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PURPOSE Pembrolizumab monotherapy is standard first-line therapy for metastatic non–small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population. METHODS In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234 ), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival. RESULTS Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo. CONCLUSION Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.

Summary Background Whole breast irradiation delivered once per day over 3–5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. Methods We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5–8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov , NCT00282035 . Findings Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3–9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9–4·0) in the APBI group and 2·8% (1·8–3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84–1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p Interpretation External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. Funding Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

9038 Background: In the phase 3 KEYNOTE-598 study (NCT03302234), OS (HR, 1.08; 95% CI, 0.85–1.37; P = 0.74) and PFS (1.06; 95% CI, 0.86–1.30; P = 0.72) were not improved for pembro + ipi vs pembro + placebo in patients (pts) with previously untreated metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR/ALK genomic alterations. Incidence of treatment-related grade 3–5 AEs, fatal AEs, and AEs leading to discontinuation was higher with pembro + ipi vs pembro + placebo. We present prespecified patient-reported outcome (PRO) analyses from KEYNOTE-598. Methods: Pts (n = 568) with previously untreated stage IV NSCLC with PD-L1 TPS ≥50% were randomized 1:1 to pembro 200 mg Q3W for up to 35 cycles + ipi 1 mg/kg or placebo Q6W for up to 18 cycles. The EORTC QLQ-C30, QLQ-LC13, EQ-5D-5L, and NSCLC-SAQ were administered at cycles 1‒7, then every 3 cycles through cycle 19, and every 4 cycles until PD or a maximum of 35 cycles. Change from baseline in global health status (GHS)/quality of life (QoL) score from the QLQ-C30 and the time to true deterioration (TTD) in the composite endpoint of cough (LC13), chest pain (LC13), or dyspnea (C30) were secondary objectives in KEYNOTE-598. Change from baseline in GHS/QoL was analyzed using a constrained longitudinal data analysis model with missing at random assumption. Difference in TTD was evaluated using a Cox proportional hazards model and stratified log-rank test. PROs were analyzed in all pts who completed ≥1 PRO assessment and received ≥1 dose of study treatment. P values are two-sided and nominal. Results: As of data cutoff (Sept 1, 2020), PRO analyses included 280 pts in the pembro + ipi group and 280 pts in the pembro + placebo group. QLQ-C30 completion rates were 95.7% in the pembro + ipi group vs 96.1% in the pembro + placebo group at baseline and 63.6% vs 70.0% at week 18. QLQ-LC13 completion rates were 95.4% vs 96.4% at baseline and 63.6% vs 69.6% at week 18. Mean QLQ-C30 GHS/QoL scores at baseline were 62.8 in the pembro + ipi group and 64.2 in the pembro + placebo group and were similar between the groups across the follow-up period. Least squares (LS) mean (95% CI) change from baseline to week 18 in GHS/QoL scores was improved in both groups (pembro + ipi: 3.7 [0.9‒6.5]; pembro + placebo: 4.1 [1.4‒6.9]), with no significant difference between groups (LS mean difference −0.4 [−4.0 to 3.1], P = 0.82). Median TTD in composite of cough, chest pain, or dyspnea was not reached (NR; 95% CI, 13.0 mo–NR) in the pembro + ipi group vs 20.0 (95% CI, 12.7–NR) mo in the pembro + placebo group (hazard ratio, 0.98 [95% CI, 0.74‒1.30]; P = 0.91). Conclusions: There was no difference in health-related QoL or TTD in lung cancer symptoms between pembro + ipi and pembro + placebo in pts with previously untreated metastatic NSCLC with PD-L1 TPS ≥50%. Clinical trial information: NCT03302234.

Single-agent regorafenib is approved in Canada and in the US for patients with metastatic colorectal cancer (mCRC) who have failed previous lines of therapy1. Identification of prognostic biomarkers is crucial to ensure the best therapeutic strategies for mCRC patients. The goal of this clinical study (NCT01949194) was to explore putative molecular signatures of response and resistance to regorafenib in metastatic tumors and serial blood samples. We used a multi-omics approach to profile metastatic tumor tissues and serial blood samples from 47 mCRC patients who received single-agent regorafenib as second-line therapy after failing first-line therapy with an oxaliplatin or irinotecan-containing regimen with or without bevacizumab. Whole exome sequencing was performed to assess both the mutational and copy number (CN) landscapes of metastatic tissues from 29 patients and the transcriptome was interrogated using RNA sequencing. A 14-gene panel was used to profile serial plasma samples. Molecular aberrations were then correlated with lesion-specific treatment response using RECIST 1.1 and progression free survival (PFS) to investigate potential associations.The copy number aberration (CNA) landscape of metastatic tumors was assessed using Nexus Copy Number Software and 20 significant focal aberrations were identified using Genomic Identification of Significant Target in Cancer (GISTIC) test (q-bound Citation Format: Karen Gambaro, Maud Marques, Suzan McNamara, Mathilde Couetoux du Tertre, Cyrla Hoffert, Archana Srivastava, Sophie Mathieu, Anna schab, Thierry Alcindor, Adrian Langleben, Lucas Sideris, Mahmoud Adbelsalam, Mustapha Tehfe, Gerald Batist, Petr Kavan. A Phase II exploratory study to identify biomarkers prognostic of clinical response to regorafenib in patients with metastatic colorectal cancer who have failed first-line therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4325.

291 Background: St Mary’s Hospital, an affiliated McGill Teaching University Hospital, receives ~700 new cancer patients yearly. In 2014-17, electronic PROs were implemented through the Improving Patient Experience and Health in Outcomes Collaborative in partnership with Cancer Care Ontario, granted by Canadian Partnership against Cancer and Rossy Cancer Network, as part of a PRO Canadian Initiative to improve the Patient Experience across Canada through standardized measurement of health-related outcomes for patients. Methods: The PROs measures included the Edmonton Symptom Assessment Scale (ESAS), additional measures for Fatigue, Anxiety, Depression, and Pain, the Social Difficulties Inventory-21 and Quality of Life. PRO-data was scored in real-time; nurses and patients received a printed summary report. Nurses were provided with an algorithm and instructions. Monthly Distress Screening Dashboard were generated with key indicators. In 2016, all patients receiving chemotherapy were assessed at each cycle of treatment. After project completion, due to nursing staff shortage, the frequency of screenings was reduced. Yearly Dashboard results were used to promote discussion with clinicians and address sustainability constraints of PROs in real-word oncology practice. Results: In 2016 1366 total screens completed ( 376 patients) and in 2018, 753 total screens (325 patients). This comparison indicates that a decrease in frequency of screenings resulted in an increase in symptom severity in all health-related outcomes. Physicians’ participation was proposed as mitigation plan to increase screening frequency. We propose to present a three year retrospectively cross analyzed patient data to examine symptom change over time, frequencies of screening, impact on patients’ health outcomes, overlapping sustainability constraints encountered and mitigation plans. Conclusions: Embedding the use of PRO into existing hospital structures requires constant review involving administrative, clinician and patient engagement.

