Showing papers by "Charles D. Blanke published in 2009"

Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665.

Abstract: Background Therapy for gastrointestinal stromal tumors (GIST) has changed significantly with the use of imatinib mesylate (IM). Despite the success of this drug in metastatic GIST, disease progression remains a perplexing clinical issue suggesting the need for multimodality management. There have been no prospective studies either evaluating the neoadjuvant use of IM in primary GIST or as a preoperative cytoreduction agent for metastatic GIST. Methods RTOG 0132/ACRIN 6665 was a prospective phase II study evaluating safety and efficacy of neoadjuvant IM (600 mg/day) for patients with primary GIST or the preop use of IM in patients with operable metastatic GIST. The trial continued postop IM for 2 years. Results Sixty-three patients were entered (52 analyzable), 30 patients with primary GIST (Group A) and 22 with recurrent metastatic GIST (Group B). Response (RECIST) in Group A was (7% partial, 83% stable, 10% unknown), in Group B (4.5% partial, 91% stable, 4.5% progression). Two-year progression free survival (Group A 83%, Group B 77%). Estimated overall survival (Group A 93%, Group B 91%). Complications of surgery and IM toxicity were minimal. Conclusion This trial represents the first prospective report of preop IM in GIST. This approach is feasible, requires multidisciplinary consultations, and is not associated with notable postop complications. J. Surg. Oncol. 2009;99:42–47. © 2008 Wiley-Liss, Inc.

Imatinib Plasma Levels Are Correlated With Clinical Benefit in Patients With Unresectable/Metastatic Gastrointestinal Stromal Tumors

Abstract: Purpose To study the pharmacokinetics (PK) of imatinib (IM) in patients with advanced GI stromal tumors (GISTs) treated in a randomized phase II study and to explore the potential relationship between IM plasma levels and long-term clinical outcomes. Patients and Methods Patients were randomly assigned to receive IM at 400 mg versus 600 mg daily. IM plasma levels were analyzed in a subset of patients (n = 73) for whom PK data on day 1 and at steady-state (SS, day 29) were available. IM PK was evaluated using a population PK approach. The relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough concentration (Cmin). The clinical outcome parameters evaluated include overall objective benefit rate (OOBR; complete response plus partial response plus stable disease) time to progression (TTP), and KIT genotyping. Results IM PK exposure showed a high inter-patient variability, and clinical outcomes were correlated with IM trough levels a...

Phase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336).

Abstract: Introduction: Patients with metastatic colorectal cancer who progress on standard chemotherapy have limited treatment options. New and effective drugs are needed for these patients. Romidepsin is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This may result in cell cycle arrest and tumor growth inhibition. Romidepsin has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xenograft models. Patients and methods: Patients were required to have pathologically verified, measurable, metastatic or locally advanced colorectal cancer that was surgically unresectable. They must have failed either one or two prior chemotherapy regimens, had performance status of 0–1, adequate bone marrow, renal and hepatic function, and no significant cardiac disease. Patients were treated with romidepsin at a dose of 13 mg/m2 as a 4-h iv infusion on days 1, 8, and 15 of a 28-day cycle. The study had a two stage design. The primary objective of the study was to determine the confirmed response probability in this group of patients treated with romidepsin. Results: Twenty-eight patients were registered to the study, two of whom were ineligible. One eligible patient refused all treatment and was not analyzed. For the 25 remaining patients, performance status was 0 in 16 patients and 1 in nine patients. Ten patients had received one prior chemotherapy regimen and fifteen 2 prior regimens. Out of the 25 eligible and analyzable patients accrued in the first stage of the protocol, no objective responses were observed and the study was permanently closed. Four patients had stable disease as the best response. Twenty-five patients were assessed for toxicity. No grade 4 or greater toxicities were seen. Fourteen of the 25 patients experienced grade 3 toxicities the most common of which were fatigue or anorexia. Conclusion: Romidepsin at this dose and schedule is ineffective in the treatment of patients with metastatic colorectal cancer after prior chemotherapy. Future trials might evaluate combinations of romidepsin with chemotherapeutic or other agents.

Gene expression signatures and response to imatinib mesylate in gastrointestinal stromal tumor.

