bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective randomized trial comparing 5-fluorouracil (5-FU), mitomycin-C (MMC), and polysaccharide-K (PSK) versus UFT and PSK as adjuvant chemoimmunotherapy (CITX) for patients with locally advanced gastric cancer with curative resection
Authors: Choi J. , Kang S. , Park J. , Lee H. , Cho Y. , Han S. , Lim H.
Published: March 2020

15074

Background: Adjuvant chemotherapy has demonstrated small but significant survival benefit in locally advanced gastric cancer in several meta-analyses, while adjuvant CITX showed improved outcome of patients (pts) compared to chemotherapy alone in a few trials. However, optimal chemotherapy regimen remains to be determined. We conducted a randomized trial comparing oral (PO) CITX with intravenous (IV) CITX in gastric cancer pts with curative resection. Methods: All enrolled pts underwent radical surgery with at least D2 dissection. After stratification for pathologic stage (IB or II vs. III) and primary tumor size (=5 cm vs. >5 cm), pts were randomized to IV CITX (5-FU 500 mg/m2 weekly for 24 weeks, MMC 8 mg/m2 every 6 weeks x 4) or PO CITX (UFT 400–600 mg/day for 12 months). Pts in both arms received PSK 3 g/day PO for 4 months. The planned target number of pts was 368 to prove the non-inferiority of PO CITX compared to IV CITX in overall survival. Results: A total of 82 pts (stage IB: 6, II: 29, IIIA: 30, IIIB: 17; 44 in IV arm, 38 in PO arm) were enrolled between May 2002 and October 2005, when the trial was closed due to poor accrual. Pts characteristics were well balanced. With a median follow-up of 39 months (14–55 months) in survivors, there were no significant differences in 3-year disease-free survival (82% vs. 61%, p=0.302) and overall survival (84% vs. 79%, p=0.838) between IV and PO arms. No grade 4 toxicity was observed in both arms. IV arm demonstrated higher incidence of grade 2 or 3 neutropenia (79% vs. 52%, p=0.025), thrombocytopenia (19% vs. 0%, p=0.008), and vomiting (36% vs. 9%, p=0.013). Conclusions: Although accrual was well below that planned, the results of this trial suggest that PO CITX with UFT might have similar efficacy with lower toxicity profile compared with 5-FU and MMC CITX in adjuvant treatment for gastric cancer.

No significant financial relationships to disclose.
A phase I/II study of belinostat (PXD101) in patients with unresectable hepatocellular carcinoma
Authors: Yeo W. , Lim R. , MA B. B. , Hui P. , Chan L. , Mo F. K. , Yu S. C. , Ho S. S. , Koh J. , Chan A. T. , Goh B.
Published: March 2020

15081

Background: Hepatocellular carcinoma (HCC) is a common cause of cancer morbidity and mortality. It is a highly aggressive tumor with 90% presenting with unresectable disease, resulting in a median survival of 3–6 months. Inhibitors of histone deacetylase (HDAC) have been demonstrated in HCC cell lines and xenografts to induce apoptosis and tumor regression, and have anti-proliferative, anti-metastatic and anti-invasive effects. Belinostat (N-hydroxy-3-[phenylsulphamoylphenyl] acryl amide) is a novel, low molecular weight, HDAC inhibitor. The Cancer Therapeutic Research Group (CTRG) is conducting a phase I/II study of belinostat as the first line therapy for pts with unresectable HCC. The phase I study aims to determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Methods: Patient eligibilities include histologically or cytologically confirmed unresectable HCC, ECOG = 2, adequate hematologic, renal and hepatic functions. The dose of belinostat was started at 600 mg/m2/day i.v. on day 1–5 every 3 weeks; with increment of 300 mg/m2/day up to 1200 mg/m2/day. Dose limiting toxicities (DLT) are defined as grade 4 hematological toxicity or grade 3 or 4 nonhematological toxicity during cycle 1 (according to NCI CTC v3), or treatment delay >2 weeks. The MTD is defined as the dose below which ≥ 2 of 3 or ≥ 2 of 6 patients experiencing DLT. After determination of the MTD, 3 additional patients will be treated at this dose to further define toxicity. Results: From June-December 2006, 12 pts were entered; 3 were treated at level I (600 mg/m2/day), 3 at level 2 (900 mg/m2/day), and 6 at level 3 (1200 mg/m2/day). There were no DLTs on level 1, 2 or 3. Therefore, the MTD of belinostat was not reached. Overall toxicities were WBC gr. 0/1/2/3/4: 12/0/0/0/0, ANC gr. 0/1/2/3/4: 12/0/0/0/0; Hb gr. 0/1/2/3/4: 4/7/0/1/0; platelet gr. 0/1/2/3/4: 8/4/0/0/0; lethargy gr. 0/1/2/3: 12/0/0/0/0, phlebitis gr. 0/1/2/3: 10/0/2/0; Cough gr. 0/1/2/3: 9/0/3/0; Nausea gr. 0/1/2/3: 7/3/2/0 and vomiting gr. 0/1/2/3: 9/3/0/0. Conclusions: At the maximum dose of 1200 mg/m2/day (level 3), MTD has not been reached. Belinostat is very well tolerated. Phase II study will be started at dose level 1200 mg/m2/day. Sponsor: The Division of Cancer Treatment and Diagnosis, National Cancer Institute, USA.