Lasting complete remission from widespread bone metastases is rare. The case of a 41-year-old premenopausal woman diagnosed with right-sided infiltrating ductal breast carcinoma andBRCA2mutation is described. She received high-dose anthracycline-based induction chemotherapy followed by autologous bone marrow transplantation with high-dose alkylator and platin-based conditioning regimens. The authors comment on the reasons for this unusual and sustained complete remission from widely metastatic breast cancer and the patient-specific factors that may have contributed to this outcome. Background. Infiltrating ductal carcinoma of the breast, staged as pT1N3, was diagnosed in a 41-year-old premenopausal French-Canadian woman. Rapid nodal recurrence progressed to diffuse bone metastases, despite tamoxifen and megestrol. Following enrollment in an in-house study protocol, she received high-dose anthracycline-based induction chemotherapy followed by tandem autologous bone marrow transplantation with high-dose alkylator and platinum-based conditioning regimens. Upon full remission, protocol-mandated locoregional breast and prophylactic cranial radiation was delivered. Complete clinical and radiologic remission has been maintained in the 11 years since study enrolment, which prompted further investigation. Investigations. Pedigree construction and BRCA1/2 mutation analysis. Diagnosis. A BRCA2 8765delAG mutation was identified, in the context of unusual and sustained complete remission from widely metastatic breast cancer. Management. The patient is now followed at a multidisciplinary high-risk prevention clinic because BRCA2 mutations are associated with increased risk of ovarian and breast cancers. This case supports the possibility of differential treatment response in BRCA2-positive breast cancer, although this remains to be conclusively demonstrated.

Purpose Prophylactic cranial irradiation (PCI) has a well-recognized role in the treatment of leukemia and small-cell lung cancer. Clinical utility has yet to be determined for breast cancer, where an emerging group at high risk of brain metastasis has fuelled consideration of PCI. Methods and Materials In reviewing our experience with PCI as part of a complex protocol for advanced breast cancer, we present descriptive data on late central nervous system outcomes in those receiving PCI. After high-dose anthracycline-based induction chemotherapy, Stage IIIB/IV breast cancer responders underwent tandem autologous marrow transplantation. Those in continued remission were referred for PCI. Whole-brain radiotherapy was delivered by usual means, at 36 Gy in 20 fractions. Results Twenty-four women, with median age 45 (28–61), were enrolled between 1995 and 1998. Disease was largely metastatic (79%), and 75% were previously exposed to chemotherapy or hormonotherapy. Ten patients received PCI, at a median of 13.4 (11.8–16.5) months from study entry. Six patients developed brain metastases, 2 despite PCI. Striking functional decline was documented in 3 patients (at 9 months, 4 years, and 5 years post-PCI), including one previously high-functioning woman requiring full care for posttreatment dementia. Conclusions We present a series of advanced breast cancer patients treated prophylactically with whole-brain radiotherapy following an aggressive chemotherapy regimen. Although the therapeutic benefit of PCI is not ascertainable here, we describe brain metastases occurring despite PCI and serious long-term neurobehavioral sequelae in PCI-treated patients. Any further investigation of PCI in high-risk breast cancer will need to be approached with caution.

Purpose Determine the relative risk of cancer users of commonly prescribed antihypertensive drugs with a focus on documenting risk in long-term users (>7.5 years). Methods We conducted a nested case–control study using the Saskatchewan Health databases. Cancer risks in users of β-blockers, calcium channel blockers (CCBs), and rennin-angiotensin system inhibitors (RASIs), respectively, were compared to risks in users of thiazide diuretics. Results A total of 11 697 first cases of cancer and the subset of 6918 subjects who died from cancer were each matched to 10 controls. The mean total duration of use of the four classes of antihypertensive drugs (estimated by dispensation of prescriptions) ranged from 3.6 to 5.7 years. A subgroup of cases was exposed long term (mean total duration of use: 9.7–11.4 years, range: 7.5–23.1 years). Modest differences in risk between users of the four classes were detected for colon, head & neck, lung, and hematological cancers but none of these associations demonstrated a clear dose response relationship for both first cancer and fatal cancer. Otherwise, for cancer at all sites combined and for the four most common cancers, we were able to rule out, with reasonable confidence, small to modest differences in the risk of cancer among users of any duration (upper 95% confidence intervals (CIs): 1.45) and modest to large differences in risk among long-term users (upper 95%CI: 3.06). Conclusions The long-term use of commonly prescribed classes of antihypertensive drugs does not appear to promote or initiate cancer. Copyright © 2008 John Wiley & Sons, Ltd.

Objective Early prediction of imminent failure during chemotherapy for malignant glioma has the potential to guide proactive alterations in treatment before frank tumor progression. We prospectively followed patients with recurrent malignant glioma receiving tamoxifen chemotherapy using proton magnetic resonance spectroscopic imaging (1H-MRSI) to identify intratumoral metabolic changes preceding clinical and radiological failure. Methods We performed serial 1H-MRSI examinations to assess intratumoral metabolite intensities in 16 patients receiving high-dose oral tamoxifen monotherapy for recurrent malignant glioma (WHO grade III or IV) as part of a phase II clinical trial. Patients were followed until treatment failure, death, or trial termination. Results Patients were officially classified as responders (7 patients) or non-responders (9 patients) 8 weeks into treatment. At 8 weeks, responders and non-responders had different intratumoral intensities across all measured metabolites except choline. Beyond 8 weeks, metabolite intensities remained stable in all responders, but changed again with approaching disease progression. Choline, lipid, choline/NAA, and lactate/NAA were significantly elevated (P < 0.02), while creatine (P < 0.04) was significantly reduced, compared to stabilized levels on average 4 weeks prior to failure. Lactate was significantly elevated (P = 0.036) fully 8 weeks prior to failure. In one patient who was still responding to tamoxifen at the conclusion of the trial, metabolite intensities never deviated from 8-week levels for the duration of follow-up. Conclusions Characteristic global intratumoral metabolic changes, detectable on serial 1H-MRSI studies, occur in response to chemotherapy for malignant glioma and may predict imminent treatment failure before actual clinical and radiological disease progression.

Background Preclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer. Methods Patients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug. Results In cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4–7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib. Conclusion The combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction. Trial Registration ClinicalTrials.gov NCT00764972

BACKGROUND The current dose-optimizing Phase II study evaluated the effect of weekly paclitaxel and gemcitabine on the response rate and survival of patients with non-small cell lung carcinoma (NSCLC) using dose modifications that permitted optimal treatment intensity. METHODS Forty-five patients (40 with TNM Stage IV and 5 with TNM Stage IIIB NSCLC) were treated with gemcitabine at 1000 mg/m2 via a 30-minute intravenous (i.v.) infusion and with paclitaxel at 100 mg/m2 via a 60-minute i.v. infusion. The first 3 patients received chemotherapy on Days 1, 8, and 15 every 4 weeks; the next 42 patients, participating in the Phase II trial, received chemotherapy on Days 1 and 8 every 3 weeks. RESULTS The 3 patients who received paclitaxel and gemcitabine on Days 1, 8, and 15 every 4 weeks tolerated the treatment poorly. One patient died suddenly after Day 15 treatment during the first cycle, and the other 2 patients discontinued the treatment because of unacceptable toxicity before the third cycle of chemotherapy. The next 42 patients, 40 of whom were evaluable, entered this trial between May 2000 and April 2001. They received paclitaxel at 100 mg/m2 i.v. followed by gemcitabine at 1000 mg/m2 i.v. on Days 1 and 8 every 3 weeks. Two patients (5%) achieved complete response, 20 (50%) achieved partial response, and 8 (20%) had stable disease. Median survival (MS) was 9.8 months; and 1-year survival was 35%. The 32 patients with performance status (PS) 0 or 1 had an MS of 11 months; the 8 patients with PS 2 had an MS of 3 months. Toxicity (especially hematologic toxicity, neuropathy, and alopecia) was minimal. CONCLUSION A weekly paclitaxel and gemcitabine regimen that incorporated the authors' dose modifications resulted in good efficacy with minimal toxicity. Cancer 2003;97:2242–7. © 2003 American Cancer Society. DOI 10.1002/cncr.11319

