Ki Young Chung

Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry

PURPOSE To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). PATIENTS AND METHODS Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximabs commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria. RESULTS Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25%; 95% CI, 4% to 46%). CONCLUSION Colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not seem to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted.

Constitutive Activation of STAT5A Promotes Human Hematopoietic Stem Cell Self-Renewal and Erythroid Differentiation

Activation of the transcription factor signal transducer and activator of transcription (STAT)5 is involved in various aspects of hematopoiesis, affecting cell proliferation, differentiation, and cell survival. Constitutive activation of STAT5 has also been associated with leukemic transformation. We overexpressed the constitutively active mutant STAT5A(1*6) in human cord blood CD34+ cells and evaluated the effects on the hematopoietic potential of stem cells in a variety of in vitro and in vivo systems. The observed phenotypic changes were correlated with differential gene expression patterns induced by STAT5A(1*6). Our data indicate that a persistent activation of STAT5A in human hematopoietic stem and progenitor cells results in their enhanced self-renewal and diverts differentiation to the erythroid lineage.

Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: An immunohistochemical and chromogenic in situ hybridization study

Recent data suggest that detection of epidermal growth factor receptor protein by immunohistochemistry (IHC) does not predict response to the antiepidermal growth factor receptor drug, cetuximab, in patients with colorectal carcinoma. In searching for foundation for further investigation to optimize patient selection for cetuximab therapy, this study sought to exploit the tissue microarray and chromogenic in situ hybridization techniques to evaluate the status of epidermal growth factor receptor gene amplification in colorectal cancer and its relationship with protein expression by IHC. The study included 158 primary or metastatic colorectal adenocarcinomas. Immunohistochemical results were scored as 0–3+ based on the intensity of membrane staining. The in situ hybridization signals were counted in 30 nuclei per tissue core. Overall, the rate of tissue loss was 7%, yielding 147 analyzable cases: 123 primary, 24 metastatic. Positive immunohistochemical staining of any intensity was detected in 85% (105/123) of primary and 79% (19/24) of metastatic tumors, whereas gene amplification (>5 gene copies/nucleus) was only seen in 12% (15/123) of primary and 8% (2/24) of metastatic tumors. Only 2/15 primary and 1/2 metastatic tumors that showed gene amplification were amplified at a high level (>10 gene copies/nucleus). Although a positive correlation was detected between the intensity of protein expression and the likelihood of gene amplification in both the primary (P=0.01) and the metastatic (P=0.05) tumors, IHC had a low specificity (17% in primary, 23% in metastatic) in predicting gene amplification. Conversely, all tumors that did not express the protein by IHC lacked gene amplification. Thus, this study shows that only a small fraction of epidermal growth factor receptor- positive colorectal carcinomas detected by IHC are associated with gene amplification. Additional studies are needed to determine whether epidermal growth factor receptor gene amplification bears any informative value in predicting response to cetuximab-based therapy.

Phase II Study of the Anti-Cytotoxic T-Lymphocyte–Associated Antigen 4 Monoclonal Antibody, Tremelimumab, in Patients With Refractory Metastatic Colorectal Cancer

PURPOSE Safety and efficacy of tremelimumab (CP-675,206), a fully human anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody, were assessed in patients with treatment-refractory colorectal cancer. PATIENTS AND METHODS A single-arm, multicenter, phase II trial was conducted in patients with Eastern Cooperative Oncology Group performance status <or= 1 and measurable colorectal carcinoma for whom standard treatments for metastatic disease had failed. Patients received 15 mg/kg tremelimumab intravenously every 90 days until progression. Primary end point was objective response status (per Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival, and overall survival. RESULTS Forty-seven patients who had received extensive prior therapies (all had received fluoropyrimidines, oxaliplatin, and irinotecan; most [91%] had also received cetuximab) were treated. Grade 3/4 treatment-related adverse events (AEs) were diarrhea (n = 5; 11%), ulcerative colitis (n = 1; 2%), fatigue (n = 1; 2%), autoimmune thrombocytopenia (n = 1; 2%), and hypokalemia (n = 1; 2%), which resolved spontaneously or with interventions. Six patients discontinued because of an AE; two were considered treatment related. Of 45 response-evaluable patients, 44 did not reach second dose (43 progressive disease; one discontinuation). Twenty-one patients (45%) lived >or= 180 days after enrollment. One patient (2%; 90% CI, < 1% to 10%) had a stable pelvic mass and substantial regression in an adrenal mass (partial response). This patient received five tremelimumab doses; response duration was 6 months (enrollment to disease progression, 15 months). CONCLUSION Tremelimumab did not demonstrate clinically meaningful single-agent activity in this patient population, although the number of survivors at 6 months and the one patient with confirmed partial response are potentially interesting. Further study of tremelimumab in combination with other agents may be warranted.