No significant financial relationships to disclose.
Impact of flaxseed supplementation and dietary fat restriction on prostate cancer proliferation and other biomarkers: Results of a Phase II randomized controlled trial (RCT) using a presurgical model
Authors: George S. L. , Polascik T. J. , Albala D. M. , Walther P. J. , Moul J. , Madden J. F. , Snyder D. C. , Hars V. , Switzer B. R. , Vollmer R. T. , Demark-Wahnefried W.
Published: March 2020

1510

Background: Diet may play a key role in the etiology of prostate cancer (PC). Dietary fat restriction (DFR) and flaxseed supplementation (FS) may reduce risk, though results are mixed. We undertook an RCT to test the comparative effects of these dietary regimens on the biology of the prostate and other biomarkers. Methods: PC patients (N=161) scheduled ≥ 21 days prior to prostatectomy were block randomized on race (black vs non-black) and biopsy Gleason sum (<7 vs 7+) to these diets: 1) control; 2) FS (30 g/day); 2) DFR (<20% total energy); or 4) FS+DFR. Blood was drawn upon accrual and prior to surgery and analyzed for prostate specific antigen (PSA), sex hormone binding globulin (SHBG), total testosterone (T), insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), c- reactive protein (CRP), and total and low density lipoprotein cholesterol (TC & LDL-C). Proliferation (MIB-1) and apoptosis (TUNEL) was assessed in the malignant and benign prostate. Results: Complete data were collected on 93% of the sample; mean length on protocol was 30 days. Median MIB-1 positive (+) cells/total nuclei ratios were: 1=2.38;2=1.71;3=2.93;4=1.58. Primary analyses suggest a significant protective effect (p=0.016) of FS. Secondary analyses of MIB-1 + nuclei (controlling for total cell counts) show increased proliferation with DFR (p=.017), and a significant interaction with FS and DFR (p<.0001). No differences were observed between groups with regard to PC apoptosis, and histology of benign tissue. No differences were observed between arms for PSA, SHBG, T, IGF1, IGFBP3 or CRP. Significant differences were observed between arms for changes in serum lipids and body weight [ΔTC = +9/-26/-46/-37 mg/dL; ΔLDLC = -14/-17/-29/-21 mg/dL and Δ weight = +0.3/-1.3/-1.7/-1.1 kg (p’s<.05)]; effects were attributed to DFR and not FS. Side effects did not differ between arms Conclusions: Preliminary findings suggest that FS is safe and exerts a protective effect (main effect or via interaction with DFR) on PC. Data also provide further support of DFR for cardiovascular disease, though its role in PC is less clear. Further controlled analyses and additional studies are needed to confirm findings.

No significant financial relationships to disclose.
Paclitaxel poliglumex (PPX), cisplatin and concurrent radiation for esophageal and gastric cancer: A phase I study
Authors: Dipetrillo T. , Evans D. , Akerman P. , Miner T. , Millis R. , Jean M. , Henderson D. , Oldham F. , Eisenfeld A. , Safran H.
Published: March 2020

15130

Background: PPX is a conjugate of paclitaxel to a polyglutamate polymer. Preclinically, PPX demonstrated a radiation enhancement factor (REF) >7.0, versus 1.5–2.0 for paclitaxel. (Milas et al Int J Rad Onc 55:2003, Li et al. Clin Cancer Res 6:2000). The maximally tolerated dose (MTD) of PPX was determined previously to be 70 mg/m2 /week with concurrent radiation. We initiated a phase I study of PPX, cisplatin, and concurrent radiation with patients with esophageal and gastric cancer. Methods: Patients with esophageal or gastric cancer receiving chemoradiation for locoregional control, adjuvant, or neoadjuvant treatment were eligible. All patients received radiation at a dose of 50.4 Gy delivered in 28 fractions (5 fractions per week for 5 1/2 weeks), and cisplatin (25 mg/m2) on days 1, 8, 15, 22, 29, and 36. PPX was given as a 10 minute infusion in escalating dosages prior to each cisplatin dose. Dose limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity, esophagitis, nausea/vomiting, or dehydration, or any other grade 3/4 non-hematologic toxicity. Patients were enrolled in successive cohorts of three. The MTD was defined as the dose level at which no more than 2 of 6 patients have DLTs. Results: Eleven patients have been entered over 2 dose levels of PPX: 50 mg/m2 (six patients, dose level 1), and 60mg/m2 (5 patients, dose level 2). Five patients had esophageal cancer and six had gastric cancer. All histologies were adenocarcinomas. One of six patients treated at dose level had a DLT (esophagitis). Three of five patients had DLTs at dose level 2, including esophagitis, nausea, vomiting, and dehydration. Conclusions: PPX is a novel radiation sensitizer for patients with esophageal and gastric cancer. The MTD for PPX is 50 mg/m2 /week in combination with cisplatin 25mg/ m2 /week for 6 weeks, and 50.4 Gy concurrent radiation for patients with esophagogastric cancer. A phase II study of PPX/cisplatin and radiation will be initiated.

No significant financial relationships to disclose.
A phase II study of amplitude-modulated electromagnetic fields in the treatment of advanced hepatocellular carcinoma (HCC)
Authors: Costa F. , de Oliveira A. C. , Meirelles R. , Zanesco T. , Surjan R. , Chammas M. , Barbault A. , Pasche B.
Published: March 2020

15155

Background: Phase I data show that low levels of electromagnetic fields modulated at specific frequencies administered intrabucally with the THERABIONIC device are a safe and potentially effective treatment for advanced cancer. The device emits a 27.12 MHz radiofrequency signal, amplitude-modulated at tumor-specific frequencies ranging from 0.2 to 23,000 Hz. The device is connected to a spoon- like coupler placed in the patient’s mouth during treatment. Patients with advanced HCC and limited therapeutic options were offered treatment with HCC-specific frequencies. Methods: From October 2005 to October 2006, 38 patients with advanced HCC were recruited in a phase II study. The patients received three daily 40 min treatments until disease progression or death. The median age was 64.0 ± 14.2 years. 32 patients were male and 29 patients had documented progression of disease (POD) by IV contrast imaging prior to study entry. 8 patients had not received prior therapy because of metastases (3), poor medical condition (3), declined chemotherapy (2). Results: As of January 2007, 12 patients are still on therapy, 20 patients died of tumor progression, 2 patients are lost to follow-up and 3 patients withdrew consent. 27 patients are eligible for response. The overall objective response rate as defined by partial response (PR) or stable disease (SD) in patients with prior documented POD was 31.6%: 3 PR and 9 SD. The median survival was 20.7 weeks with a median duration of therapy of 17.5 weeks. 13 patients have received therapy for more than six months. The median duration of response is 12.9 weeks. 12 patients reported pain at study entry: 8 of them (66%) experienced decreased pain during treatment. There were no NCI grade 2/3/4 toxicities. One patient had grade 1 mucositis and grade 1 fatigue. Conclusion: In patients with advanced HCC, THERABIONIC is a safe and effective novel therapeutic option, which has significant anti-tumor effect and provides pain relief in the majority of patients.