Background. Secreted clusterin (sCLU) promotes survival and stimulates epithelial to mesenchymal transition (EMT) in cancer cells, leading to tumor invasion, metastasis and chemoresistance. AB-16B5 is a humanized IgG2 mAb specific for the EMT-inducing region in some isoforms of sCLU produced by tumor cells, with much less affinity for sCLU found in healthy individuals. Pre-clinical models showed that AB-16B5 inhibits EMT and displays synergy with chemotherapeutic agents. We performed a first-in-human phase I trial to assess safety and tolerability of AB-16B5 and to determine a recommended dose for phase II studies. Methods. Patients (pts) with evaluable and refractory advanced solid malignancies were eligible with adequate organ and bone marrow functions and an ECOG of 0-2. AB-16B5 was administered as a 60-min IV weekly infusion (21-day cycles). Dose escalation followed an accelerated scheme for the 1.5 and 3 mg/kg dose levels and a standard 3 + 3 design for subsequent levels (6, 9 and 12 mg/kg). All pts underwent collection of blood samples for PK analysis. Pre-treatment and post-treatment (end of cycle 2) tumor biopsies were collected if feasible in pts dosed at 9 and 12 mg/kg. Biopsies were used to evaluate EMT status and to investigate the presence of AB-16B5. Radiological imaging was performed every 6 weeks for the first 8 cycles, then every 9 weeks thereafter. Results. 15 pts (13 carcinomas of various origins, 1 melanoma and 1 sarcoma) were enrolled from May 2015 to October 2016. Pts received between 1 and 53 weekly doses (median: 9 doses). The most frequently reported adverse events (AEs, all causalities) were nausea, abdominal pain, constipation, vomiting, back pain, pruritus and dyspnea. Most of the AEs were of Grade 1 or 2. Among the AEs ≥ Grade 3, only 2 (Grade 3 infusion related reaction and rash) were judged related to AB-16B5. No dose-limiting toxicities were identified during the first cycle of treatment for any pt. 5 serious AEs were reported (sepsis, pyrexia, dyspnea, intra-abdominal hemorrhage and main stem bronchus obstruction), none of which were judged related to the study treatment. PK analysis across all dose levels confirmed that systemic exposure to AB-16B5 increased in a dose proportional manner. The presence of AB-16B5 at the tumor site was confirmed in all 5 pts where a post-treatment tumor lysate could be generated. Biomarker analysis in paired tumor biopsies provided some evidence for EMT inhibition as seen by increased E-cadherin expression after treatment with AB-16B5 in 2 pts. In one of these 2 pts with advanced gastric cancer, this was also accompanied by a loss of vimentin expression. This pt had stable disease (SD) with clinical benefit and remained on treatment for 24 weeks. Another pt with follicular thyroid cancer had SD for almost 1 year. Conclusion. Weekly infusions of AB-16B5 are well tolerated up to 12 mg/kg. This dose level is the recommended phase II dose for future trials. Early correlative studies on tumor tissue provide evidence of molecular modulation of the tumor environment in humans. Clinical trial registry number: NCT02412462 Citation Format: Cristiano Ferrario, Julie Laurin, Leon Van Kempen, Caroline Lambert, Alan Spatz, Oksana Markova, Gerald Batist, Adrian Langleben, Mario Filion, Jacques Jolivet. Phase 1 first-in-human study of anti-clusterin antibody AB-16B5 in patients with advanced solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT098. doi:10.1158/1538-7445.AM2017-CT098

1084 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, Napabucasin plus weekly paclitaxel was well tolerated. A phase II expansion cohort was opened for pts with previously treated metastatic breast cancer (MBC). Methods: Pts with metastatic MBC for whom weekly PTX was a reasonable treatment option received Napabucasin 240, 480, or 500 mg orally, twice daily in combination with paclitaxel 80 mg/m2 IV weekly on 3 of every 4 weeks. Adverse events were evaluated using CTCAE v4.03 and objective tumor assessments were obtained every 8 weeks per RECIST 1.1 criteria. Results: A total of 50 pts were enrolled including 34 with triple-negative disease (negative for estrogen receptor [ER], progesterone receptor [PR], and Her2 and no prior history of positive receptor status). There were 9 pts positive for ER, PR, or Her2 and refractory to targeted agents, and 7 pts with conversion to triple-negative disease from pathology previously positive for ER, PR or Her2. Pts were heavily pre-treated, having received a median of 5 prior lines of systemic therapy. All but 3 patients had received previous systemic treatment with a taxane. Napabucasin + PTX was well tolerated. Grade 3 AE occurring in ≥ 5% patients was diarrhea (n = 4), and 1 pt had grade 4 diarrhea. The objective response rate (ORR), disease control rate (DCR), median progression free survival (mPFS), and median overall survival (mOS) for all pts and for each sub-group are summarized in the table. Conclusions: Napabucasin (BBI-608) plus weekly paclitaxel has demonstrated safety, tolerability, and encouraging signs of anti-cancer activity in pts with pretreated metastatic breast cancer. Further clinical evaluation of this combination regimen in controlled trials is warranted. Clinical trial information: NCT01325441. [Table: see text]

5548 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for patients with platinum resistant ovarian cancer. Methods: Pts with advanced ovarian cancer who had disease progression either during or in the 6 months following platinum-based systemic therapy were enrolled. napabucasin was administered orally at a starting dose of 240, 480, or 500 mg twice daily with PTX 80 mg/m2 IV weekly on 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed per RECIST 1.1 every 8 weeks. Results: A total of 98 pts were enrolled. The average number of prior lines of systemic treatment was 3.5, including prior taxane-based therapy in 100% of patients. Treatment was well tolerated. Related grade 3 adverse events occurring ≥ 5% of pts included diarrhea (12.2%) and vomiting (5.1%). Among pts who received RECIST evaluation (n = 76), the disease control rate (DCR, proportion with SD at 8 weeks + PR + CR) was 65%, and the objective response rate (ORR, PR+CR) was 20%, with complete response in 3 pts (4%). In all patients (ITT, n = 98), the median progression-free survival (mPFS) was 3.0 months and median overall survival (mOS) was 9.3 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity, including three complete responses, were observed in pts with pre-treated platinum resistant ovarian cancer who received treatment with napabucasin plus weekly PTX. Further clinical evaluation in controlled trials is warranted. Clinical trial information: NCT01325441.

9052 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for pts with advanced non-small cell lung cancer (NSCLC). Methods: Pts with metastatic non-squamous NSCLC were enrolled to confirm safety and preliminary anti-cancer activity. Prior platinum-based systemic therapy was required, and patients with an EGFR or ALK mutation required appropriately targeted therapy. Napabucasin was administered orally at a starting dose of 240 or 480 mg BID with PTX 80 mg/m2 IV weekly 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed every 8 weeks per RECIST 1.1. Results: A cohort of 23 pts with advanced non-squamous NSCLC was evaluated. The median number of prior systemic treatment lines was 3, including taxane-based therapy in 100% and immune checkpoint inhibitor in 48% (n = 11). Treatment was well tolerated; related grade 3 AE included diarrhea (n = 4) and fatigue (n = 1). The objective response rate was 26% (6 partial responses [PR]) and the disease control rate (DCR; proportion with SD at 8 weeks plus PR per RECIST) was 70% (n = 16). Tumor regression, including PR, occurred in 35% (n = 8). The median progression-free survival (mPFS) was 5.4 months, and 43% (n = 10) of pts were alive and free of progression at the 24 week time-point or longer. The median overall survival (mOS) was 11.0 months, and 30% (n = 7) of pts were alive for 52 weeks or longer. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with heavily pretreated non-squamous NSCLC who received napabucasin plus weekly paclitaxel. The objective response rate, progression free survival, and overall survival in this population warrant further clinical evaluation and a controlled phase 2/3 trial (CanStem43L) has been initiated. Clinical trial information: NCT01325441.

