 1), 125 (line 2), 133 (line 3) and 129 (line 4). Pts treated at academic centers, pts who received longer duration of line 1 therapy, and pts treated in the West US were significantly more likely to ever receive cet. Cet use decreased by 18% following FDA label change restricting use to KRAS wt pts in Jun 2009 (p <0.001). Of all pts, 6% received panitumumab at some point. Of those, 39% had previously received cet. Conclusions: This population-based study provides insight into treatment patterns of mCRC in the US. Usage of biologic agents varies significantly according to patient, practice, and provider characteristics.
Utilization and outcomes of primary tumor surgery for stage IV colon cancer in the United States: A population-based study.
Authors: Sada Yvonne , Duan Zhigang , El-Serag Hashem , Davila Jessica
Published: March 2020

3542

Background: Stage IV colon cancer treatment may include resection of the primary tumor. Current use of primary tumor surgery (PTS) in clinical practice is unknown. This study examined utilization and determinants of PTS and evaluated its effect on survival. Methods: Using national Surveillance, Epidemiology, and End Results registry data, stage IV colon cancer patients diagnosed from 1998-2008 were identified. Data on demographics, PTS, and tumor features were collected. Temporal changes in receipt of PTS were examined over 3 periods (1998-2000, 2001-2004, 2005-2008). Multiple logistic regression was used to identify significant determinants of PTS. 1- and 3-year cancer-specific survival was calculated in PTS and non-PTS patients. Cox proportional hazards models examined the effect of PTS on mortality risk. Results: 16,029 patients were identified. Median age was 69 (IQR: 57-78), and 50% were male. Approximately 67% of patients received PTS. Receipt of PTS significantly declined from 72% in 1998-2000 to 68% in 2001-2004, and 63% in 2005-2008 (p<0.01). Results from the logistic regression analysis showed that patients who were younger, white, married, had right sided cancer and higher tumor grade were more likely to receive PTS (all p<0.01). The 1- and 3-year survival was higher in patients who received PTS compared with those who did not (1-year: 55% (95% CI: 54-56) vs. 24% (95% CI: 23-26); 3-year: 19% (95% CI: 19-20) vs. 4% (95%CI: 3.4-4.9)). Adjusted for demographics and tumor features, risk of mortality was 54% (HR=0.46; 95% CI: 0.44-0.48) lower in patients who received PTS than those without PTS. Recent year of diagnosis (HR=0.88; 95% CI: 0.75-0.80) and being married (HR=0.90, 95% CI: 0.86-0.95) were associated with lower mortality. Older age (HR=1.48; 95% CI: 1.39-1.56), black race (HR=1.09; 95% CI: 1.03-1.15), right sided cancer (HR=1.21; 95% CI: 1.17-1.26), and poorly differentiated tumors (HR= 1.62; 95% CI: 1.46-1.80) were associated with increased mortality. Conclusions: PTS utilization for stage IV colon cancer has significantly declined, yet survival was higher in patients who received PTS. However, these findings are limited by the absence of co-morbidity and chemotherapy data.
Effect of bevacizumab on rate of oxaliplatin-induced thrombocytopenia and splenomegaly.
Authors: Raghav Kanwal Pratap Singh , Kalil Karime , Ferrarotto Renata , George Binsah , Eng Cathy , Garrett Chris R. , Loyer Evelyn , Hoff Paulo , Charnsangavej Chusilp , Kopetz Scott , Overman Michael J.
Published: March 2020