[Table: see text]

No significant financial relationships to disclose.
The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Subset analysis of patients (pts) with brain metastases (BM)
Authors: Henderson C. A. , Bukowski R. M. , Stadler W. M. , Dutcher J. P. , Kindwall-Keller T. , Hotte S. J. , Logie K. , Baltz B. , Wilson K. , Figlin R. A.
Published: March 2020

15506

Background: Sorafenib (SOR) was demonstrated to be safe and effective in a phase III trial of previously treated RCC pts; however, pts with BM were excluded. BM occur in 5–10% of RCC pts, and generally portend a poor prognosis. Safety and efficacy of SOR in this pt population was therefore explored in a subset analysis of ARCCS, a community-based expanded access program. Methods: Pts received SOR 400 mg bid in this open-label, nonrandomized trial if they were =15 years old with advanced RCC and had ECOG PS of 0–2. Pts with BM were included but required to have some prior local therapy for their brain lesions. Prior treatment did not have to be successful, and pts whose BM had been surgically removed were also eligible for this protocol. BM were excluded as target lesions for RECIST unless they were the only lesions being followed. Major exclusion criteria included treatment with other investigational drugs within 4 wks of enrollment; life expectancy <2 mos; active coronary artery disease, ischemia, or hypertension; and severe renal impairment requiring dialysis. The primary endpoints were safety and efficacy (per investigator assessed RECIST criteria). Results: Of 2,488 ARCCS pts valid for safety, 65 (2.6%) had been previously treated for BM: 72.3% male with median age 59.5 yrs. 99% had =1 prior therapy for non-brain disease including 81.5 % radiotherapy, 78.5% nephrectomy and 47.7% prior systemic therapy. Grade 3 adverse events (AE) occurring >2% in this subset were fatigue and seizure (6.2% each) and hand-foot skin reaction, diarrhea, hemoglobin, mucositis, dehydration, vomiting, hyperglycemia, and thrombosis (3.1% each). In the total ARCCS population vs the BM subset, Grade 3 AEs were 35.2% vs 26.2% and Grade 4 AEs were 6.1% vs 9%. There were no CNS-related bleeding events in pts with BM. Of the 47 pts evaluable for response, partial response was reported in 2 (4%), stable disease in 33 (70%), and progressive disease in 12 (26%). Conclusions: The toxicity and efficacy of SOR in pts with brain mets in ARCCS were comparable to those observed in the whole study population. Of note, SOR was well tolerated in this study with no reports of cerebral hemorrhagic events.

[Table: see text]
A phase II trial of gefitinib monotherapy in patients with unresectable adrenocortical carcinoma (ACC)
Authors: Samnotra V. , Vassilopoulou-Sellin R. , Fojo A. T. , Oh W. K. , LaRocca R. V. , Ernstoff M. S. , Memoli V. A. , Cole B. F. , Quinn D. I. , Simmons P. A. , Tretter C. P.
Published: March 2020

15527

Background: ACC is a rare malignancy with a very poor prognosis. Surgery is the only potential curative option. Gefitinib is an oral EGFR inhibitor that may have activity in solid tumors that express EGFR. ACC over expresses EGFR in a high proportion of cases. Methods: From April 2004 through December 2006, the ACC Working Group conducted a phase II trial of Gefitinib as second line, monotherapy in patients with pathologically confirmed unresectable ACC who had progressed on mitotane or chemotherapy. All prior systemic therapy was discontinued 28 days prior to starting gefitinib. Patients were ineligible if: had received prior therapy with any EGFR inhibitor, pregnant or breast feeding, had other co-existing malignancies (other than basal cell carcinoma or cervical cancer in situ), had an ECOG PS > 2, absolute neutrophil counts < 1,500, or platelets < 20,000. Patients were not allowed concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, or St John’s Wort. Patients took gefitinib 250 mg orally once a day. Each cycle was 21 days with radiological assessment every 6 weeks.Response rate as determined by RECIST criteria was the primary endpoint. Results: 19 patients accrued to the study (18 with measurable disease and 1 without). Pt Characteristics: Female 79% (15/19); Median age 48 (range 26–74); 84% (12 female and 4 male =15/19) of the patients had steroid secreting tumors. Grade 3 toxicity was noted in 2 patients and included, hypertension and lower extremity edema and elevated liver transaminases. No grade 4 toxicities occurred. Of 19 patients evaluable, there were no complete responders, partial responders or patients with stable disease (0% response rate; 95% CI: 0%-18%). Conclusions: Gefitinib demonstrated no activity in patients with unresectable ACC. This study is now closed. This study demonstrated the ability to successfully accrue to a trial of novel agents in rare tumors in a multicenter setting.

[Table: see text]
Sunitinib-related macrocytosis in patients with advanced renal cell cancer (RCC)
Authors: Price J. A. , Shaarbaf R. , Wood L. A.
Published: March 2020

15580

Background: Sunitinib is an oral multi-targeted tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity approved and widely used for the treatment of advanced RCC. Based on a clinical observation that several RCC patients receiving Sunitinib developed macrocytosis, this study was performed to describe and examine macrocytosis in this patient population. Methods: A retrospective review of all patients treated with Sunitinib for RCC from 08/05–11/06 was performed. Data regarding hematologic parameters (e.g. CBC, mean corpuscular volume- MCV), concomitant medications, liver function, and time on therapy (cycle length varied from 4–7 weeks) was recorded. Vitamin B12 and folate levels, iron studies, and thyroid function were recorded if available. A standardized, laboratory-specific MCV was used to define macrocytosis. Results: 43 patients formed the study cohort, receiving a median of 4 cycles (24 weeks) of Sunitinib. Overall 19 (44%) patients developed macrocytosis, at a median of 3 cycles (16 weeks). Of the 31 patients who received > 2 cycles of Sunitinib, 48% developed macrocytosis compared to 33% of the 12 patients receiving =2 cycles. Among all patients with macrocytosis, only 8 (42%) had anemia at the time. Of the 24 patients who did not become macrocytic, 19 (79%) had a continual rise in their MCV during therapy. Other causes of macrocytosis including vitamin B12 and folate deficiency, hypothyroidism, and other medications, did not contribute to the macrocytosis identified in this cohort. On preliminary analysis, it did not appear that macrocytosis was associated with response or toxicity. Conclusions: This is the first study to document the common occurrence of Sunitinib-associated macrocytosis in RCC patients. The risk of macrocytosis increased with duration of treatment. Macrocytosis did not appear to be associated with significant clinical sequelae; however this, as well as the mechanism of macrocytosis, requires further study.