BACKGROUND Both locoregional and distant disease control remains poor in the treatment of Stage III nonsmall cell lung carcinoma (NSCLC). This trial was conducted to evaluate the tolerance and responses of patients with NSCLC given a neoadjuvant regimen of cisplatin and vinorelbine chemotherapy followed by accelerated thoracic radiotherapy. METHODS Forty-two patients with Stage IIIA and IIIB NSCLC were entered into the study. Treatment consisted of cisplatin 100 mg/m2 given on Days 1 and 29 and vinorelbine 30 mg/m2 given weekly for 5 weeks, with a planned 50% dose reduction to 15 mg/m2 planned for Week 2. This was followed by thoracic irradiation of 60 gray (Gy) in 30 fractions of 2 Gy over 4 weeks (once daily during Weeks 1 and 2 and twice daily during Weeks 3 and 4). RESULTS With a median follow-up time of 12.2 months (27–65 months for survivors), the median survival was 12.2 months (16.6 months for patients with no prior weight loss and 7.8 months for those with prior weight loss). The response rate after induction chemotherapy was 46.1%, increasing to 74.4% after radiation therapy (8 complete responses and 21 partial responses). The rate of progression was 13 of 18 (72%) for those who responded to chemotherapy (4 distant, 9 local) and 18 of 21 (86%) for those who did not respond to chemotherapy (14 distant, 7 local). The most frequent acute Grade 3 toxicity was nausea (21.4%). CONCLUSIONS Accelerated thoracic irradiation after induction chemotherapy is well tolerated and yields therapeutic results that compare favorably with those reported for other regimens of chemotherapy and standard fractionated radiotherapy. The data from this study suggest that the responses of patients with clinically apparent disease to induction chemotherapy might indicate a likelihood of controlling microscopic distant metastases. Cancer 1999;85:2562–9. © 1999 American Cancer Society.

Patients with solid tumors, including carcinoma of the pancreas, express high levels of matrix metalloproteinases (MMP), and these enzymes are believed to be important for the growth, spread, and dissemination of most solid malignant tumors. Marimastat is the first orally available MMP inhibitor (MMPI) to be tested in humans and has been shown to inhibit the spread and growth of pancreatic cancer in animal models. The purpose of the present study was to define the toxicities, safety, and tolerance of various doses of marimastat and also to get an early indication of potential biologic activity in patients with advanced pancreatic cancer. The authors prospectively studied 64 patients with advanced carcinoma of the pancreas in whom standard treatments had failed. Eligible patients had a progressive rise in CA 19/9 levels of25% over the 4-week period preceding their entry into the study. Patients were studied in groups of 8 to 10, with each group receiving escalating dosages ranging from 5 mg twice daily to 75 mg twice daily and 10 to 25 mg daily. Patients were considered for long-term (beyond 4 weeks) continuation treatment if clinical benefit, in the view of the investigator, was derived. Study endpoints were safety, tolerance, and changes in the rate of rise of CA 19/9, which were used as surrogate markers for disease progression. Marimastat was well tolerated. Musculoskeletal pain, stiffness, and tenderness emerged as dose-limiting toxicity. No other dose-related toxicities were observed. A reduced rate of rise of CA 19/9 was observed at dose levels of 5, 10, and 25 mg twice daily. The overall median survival was 160 days, with a 1-year survival of 21%. Marimastat was associated with an acceptable toxicity profile, and these preliminary data suggest that long-term oral administration is feasible and safe. Doses of 5, 10, and 25 mg twice daily were identified as the optimal doses to be tested in larger randomized studies.

BACKGROUND. Pulmonary blastoma is a rare malignant neoplasm for which there currently are no treatment guidelines. METHODS. A patient with locally advanced pulmonary blastoma is described. The treatment modality is discussed and the world literature is reviewed with respect to the use of chemotherapy. RESULTS. A 54-year-old man had a 7-year disease free survival despite subtotal resection. He was treated with adjuvant radiotherapy and combination chemotherapy. Three cycles of cisplatin and etoposide were administered. The world literature was reviewed with regard to the use of adjuvant chemotherapy in the treatment of pulmonary blastoma. CONCLUSIONS. Surgery, adjuvant radiotherapy, and combination chemotherapy with cisplatin and etoposide should be considered in the treatment of patients with this rare pulmonary neoplasm.

Objective. The objective was to evaluate the efficacy of Org 2766 (a hexapeptide analogue of ACTH) in the prevention or delay of cisplatin-induced neuropathy during chemotherapy in women with ovarian cancer as measured by vibration perception threshold (VPT). Methods. In this randomized, multicenter, double-blind, placebo-controlled study, 196 women with ovarian cancer were treated with cisplatin 75–100 mg/m 2 , cyclophosphamide 600–1000 mg/m 2 plus placebo or two dose levels of Org 2766. The cisplatin-induced neuropathies were monitored by determining the VPT with the Vibratron II. VPT was determined for both the most sensitive great toe and the index finger on a monthly basis during treatment and months 1, 2, and 3 postchemotherapy. Once the blind was broken, it was found that 174 women (59 in placebo, 58 in 2 mg, and 57 in 4 mg) had enough data to allow evaluation. Results. Over the course of follow-up, the VPT was found to increase. This is consistent with the development of cisplatin-induced peripheral neuropathies. The baseline VPT for the index finger was less than that of the great toe (0.65 vs 2.13), but the percentage change in VPT was the same for both (percentage increase in VPT of about 350%). When the VPTs are compared according to the dose of Org 2766 given, there appears to be no difference in the rate of change or degree of neuropathies that developed in these women receiving cisplatin and cyclophosphamide. Conclusions. The development of cisplatin-induced neuropathies is confirmed by measurement of the VPT. The rate of development of neuropathies seems to accelerate after the sixth course of cisplatin. When the development of neuropathies is evaluated on the basis of Org 2766 dosage, it is found that there is no difference in the rate or degree of neuropathies seen. Instead of providing protection from and delay of onset of peripheral neuropathies caused by cisplatin, these results suggest that the administration of Org 2766 appears to cause an increase in the rate of change and degree of neuropathies ( P > 0.05).

9093Background: Napabucasin (BBI-608, BB608) is a first-in-class cancer stemness inhibitor that works through inhibiting the STAT3 pathway, and it has shown potent synergistic anti-tumor activity w...

5578Background: Napabucasin (BBI-608, BB608) is a first-in-class cancer stemness inhibitor targeting the STAT3 pathway that has shown potent synergistic anti-tumor activity with paclitaxel in vivo....

1094Background: Napabucasin (BBI-608, BB608) is a first-in-class cancer stemness inhibitor that targets the STAT3 pathway that has shown potent synergistic preclinical anti-tumor activity with pacl...

Determine the relative risk of cancer users of commonly prescribed antihypertensive drugs with a focus on documenting risk in long-term users (7.5 years).We conducted a nested case-control study using the Saskatchewan Health databases. Cancer risks in users of beta-blockers, calcium channel blockers (CCBs), and rennin-angiotensin system inhibitors (RASIs), respectively, were compared to risks in users of thiazide diuretics.A total of 11,697 first cases of cancer and the subset of 6918 subjects who died from cancer were each matched to 10 controls. The mean total duration of use of the four classes of antihypertensive drugs (estimated by dispensation of prescriptions) ranged from 3.6 to 5.7 years. A subgroup of cases was exposed long term (mean total duration of use: 9.7-11.4 years, range: 7.5-23.1 years). Modest differences in risk between users of the four classes were detected for colon, headneck, lung, and hematological cancers but none of these associations demonstrated a clear dose response relationship for both first cancer and fatal cancer. Otherwise, for cancer at all sites combined and for the four most common cancers, we were able to rule out, with reasonable confidence, small to modest differences in the risk of cancer among users of any duration (upper 95% confidence intervals (CIs): 1.45) and modest to large differences in risk among long-term users (upper 95%CI: 3.06).The long-term use of commonly prescribed classes of antihypertensive drugs does not appear to promote or initiate cancer.