Abstract: Despite initial efficacy of imatinib mesylate in most gastrointestinal stromal tumor (GIST) patients, many experience primary/secondary drug resistance. Therefore, clinical management of GIST may benefit from further molecular characterization of tumors before and after imatinib mesylate treatment. As part of a recent phase II trial of neoadjuvant/adjuvant imatinib mesylate treatment for advanced primary and recurrent operable GISTs (Radiation Therapy Oncology Group S0132), gene expression profiling using oligonucleotide microarrays was done on tumor samples obtained before and after imatinib mesylate therapy. Patients were classified according to changes in tumor size after treatment based on computed tomography scan measurements. Gene profiling data were evaluated with Statistical Analysis of Microarrays to identify differentially expressed genes (in pretreatment GIST samples). Based on Statistical Analysis of Microarrays [False Discovery Rate (FDR), 10%], 38 genes were expressed at significantly lower levels in the pretreatment biopsy samples from tumors that significantly responded to 8 to 12 weeks of imatinib mesylate, that is, >25% tumor reduction. Eighteen of these genes encoded Kruppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors. Importantly, 10 KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset predicted likely response to imatinib mesylate-based therapy in a naive panel of GIST. Furthermore, we found that modifying expression of genes within this predictive signature can enhance the sensitivity of GIST cells to imatinib mesylate. Using clinical pretreatment biopsy samples from a prospective neoadjuvant phase II trial, we have identified a gene signature that includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely response to short-term imatinib mesylate treatment.

Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer.

Abstract: Purpose: To determine the safety and efficacy of weekly high-dose oral calcitriol and docetaxel, given to patients with non-resectable, incurable pancreatic cancer. Patients and Methods: Twenty-five patients were enrolled onto this phase II study. Patients were treated with oral calcitriol 0.5 μg/kg on day 1, followed by docetaxel 36 mg/m2 IV on day 2, administered weekly for three consecutive weeks, followed by 1 week without treatment. Patients followed a low-calcium diet and increased their hydration. The primary end-point of the trial was time-to-progression. Results: Three of 25 patients attained a partial response (12%, 95% CI 3 to 31) and seven (28%) achieved stable disease. Median time-to-progression was 15 weeks, and median overall survival was 24 weeks. Toxicities observed (hyperglycemia, fatigue) were mostly attributable to the docetaxel or its pre-treatment. Conclusions: This regimen of high-dose calcitriol with docetaxel may have activity in incurable pancreatic cancer, with a modest increase in TTP when compared to historical findings using single-agent docetaxel. However, results do not appear superior to those seen with gemcitabine, with or without erlotinib.

Perioperative treatment of gastrointestinal stromal tumors.

Abstract: This review describes the current multidisciplinary management of gastrointestinal stromal tumor (GIST), which is the most common sarcoma of the gastrointestinal tract. Before 2001, surgery was the only effective therapy for GIST. The discovery of the central role of KIT proto-oncogene mutations in the pathogenesis of this tumor, and the development of specific inhibitors of KIT tyrosine kinase (TK) function, has changed the paradigm of treatment for GISTs. Imatinib and sunitinib are TK inhibitors with activity against GISTs. Their major established role in GIST is in the treatment of advanced disease. A growing body of literature and clinical experience support the potential perioperative use of these drugs. The adjuvant use of imatinib is based on retrospective series and limited prospective studies demonstrating that imatinib reduces the risk of recurrence. Ongoing studies are further defining the length of adjuvant therapy, as well as identifying the patients that could achieve the best results. Neoadjuvant treatment often decreases the tumor size, allowing a less morbid surgery, appears to be safe and beneficial for some patients, and therefore deserves further study.

Dual-antibody therapy in advanced colorectal cancer: gather ye rosebuds while ye may.