Adjuvant Therapy of Colon Cancer : Current Status and Future Directions

Adjuvant treatment of colon cancer is a relatively new concept, having been first validated less than 20 years ago. Fluoropyrimidines including 5-fluorouracil (5-FU), introduced in clinical trials in the 1950s, are an integral component of the treatment of colon cancer in the adjuvant setting. Whereas both irinotecan and oxaliplatin have demonstrated clinical activity in metastatic colorectal cancer, only oxaliplatin has demonstrated efficacy in the adjuvant setting when added to 5-FU–based therapy. Irinotecan, despite showing a survival advantage in the second-line metastatic cancer setting and a survival advantage when added to first-line metastatic cancer treatment, has failed to show a survival or disease-free survival benefit in the adjuvant setting. In contradistinction, the addition of oxaliplatin to 5-FU plus leucovorin has improved disease-free survival in 2 large randomized adjuvant trials. Oxaliplatin/5-FU/leucovorin should therefore be regarded as a reference standard for adjuvant therapy. This comprehensive review of adjuvant therapy for colon cancer will cover the role of fluoropyrimidines and oxaliplatin, the controversies of adjuvant therapy for patients with stage II cancer, and the ongoing clinical trials that will define the future role, or lack thereof, of newer agents in adjuvant therapy.

NUP98 dysregulation in myeloid leukemogenesis.

Abstract:  Nucleoporin 98 (NUP98) is a component of the nuclear pore complex that facilitates mRNA export from the nucleus. It is mapped to 11p15.5 and is fused to a number of distinct partners, including nine members of the homeobox family as a consequence of leukemia‐associated chromosomal translocations. NUP98‐HOXA9 is associated with the t(7;11)(p15;p15) translocation in acute myeloid leukemia (AML), myelodysplastic syndrome, and blastic crisis of chronic myeloid leukemia. Expression of NUP98‐HOXA9 in murine bone marrow resulted in a myeloproliferative disease progressing to AML by 7–8 months. Transduction of NUP98 fusion genes into human CD34+ cells confers a proliferative advantage in long‐term cytokine‐stimulated and stromal cocultures and in NOD‐SCID engrafted mice, associated with a five‐ to eight‐fold increase in hematopoietic stem cells. NUP98‐HOXA9 expression inhibited erythroid and myeloid differentiation but enhanced serial progenitor replating. NUP98‐HOXA9 upregulated a number of homeobox genes of the A and B cluster as well as MEIS1 and Pim‐1, and downmodulated globin genes and C/EBPα. The HOXA9 component of the NUP98‐HOXA9 fusion protein was protected from cullin‐4A–mediated ubiquitination and subsequent proteasome‐dependent degradation. In NUP98‐HOX–transduced CD34+ cells and cells from AML patients with t(7;11)(p15;p15) NUP98 was no longer associated with the nuclear pore complex but formed intranuclear aggregation bodies. Analysis of NUP98 allelic expression in AML and myelodysplastic syndrome showed loss of heterozygosity observed in 29% of the former and 8% of the latter. This was associated with poor prognosis.

A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-Allylamino-17-Demethoxygeldanamycin in Patients with Solid Tumors

Purpose: Both heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors. Experimental Design: During the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity. Results: Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m2 irinotecan and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G2-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD. Conclusions: The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 irinotecan and 300 mg/m2 17AAG.

Bevacizumab 5 mg/kg Can Be Infused Safely Over 10 Minutes

PURPOSE Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor. As a result of concerns for potential infusion-related hypersensitivity reactions (HSRs), initial phase I trials used a 90-, 60-, 30-minute initial infusion sequence. We sought to determine if the initial prolonged infusion was still necessary and if an infusion time of fewer than 30 minutes could be safely used. METHODS We used computerized pharmacy records to identify all patients who received bevacizumab at our institution in the first 2 years of commercial availability (February 1, 2004, to June 30, 2006). Our institutional adverse drug reaction reporting program was used to identify any infusion reactions possibly related to bevacizumab, and patient medical records were reviewed for confirmation. RESULTS A total of 1,077 patients were treated with 10,606 doses of bevacizumab, and 765 of these patients received a 5-mg/kg dose (total of 8,494 doses). No HSRs occurred with the 90-, 60-, 30-minute infusion sequence in the first 202 patients. The standard infusion rate was then modified to 30 minutes for all bevacizumab doses. No HSRs were encountered. The infusion was again modified to a rate of 0.5 mg/kg/min. Of the 370 patients who received a total of 2,311 doses of bevacizumab at 5 mg/kg over 10 minutes, six (1.6%) experienced events of minor clinical consequence that were possibly consistent with nonserious HSRs. CONCLUSION Ninety- and 60-minute initial infusion times are unnecessary. Use of a standard infusion rate of 0.5 mg/kg/min is safe, logical, and the current policy at our institution.

G3139 (Genasense) in patients with advanced merkel cell carcinoma.

Objectives:Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine malignancy of the skin. Preclinical studies have identified up-regulation of the critical antiapoptosis gene bcl-2 in MCC. We conducted a multicenter phase II trial of the novel bcl-2 antisense agent (G3139, Genasense) in patients with advanced MCC. Methods:Twelve patients (9 men, 3 women) with histologically confirmed metastatic or regionally recurrent MCC were enrolled. Ten patients (83%) had received prior chemotherapy. Eight patients (67%) had Karnofsky performance status of 90 to 100. Patients received continuous IV infusion of G3139 (7 mg/kg/d) via central venous access in an outpatient setting for 14 days, followed by a 7-day rest period. Response was assessed at 6-week intervals. Patients were allowed to continue therapy until unacceptable toxicity or disease progression. Results:No objective responses were observed. The best response was stable disease in 3 patients and progressive disease in 9 patients. A median of 4 doses per patient (total 46 doses) was administered. Dose delays and/or reductions were required in 6 patients. One patient developed grade 4 lymphopenia. One patient developed grade 3 renal failure characterized by grade 3-elevated creatinine and grade 4 hyperkalemia. Other grade 3 events included cytopenia (n = 5), aspartate aminotransferase/alanine aminotranferease elevation (n = 3), hypophosphatemia (n = 2), and pain (n = 1). The most frequent grade 1 to 2 toxicities were elevated creatinine, ALT elevation, hypokalemia, lymphopenia, and fatigue. Conclusions:Bcl-2 antisense therapy (G3139) was well tolerated among patients with advanced MCC. Although probable antitumor activity was documented in 1 patient, no objective responses per Response Evaluation Criteria in Solid Tumors criteria were observed.

Pneumatosis intestinalis: a variant of bevacizumab related perforation possibly associated with chemotherapy related GI toxicity

A 54 year old male with metastatic low grade neuroendocrine tumor originating from the pancreas presents with air within the wall of the small intestine while receiving systemic chemotherapy plus bevacizumab. The patient had metastatic disease to the liver, peritoneum, and bone, and had received octreotide LAR injections for 2 years. Disease progression of the hepatic metastasis was found in February 2006 and he began systemic chemotherapy with oxaliplatin (130 mg/m), S1 (30 mg; an oral fluoropyrimidine approved in Japan and under active investigation in the USA and Europe) and bevacizumab 7.5 mg/kg every 3 weeks, as per a clinical trial. The oxaliplatin was stopped after two months as per the study design and the patient continued on S1 and bevacizumab. Six months into treatment, a routine computed tomography (CT) revealed a small amount of pneumoperitoneum (Fig. 1), and extensive small bowel pneumatosis (Fig. 2). Except for constipation, the patient had no symptoms of fever, abdominal pain, nausea, or vomiting. He had no history of recent operative procedure, biopsy or endoscopy. His laboratory parameters were normal including a normal serum lactate. The S1 and bevacizumab were stopped and an adverse event was reported. The pneumatosis persisted on a CT scan performed 3 weeks following discovery, but subsequently resolved at 6 weeks. The patient remained asymptomatic throughout and was managed with close observation alone, and specifically without any invasive procedures.