196 Background: Cancer stemness is thought to be associated with resistance to chemotherapies. BBI608, a first-in-class cancer stemness inhibitor that works through inhibiting the Stat3 pathway, has shown potent synergistic anti-tumor activity with paclitaxel in vivo. In a phase Ib dose escalation study in patients with advanced solid tumors, BBI608 plus weekly paclitaxel was well tolerated and a RP2D of BBI608 480 mg BID was determined. Methods: Patients with heavily pretreated metastatic pancreatic adenocarcinoma were enrolled in a phase Ib/II extension study to assess safety, tolerability, and preliminary anti-cancer activity in patients with this diagnosis. BBI608 was administered orally at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel 80 mg/m2 IV weekly 3 of every 4 weeks. A sample size of 40 set the bounds of the 90% CI at ±10% to 14%, assuming a DCR of 60% to 80%. Safety and efficacy results for the cohort will be presented as late breaking data. Results: 41 patients were enrolled. Patients had received a median of 2 prior lines of treatment including FOLFIRINOX (71%), gemcitabine/nab-paclitaxel (44%), or both (37%). Overall, prior therapy included gemcitabine in 90%, a thymidylate synthetase inhibitor (eg 5FU, capecitabine) in 81%, platinum in 76%, irinotecan in 73%, and taxane in 44%. Protocol therapy was well tolerated. Related grade 3 AE included diarrhea (N = 2, 4.9%), abdominal pain (N = 2, 4.9%), and nausea (N = 1, 2.4%), and were rapidly reversible. For evaluable patients (N = 31), response rate (PR+CR) was 7% and disease control rate (SD+PR+CR) was 52%. In evaluable taxane-naïve patients (N = 19), response rate was 11%, disease control rate was 63%, and 16% were progression free at 24 weeks. Overall (ITT, N = 41) mPFS was 10 weeks and mOS was 24 weeks. For the taxane-naïve patients (ITT, N = 23) mPFS was 16 weeks and mOS was 30 weeks. Conclusions: BBI608 plus weekly paclitaxel has demonstrated safety, tolerability, and promising activity in patients with refractory, heavily pretreated pancreatic cancer; particularly in taxane-naïve patients. Durable disease control and prolonged overall survival in this pre-treated population are notable. Clinical trial information: NCT01325441.

Adjuvant nitrosourea chemotherapy fails to prolong patient survival significantly as many tumors demonstrate resistance to these drugs. It has been documented in cell lines that O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in chloroethylnitrosourea (CENU) drug resistance. The authors evaluated MGMT expression in 22 glioma specimens by using an immunofluorescence assay and compared the results with clinical response of the patients to CENU-based chemotherapy. The patients were treated with CENU after evidence of progressive disease following surgery and radiotherapy. Eight tumor samples had no detectable MGMT, whereas other samples had from 9989 to 982,401 molecules/nucleus. In one group (12 patients), the tumor decreased in size or was stable (effective group), whereas in the other group (10 patients), the tumor demonstrated continuous growth during chemotherapy (progressive group). The median time to progression (TTP) was 6.7 months with a median survival of 13 months. The Mer− patients (MGMT < 60,000 molecules/nucleus) appeared to have more chance of stable disease or response to CENU therapy than the Mer+ patients (MGMT > 60,000 molecules/nucleus) (chi-square = 4.791, p = 0.0286). In patients with glioblastomas multiforme (GBMs), the TTP of Mer+ patients was shorter than that of Mer− patients (t = 2.04, p = 0.049). As a corollary, the MGMT levels were significantly higher in GBM tumors from the progressive group than those from the effective group (t = -2.26, p = 0.029). The TTP and survival time in the effective GBM group were also longer than those in the progressive GBM group. However, there was no significant correlation between MGMT levels and either the survival time (r = 0.04, p = 0.8595) or TTP (r = 0.107, p = 0.6444). Results from this study suggested that MGMT positivity is indicative of more aggressive disease that progresses more rapidly when exposed to CENU therapy. However, MGMT-negative tumors are not always sensitive to CENU agents, suggesting that other factors may also be important.

To provide context in oncology for the significance of the benefits and cost of combined androgen blockade (CAB) in the treatment of advanced prostate cancer.Canadian drug costs for the survival benefit with CAB in advanced prostate cancer were compared with the costs of benefit with new treatments in advanced non-small-cell lung cancer (NSCLC), metastatic colorectal cancer, and metastatic breast cancer. Clinical toxicities were also compared.The survival benefit with CAB in advanced prostate cancer appears to be approximately 3 months. The survival benefit with the addition of vinorelbine to cisplatin for the treatment of advanced NSCLC is approximately 2 months, and the survival benefit with the addition of irinotecan to fluorouracil (and leucovorin) for the treatment of metastatic colorectal cancer is approximately 2 to 3 months. The survival benefit with anastrozole or exemestane in advanced breast cancer, or with the addition of trastuzumab to standard chemotherapy in metastatic breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2), is approximately 4 to 5 months. The calculated cost per month of survival benefit with bicalutamide in CAB for prostate cancer is 437 US dollars to 1107 US dollars. The cost per month of survival benefit with vinorelbine for NSCLC is 1241 US dollars and with irinotecan for colorectal cancer is 6812 to 11,214 US dollars. The calculated cost per month of survival benefit with anastrozole for breast cancer is 170 US dollars, for exemestane is 185 US dollars, and the cost per month with the addition of trastuzumab is 5230 US dollars. Vinorelbine and irinotecan are associated with severe grade 3 or 4 clinical toxicities, and an increased frequency of heart failure has been observed when trastuzumab is added to anthracyclines. Anastrozole, exemestane and nonsteroidal antiandrogens are associated with mild to moderate side effects.The advantages offered by CAB (including the cost per month of survival benefit and minimal associated clinical toxicities) are comparable to the reported advantages of new treatments for other common cancers such as NSCLC, colorectal cancer, and breast cancer.

We present a case of recurrent glioma, previously treated with maximal surgery and radiation in which a high dose of tamoxifen has stabilized the tumour clinically and has resulted in it's radiologic regression. Given tamoxifen's relative lack of toxicity, it might serve as a useful adjuvant in the treatment of recurrent glioma.

TPS3656 Background: Biopsy-driven trials offer unique opportunities for discovery and validation of molecular signatures. We began a Phase II investigator-initiated study (IIS) to identify biomarke...

BACKGROUND This Phase II study evaluated a flexible 3- or 4-week dosing schedule of gemcitabine and vinorelbine to determine its effect on response rate and survival of patients with metastatic nonsmall cell lung carcinoma (NSCLC). METHODS Thirty-four response-evaluable patients, 24 with performance status (PS) 0–1 and 10 with a PS of 2, 30 with Stage IV, and 4 with Stage IIIB NSCLC were treated with gemcitabine 1000 mg/m2 intravenously and vinorelbine 25 mg/m2 intravenously (first 15 patients) or 30 mg/m2 intravenously (next 19 patients) on Days 1, 8, and 15 of a 4-week cycle, if on Day 15 neutrophils were ≥ 1500/uL and platelets ≥ 100,000/uL. If chemotherapy could not be administered on Day 15, then Day 22 became Day 1 of the next cycle. RESULTS When vinorelbine 25 mg/m2 was given with gemcitabine 1000 mg/m2, 11 patients received 4-week cycles, 3 patients 3-week cycles, and 1 patient both 3- and 4-week cycles. With vinorelbine 30 mg/m2 and gemcitabine 1000 mg/m2, 7 patients received 4-week cycles, 2 patients 3-week cycles, and 10 patients both 3- and 4-week cycles. The partial response rate for 34 patients was 53% (18 patients). Median survival (MS) was 11.1 months, and 1-year survival 50% (17 patients). Patients with PS 0+1 had a MS of 17.5 months compared with patients with PS 2, who had MS of 3.3 months. Patients < 70 years of age had a MS of 18 months, and those ≥ 70 years had a MS of 5.5 months. CONCLUSION This flexible schedule with gemcitabine and vinorelbine enabled optimal dose delivery and suggested excellent efficacy but less toxicity than treatment with platinum regimens. Cancer 2001;92:830–5. © 2001 American Cancer Society.