3544

Background: Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI) leading to portal hypertension. This results in splenic sequestration of platelets and thrombocytopenia. Evidence suggests that bevacizumab may protect against HSI, although the clinical impact of this has not been well examined. The purpose of our study was to evaluate rate of thrombocytopenia and splenomegaly as clinical end-points indicative of bevacizumab mediated modulation of oxaliplatin-induced hepatic toxicity. Methods: We performed a retrospective review of metastatic colorectal cancer patients treated at M D Anderson Cancer Center from 1/2003 to 1/2010 with ≥ 3 months of frontline fluoropyrimidine and oxaliplatin (FOLFOX) with or without bevacizumab. Patients with prior liver disease, liver surgery or absence of spleen were excluded. Splenic volumes pre, during and post FOLFOX therapy were determined with CT scans and correlated with platelet counts and treatment. Results: A total of 184 patients [Bev cohort: FOLFOX/Bev (n =138); Non-Bev cohort: FOLFOX alone (n = 46)] were identified. Baseline characteristics (age, gender, spleen size and platelet counts) were similar in both groups. Median number of oxaliplatin cycles for each cohort was 9.00 (p = 0.9). The median total oxaliplatin dose did not differ between the two cohorts (p = 0.9). Development of splenomegaly (volume increase ≥ 30%) was more common in the Non-Bev cohort (48% vs. 32%; p = 0.013). The median time to develop splenomegaly was significantly longer in the Bev cohort (7.6 vs. 5.5 months; p = 0.023). Splenomegaly correlated with a higher rate of thrombocytopenia (defined as platelets < 150K) at 3 months (40% vs. 16%, p = 0.0005) and beyond (during 3 to 6 months of treatment, p < 0.0001). Correspondingly, bevacizumab therapy was associated with lower rates of thrombocytopenia at 3 months (24% in Bev cohort vs. 43% in Non-Bev cohort, p = 0.006) and beyond (p = 0.003). Conclusions: In our cohort, addition of bevacizumab to oxaliplatin chemotherapy reduces the occurrence of splenic enlargement, which correlates with a decreased rate of thrombocytopenia. Further studies to understand the potential hepato-protective mechanism of anti-VEGF therapy are needed.
First European phase II trial of intravenous (iv) cetuximab (Cet) and hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin in patients with unresectable liver metastases from wt KRAS colorectal cancer (CRC) after systemic therapy failure (OPTILIV, NCT00852228).
Authors: Levi Francis , Ducreux Michel , Hebbar Mohamed , Rougier Philippe , Focan C. N. J. , Guimbaud Rosine , Carvalho Carlos , Tumolo Salvatore , Innominato Pasquale F. , Ajavon Yves , Castaing Denis , De Baere Thierry , Karaboué Abdoulaye , Lepere Celine , Boige Valerie , Proux Laetitia , Adam Rene , Bouchahda Mohamed ,   on behalf of ARTBC International
Published: March 2020

3547

Background: HAI of chronomodulated (Chrono) irinotecan (I), 5-Fluorouracil (F) and oxaliplatin (O), or flat O combined with iv F-leucovorin allowed secondary metastases resections and prolonged survival in patients (pts) with CRC liver metastases despite prior chemotherapy failure (Bouchahda, Cancer 2009; Goere, Ann Surg 2010). Purpose: To prospectively evaluate safety and efficacy of combining iv Cet with HAI of IFO in pts with CRC liver metastases. Methods: This Phase II trial involved previously treated pts with unresectable CRC liver metastases. Pts received iv Cet (500 mg/m²) and Chrono or conventional HAI of I (180 mg/m²), F (2800 mg/m²), and O (85 mg/m²) q2 weeks. Liver metastases were resected if adequately downstaged. Results: Planned accrual of 60 pts was reached on 01/24/2012. 3 pts were not treated, 9 are ongoing. 48 consecutive treated pts (18F, 30 M; aged 32-76 years) are fully assessed and monitored. They had PS 0-1 (98%), bilobar liver lesions (69%), a median of 8 metastases (1-50; largest diameter, 57 mm – 15-172). Prior chemotherapy involved one (43%), or two or three (57%) lines. A median of 5 protocol courses (1-13) was given. Main grade 3-4 toxicities per pt were neutropenia (40%), abdominal pain (15%), fatigue (15%), nausea (15%), diarrhea (13%) and sensory neuropathy (4%). Objective response rate was 44% [30-58], with 6% radiological complete responses. Disease control rate was 85%. Secondary liver surgery was performed in 15 pts (31.3%).One pt with 25 metastases (1-6 cm) in all liver segments had pathologic complete response in 24 lesions removed through three-stage hepatectomy. She currently has an off treatment disease-free survival of 17+ months.With a follow up of 4 to 47 months, median progression-free survival is 14.2 months [9.7-18.8], 1- and 2-year survival rates are 92.8% and 59.2% respectively. Conclusions: OPTILIV offers a safe and unusually effective treatment option for patients with CRC liver metastases after failure of systemic chemotherapy within a coordinated medico-surgical strategy.
Plasma concentrations of YKL-40 in chemo-naive patients with metastatic colorectal cancer treated with FLOX with or without cetuximab: Results from the NORDIC VII study.
Authors: Tarpgaard Line Schmidt , Guren Tormod Kyrre , Glimelius Bengt , Pfeiffer Per , Kure Elin , Yilmaz Mette K. N. , Sorbye Halfdan , Keldsen Nina , Skovlund Eva , Johansen Julia S. , Tveit Kjell Magne
Published: March 2020

3548

Background: KRAS status is presently the best biomarker to select patients with metastatic colorectal cancer (mCRC) for therapy with EGFR inhibition even though not confirmed in all phase III studies. In the NORDIC VII study a survival benefit of adding cetuximab to the Nordic FLOX regimen could not be confirmed. Identification of new predictive and prognostic biomarkers is essential. Plasma concentration of YKL-40 is emerging as a new biomarker in patients with cancer and inflammatory diseases. We tested the hypothesis that high plasma YKL-40 associates with short progression free survival (PFS) and short overall survival (OS) in patients included in the NORDIC VII Study. Methods: 566 patients with mCRC were randomized to: A) Nordic FLOX; B) FLOX + cetuximab; and C) FLOX for 16 weeks + cetuximab continuously. Plasma samples were available from 510 patients (90%). Pretreatment plasma YKL-40 was determined by ELISA (Quidel), and the plasma YKL-40 concentration was dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects. Results: Plasma YKL-40 was elevated in 204 patients (40%) and the median plasma YKL-40 was higher in the study group compared to healthy subjects (120 mg/l vs. 40 mg/l, p<0.001). Elevated plasma YKL-40 was associated with short PFS (HR=1.25, 95% CI 1.04-1.51, p=0.02). This relationship was demonstrated only in patients treated with FLOX chemotherapy alone (HR=1.42, 1.02-1.98, p=0.04). High plasma YKL-40 was associated with short OS in all patients (HR=1.55, 1.25-1.92, p<0.001) and in the different treatment groups (A: HR=1.54, 1.05-2.26, p=0.03; B: HR=1.40, 0.97-2.01, p=0.07; C: 1.79, 1.23-2.60, p=0.002). Multivariate analysis (YKL-40, performance status, number of metastatic sites) demonstrated that elevated plasma YKL-40 was an independent biomarker of short OS (HR=1.46, 1.17-1.81, p=0.001). Conclusions: Plasma YKL-40 may be a new prognostic biomarker in patients with mCRC treated with 1st line FLOX chemotherapy, with or without cetuximab. The predictive value of plasma YKL-40 is not yet clarified.
Phase II study of panitumumab (P) in combination with FOLFOXIRI as first-line treatment of metastatic colorectal cancer (mCRC): Activity in molecularly selected patients (pts).
Authors: Lonardi Sara , Fornaro Lorenzo , Bergamo Francesca , Schirripa Marta , Aprile Giuseppe , Morvillo Manfredi , Masi Gianluca , Loupakis Fotios , Calvetti Lorenzo , Cremolini Chiara , Salvatore Lisa , Zaniboni Alberto , Zagonel Vittorina , Falcone Alfredo
Published: March 2020