No significant financial relationships to disclose.
Induction cetuximab (C) followed by C, paclitaxel (P), carboplatin (CP) and concurrent radiation (RT) for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: Birnbaum A. E. , Johnson T. T. , Rathore R. , Khurshid H. , Puthawala M. , Radie Keane K. , Ruhl C. , Wanebo H. , Kennedy T. , Ready N.
Published: March 2020

16504

Background: C is an IgG1 chimerized, monoclonal antibody that binds specifically to the epidermal growth factor receptor, which is expressed in 90–100% of HNC. We conducted a phase II study to evaluate the toxicity and efficacy of induction C followed by concurrent C with chemoRT for patients (pts) with SCCHN. Methods: Eligible pts had untreated stage III or IV, SCCHN. All pts received induction, single agent, C, 400 mg/m2 week 1, followed by 250 mg/m2 weeks 2, 3, and 4. Potentially operable pts then received C, 250 mg/m2, P 40 mg/m2 and CP AUC=1, weekly x 5 wks, with 45 Gy RT then underwent endoscopic biopsy. If the biopsy was negative, pts received 3 additional weekly doses of C, P, CP and 22–27 Gy boost RT. Inoperable pts received 8 weeks of C, P and CP and 66.6–72 Gy RT. All pts then received maintenance C 250 mg/m2/week x 24 weeks. Results: 29 pts have been enrolled. Male:Female 18:11. Median age = 55 (38–75). Primary sites included oral cavity (10 pts), oropharynx (1), larynx (12), hypopharynx (2), and glottis (4). The tumor stages were III (10 pts), IV (19). Toxicity data are available for 23 pts. 2 of 23 (9%) had grade (G) 4 toxicities (hypokalemia =1, ischemic colitis=1) however there were no treatment related deaths. G 2 toxicities included rash (52%), dysphagia (35%), mucositis (43.5%) and hypomagnesemia (9%). G 3 toxicities included rash (9%), dysphagia (44%), mucositis (26%) and XRT dermatitis (18%). Induction C responses by RECIST criteria were SD (14 pts) 61%, PR (7) 30%, and CR (1) 4%. Conclusion: C can be safely administered with chemoRT (CRT) for pts with HNC. C increases cutaneous toxicity but does not increase in-field CRT side effects. There were no unexpected high-grade adverse events. Preliminary single agent activity of C in untreated SCCHN is promising.

No significant financial relationships to disclose.
Phase II trial of satraplatin and paclitaxel in the first-line treatment of advanced non-small cell lung cancer
Authors: Shipley D. , Spigel D. R. , Cavanaugh C. , Moore Y. , Hainsworth J. D. , Jones S. , Burris H. A. , Sade L. , Yardley D. A. , Greco F.
Published: March 2020

18073

Background: Satraplatin (S) is a novel oral platinum analogue that has shown promising activity in a number of solid tumor settings. Our center previously conducted a phase I trial combining S and paclitaxel (P) in patients (pts) with refractory malignancies, establishing safety for this combination. This single center community-based trial was designed to examine the role of S/P in pts with newly diagnosed advanced non-small cell lung cancer (NSCLC). Methods: The primary endpoint is the objective response rate (ORR). Eligibility criteria: newly diagnosed and unresectable stage IIIB/IV NSCLC, measurable disease, ECOG PS 0–2, and informed consent. Treatment: S 80 mg/m2 PO days 1–5 and P 200mg/m2 IV day 1, every 28 days for a maximum of 6 cycles. Pts were restaged every 8 weeks. Results: 28 pts were enrolled from 2/06 to 12/06 (trial ongoing, n = 40 planned). Data are available on 24 pts for analysis. Baseline characteristics: median age 67 years; male/female, 58%/42%; and ECOG PS 0/1/2, 25%/63%/12%; adenocarcinoma/squamous/large cell/unspecified, 33%/42%/1%/24%. The ORR was 17% (95% CI 5%-37%). 10 pts (42%) had stable disease (SD) and 5 pts (21%) had progressive disease. The disease control rate (ORR + SD) was 59%. 5 pts were not evaluable due to: death (3 pts - 1 possibly due to treatment- related sepsis), and physician/pt preference (1 pt each). With a median follow-up of 8.3 months, the median time to progression is 4 months. Grade (G) 3/4 non-hematologic toxicity occurring in = 5%: infection (29%), nausea, vomiting (17% each), anorexia, hyperglycemia (13% each), and fatigue (8%). G3/4 hematologic toxicity: leukopenia (21%), neutropenia (41%), and thrombocytopenia (29%). Conclusions: In this preliminary analysis, S/P appears to have comparable activity to other platinum-based regimens. In an effort to reduce myelosuppression this trial has been amended to a S dose of 70 mg/m2. Additional accrual and follow-up are needed to better assess the safety and efficacy of this combination regimen.