Abstract: Antibodies directed at either vascular endothelial growth factor (VEGF) or the epidermal growth factor receptor (EGFR) are certainly successful in treating metastatic colon cancer (mCRC). Bevacizumab, a VEGFA antagonist, enhances the efficacy of irinotecanand oxaliplatin-based chemotherapy when added during firstor second-line therapy, particularly in regard to prolonging progressionfree survival (PFS). Cetuximab and panitumumab, antibodies to the EGFR, have single-agent activity against mCRC; cetuximab also augments the effects of irinotecan-based chemotherapy across at least three lines of treatment. Of course, in oncology we are all taught that “more is always better.” With cross-talk between the VEGF and EGF pathways, dual inhibition through simultaneous use of both classes of antibodies is attractive. Indeed, BOND-2 (Bevacizumab and Irinotecan Compared With Cetuximab and Bevacizumab Alone in Irinotecan-Refractory Colorectal Cancer), a randomized phase II feasibility study, showed that the triple combination of irinotecan, cetuximab, and bevacizumab achieved surprisingly strong results in irinotecan-refractory mCRC, with an objective response rate of 37%, time to progression of 7.3 months, and median overall survival of 14.5 months. Two articles published in this issue of Journal of Clinical Oncology address different methods of using antibody therapy in mCRC; both answer some important questions but also potentially raise even more. Bokemeyer et al report a randomized phase II study of oxaliplatin-based chemotherapy, with or without cetuximab, concluding that a subset of patients receiving first-line therapy dramatically benefits from the addition of that antibody. Hecht et al present a randomized phase III trial utilizing oxaliplatinor irinotecan-based chemotherapy plus bevacizumab, with or without the anti-EGFR antibody panitumumab, which resulted in a worse outcome for previously untreated patients who received both antibodies when given with cytotoxic drugs. The OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of mCRC) study compared the use of fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) plus cetuximab versus FOLFOX-4 alone in patients with previously untreated incurable mCRC. The primary objective was to see whether the addition of the antibody improved the overall response rate (ORR) compared with chemotherapy alone. Important secondary objectives included the determination of rates of potentially curative metastasectomy, duration of response, PFS, overall survival (OS), and safety. A retrospective subgroup analysis done “on regulatory request” investigated the potential relationship between PFS/ORR and tumor KRAS mutational status. Minor study quirks included analyzing efficacy only in patients who received at least one dose of study treatment (not the more common standard of assessing all randomly assigned patients by intent to treat) and selecting an extraordinarily high bar—an odds ratio of 2.33—for benefit with the addition of cetuximab. In the original patient population, adding cetuximab improved the ORR by an absolute increase of 10% (36% to 46%), which did not reach the original goal (the achieved odds ratio was 1.52). Median PFS was identical on both arms at 7.2 months. However, cetuximab was effective in the population with tumors that demonstrated wild-type KRAS. The ORR increased from 37% to 61% (odds ratio, 2.544; P .011), and PFS improved as well. There was no major change in median PFS at 7.2 v 7.7 months. However, simple visual inspection of the PFS curves shows an early, potentially clinically significant, and maintained separation between those receiving chemotherapy alone and those receiving FOLFOX-4 plus cetuximab, with a hazard ratio of 0.570. Remarkably, in the KRAS mutant population, the ORR, median PFS, and overall PFS were markedly worse for patients who received cetuximab. Although this might be explained by an imbalance in performance status on the mutant tumor arm that favored those treated with chemotherapy alone, the possibility of a negative interaction between chemotherapy and cetuximab in this population cannot be ruled out. The authors correctly conclude that the addition of cetuximab to chemotherapy meaningfully improved the ORR in firstline treatment of mCRC patients with wild-type KRAS tumors. In the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) study, healthy advanced mCRC patients without previous treatment for metastatic disease were randomly assigned between bevacizumab and chemotherapy or bevacizumab, chemotherapy, and panitumumab. At the investigators’ choice, patients could be given oxaliplatinor irinotecan-based cytotoxic treatment, with the doses and schedules of the selected regimens also unspecified. The primary objective of the trial was to see whether the addition of the anti-EGFR antibody improved PFS in the oxaliplatin-based cohort. Because of anticipated (and realized) small numbers enrolled onto irinotecanbased treatment, this cohort had a primary safety objective, while all efficacy end points were descriptive. After one of many planned safety and response analyses, panitumumab was discontinued in both cohorts because of decreased PFS and increased toxicity associated with that agent. Again, statistical assumptions on PACCE were a bit uncharacteristic; the 12-month PFS assumed for the control arm was quite long (in comparison, results from NO16966, which compared JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 5 FEBRUARY 1

Biomarkers in GIST: Partly Ready for Prime-Time Use

Abstract: Gastrointestinal stromal tumors, or GISTs, are now among the most treatable of solid malignancies. Assessing actual tumor response remains challenging; however, in this issue of Clinical Cancer Research, two articles discuss biomarkers potentially helpful in predicting response or other long-term benefits with standard tyrosine kinase therapy use.

Successes and challenges in translational research: the development of targeted therapy for gastrointestinal stromal tumours.

Abstract: Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms that most commonly affect the stomach or small intestine, but that can occur anywhere within the gastrointestinal tract. The annual incidence of GISTs is estimated to be 10 to 20 cases per million. Traditionally, the only effective treatment was surgical resection, and recurrences were common even with complete removal of tumor. Systemic therapy with standard cytotoxic chemotherapeutic agents was completely ineffective. A series of exciting laboratory developments led to the discovery that the small molecule tyrosine kinase inhibitor STI571 (imatinib mesylate) has significant clinical activity in GISTs, representing one of the first therapeutic uses of a targeted agent directed against a solid tumor. In this article we will describe the key steps that led to the initial clinical trials of imatinib in GISTs, and we will also discuss the process of incorporating this novel therapy into mainstream oncologic practice.

S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach.

Abstract: Objective The primary objective of this trial was to evaluate the response rate for trimetrexate (TMTX) in conjunction with 5FU and leucovorin (LV) (=TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting.