PDF file, 2119K, Figure S5. Changes in chromosome alignment and spindle bipolarity on days 1 and 21.

PDF file, 92K, Supplementary Table S1. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 7-day schedule. Supplementary Table S2. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 14-day schedule. Supplementary Table S3. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 21-day schedule. Supplementary Table S4. Summary of pharmacokinetic parameters for MLN8237 twice-daily dosing on the 7-day schedule.

Supplementary Data - PDF file 104K, Supplementary Data: Eligibility criteria and Pharmacodynamic analysis: methodology sections

CCR Translation for This Article from Phase I Pharmacokinetic and Pharmacodynamic Study of the First-in-Class Spliceosome Inhibitor E7107 in Patients with Advanced Solid Tumors

PDF file, 1749K, Figure S4. Changes in tumor mitotic index on days 1, 7, and 21.

PDF file, 1635K, Figure S1. MLN8237 dose-escalation and schedule extension schema.

e20555 Background: EGFR mutant(EGFRm) NSCLC patients develop adquired resistance after 12 months on EGFR TKI. Acquired T790mutation(T790M) is the most common mechanism of resistance in around 60% of patients, followed by MET amplification in 20% of cases. Inclusion in a clinical trials at progression may have an impact in patients’ outcome. Methods: We retrospectively assessed the overall survival in EGFRm patients according to post-progression treatment on 1st/2nd generation EGFR TKI: standard vs. experimental (clinical trial). Also, we assessed the survival in the cohort of acquired T790M NSCLC patients(p). X2 test and long rank test P values are described. OS was defined since progression 1st/2nd generation EGFR TKI to death or last follow up Results: 42p EGFRm were enrolled. According to EGFRm subtype (24 p EGFR del19, 14p EGFR L858R, 1p EGFR exon18, 1 EGFR exon20 ,2p unknown). Median age was 58 (33-83) and 27 (64%) females. First-line EGFR TKI was 30% gefitinib / 58 % erlotinib /10 % afatinib/2% dacotinib At PD, in 51 biopsies (b) were performed,11p were biopsy twice.Tumor tissue for molecular determinations was available in in 86% of cases. Druggable molecular alterations were detected in 57% of cases: 20 acquired T790M and 4 MET amplification. According to these results all 24 p were enrolled in a clinical trial (NCT02108964,NCT01802632,NCT02147990,NCT02335944, NCT02151981), and 18p were screening failure; 8p (45%) of them due to abscense of adquired resistance mechanisms. 10 received platinum-based chemotherapy and 6 only received best supportive care. OS metastatic disease was 51 months for patients included in a clinical trial vs 22 months for those on standard treatment (p < 0.001; 95%CI: 14.4-47). OS was: 34 months vs 10 months for those included in a clinical trial vs standard, respectively (p < 0.001; 95%CI: 8.88-25). For T790M tumours, OS post-progression was 25 months Conclusions: Enrolling patients in clinical trials may allow personalised treatment according to mechanisms of resistance improving survival after 1st/2nd generation EGFR TK progression disease.

Effectiveness of immunotherapy has been observed in around 20% of cases, nowadays there is no accurate biomarker to select those patients (pts) who will benefit the most. We evaluated retrospectively pretreatment (baseline) and post-treatment (every 2 months) serum-LDH in 94 pts with NSCLC treated with anti-PD1/PDL1. Repeated measures ANOVA, Kaplan-Meier and the proportional COX model were used to examine the association of LDH with overall survival (OS). The cutoff level of LDH was 400 based on the median of the sample. (normal range 105-333 UI/L). From July 2013 to February 2016, 94 pts were treated with immunotherapy based in anti-PD1 (77,6%) and anti-PDL1 (22,4%), in trials at VHIO. Median age was 62 (39-86). Histological subtypes were: adecocarcinoma 53.2%, squamous 42.5%, others 4.2%. The OS was significantly different in pts treated with immunotherapy according to baseline LDH, if LDH ≥ 400 median OS was 8.2 months, while in pts with LDH <400 median survival was not reached (Figure 1). There were statistically significant differences in the evolution of LDH, with better responses if there was a downward trend in LDH levels. In long responding pts (45 of 94 pts), defined as ≥ 3 evaluations (6 months), a LDH level at the time of 6 months treatment below than the baseline LDH predicts better responses (22/45 pts): 68.2% partial response (RP); 18.2% stable disease (SD); 13.6% disease progression (PD). In contrast, when LDH at third evaluation was higher than baseline LDH (23/45 pts): 39.1% PR; 56.5% SD; 4.3% PD, (p=0.022). There were differences between the level of LDH pre and post-progression. 66.67% of patients who progressed had a higher level of LDH at the time of progression than at the previous assessment (p=0.03). LDH may be a potential predictive biomarker of survival benefit conferred by immunotherapy in patients with NSCLC.

e20582 Background: Median age at diagnosis of lung cancer is 70 years (y) and approximately 45% of patients (pts) are 70y or older. No consensus guidelines for the management of these older pts exists. Older pts with thoracic malignancies are under represented in clinical trials and treatment decisions for old pts are mostly determined by extrapolation from trials with younger pts. Methods: The aim of this retrospective study was to describe characteristics from pts older than 70y ( ≥ 70y) included in clinical trials and to compare findings with those observed in younger pts (< 70y). The ≥ 70y group (n = 110) was compared with a similar randomly selected < 70y group (n = 111) from the same period. Objectives were to compare Overall Survival (OS), Progression Free Survival (PFS) from the time of inclusion to death or last follow up; Response rate was based on RECIST v-1.1 and adverse events (AEs) were extracted from the individual clinical trials. Results: The 2012-14 VHIO experience included 410 pts with thoracic malignancies recruited in clinical trials. A total of 110 pts included in clinical trials were ≥ 70y (26%).Among ≥ 70y group median age was 74y. Distribution in phase I, II or III clinical trials was 23.6%, 34.5.5% and 41.8% respectively. Most patients had stage IV disease (74.5%). Histology was non-squamous carcinoma in 42.73%, squamous carcinoma in 31.82%, small cell carcinoma in 19.09% and malignant pleural mesothelioma in 6.36%. A 47.28% of the pts had received ≥ 1 line of treatment in metastatic setting (p = 0.922). Best treatment response was 36.6%, 40.9% and 18.1% as partial response, stable disease and progressive disease respectively (p = 0.421). OS in the ≥ 70y group was 11.8 vs 11months (m) in < 70y (HR 1.03 CI 95% 0.75-1.43, p = 0.845). PFS in the ≥ 70y group was 6.3 vs 5.8m in < 70y (HR 0.92 CI 95% 0.68-1.27, p = 0.625). SAEs were presented 21.8% in ≥ 70y compared with 14.4% in < 70y (p = 0.210). Conclusions: Age over 70 years represents a quarter of our pts included in clinical trials. No difference in OS neither PFS are found between older and younger pts. Older age should not be an exclusion criteria to recruit pts with thoracic malignancies in clinical trials.

e20550Background: Non-small cell lung cancer (NSCLC) harboring anaplastic lymphoid kinase (ALK) rearrangements represents a selective population who responds to targeted therapies. This study explo...

The molecular profiling of patients (p) with advanced NSCLC identifies several oncogenic drivers that can be targeted with selective inhibitors. We aimed to assess the characteristics and prognostic factors of p with molecular alterations at our center treated with targeted agents. EGFR, KRAS,HER2 mutated p and ALK, ROS1 and RET rearrangements positive p enrolled onto clinical trials between 2009 and 2015 at our center were included in this analysis. A cohort of wild type (WT) adenocarcinoma p was selected as comparator. Survival was estimated by the Kaplan-Meier method. 200 p were collected (76 WT, 45 EGFR, 51 ALK, 21 KRAS, 3 ROS1, 2 HER2 and 2 RET). Median age 57 years (26-82), 52% men, 60% performance status (PS) 1, 59% smokers, 98% stage IV and 92% adenocarcinoma. First treatment was selective inhibitor in 73% of EGFR and 58% of ALK p. Median follow up was 23 months (m) (95% CI 1.6-104.6). The overall survival (OS), still immature with 58% of deaths, was 33m for all p and 57m EGFR, 40m ALK, 31m KRAS and 19m WT. We found differences in OS for molecular selected population vs WT (55m vs 19 m p < 0.001), women (55m vs 23m, p = 0.002), PS 0/1 vs PS2 (21 vs 7m, p < 0.001) and non-smokers (51 vs 23 m smokers, p = 0.002). Brain metastases were detected in 86 p (36 ALK, 25 WT, 14 EGFR, 8 KRAS, 2 ROS and 1 RET) and 87% received local therapy. BM were more frequent in women, non-smokers and ALK p (p < 0.001). BM developed at a median of 6m from diagnosis of NSCLC (6m molecular selected and 5m WT, p = 0.44) and median OS after development of BM was 14m (28m EGFR, 26m ALK and 8m WT, p < 0.001). No differences in OS were detected in p with or without BM (p > 0.05). Independently of target agent, we did not found significant differences in OS p with BM treated with local therapy vs systemic treatment (p > 0.005).P who initiated the EGFR and ALK inhibitors after diagnosis of BM had greater benefit than those p who began treatment before diagnosis of BM (86m vs 57m for EGFR and 55m vs 35m for ALK respectively, p > 0.05 in both). Molecular selected p treated with targeted agents have prolonged survival. Brain metastases is a frequent site of disease progression, but the prognosis of these p is impressive independently of local therapies.

Purpose: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule. Experimental Design: Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6 to 4.5 mg/m were explored. Results: Forty patients [24M/16F, median age 61 years (45–79)] were enrolled. At 4.5 mg/m, doselimiting toxicity (DLT) consisted of grade 3 diarrhea, nausea, and vomiting and grade 4 diarrhea, respectively, in two patients. At 4.0 mg/m, DLT (grade 3 nausea, vomiting, and abdominal cramps) was observed in one patient. Frequently occurring side effects were mainly gastrointestinal. After drug discontinuation at 4.0 mg/m, one patient experienced reversible grade 4 blurred vision. The maximum tolerated dose (MTD) is 4.0 mg/m. No complete or partial responses during treatment were observed; one patient at 4.0 mg/m had a confirmed partial response after drug discontinuation. Pharmacokinetic analysis revealed a large volume of distribution, high systemic clearance, and a plasma elimination halflife of 5.3 to 15.1 hours. Overall drug exposure increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes monitored in peripheral blood mononuclear cells showed a reversible 15to 25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a reversible 10to 25-fold increase. Conclusion: TheMTD for E7107 using this schedule is 4.0 mg/m. Pharmacokinetics is dose-dependent and reproducible within patients. Pharmacodynamic analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107. Clin Cancer Res; 19(22); 6296–304. 2013 AACR.

Abstract Purpose: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule. Experimental Design: Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6 to 4.5 mg/m2 were explored. Results: Forty patients [24M/16F, median age 61 years (45–79)] were enrolled. At 4.5 mg/m2, dose-limiting toxicity (DLT) consisted of grade 3 diarrhea, nausea, and vomiting and grade 4 diarrhea, respectively, in two patients. At 4.0 mg/m2, DLT (grade 3 nausea, vomiting, and abdominal cramps) was observed in one patient. Frequently occurring side effects were mainly gastrointestinal. After drug discontinuation at 4.0 mg/m2, one patient experienced reversible grade 4 blurred vision. The maximum tolerated dose (MTD) is 4.0 mg/m2. No complete or partial responses during treatment were observed; one patient at 4.0 mg/m2 had a confirmed partial response after drug discontinuation. Pharmacokinetic analysis revealed a large volume of distribution, high systemic clearance, and a plasma elimination half-life of 5.3 to 15.1 hours. Overall drug exposure increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes monitored in peripheral blood mononuclear cells showed a reversible 15- to 25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a reversible 10- to 25-fold increase. Conclusion: The MTD for E7107 using this schedule is 4.0 mg/m2. Pharmacokinetics is dose-dependent and reproducible within patients. Pharmacodynamic analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107. Clin Cancer Res; 19(22); 6296–304. ©2013 AACR.

PM00104 (Zalypsis®) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk).

AbstractPurpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma. Clin Cancer Res; 18(17); 4764–74. ©2012 AACR.

3089 Background: Sym004 is a recombinant antibody 1:1 mixture of two chimeric anti-EGFR mAbs, which elicits superior cancer cell growth inhibition in preclinical models. Uniquely, Sym004 mediates cell surface receptor removal by triggering EGFR internalization and degradation. Results from a first-in-human multicenter trial evaluating safety and tolerability of multiple doses of Sym004 are reported. Methods: The trial comprises a dose-escalating part A (0.4 mg/kg-12 mg/kg) with classical 3+3 design after the first 2 cohorts and an extension part B at maximum tolerated dose (MTD). Patients (pts) received weekly IV infusions of Sym004 until disease progression or unacceptable toxicity. Pharmacokinetics and safety is evaluated weekly, with dose-limiting toxicities (DLT) assessed in the first 4 weeks, and tumor response every 8 weeks. Results: In part A, 17 pts (median age 60 years) were treated with doses up to 9 mg/kg without reaching the MTD: 0.4 mg/kg (1 had 6 doses), 0.75 mg/kg (1 had 35* doses), 1.5 mg/kg (3 pts had 6, 6 and 21 doses), 3 mg/kg (3 pts had 3, 5 and 6 doses), 6 mg/kg (3 pts had 3, 12* and 13 doses) and 9 mg/kg (6 had 1, 4*, 4*, 5*, 6* and 9* doses [*ongoing]). Most common tumor types were colorectal (11 pts) and pancreatic carcinomas (3 pts). 90% of adverse events (AEs) were CTCAE grade 1 or 2. The most frequent events were skin toxicities, diarrhea, nausea, infusion related reaction and electrolyte disturbances, similar to marketed anti-EGFR mAbs. 5 pts had non-serious, grade 1 mucositis. 4 pts had serious AEs related to Sym004: grade 2 rash and grade 1 allergic reaction (6 mg/kg), grade 3 acneiform rash (6 mg/kg), grade 3 hypomagnesemia (9 mg/kg) and grade 3 infusion related reaction (9 mg/kg). The latter event led to the introduction of an intensified pre-medication scheme with steroids, antihistamines and paracetamol before the first 4 infusions and lowered infusion rate. No further infusion reactions were observed thereafter. Of the 11 pts treated with doses up to 6 mg/kg, 4 remained in the trial for more than 8 weeks. AUC and Cmax for both mAbs constituting Sym004 were similar and increased with dose. Conclusions: Sym004 is well tolerated with no unexpected toxicities and shows preliminary signs of clinical activity.

2568 Background: PM00104 is a novel synthetic alkaloid related to the marine compounds jorumycin and renieramycins. Preliminary preclinical studies suggest changes in cell cycle and DNA binding properties and transcriptional inhibition as main mechanisms of action. PM00104 has shown broad in vitro and in vivo anti-tumor activity (IC50 ≤ 10-8 M) with an acceptable toxicology profile. Methods: The aim of this phase I study was to assess the safety profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK), relationship between PK and pharmacodynamics (PD) and anti-tumor activity of PM00104 administered as a 24-hour i.v. infusion q3w. Sequential cohorts of 3–6 pts were treated at 133, 266, 400, 800, 900, 1600, 3200, 4000 and 5000 μg/m2. Results: Twenty nine pts have been treated (18 male, 11 female; median age: 59, range: 44–78; ECOG PS ≤2). Five pts developed DLTs: 2 pts at 5000 μg/m2 (grade 4 thrombocytopenia/neutropenia and grade 3 nausea/vomiting in 1 pt; and grade 3 nausea in 1 pt); 1 at 4000 μg/m2 (grade 4 neutropenia/thrombocytopenia and grade 3 asthenia); 1 at 3200 μg/m2 (grade 3 tumor pain) and 1 at 266 μg/m2 (grade 3 transaminase increase). The MTD was reached at 5000 μg/m2 and the RD at 4000 μg/m2. At the RD 6 more pts have been included in order to further evaluate the safety profile and anti-tumor activity. Other adverse events included nausea and vomiting (more frequent at doses ≥800 μg/m2), fatigue, anorexia and diarrhea; most of them being of ≤grade 2 severity. No objective responses were seen but 3 pts with pancreatic adenocarcinoma, hepatocarcinoma and lower esophagus adenocarcinoma presented stable disease lasting >3 months. PM00104 shows a dose-proportional PK profile, the half-life being 20–30 hours and the volume of distribution around 1000 L. Conclusions: PM00104 has shown an acceptable safety profile with signs of anti-tumor activity in pts with advanced malignancies when administered as a 24-hour i.v. infusion q3w. PM00104 is also being evaluated with other administration schedules as monotherapy and in combination with other anti-tumor agents. [Table: see text]