Tamoxifene a haute dose et radiotherapie postoperatoire chez des patients atteints de glioblastome multiforme: etude de phase IB. Objectif: Evaluer la praticabilite et la toxicite d'un traitement adjuvant par le tamoxifene a haute dose (TAM) et la radiotherapie cerebrale chez les patients ayant un diagnostic recent de glioblastome multiforme (GBM). Materiel et methodes: Douze patients ayant un GBM confirme par anatomopathologie ont ete recrutes. Il s'agissait de neuf hommes et trois femmes dont l'âge median etait de 48.8 ans (fourchette de 30 a 75 ans). L'indice de Karnofsky etait de 60 a 70% chez quatre patients et de 80 a 100% chez huit patients. Selon l'analyse de partition recursive du Radiation Therapy Oncology Group, il y avait trois patients de classe III, six de classe IV, un de classe V et deux de classe VI. Onze patients ont subi une resection chirurgicale partielle et un patient a subi une resection presque complete de la tumeur. Deux semaines apres la chirurgie, on a commence a administrer le TAM a haute dose (120 mg/m2 p.o. b.i.d. pendant trois mois). Deux semaines apres le debut du TAM, un traitement de radiotherapie externe (RT) a ete administre pour une dose totale de 59.4 Gy/33 q.d. fractionnee sur 6.5 semaines. Les patients etaient evalues a chaque semaine quant a la toxicite du traitement. Des etudes d'imagerie ont ete realisees apres deux semaines de TAM et mensuellement par la suite. Resultats: La duree mediane de suivi etait de 40 semaines (fourchette de 22 a 84 semaines). Chez un patient, le TAM a ete associe a des vomissements importants necessitant une reduction de la posologie du TAM apres trois semaines de traitement et un arret apres deux mois. Un autre patient a presente une thrombophlebite profonde bilaterale apres 51/2 semaines de TAM, bien que la relation avec le TAM n'ait pas ete etablie avec certitude. Il n'y a pas eu de reponse radiologique apres deux semaines de TAM ou a la fin de la RT. Le temps median jusqu'a la progression etait de 17.7 semaines (fourchette de 5.1 a 43.8 8 semaines). La survie moyenne etait de 33.4 semaines (fourchette de 10 a 79.7 semaines). La survie actuarielle a 48 et 74 semaines etait de 40% et 15% respectivement. Conclusion: Notre etude demontre qu'un traitement d'appoint par le TAM est faisable et relativement bien tolere. De plus, l'utilisation combinee de doses elevees de TAM et de radiotherapie postoperatoire n'etait pas associee a une augmentation significative de la toxicite neurologique induite par la radiotherapie. Cependant, le TAM a haute dose ne semble pas ameliorer les resultats du traitement.

OBJECTIVE: Most patients with a malignant glioma spend considerable time on a treatment protocol before their response (or nonresponse) to the therapy can be determined. Because survival time in the absence of effective therapy is short, the ability to predict the potential chemosensitivity of individual brain tumors noninvasively would represent a significant advance in chemotherapy planning. METHODS: Using proton magnetic resonance spectroscopic imaging ( 1 H MRSI), we studied 16 patients with a recurrent malignant glioma before and during treatment with high-dose orally administered tamoxifen. We evaluated whether 1 H MRSI data could predict eventual therapeutic response to tamoxifen at the pretreatment and early treatment stages. RESULTS: Seven patients responded to tamoxifen therapy (three with glioblastomas multiforme; four with anaplastic astrocytomas), and nine did not (six with glioblastomas multiforme; three with anaplastic astrocytomas). Responders and nonresponders exhibited no differences in their age, sex, tumor type, mean tumor volume, mean Karnofsky scale score, mean number of weeks postradiotherapy, or mean amount of prior radiation exposure. Resonance profiles across the five metabolites measured on 1 H MRSI spectra (choline-containing compounds, creatine and phosphocreatine, N-acetyl groups, lactate, and lipids) differed significantly between these two groups before and during treatment. Furthermore, linear discriminant analyses based on patients' in vivo biochemical information accurately predicted individual response to tamoxifen both before and at very early treatment stages (2 and 4 wk). Similar analyses based on patient sex, age, Karnofsky scale score, tumor type, and tumor volume could not reliably predict the response to tamoxifen treatment at the same time periods. CONCLUSION: It is possible to accurately predict the response of a tumor to tamoxifen on the basis of noninvasively acquired in vivo biochemical information. 1 H MRSI has potential as a prognostic tool in the pharmacological treatment of recurrent malignant gliomas.

States, reviewed an oncology protocol presenting serious risk to research participants. Given the degree of risk to subjects posed by the study and the potential vulnerability of the study population, the IRB decided that direct monitoring of the informed consent process was required to ensure that subjects were adequately informed and that the decision to participate was voluntary. In this paper, we describe the consent monitoring process devised by the IRB and the results obtained. The study in question was a phase II regimen of dose intensification therapy for women with advanced (stage IIIB, IV, or inflammatory carcinoma) breast cancer ineligible for hormonal therapy (estrogen-receptor negative tumor or failure of two hormonal therapies).' The protocol combined a variety of aggressive (and investigational) treatments for advanced cancer. The induction regimen consisted of treatment with a very high dose of an anthracycline, an experimental cardio-protective drug, methotrexate, and 5-flourouracil. After 6 cycles of induction chemotherapy, patients received 2 sequential autologous bone marrow transplants (ABMT). If after the second ABMT no evidence of tumor was seen in biopsy samples, patients received irradiation to any (previous) areas of bulky disease and to the cranium. Finally, patients received tamoxifen for up to 5 years after completion of radiation therapy. The entire regimen (excluding the tamoxifen) took 10 months to complete, of which an estimated 110 days were spent in hospital. Intensive supportive measures were required, including growth factors, peripheral stem cell transfusion, parenteral nutrition, antibiotics, and, if necessary, admission to the intensive care unit. The anticipated treatment mortality rate was 10 to 15%.

2542 Background: Cancer Stem Cells (CSC) are considered to be fundamentally responsible for malignant growth, relapse, metastasis, and resistance to conventional therapies. BBI608 is an orally-administered first-in-class cancer stemness inhibitor which blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells by inhibition of the Stat3, Nanog and b-catenin pathways, and has shown potent anti-tumor and anti-metastatic activities pre-clinically. Methods: A phase 1 dose escalation studyin adult patients with advanced cancer who had failed standard therapies was conducted to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary anti-tumor activity of BBI608. A modified Simon accelerated titration scheme was used for dose escalation, with a cycle consisting of twice-daily oral administration of BBI608 for 4 weeks. Cycles were repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or other discontinuation criteria were met. Results: Fourteen cohorts (N=41) were dosed from 20 mg to 2000 mg/day with adverse events being generally mild; the most common being grade 1-2 diarrhea, nausea, anorexia and fatigue. Four grade 3 events included diarrhea (n=3) and fatigue (n=1). MTD was not reached and further dose escalation was limited by pill burden. By the 400 mg/day dose level the plasma concentration of BBI608 was sustained for over 8 hours at a concentration above 1.5 uM (several fold above the IC50). 17/26 patients evaluable for tumor response achieved SD, for a DCR of 65%. Prolonged TTP was observed in 12/26 evaluable patients (46%), including patients with colorectal (CRC), head and neck, gastric, ovarian, melanoma, and breast cancer. In the subset of patients with CRC (N=18), SD was seen in 8/12 evaluable (67%). A median PFS of 14 weeks and median OS of 47 weeks were observed in evaluable CRC patients. Conclusions: Dose escalation of BBI608, a first-in-class cancer stem cell pathway inhibitor, has been achieved without dose limiting toxicity. BBI608 has shown an excellent safety profile, favorable pharmacokinetics, and encouraging signs of clinical activity particularly in CRC Clinical trial information: NCT01775423.

To determine the maximum tolerated dose (MTD) of escalating doses of interferon-alpha-2b (IFN, Intron A) with 5-fluorouracil (5-FU) and cisplatin (DDP) in patients with advanced cancer, 15 patients were accrued between May 1990 and July 1991. Primary sites were unknown (3), colorectal (3), head and neck (2), lung (2), gynecologic (1), gallbladder (1), sarcoma (1), anal canal (1) and pancreas (1). IFN was given s.c. on days 1-5 and then three times weekly with DDP (75 mg/m2, day 1) and 5-FU [750 mg/m2, days 1-5, continuous infusion (CI) on a 28-day cycle. The first two patients treated at level I (3 x 10(6) U/m2 s.c.) experienced possible neurotoxic deaths [massive cerebrovascular accident (CVA) and metabolic encephalopathy], and patient 3 had a grade 4 toxicity of performance status decline. Analysis of these events led us to exclude the enrollment of patients on i.v. morphine and of those with prior exposure to DDP. This resulted in grade 3 toxicity in terms of nausea, vomiting, fatigue and leukopenia but in no further CNS event. All patients were evaluable for toxicity but only ten were evaluable for response. Only two partial responses were seen, one in a patient with an unknown primary tumour and one in a patient with head and neck cancer. The combination of IFN is possible with 5-FU and DDP. The recommended dose of IFN is 2 x 10(6) U/m2 s.c. in patients with no prior exposure to DDP or i.v. morphine, given together with 5-FU (750 mg/m2, days 1-5, CI) and DDP (75 mg/m2, day 1) on a 28-day cycle.

1099 Background: S inhibits pathways involved in cancer resistance to treatments (Raf, VEGFR, PDGFR). This phase 2 trial aimed to define tolerability and efficacy of full doses of S and V in mBC. Toxicity data were previously reported: frequent dose reductions were noted, for which we investigated a possible PK interaction. Indeed, the metabolism of both S and V depends on hepatic CYP3A isoenzymes. Methods: Patients with measurable (RECIST), HER2 negative mBC received first-line therapy with V (30 mg/m2 days 1, 8 every 21) + S (400 mg bid). After 8 cycles patients could be switched to S alone. For PK analysis 6 patients started S on day 4 of cycle 1, to compare plasma levels of V, S and M2 (N-oxide active metabolite of S) when V and S were administered apart from each other versus concomitantly. Plasma samples were collected at time 0 (oral intake of S or right before V infusion), at completion of V infusion and after 0.5, 1, 2.5, 5, 7, 24, 48 and 72 hours from time 0 (cycle 1 day 1 for V and day 21 for S+M2; cycle 2 day 1 for both). Samples were analyzed using validated LC-MS/MS assays. Results: 27 patients (median age 57, 35-71) received a median of 8 cycles (1-28), with one patient still on treatment. With repeated cycles 48% of patients required at least 1 dose reduction and 3 patients discontinued therapy for toxicity. 30% of patients had a partial response, 85% had clinical benefit (including stable disease ≥ 4 cycles). Median progression-free survival was 5.7 months (95% CI 4.4-7.6). Plasma levels of V were influenced by S, with a mean Cmax right after the infusion of 1301 ng/mL for V administered alone (cycle 1 day 1) versus 2039 ng/mL with concomitant S (cycle 2 day 1; paired t-test, p=0.004). Plasma levels of S and M2 showed a greater degree of interpatient variability, with no significant difference observed in the presence or absence of concomitant V. Conclusions: Combining S with V at full doses is feasible, but not devoid of toxicity. A PK interaction may contribute to the frequent dose reductions. A reasonable option in clinical practice is to start therapy at lower doses of both agents, with a gradual dose increase if well tolerated. Promising efficacy of this combination is documented, with a very high rate of disease control.

Background Sorafenib (S) is an oral inhibitor of the Raf, VEGFR and PDGFR pathways that contribute to chemoresistance in cancer cells. The combination of S with chemotherapy agents (capecitabine, paclitaxel) in metastatic breast cancer (BC) resulted in improved progression-free survival. In preclinical models of BC, favorable effects were noted combining S and vinorelbine (V). S and V are both metabolized through hepatic isoenzymes CYP3A, with the potential of PK interactions. A previous phase 1b study documented the feasibility of this combination. We aimed to define the activity and safety of this regimen in advanced BC and to investigate PK interactions of the 2 drugs at full doses. Methods Eligible patients were affected by Her2 negative, chemotherapy-naive metastatic BC, with measurable (RECIST) disease, adequate renal, liver and bone marrow functions and LVEF Δ50%. Treatment included V (30 mg/m2 days 1, 8 every 21) + S (400 mg bid continuously), with dose reductions for grade 2-4 toxicities. Patients still benefiting after 8 cycles of treatment could continue on single-agent S. Six patients underwent PK analysis, starting treatment with S on day 4 of the first cycle, allowing for comparison of PK of each agent (V and S) administered alone versus during concomitant treatment with the other agent. Results 27 evaluable patients started on treatment, median age 57 (35-78); they received a median of 8 cycles to date (1-28), with 4 patients still on treatment. 44% of patients required at least one dose reduction for toxicity. One patient died of complicated sepsis after febrile neutropenia. Other significant toxicities included: febrile neutropenia (8%), uncomplicated Grade 3 (G3)-G4 neutropenia (60%); G3 fatigue (20%), hand-foot syndrome (12%), diarrhea (4%), enteritis (4%), hypertension (4%), asymptomatic increase of AST/ALT (16%), amylase (12%), lipase (8%), GGT (4%); G2 decrease in LVEF (4%), rash (16%), alopecia (20%). 33% of patients had a partial response, 85% experienced a clinical benefit (including stable disease after at least 4 cycles of treatment). Median progression-free survival was 5.5 months (95% CI 4.6-7.5). PK analysis showed no statistically significant interaction between S and N. Also the conversion of S to its metabolite S-N-oxide was not affected by the concomitant treatment with V. A non-significant trend was noticed for higher Cmax/AUC of V in the first 30 minutes after infusion when administered with ongoing treatment with S. Conclusions Combining S with V is feasible, but not devoid of toxicity, for which frequent dose reductions are necessary. A PK interaction could not be ruled out with the small sample size analyzed. More frail patients should start at a lower dose of both agents and we recommend close monitoring for the first 2 cycles, including amylase and lipase. Promising efficacy of this combination was observed, with a very high rate of disease control. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2706. doi:1538-7445.AM2012-2706

On the basis of preclinical data showing synergy between 5-fluorouracil (5-FU), leucovorin (LV) and IFN-alpha-2a, a phase I study was carried out to determine the maximum tolerable dose (MTD) of IFN-alpha-2a with this combination in patients with gastrointestinal malignancies. The treatment consisted of 370 mg/m2 5-FU and 200 mg/m2, LV on days 1 to 5, and IFN-alpha-2a on days 1 to 5 of the first week of chemotherapy and on days 1, 3, 5 of each subsequent week, on a 28-day cycle. Six patients with colorectal, 3 with pancreas, 2 with oesophagus, 2 with hepatocellular and one with gastric cancer were treated. At level III (5 x 10(6) U/m2) all patients experienced grade 3 or 4 toxicity during the first 56 days of treatment and the MTD was declared level II. Grade 3 toxicity comprised of anorexia, mucositis, diarrhoea, and fatigue; in one instance, grade 4 neutropenia occurred. Ten patients were evaluable for response, one patient with an oesophageal cancer had a minor response and one patient with rectal cancer and liver metastases had a radiological complete response lasting 3 months. The recommended dose for this schedule in phase II studies is 5-FU 370 mg/m2, LV 200 mg/m2, and IFN-alpha-2a 4 x 10(6) U/m2.

1093 Background: Sorafenib is an oral inhibitor of Raf and VEGFR/PDGFR. In preclinical models, favorable effects were noted combining sorafenib and vinorelbine. Both vinorelbine and sorafenib undergo hepatic metabolism. We aimed to determine the recommended doses in a phase 1b study. Methods: Patients were eligible with HER2-negative metastatic breast cancer, measurable (RECIST), not previously treated with chemotherapy for advanced stage; ECOG PS 0-1, adequate renal, liver and bone marrow functions, and LVEF ≥50%. Treatment was in two subsequent cohorts of 6 patients each: vinorelbine (30 mg/m2 days 1, 8 every 21) + sorafenib 200 mg BID continuously (cohort 1); vinorelbine (same as cohort 1) + sorafenib 400 mg BID continuously (cohort 2). Patients still benefiting after 8 cycles of treatment were allowed to continue on single-agent sorafenib. Results: Six patients in each cohort (n=12) were evaluated. Patients received a median of 8 cycles of treatment. Dose-limiting toxicities with the first cycle inclu...

Background: Cancer stem cells (CSC) have self-renewal capability and can differentiate into heterogeneous cancer cells. CSC have been isolated from a variety of human cancers and are considered to be fundamentally responsible for malignant growth, relapse, metastasis, and resistance to conventional therapies [J Clin Oncol. 2008 Jun 10;26(17)]. Therefore, targeting CSC may hold significant clinical promise for treating cancer. BBI608 is the first-in-class cancer cell stemness inhibitor discovered from Boston Biomedical’s cancer stem cell pathway inhibitor program (BBI6000). This novel orally-administered cancer cell stemness inhibitor blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells. In preclinical models, BBI608 showed potent and broad-spectrum anti-tumor and anti-metastatic activities in vitro and in vivo. Methods: A phase 1 dose escalation study in adult patients with advanced cancer who had failed standard therapies was initiated to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary anti-tumor activity of BBI608. A cycle consists of twice-daily oral administration of BBI608 for 4 weeks. Cycles were repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or another discontinuation criterion was met. A modified Simon accelerated titration scheme was used for dose escalation. Results: As of March 26th, 2010, eighteen patients have been enrolled with safety data available for 15 patients. Thus far, seven cohorts have been dosed from 20 mg to 600 mg/day and the dose escalation has been well tolerated. Adverse events have generally been mild with the most common being grade 1-2 diarrhea and nausea. Two grade 3 events included fatigue and diarrhea. To date, neither MTD nor RP2D has been reached. Thus far, BBI608 has exhibited favorable pharmacokinetics. At the 400 mg/day dose level the plasma concentration of BBI608 was sustained for over 8 hours at a concentration above 1.5 μM (several folds above the IC50). Of the patients enrolled to date, 9 were evaluable for tumor response; 6 (6/9 evaluable patients) have achieved stable disease for at least 8 weeks. Prolonged stable disease was observed in two patients with colon cancer (54+ and 20+ weeks) and one with head and neck cancer (17 weeks). Complete regression of a metastatic lesion to the kidney was also observed in one colon cancer patient. No new metastatic lesions have been observed in any patients except one patient with gastric adenocarcinoma on 40mg/day of BBI608. Conclusions: Initial dose escalation of BBI608, a first-in-class cancer stem cell pathway inhibitor, has been achieved without dose limiting toxicity. Thus far, BBI608 has shown an excellent safety profile, favorable pharmacokinetics, and preliminary signs of clinical activity. Enrollment and dose escalation are continuing and updated results will be presented. Citation Format: Adrian Langleben, Jeffrey G. Supko, Sebastien Hotte, Patricia Lorusso, Wilson H. Miller, Annie Hurtubise, David S. Leggett, Wei Li, Laura Borodyanski, Chiang J. Li. A phase 1 dose escalation study of BBI608, a first-in-class cancer stem cell pathway inhibitor in patients with advanced malignancies [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-171.

14128 Background: ECO-4601 is a structurally novel farnesylated dibenzodiazepinone with broad μM in vitro cytotoxic activity, and in vivo antitumor efficacy in rat glioma, hormone-independent human prostate, breast tumor xenograft tumor models. Preclinical data suggest ECO-4601 is a targeted anticancer drug with dual activity: selective binding to the peripheral benzodiazepine receptor (PBR), resulting in apoptosis, and inhibition of the Ras-MAPK pathway. Greatest efficacy was observed with continuous exposure, and a target plasma ECO-4601 efficacy concentration was determined. Preclinical toxicity studies did not demonstrate significant or dangerous side-effects. ECO-4601 is currently in phase I clinical trial testing to determine toxicity, pharmacologic profile and antitumor efficacy. Methods: ECO-4601 is administered as a 2-week continuous i.v. infusion (CIV), followed by 1 week off in repeated 21 day cycles. The trial includes dose- escalation and dose-extension portions, with comprehensive pharmacokinetics (PK) during the first cycle. Dose-escalation consists of increased doses in single pts until grade 3 toxicity is observed during cycle 1 of treatment, with up to five additional pts dosed to confirm dose-limiting toxicity (2/6 pts with grade 3 toxicities). The extension portion includes up to 15 pts at the dose determined in the first portion. Patients with a variety of cancers have been treated, including colorectal (10), ovarian (2), duodenal (1), and glioma (1). Results: ECO-4601 doses of 30, 60, 120, 180, 270, 360, and 480 mg/m2/day were evaluated in 14 patients. The number of cycles ranged from 1 to 8 with 7 pts completing at least 3 cycles of treatment. ECO-4601 is well tolerated and a maximum tolerated dose (MTD) has not been reached. Stable disease was observed in 6 of 7 evaluable pts; 4 colorectal, 1 ovarian, 1 duodenal. Preliminary PK shows steady state concentrations following 24 h CIV, dose proportionality, plasma concentrations above the preclinical efficacy threshold, rapid elimination post-infusion. Conclusions: ECO-4601 is a bifunctional targeting agent, against a novel combination of targets, that is well tolerated and demonstrates evidence of biological activity in an early phase clinical trial. The extension portion is currently ongoing. [Table: see text]

A mediastinal germ cell tumor is described that reacts with the anti-common acute lymphoblastic leukemia-associated antigen antibody J5 using both immunofluorescence and immunoperoxidase techniques. This antigen has been reported recently on various cell lines including melanoma, colon, and breast. It has also been seen on normal fibroblasts and peripheral granulocytes. This is believed to be the first description of a solid nonlymphoid neoplasm possessing this antigen, and the implications regarding prognosis and therapy are discussed.

In short, we have developed a successful and non-toxic yet simple, rapid, and inexpensive method of BM cryopreservation that should allow for a wider application of autologous BM transplantation as a therapeutic alternative for patients with malignant diseases.