No significant financial relationships to disclose.
Randomized phase II trial of erlotinib (E) versus temozolomide (TMZ) or BCNU in recurrent glioblastoma multiforme (GBM): EORTC 26034
Authors: Van Den Bent M. J. , Brandes A. , Rampling R. , Kouwenhoven M. , Kros J. M. , Carpentier A. F. , Clement P. , Klughammer B. , Gorlia T. , Lacombe D.
Published: March 2020

2005

Background: In 40–50% of GBM epidermal growth factor receptor (EGFR) is amplified, and often constitutively activated (EGFRvIII mutant). EGFR is therefore a potential therapeutic target. Previous studies suggested activity of EGFR tyrosine-kinase inhibitors in recurrent GBM, particularly in specific molecular subsets. This study explored erlotinib (E) activity in recurrent GBM. Methods: Randomized phase II trial. Eligibility criteria: histologically proven GBM, recurrent >3 months after radiotherapy, Karnofsky performance status (KPS) =70, no prior chemotherapy for recurrent disease, tissue sample for EGFR studies. Patients (pts) received E 150mg/day (300mg/day if on enzyme inducing anti-epileptic drugs [EIAEDs]), or control (TMZ 150–200mg/m2, day 1–5 q4wk or BCNU 60–80mg/m2 i.v., day 1–3 q8wk). If no significant toxicity, E was escalated to 200mg (500mg in patients on EIAEDs). The primary endpoint was 6 months’ PFS in =10/50 pts on E (20%); P0 was set at 15%, and P1 at 30%. Response was assessed with Macdonald’s criteria. EGFR amplification (FISH) and expression of EGFR, EGFRvIII and PTEN (immunohistochemistry [IHC]) were assessed. Results: 110 patients were randomized (54 E, 56 control: 27 TMZ; 29 BCNU). Median age 55 years; median KPS 90. All but 1 patient started treatment; median number of cycles was 2 for E, 4 for TMZ and 1 for BCNU. Grade 3/4 toxicities likely related to E: dermatological (5); hemorrhage (1). Grade 3/4 toxicities for control were mainly hematological (3 TMZ, 13 BCNU). Three pts discontinued E due to toxicity. Six-month PFS was 12% for E, 24% for control. Six and 12-month survival were 61% and 24% for E, and 63% and 26% for control. Two responses were seen on control; the best response on E was SD (n=6). Patients with EGFRvIII mutations (13 in E arm, 8 in control arm) had shorter PFS (p=0.007) and OS (p=0.004) regardless of treatment. Response to E was not correlated with EGFR expression, EGFR amplification or EGFRvIII mutation. Conclusions: This randomized, controlled phase II study did not find sufficient activity for erlotinib in the general population of recurrent GBM. The presence of EGFRvIII mutations was not predictive for response.

No significant financial relationships to disclose.
Outcome for metastatic (M+) medulloblastoma (MB) treated with carboplatin during craniospinal radiotherapy (CSRT) followed by cyclophosphamide (CPM) and vincristine (VCR): Preliminary results of COG 99701
Authors: Jakacki R. , Burger P. , Zhou T. , Holmes E. , Packer R. , Goldwein J. , Mehta M. , Pollack I.
Published: March 2020

2017

Background: The outcome for patients with metastatic medulloblastoma has historically been poor. Carboplatin is both a potent radiosensitizer and has activity against medulloblastoma. In this study, we evaluated the feasibility of administering carboplatin during CSRT and the impact of anaplasia as an independent predictor of outcome. Methods: All patients underwent surgical debulking followed by 36 Gy CSRT with boosts to the posterior fossa and sites of bulk disease. During CSRT, patients received weekly VCR as well as carboplatin doses ranging from 30 mg/m2/dose x 15 to 45 mg/m2/dose x 30 given 1–4 hours prior to each RT fraction, using a Phase I design. G-CSF was given for neutropenia during CSRT. Six weeks after completing chemoradiotherapy, patients received six courses of monthly CPM (2 gm/m2) and VCR. Central pathology review was performed to confirm the diagnosis and assess for anaplasia. Results: 57 patients (median age 7.3 yrs, range 3.1–18.1 years, M/F ratio of 2.6:1) with centrally reviewed M+ MB were enrolled. Thrombocytopenia was dose limiting and 35 mg/m2/dose x 30 was selected as the maximum tolerated carboplatin dose. 20 patients (35%) had severe anaplasia. There was no difference in age, M/F ratio or distribution of M-stage between those with or without anaplasia. Median follow-up for surviving patients is 4.5 yrs. Four-year overall survival (OS) and event-free survival (EFS) for the entire group is 81 ± 5% and 66 ± 6%. Four-year OS is 89 ± 5% for patients without anaplasia vs. 65 ± 11% for those with anaplasia (log-rank p=0.002). Four-year EFS is 76 ± 7% for patients without anaplasia vs. 48 ± 12% for those with anaplasia (log-rank p=0.02). There was no difference in survival based on M-stage. Conclusions: The use of daily carboplatin as a radiosensitizer appears to be a promising strategy for patients with metastatic MB. The presence of anaplasia is a significant negative predictor of outcome.

No significant financial relationships to disclose.
Prospective monitoring of circulating tumor cells in breast cancer patients treated with primary systemic therapy—A translational project of the German Breast Group study GeparQuattro
Authors: Mueller V. , Riethdorf S. , Loibl S. , Komor M. , Houber J. , Schrader I. , Conrad U. , Untch M. , vMinckwitz G. , Pantel K.
Published: March 2020

21085

Background: The impact of circulating tumor cells (CTC) in patients with primary breast cancer is still unclear. Primary systemic treatment (PST) allows the assessment of therapeutic efficacy in breast cancer patients without long follow-up periods. Here we present first results on the presence of CTC in peripheral blood of patients enrolled in the “GeparQuattro” study. Methods: This study incorporates three different chemotherapy approaches and additional Trastuzumab (Herceptin®) treatment for patients with HER-2/neu-positive tumors. Recruitment finished in November 2006 and not all patients have completed therapy yet. We used the CellSearch™ system to evaluate CTC before PST from 245 patients and after PST from 67 patients. CTC from 45 samples were also examined for HER-2/neu expression by immunocytochemistry in the CellSearch™ system. Results: Before PST we detected CTC in 54/245 patients (22%). CTC numbers in 7.5 mL blood ranged between 1 and 200 (mean 6.5). In 8 CTC-positive samples (3.3%) = 5 CTC were found. Her-2/neu-positive CTC were observed in 25/45 cases (55.6%). CTC could be detected in 7/67 patients (10.4%) after PST (1 or 2 CTC). Before and after PST blood was analyzed from 43 patients, 27 of them were CTC-negative at both time points. Ten initially CTC-positive cases were CTC-negative after PST whereas 6 cases were detected CTC-positive after PST although no CTC could be found before PST. Conclusions: With the CellSearch™ system CTC can be detected in non-metastatic breast cancer patients at primary diagnosis and also after PST. To our knowledge, this is the largest study evaluating the presence of CTC in this context. With the availability of response information from more patients, it will be possible to examine the correlation between the incidence of CTC and response as well as kinetics of HER-2/neu expression during Trastuzumab treatment.

