Joseph A. Bokar

A Phase II Trial of Fosbretabulin in Advanced Anaplastic Thyroid Carcinoma and Correlation of Baseline Serum-Soluble Intracellular Adhesion Molecule-1 with Outcome

BACKGROUND Fosbretabulin is a novel vascular-disrupting agent that has antitumor activity against anaplastic thyroid cancer (ATC) cell lines, xenografts, and demonstrable efficacy in a phase I trial. This phase II study determined the efficacy and safety of fosbretabulin in patients with advanced ATC and whether fosbretabulin altered the natural history of ATC by virtue of doubling the median survival. A secondary aim evaluated the prognostic value of serum soluble intracellular adhesion molecule-1 (sICAM). METHODS Twenty-six patients received fosbretabulin 45 mg/m(2) as a 10-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. sICAM levels were obtained at baseline, over the first two cycles, and end of therapy. Treatment was continued until disease progression. RESULTS Fosbretabulin was well tolerated; grade 3 toxicity was observed in nine patients (35%), and grade 4 toxicity in one (4%). QTc prolongation delayed treatment in four causing one to stop treatment. Median survival was 4.7 months with 34% and 23% alive at 6 and 12 months, respectively. Median duration of stable disease in seven patients was 12.3 months (range, 4.4-37.9 months). Baseline serum sICAM levels were measured in 24 patients with a median 253.5 ng/mL. There was a significant difference in event-free survival among tertiles of baseline sICAM levels (p < 0.009). CONCLUSIONS There were no objective responses seen with single-agent fosbretabulin as administered in this trial, and we did not observe a doubling of survival as our primary endpoint. This is among the largest prospective trials ever conducted for ATC. Fosbretabulin has an acceptable safety profile in patients with advanced ATC, and one-third survived more than 6 months. Despite a small sample size, low baseline sICAM levels were predictive of event-free survival. Further prospective validation of sICAM as a therapeutic biomarker and exploring combination regimens with fosbretabulin are warranted.

A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors

Purpose: Bevacizumab is an antibody against vascular endothelial growth factor; sunitinib is an inhibitor of vascular endothelial growth factor and related receptors. The safety and maximum tolerated dose of sunitinib plus bevacizumab was assessed in this phase I trial. Experimental Design: Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level, 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level, 5 mg/kg) on days 1, 15, and 29 of a 42-day cycle. Dose-limiting toxicities during the first 6-week cycle were used to determine the maximum tolerated dose. Results: Thirty-eight patients were enrolled. Patients received a median of 3 cycles of treatment (range, 1-17+). There was one dose-limiting toxicity (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed Response Evaluation Criteria in Solid Tumors–defined partial response (18%; 95% confidence interval, 8-34%). Nineteen of the 32 patients with a postbaseline scan (59%) had at least some reduction in overall tumor burden (median, 32%; range, 3-73%). Conclusions: The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Antitumor activity was observed across multiple solid tumors. (Clin Cancer Res 2009;15(19):6277–83)

Toxicity of Sunitinib Plus Bevacizumab in Renal Cell Carcinoma

TO THE EDITOR: Inhibition of vascular endothelial growth factor (VEGF), either via antibody-mediated binding of the ligand or small molecule inhibition of the VEGF receptor, has demonstrated clinically relevant benefits in metastatic renal cell carcinoma (RCC) and other solid tumors. Recently, combinations of VEGFinhibiting approaches have been studied in an attempt to maximize VEGF blockade and extend the clinical benefit of these approaches. Sunitinib (Sutent; Pfizer Inc, New York, NY), a small-molecule tyrosine kinase inhibitor of a family of receptors including VEGF receptor and bevacizumab (Avastin; Genentech, South San Francisco, CA), a recombinant humanized monoclonal antibody that binds and neutralizes circulating VEGF, have been previously combined in two separate phase I trials. A phase I trial conducted exclusively in metastatic renal cell carcinoma (RCC) and with fixed bevacizumab dosing at 10 mg/kg intravenously every 2 weeks reported unacceptable toxicity, including thrombotic microangiopathy (TMA). We previously reported a similar phase I trial of this combination in 38 patients with advanced solid tumors, notable for the diverse tumor type as well as lower initial doses of bevacizumab. This trial failed to demonstrate laboratory or clinical evidence of TMA in any patent, including the six RCC patients (median, 8 cycles of therapy; range, 2 to 13), all of whom had undergone nephrectomy, and including all patients treated at the highest dose levels up to 20 months of treatment. Due to increased toxicity seen with chronic dosing at higher dose levels in our study and the TMA seen in the other trial, an expanded cohort of patients with RCC was planned to collect more safety experience at dosing of 37.5 mg sunitinib 4 weeks on followed by 2 weeks off and bevacizumab 5 mg/kg intravenously on days 1, 15, and 29 of a 42-day cycle. Five patients were enrolled in this expanded cohort. Three of five patients demonstrated laboratory evidence of TMA. This included low haptoglobin, thrombocytopenia, and schistocytes on peripheral blood smear at the end of cycles 2 and 4 for two patients, and an isolated single low haptoglobin value for the third patient. None of the patients had any clinical signs or symptoms associated with the laboratory abnormalities. Table 1 depicts the patient characteristics and relevant data for the three cases of TMA and the remainder of the patients with RCC enrolled on the initial study and expanded cohort. The first two TMA patients continued to have haptoglobin levels lower than 20 mg/dL for 2 and 20 weeks after discontinuation of bevacizumab (both patients continued on sunitinib monotherapy). The third patient developed the isolated low haptoglobin while receiving sunitinib monotherapy after bevacizumab had been discontinued 8 weeks prior. The haptoglobin normalized 2 weeks later and remained in normal range with continued sunitinib monotherapy for this patient. All five patients on the expanded cohort discontinued bevacizumab when TMA was observed in the initial two patients. Further accrual of patients with RCC was suspended due to this safety signal.

Phase II Study of Dasatinib (BMS-354825) in Patients With Metastatic Adenocarcinoma of the Pancreas

BACKGROUND Src, EphA2, and platelet-derived growth factor receptors α and β are dysregulated in pancreatic ductal adenocarcinoma (PDAC). METHODS Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor β, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC. METHODS Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected. RESULTS Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8-6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6-3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival. CONCLUSION Single-agent dasatinib does not have clinical activity in metastatic PDAC.

N6-adenosine methylation in mRNA: substrate specificity and enzyme complexity.

The N6-methylation of internal adenosine residues is a common post-transcriptional modification of eukaryotic pre-mRNA sequences. An in vitro methylation system which retains the precise selectivity of in vivo methylation sites has been used to further define the nature of RNA site recognition. In addition to short consensus sequences, other structural features or context effects contribute to the selection of methylation sites in pre-mRNAs. Partial purification of the mRNA N6-adenosine methyltransferase revealed unexpected levels of complexity. The methyltransferase is composed of three separate components with molecular masses of 30, 200 and 875 kDa, respectively. These components are readily separated under non-denaturing conditions and each is required for mRNA methylation activity.

SR proteins Asf/SF2 and 9G8 interact to activate enhancer-dependent intron D splicing of bovine growth hormone pre-mRNA in vitro.

The alternative splicing of the last intron (intron D) of bovine growth hormone (bGH) pre-mRNA requires a down-stream exonic splicing enhancer (FP/ESE). The presence of at least one SR protein has been shown to be essential for FP/ESE function and splicing of intron D in in vitro splicing assays. However, in vitro reconstitution of splicing using individual purified SR proteins may not accurately reflect the true complexity of alternative splicing in an intact nucleus, where multiple SR proteins in varying amounts are likely to be available simultaneously. Here, a panel of recombinant baculovirus-expressed SR proteins was produced and tested for the ability to activate FP/ESE-dependent splicing. Individual recombinant SR proteins differed significantly in their activity in promoting intron D splicing. Among the recombinant SR proteins tested, SRp55 was the most active, SC35 showed very little activity, and ASF/SF2 and 9G8 individually had intermediate activity. At least one SR protein (ASF/SF2) bound to the FP/ESE with characteristics of a cooperative interaction. Most interestingly, low concentrations of ASF/SF2 and 9G8 acted synergistically to activate intron D splicing. This was due in part to synergistic binding to the FP/ESE. Splicing of bGH intron D is inherently complex, and is likely controlled by an interaction of the FP/ESE with several trans-acting protein factors acting both independently and cooperatively. This level of complexity may be required for precise control of alternative splicing by an exon sequence, which simultaneously is constrained to maintain translational integrity of the mature mRNA.

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

SummaryPurpose: Pre-clinical models have demonstrated the benefit of metronomic schedules of cytotoxic chemotherapy combined with anti-angiogenic compounds. This trial was undertaken to determine the toxicity of a low dose regimen using docetaxel and thalidomide. Patients and Methods: Patients with advanced solid tumors were enrolled. Thalidomide 100mg twice daily was given with escalating doses of docetaxel from 10 to 30mg/m2/week. One cycle consisted of 12 consecutive weeks of therapy. The maximal tolerated dose (MTD) was defined as the dose of thalidomide along with docetaxel that caused ≤grade 1 non-hematologic or ≤grade 2 hematologic toxicity for cycle one. Results: Twenty-six patients were enrolled. Dose-limiting toxicities (DLTs) were bradycardia, fatigue, fever, hyperbilirubinemia, leukopenia, myocardial infarction, and neutropenia. Prolonged freedom from disease progression was observed in 44.4% of the evaluable patients. Conclusions: This anti-angiogenic regimen was well tolerated and demonstrated clinical benefit. The recommended phase II dosing schedule is thalidomide 100mg twice daily with docetaxel 25mg/m2/week.

Advances in oncology care: Targeted therapies

The start of the 21st century has produced advances in cancer care that have improved both survival rates and quality of life for many persons diagnosed with cancer. Targeted therapy has given new hope for controlling cancer as a chronic illness. Alone, or in combination with traditional therapies such as surgery, radiation, and/or chemotherapy, this new form of therapy targets malignant cells, halting tumor growth and the potential metastatic spread of disease. Toxicities are limited, but some are serious and may require intensive care. It is imperative for the experienced critical care nurse to have an understanding of these new treatment options and those on the horizon, as these therapies are the future of cancer care. Whereas in previous decades, patients with cancer may not have survived an intensive care admission for treatment complications or advanced disease, many patients now are recovering from life-threatening events, continuing treatment for their disease, and going on to live meaningful, good-quality lives.

Timeliness of care in patients with non-small cell lung cancer (NSCLC) at the Louis Stokes Veteran Affairs Medical Center (LSVAMC).

50 Background: Timeliness of care in patients with newly diagnosed lung cancer is a controversial topic. Although some studies have concluded that timeliness does not improve clinical outcomes, many experts agree that timeliness is an important aspect of quality care as it leads to shorter duration of emotional distress during the diagnostic process and treatment initiation. METHODS At the LSVAMC, we have established a 60-day time interval from first abnormal radiology to treatment initiation as our institutional standard of care. We have initiated several interventions to improve timeliness of care through our new lung cancer program launched in July 2012. These interventions, which were implemented over a 1 year period, include: 1) Weekly interdisciplinary lung nodule rounds. 2) A cancer care tracking system. 3) A lung cancer-specific case manager who collaborates with all disciplines to expedite workup and treatment initiation. We have retrospectively reviewed all NSCLC cases since the launch of the new lung cancer program (group 1) and compared the timeliness to a sample of patients before the interventions (group 2). RESULTS 58 patients (group 1) and 107 patients ( group 2) with NSCLC were diagnosed and treated at the LSVAMC from January to July 2011 and July 2012 to May 2013 respectively. Median time from first abnormal radiology to first treatment was 104 days (range 13-375, mean 113.4) in group 1 and 81 days (range 1-261, mean 84.9) in group 2. Median time from diagnostic radiology to tissue diagnosis was 39 days (range 2-226, mean 66) in group 1 and 29 days (range 2-206, mean 42.6) in group 2. Median time from tissue diagnosis to first treatment was 23 days (range 0-177, mean 38) in group 1 and 28 days (range 0-254, mean 36.5) in group 2. CONCLUSIONS Timeliness of care in NSCLC patients at our center has improved. We still have not reached our target. Continued progress is expected as we transition to a multidisciplinary multi specialty care lung cancer program.

A phase I study of the combination of oxaliplatin/docetaxel and vandetanib for the treatment of advanced gastroesophageal cancer.

e14644 Background: Metastatic gastroesophageal carcinoma is a devastating illness and there is a strong need for improved therapies incorporating novel targeted agents, such as anti-angiogenic agents into active chemotherapy programs. We set out to assess the safety and tolerability of the dual VEGFR/EGFR inhibitor, vandetanib (V) in combination with two active chemotherapeutic agents in this illness, oxaliplatin (O) and docetaxel (D). METHODS Phase I study ( NCT00732745 ) with a standard 3+3 dose escalation design with the primary aim to determine the MTD of V added to OD chemotherapy in advanced GE cancer. GE cancer pts with either adeno or squamous cell histology were eligible with adequate organ function and ECOG PS of 0-1. Patients could not have received prior chemotherapy for advanced disease. RESULTS Initial treatment for the first cohort consisted of O at 100mg/m2 day 1, D at 35 mg/m2 days 1, 8 and V 100 mg PO QD of 21-day treatment cycles. Due to DLT reached in 2/3 patients in cohort 1 (one grade 3 and one grade 4 diarrhea/dehydration), 6 patients were treated then at dose level -1 (O 80 mg/m2 day 1, D 30 mg/m2 days 1,8, V 100 mg PO QD days 1-21). At dose level -1 no further DLTs were noted and the combination overall was well-tolerated with expected hematological toxicities and one grade 3 episode of anorexia noted and this dose was assessed as MTD and RP2D. All enrolled patients had adenocarcinoma histology. At dose level 1, 1/3 documented PR and 2SD and at dose level -1 2/6 SD and 1 documented CR was noted (the patient with CR completed 8 cycles of therapy and continues in CR on maintenance V). 3/6 had PD as best response at dose level -1. The median number of cycles received was 4 (range 2-8+). CONCLUSIONS The MTD of the combination of oxaliplatin/docetaxel and vandetanib is O 80 mg/m2 day1, D 30 mg/m2 days 1,8 and V 100 mg PO QD and the DLT is gastrointestinal toxicity, such as diarrhea and concomitant dehydration. At this dose the regimen has manageable toxicity and shows promising activity in the management of advanced gastroesophageal carcinoma. This study was supported by an ISS research grant from Aventis and investigational drug by AstraZeneca.