3555

Background: GONO-FOLFOXIRI demonstrated higher activity and efficacy compared to FOLFIRI. P with oxaliplatin- or irinotecan-based doublets is feasible and associated with improved activity in KRAS codon 12-13 wild-type pts. BRAF and other RAS rare mutations have been suggested as additional potential biomarkers for anti-EGFR agents. Methods: Pts with untreated unresectable mCRC and wild-type BRAF-RAS genes were enrolled in this GONO multicenter phase II trial of biweekly P 6 mg/kg d1 with a modified FOLFOXIRI regimen (IRI 150 mg/m2 d1, OXA 85 mg/m2 d1, l-LV 200 mg/m2 d1 and 5FU 3000 mg/m2 48-h continuous infusion d1, reduced to 2400 mg/m2 due to grade 3-4 toxicity in 2 of first 3 pts enrolled). Primary end-point was response rate (RR, RECIST Criteria). Based on a two stage Simon’s Minimax design (p0=60%, p1=80%; a=0.05, β =0.2) at least 26 responses on 36 evaluable pts should be observed to satisfy the primary end-point. Results: 37 out of 87 screened pts were enrolled (M/F, 57/43%; median age 63 years, range 33-72; ECOG PS 0/1-2, 76/24%; primary colon/rectum, 70/30%; primary on site, 42%; sites of disease single/multiple, 54/46%; liver only mts, 35%). Among the first 3 pts treated with 5FU 3000 mg/m2, 2 experienced SAEs (1 grade 4 diarrhea and neutropenia; 1 grade 3 diarrhea). Grade 3-4 toxicities observed among the 34 pts treated at the amended dose were: neutropenia 53% (2 febrile neutropenia); diarrhea 32%; stomatitis 15%; neurotoxicity (grade 2-3) 30%; cutaneous rash 24%. Delays or dose reductions were needed only in 9% and 10% of the total 310 cycles, respectively. One SAE (febrile neutropenia and sepsis) resulting in pt death occurred after amendment. 32 partial responses, 4 disease stabilizations and 1 progression were observed, with a RR of 86% (95% CI: 75-97%). 9 pts underwent local procedures on metastases, achieving an R0 resection in 8 and a pathologic complete response in 3 of them. At a median follow-up of 7.4 months mPFS has not been reached. Conclusions: In molecularly selected unresectable pts adding P to FOLFOXIRI resulted in high activity and interesting resection rate. The regimen appears feasible. Further follow-up is needed to assess long-term outcome.
Relationship of Src activity and prior oxaliplatin on outcomes after hepatectomy for metastatic colorectal cancer.
Authors: Morris Van Karlyle , Parikh Nila , Overman Michael J. , Jiang Zhi-Qin , Maru Dipen M , Elvin Paul , Kopetz Scott , Gallick Gary E.
Published: March 2020

3561

Background: The nonreceptor tyrosine kinase Src regulates pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. In vitro, Src is activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance, but not after 5-FU alone. Activation of Src and its substrate FAK in metastatic colorectal cancer treated with oxaliplatin has not been studied in human specimens. Methods: Samples from 170 hepatic resections from two cohorts of patients with metastatic colorectal cancer were examined by IHC for expression of activated Src (pSrc) and FAK (total and pFAK). In the first cohort (n=50), tissue was collected at consecutive hepatic resections before and after oxaliplatin. Patients in the second cohort (n=120) were compared based on whether or not oxaliplatin was administered after resection. IHC was graded semi-quantitatively, 0 to 4 based on intensity (first cohort), and by automated image analysis (second cohort). Results: In the first cohort, pFAK expression increased after oxaliplatin exposure (mean IHC score 2.04 vs. 1.18, p<0.01). In the second cohort, Src activation was correlated with pFAK expression (p<0.01). Patients pretreated with oxaliplatin demonstrated increased expression of activated FAK (p=0.02) compared to 5-FU alone or irinotecan regimens. There was a weak association between total Src expression and the number of oxaliplatin cycles (p=0.06). Among patients in the second cohort, five-year relapse-free survival was inversely related to levels of pFAK (21.1%, 16.5%, and 7.4% for low, medium, and high levels of pFAK, respectively; p=0.02) and of pSrc (19.6%, 13.6%, and 8.2% for low, medium, and high levels of pSrc, respectively; p= 0.01). Conclusions: Patients treated with neoadjuvant oxaliplatin demonstrated increased Src signaling in liver metastases, a finding associated with worse relapse-free survival. These results are consistent with prior in vitro studies correlating oxaliplatin exposure with Src pathway activation and support the idea that inhibition of Src, when used in combination with platinum chemotherapy, warrants further investigation in patients with metastatic colorectal cancer.