[Table: see text]
Results of a phase II clinical trial of 2 doses and schedules of CP-675,206, an anti-CTLA4 monoclonal antibody, in patients (pts) with advanced melanoma
Authors: Ribas A. , Antonia S. , Sosman J. , Kirkwood J. M. , Redman B. , Gajewski T. F. , Pavlov D. , Bulanhagui C. , Gomez- Navarro J. , Camacho L. H.
Published: March 2020

3000

Background: CP-675,206 has antitumor activity in pts with metastatic melanoma. A 2-stage, 2-arm phase II trial was conducted to choose the optimal dosing regimen for pivotal clinical trial testing. Methods: Eligible pts had measurable melanoma (stage IIIc or IV) progressing on or after prior therapy with ECOG PS = 1. In stage 1, 18 pts per arm were randomized to either 10 mg/kg monthly (10 Q1M) or 15 mg/kg every 3 months (15 Q3M). If 3 or more pts in either arm had CR or PR, then 25 more pts were entered to that arm. Primary endpoint was objective tumor response, and secondary endpoints were safety and survival. Results: 89 pts received at least 1 dose (44 at 10 Q1M, 45 at 15 Q3M), with both study arms moving to stage 2. 96% of pts had stage IV disease, and 57% had elevated LDH. There were no significant differences in age, sex, stage, or baseline LDH levels between study groups. A median of 3 doses (range, 1 to 26) at 10 Q1M and 1 dose (range, 1 to 9) at 15 Q3M were administered with 100% compliance. Dose delays occurred in 30% of pts treated at 10 Q1M and 16% at 15 Q3M. 2 pts at 10 Q1M and 5 pts at 15 Q3M continued on study beyond 12 months (mo). To date, 6 pts at 10 Q1M have been discontinued due to toxicity (3 diarrhea/colitis [1 requiring colectomy], Grave’s ophthalmopathy, pancreatitis, hypersensitivity reaction) and 2 pts at 15 Q3M (colitis and pancreatitis, diarrhea) (P = 0.14). There were no toxic deaths. 15 Q3M was associated with lower incidence of grade 3 or 4 AEs (31% vs 41% at 10 Q1M; P = 0.42). Responses by investigator assessment were 1 CR and 3 PRs at 10 Q1M, and 1 CR and 2 PRs at 15 mg/kg Q3M, including responses in skin, LN, bone, liver, lung, and adrenal glands. To date, only 1 pt with PR at 10 Q1M has relapsed, and the remaining responses are ongoing (18+ to 28+ mo). Median survival is 10.3 mo at 10 Q1M and 11.0 mo at 15 Q3M (P = NS). Conclusions: The 15 mg/kg Q3M regimen was chosen for further clinical testing based on comparable antitumor efficacy and a trend to improved feasibility and safety compared with 10 mg/kg Q1M. CP-675,206 at this dose and schedule is being examined in pivotal phase II and III clinical trials for pts with melanoma, and in early phase II trials in pts with CRC and NSCLC.

No significant financial relationships to disclose.
Phase I study of intraperitoneal MHC unrestricted adoptive cell therapy with TALL-104 cells in patients with peritoneal carcinosis
Authors: Bengala C. , Rasini V. , Sternieri R. , Dominici M. , Andreotti A. , Gelmini R. , Cafarelli L. , Bevini P. , Berti A. , Conte P.
Published: March 2020

3054

Background: TALL-104 is an irradiated human leukemic T cell line (CD3+, CD4- CD8+, CD56+, CD16-) grown in IL-2- containing medium, that has the ability to kill tumor cells in preclinical models in a MHC unrestricted way. A phase I trial in metastatic breast cancer patients, has shown that multiple i.v. infusions (infs) of TALL-104 cells can be given safely. In order to optimise the tumor:effector cell ratio, we have designed a phase I study of intraperitoneal infs of γ-irradiated TALL-104 cells. Methods: Patients (pts) with peritoneal carcinosis from ovarian or gastrointestinal tumors not responding to at least 2 lines of chemotherapy were eligible for study entry. The treatment included 5 i.p. infs (day 1, 3, 5, 15, 30) and the study aimed to test three cell dose levels: 1 x 108, 5 x 108, 2.5 x 109. End points of the study were: safety, kinetic of TALL-104 cells on ascites (if present) and peripheral blood (PB) by PCR, levels of cytokines (TGF-β, GM-CSF, IL-2, IL-4, IL-10, IFN-γ, TNF-a and -β, HGF, sIL-2R, sICAM-1) on ascites and serum, and cytotoxicity of autologous PB mononuclear cells (MNC) against K562 cells. Results: So far 10 pts have been treated: 6 with GI and 4 with ovarian cancer; 7 patients had ascites. Five pts have been treated at the 1st and 5 pts at the 2nd dose level. No treatment-related adverse events were observed. TALL-104 cells were detected in ascites (100 % of the pts) and PB (43 % of the pts) up to 48 hrs after the infs. Cytotoxicity of MNC showed a mean 5-fold increase at day 3 through 7 and it was still evident at day 30 in both dose levels. Cytokine levels are available for the first 5 pts. In one pt 18-fold increase of TNF-a was observed in ascites after the first infusion with a peak of 40-fold at day 15. sIL-2R and sICAM-1 showed both a mean 1.2-fold and 1.5-fold increase in serum in ascites respectively up to day 45. TGF-β1 level increased in average 3.3-fold in serum and 1.5-fold in ascites during the same observation period. HGF showed a mean 1.2-fold increase both in serum and ascites. Conclusions: These preliminary results show that the i.p. infusion of TALL-104 is safe. Moreover, the increased autologous cell-mediated cytotoxicity and the levels of soluble cytokines after i.p. infs indicate that TALL-104 cells may elicit potential antitumor activity.

No significant financial relationships to disclose.
Phase I trial of a sequence-specific combination of the HDAC inhibitor, vorinostat (SAHA) followed by doxorubicin in advanced solid tumor malignancies
Authors: Daud A. , Schmitt M. , Marchion D. , Bicaku E. , Minton S. , Egorin M. , Zwiebel J. , Chiappori A. , Sullivan D. , Munster P.
Published: March 2020

3502

Background: Preclinical cell culture and xenograft studies suggest that pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) may potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explores the safety, tolerability and maximum tolerated dose (MTD) of a weekly schedule of escalating vorinostat doses (twice daily days 1–3) followed by doxorubicin (20 mg/m2) on day 3 (3 out of 4 weeks). Histone acetylation and topo II expression are evaluated in pre-and post-vorinostat peripheral blood mononuclear cells and in tumor cells of the 30 patients treated at the MTD. Results: To date, 15 patients [median age 54 (38–73)] have been treated in 4 vorinostat cohorts: 200, 300, 400, 500 mg bid. Tumor types included: breast (3), melanoma (3), pancreatic (2) and one each of SCLC, sarcoma, endometrial, colon, prostate, renal cell and bladder cancer. Dose-limiting toxicities included a grade 3 thrombocytopenia (1/6) at the 400 mg bid dose. Non-dose limiting Grade 3 and 4 toxicities include neutropenia, thrombocytopenia, fatigue, pulmonary embolus, and anemia (1 pt each). Currently, vorinostat doses of 500 mg bid are being evaluated. One confirmed partial response in a breast cancer patient, as well as minor responses in a melanoma and a prostate cancer patient were seen in 10 evaluable patients. Patients received a median number of 2 (1–9+) treatment cycles. Doxorubicin is stopped after 6 cycles and patients continue on vorinostat alone. H3 and H4 histone acetylation and topo II expression will be correlated with vorinostat dose, plasma concentration and response. Conclusion: A sequence-specific combination of vorinostat and doxorubicin is active without exacerbation of doxorubicin toxicity. The tolerated vorinostat dose exceeds the proposed single agent dose for vorinostat derived from patients with hematological malignancies. Histone hyperacetylation occurs in peripheral blood mononuclear cells at all levels. The anti-tumor activity in breast cancer and melanoma will be further explored.

No significant financial relationships to disclose.
Phase I experience with c-MET inhibitor XL880 administered orally to patients (pts) with solid tumors
Authors: Eder J. P. , Heath E. , Appleman L. , Shapiro G. , Wang D. , Malburg L. , Zhu A. x. , Leader T. , Wolanski A. , LoRusso P.
Published: March 2020

3526

Background: XL880 is a sub-nM inhibitor of the hepatocyte growth factor receptor (Met) and VEGF receptor family with low in vitro nM inhibition of PDGFRβ, KIT, FLT3, Tie-2 and Ron. Methods: The safety of XL880 was evaluated in two phase 1 studies. XL880 was administered mass-based on a 5 days on / 9 days off schedule (study 1) or as a fixed daily dose (study 2). Inclusion criteria include ECOG performance status = 2, adequate liver, cardiac, and renal function and no brain metastases. Tumor response is assessed every 8 wks by RECIST criteria. Pharmacokinetics, pre and post treatment tumor biopsies and plasma markers of angiogenesis (VEGF, sVEGFR and Ang2) were collected. Results: To date, 51 pts have been dosed in studies 1 & 2. In study 1, dose limiting toxicities (DLT) included reversible Gr3 elevations of lipase, hepatic transaminases and proteinuria. The maximum tolerated dose (MTD) was 3.6 mg/kg. In study 2, the MTD has not been defined. Common adverse events include hypertension and fatigue with loss of concentration. In study 1, 5 of 40 pts had partial responses (2+ -12+ months[m]), 3 pts had minimal responses and 8 pts had stable disease (SD) > 3 m. In study 2, 5 of 8 evaluable pts had SD > 3 m (4 ongoing) and 3 are too early to evaluate. Correlative studies in tumor biopsies show marked inhibition of phospho (p)-met, p-RON, p- ERK, p-AKT and increased apoptosis at less than the MTD. Patients in study 2 pts showed lower XL880 Cmax values with consistent mean concentrations (Css)compared with study 1 MTD pts. Css levels are reached in 15 d. Conclusions: XL880 as daily oral or 5 day on / 9 day off administration is generally well tolerated for > 1 year, although hypertension is nearly universal but manageable. XL880 has demonstrated substantial phase I antitumor activity with both dosing regimens. Correlative studies indicate significant activity against Met and Ron signaling. Enrollment continues on study 2. Phase II trials in gastric cancer and head and neck cancer will begin soon.

No significant financial relationships to disclose.
Interim results from a first-in-human study with AMG102, a fully human monoclonal antibody that neutralizes hepatocyte growth factor (HGF), the ligand to c-Met receptor, in patients (pts) with advanced solid tumors
Authors: Gordon M. S. , Mendelson D. S. , Sweeney C. , Erbeck N. , Patel R. , Kakkar T. , Yan L. , Eckhardt S. G. , Gore L.
Published: March 2020

3551

Background: AMG102 is a fully human IgG2 monoclonal antibody against HGF that prevents tumorigenesis in preclinical models through blockade of the HGF/c-Met receptor tyrosine kinase pathway. We describe interim results from the first-in-human study of AMG102. Methods: This ongoing phase 1, open-label, dose-escalation study is evaluating safety, pharmacokinetics (PK), and preliminary pharmacodynamics (PD) of AMG102 after single and multiple intravenous doses in pts with advanced solid tumors. Sequential dose cohorts of 4–6 pts were administered AMG102 at 0.5, 1, 3, 5, 10, or 20 mg/kg. Pts received a single dose, followed by a 4-wk treatment- free period during which safety and PK were assessed. If no dose-limiting toxicity (DLT) was observed, treatment was resumed every 2 wks at the same dose until pts exhibited drug intolerance or disease progression. Results: As of 10 August 2006, 31 pts have been treated with AMG102 at doses up to 20 mg/kg ( Table ). AMG102 appears to be well tolerated. One pt with non-small cell lung cancer had a grade 3 DLT of dyspnea/hypoxia after the first dose (0.5 mg/kg); a second pt with pancreatic cancer had a grade 3 DLT/serious adverse event of gastrointestinal hemorrhage after the first dose (1 mg/kg). The most frequently reported, treatment-related adverse events (AEs) have been fatigue (13%), constipation (10%), anorexia (6%), nausea (6%), and vomiting (6%). No anti-AMG102 antibodies have been detected. Initial PK analysis indicates approximately linear PK in the dose range of 0.5 to 20 mg/kg. The overall mean (SD) [median] clearance and half-life estimates based on day-1 dosing were 12.1 (5.21) [10.7] mL/hr and 15.4 (5.84) [15.5] days, respectively. Tumor response is described ( Table ). Conclusions: In this study, interim results suggest that AMG102 at doses up to 20 mg/kg appears to be well-tolerated, with preliminary PK data supporting every-2-wk administration.

[Table: see text]

No significant financial relationships to disclose.
A phase I dose escalation and pharmacokinetic study of BIBF 1120 in combination with paclitaxel and carboplatin in patients with advanced gynecological malignancies
Authors: Harter P. , Huober J. , Pfisterer J. , Wimberger P. , Loibl S. , Stopfer P. , Kaiser R. , Reichardt V. , du Bois A.
Published: March 2020

3561

Background: BIBF 1120 is an oral triple angiokinase inhibitor targeting VEGFR, PDGFR, FGFR kinases which might be interesting targets for gynecologic tumor therapy. Therefore, we performed a phase I study to evaluate maximal tolerated dose (MTD), safety, and pharmacokinetics (PK) of twice daily BIBF 1120 in combination with carboplatin AUC 5 and paclitaxel 175 mg/m2 q21 (CP) in patients with advanced or recurrent gynecological malignancies. Methods: 6 courses of CP and escalating bid doses of BIBF 1120 (2x100 mg to 2x250 mg) on the days without i.v. chemotherapy were administered. A 3 + 3 dose escalation design was followed. An additional cohort of 6 pts was treated on the MTD level. Results: Twenty-three pts were enrolled and 21 pts were treated with at least one cycle of CP and BIBF 1120. At 2x250 mg of BIBF 1120, two pts developed reversible CTCAE °3 and °4 elevations of AST and ALT in the first treatment course. MTD was determined as 200 mg BIBF 1120 bid for the combination with CP. Within the other dose cohorts (2x100 mg, n= 3, 2x150 mg, n= 4, 2x200 mg, n= 13) no dose limiting toxicities were observed. There was no increase in hematological toxicity with the addition of BIBF 1120 compared to standard CP. Further non-hematological °3 toxicities were: diarrhea (n=4), ascites (n=1), dyspnoe (n=1), nausea (n=3).Thus far, the PK profiles of carboplatin, paclitaxel, and BIBF 1120 have been evaluated in seven pts (2x100 mg, n=3 and 2x150 mg, n=4). There was no significant change of the individual and geometric mean plasma concentrations of C and P before and after 3 weeks of continuous daily bid dosing with BIBF 1120. Conclusions: BIBF 1120 can be given safely at a dose of 200 mg bid together with standard doses of CP in pts with advanced gynecological malignancies. Preliminary PK analyses did not reveal any interaction of CP and BIBF 1120.

[Table: see text]
Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) administered twice weekly
Authors: Murgo A. J. , Kummar S. , Gardner E. R. , Figg W. , Chen X. , Yancey M. , Ivy P. , Conley B. , Doroshow J. H. , Gutierrez M. E.
Published: March 2020

3566

Background: 17-DMAG binds to heat-shock protein 90, leading to degradation of oncogene client proteins, inhibiting tumor growth. Preclinically, 17-DMAG has potent antitumor activity. Methods: 17-DMAG was given by 1–2 hour infusion twice weekly for 4 weeks/28-day cycle. Starting dose: 1mg/m2/dose. Eligibility: ECOG = 2, adequate organ function. Exclusions: prolonged QTc/uncontrolled illness. An accelerated titration escalation design was used; one patient (pt)/dose level was entered until a single pt experienced dose-limiting toxicity (DLT) or 2 pts have grade (gr) = 2 toxicity during the first cycle. Ending the accelerated phase, it converts to a standard 3–6 pt/cohort design. Objectives: To determine the toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD) and MTD of twice weekly 17-DMAG. Plasma samples collected before and up to 48 hours after 17-DMAG infusion were analyzed by LC-MS. Results: 23 pts were accrued and treated; Diagnosis: renal cell-1, pancreatic-2, medullary thyroid-1, NSCLC-3, colorectal -5, peritoneal mesotelioma-1 adrenocortical carcinoma-1, pheochromocytoma-2, malignant thymoma-1, melanoma-2, sarcoma-1, hepatocarcinoma-1 and head & neck -1 and ovary-1. 2 DLTs (gr 3 peripheral neuropathy and renal failure) were observed at 27 mg/m2/dose. Toxicities at the MTD dose (21 mg/m2/dose) have been acceptable: Myalgias/arthralgias being the most common. Other gr 1–2 toxicities included: diarrhea, weight loss, fatigue, elevated transaminases, hair loss, electrolyte abnormalities (hyponatremia and hypo/hyper-magnesemia) and leukocytopenia. PK is linear, with AUC and Cmax increasing as dose was escalated. Drug clearance is independent of dose, but highly variable (10.75 ± 5.56 L/hr/m2). Half-life: 10.0 to 31.7 h, with a median of 17.2 h. At the MTD: Cmax was 523.6 ± 265.3 ng/mL; Very high interindividual variability (CV = 70.3%) and a mean AUCinf of 2467.5 ± 1733.8 hr*ng/mL. Disease stabilization was achieved in a pt with mesothelioma (19 mos +) and another with head and neck cancer (8 mos +). Conclusions: We recommend 21mg/m2/dose twice weekly as the Phase II dose. The study continues to accrue at the MTD to collect paired biopsies for proteomic evaluation on Hsp90 client proteins analysis.

No significant financial relationships to disclose.