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Investigator(s) |
Koch KM, Reddy NJ, Cohen RB, Lewis NL, Whitehead B, Mackay K, Stead A, Beelen AP, Lewis LD. Effects of Food on the Relative Bioavailability of Lapatinib in Cancer Patients. 2009;:1191-6.
Purpose This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. Patients and Methods A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. Results The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C-max) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and Cmax of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. Conclusion These large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.
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Cohen
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Koch KM, Reddy NJ, Cohen RB, Lewis NL, Whitehead B, Mackay K, Stead A, Beelen AP, Lewis LD. Effects of Food on the Relative Bioavailability of Lapatinib in Cancer Patients. J Clin Oncol. 2009 Mar;27(8):1191-6.
Purpose This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. Patients and Methods A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. Results The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C-max) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and Cmax of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. Conclusion These large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.
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Cohen
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Cohen RB, Jones SF, Aggarwal C, von Mehren M, Cheng J, Spigel DR, Greco FA, Mariani M, Rocchetti M, Ceruti R, Comis S, Laffranchi B, Moll J, Burris HA. A Phase I Dose-Escalation Study of Danusertib (PHA-739358) Administered as a 24-Hour Infusion with and without Granulocyte Colony-Stimulating Factor in a 14-Day Cycle in Patients with Advanced Solid Tumors. Clin Cancer Res. 2009 Nov;15(21):6694-701.
Purpose: This study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the i.v. pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors. Experimental Design: In part 1, patients received escalating doses of danusertib (24-hour infusion every 14 days) without filgrastim (granulocyte colony-stimulating factor, G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was done in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3). Results: Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose-limiting toxicity in part 1 without G-CSF. Most other adverse events were grade 1 to 2, occurring at doses >= 360 mg/m(2) with similar incidence in parts 1 and 2. The maximum tolerated dose without G-CSF is 500 mg/m(2). The recommended phase 2 dose in part 2 with G-CSF is 750 mg/m(2). Danusertib showed dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18 to 26 hours. pH3 modulation in skin biopsies was observed at >= 500 mg/m(2). One patient with refractory small cell lung cancer (1,000 mg/m(2) with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline. Conclusions: Danusertib was well tolerated with target inhibition in skin at >= 500 mg/m(2). Preliminary evidence of antitumor activity, including a partial response and several occurrences of prolonged stable disease, was seen across a variety of advanced refractory cancers. Phase II studies are ongoing. (Clin Cancer Res 2009;15(21):6694-701)
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Cohen
von Mehren
Cheng
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Lewis NL, Lewis LD, Eder JP, Reddy NJ, Guo F, Pierce KJ, Olszanski AJ, Cohen RB. Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers. J Clin Oncol. 2009 Nov;27(31):5262-9.
Purpose This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596. Patients and Methods Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups. Results Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased gamma-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months). Conclusion CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.
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Cohen
Olszanski
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Oostendorp RL, Loftiss J, Goel S, Smith DA, Dar MM, Witteveen PO, Cohen RB, Lewis LD, Kurian S, Patnaik A, Rosing H, Beijnen JH, Voest EE, Burris H, Schellens JH. Bioequivalence study of a new oral topotecan formulation, relative to the current topotecan formulation, in patients with advanced solid tumors. Int J Clin Pharmacol Ther. 2009 Mar;47(3):195-206.
Objective: The aims of this Study were to investigate the bioequivalence of a new oral topotecan formulation (i.e., proposed commercial formulation) relative to the Current oral formulation (formulation used in previous clinical trials), the effect of food oil the absorption and disposition of the new oral topotecan and its safety and tolerability in patients with advanced solid tumors. Patients and methods: This was a multi-center, pharmacological Phase I, multiple-dose, randomized, open-label, cross-over bioequivalence study. In the bioequivalence part, 85 patients were randomized to receive either a 4 mg (4 x 1 mg) dose of the new or current formulation on Days 1 or 8. In the food-effect part, 23 patients received a 4 mg (4 x 1 mg) dose of the new formulation in a fasted and fed state. Total topotecan and topotecan lactone were determined and pharmacokinetic data were analyzed by non-compartmental method. Results: Bioequivalence was demonstrated as the 90% confidence intervals of the ratio of the new to Current formulation for both the area under the plasma concentration-time Curve (AUC) and the maximal drug concentration (C-max) for topotecan lactone were contained within the 0.8 - 1.25 boundary. The AUC and C-max were similar in the fed and fasted state whilst food delayed the t(max) for topotecan lactone and total topotecan. Safety data were collected Oil all Subjects enrolled (n = 108) and were consistent with observations from previous Studies of oral topotecan. All subjects experienced at least one adverse event, the majority of which were graded as mild to moderate in severity. Conclusion: The new oral topotecan formulation demonstrated bioequivalence to the current formulation and demonstrated it call be administered to patients with solid tumors in the fed or fasted state with similar systemic exposure.
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Cohen
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Borghaei H, Alpaugh K, Hedlund G, Forsberg G, Langer C, Rogatko A, Hawkins R, Dueland S, Lassen U, Cohen RB. Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2009 Sep;27(25):4116-23.
Purpose Two phase I studies were conducted of ABR-217620 alone or in combination with docetaxel. This is a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to fragment antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T4. Patients and Methods Patients with non-small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose escalation monotherapy [MONO] study). Doses were selected based on individual patient anti-SEA/E-120 titers pretreatment. Patients with NSCLC received 4 daily, escalating doses of ABR-217620 followed by docetaxel in 21-day cycles (ABR-217620 dose escalation combination with docetaxel [COMBO] study). Results Thirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 mu g/kg (NSCLC and PC) and 15 mu g/kg (RCC). Dose-limiting toxicities (DLTs) in the MONO study were fever, hypotension, acute liver toxicity, and vascular leak syndrome. In the COMBO study, the MTD was 22 mu g/kg (neutropenic sepsis). Adverse events included grade 1 to 2 fever, hypotension, nausea, and chills. Treatment caused a systemic increase of inflammatory cytokines and selective expansion of SEA/E-120 reactive T-cells. Tumor biopsies demonstrated T-cell infiltration after therapy. Fourteen patients (36%) had stable disease (SD) on day 56 of the MONO study. Two patients (15%) in the COMBO study had partial responses, one in a patient with progressive disease on prior docetaxel, and five patients (38%) had SD on day 56. Conclusion ABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.
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Cohen
Borghaei
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Leong S, Cohen RB, Gustafson DL, Langer CJ, Camidge DR, Padavic K, Gore L, Smith M, Chow LQ, von Mehren M, O'Bryant C, Hariharan S, Diab S, Fox NL, Miceli R, Eckhardt SG. Mapatumumab, an Antibody Targeting TRAIL-R1, in Combination With Paclitaxel and Carboplatin in Patients With Advanced Solid Malignancies: Results of a Phase I and Pharmacokinetic Study. J Clin Oncol. 2009 Sep;27(26):4413-21.
Purpose A phase I study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor effect of mapatumumab, a fully-human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1, DR4), in combination with paclitaxel and carboplatin. Patients and Methods Patients with advanced solid malignancies received 3, 10, or 20 mg/kg of mapatumumab with standard doses of paclitaxel and carboplatin every 21 days for up to six cycles in the absence of disease progression. Additional cycles of paclitaxel and/or mapatumumab were permissible in selected cases. Results Twenty-seven patients (21 males), with a median age of 54 years, received mapatumumab in the following three cohorts: 3 mg/kg (n = 4), 10 mg/kg (n = 11), and 20 mg/kg (n = 12). The median number of cycles was four. Dose-limiting toxicities (DLTs) were grade 3 hypersensitivity reaction (n = 1) and neutropenic fever (n = 1), both at 10 mg/kg. Non-DLT treatment-related adverse events occurring in more than 10% of administered doses included alopecia, neutropenia, fatigue, nausea, anemia, thrombocytopenia, anorexia, and neuropathy. Paclitaxel and carboplatin exposures were similar in the presence or absence of mapatumumab. Plasma mapatumumab concentrations seemed similar to data from previous phase I monotherapy studies. Five patients (19%) achieved a confirmed radiologic partial response (including one pathologic complete response), and 12 patients (44%) had stable disease as their best response. Conclusion Mapatumumab is well-tolerated up to 20 mg/kg in combination with paclitaxel and carboplatin. There are no apparent pharmacokinetic interactions among the drugs. Preliminary anticancer activity demonstrated clinical benefit for the majority of these patients.
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Cohen
Smith
von Mehren
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Cohen
Borghaei
Simon
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Kozloff MF, Martin LP, Krzakowski M, Samuel TA, Rado TA, Arriola E, Carpeno JD, Tarazi J, Rosbrook B, Tortorici M, Olszanski AJ, Cohen RB. Axitinib (AG-013736) combined with paclitaxel/carboplatin (Pac/Car), gemcitabine/cisplatin (Gem/Cis), or pemetrexed (Pem)/Cis in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumors. Journal of Thoracic Oncology. 2009 Sep;4(9):S415-S415.
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Cohen
Martin
Olszanski
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Cohen SJ, Cohen RB, Meropol NJ. Targeting signal transduction with antibodies. In: DeVita VT, Lawrence TS, Rosenberg SA, editors. DeVita, Hellman, and Rosenberg's cancer : principles & practice of oncology. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2008. p. 469-76.
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Cohen
Meropol
Cohen
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Cohen
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Infante J, Dees EC, Cohen RB, Burris H, O'Neil B, Murphy P, Lee Y, Pappas J, Ecsedy JA, Eton O. Phase 1 study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MLN8237, a selective Aurora A kinase inhibitor, in the United States. 2008;:90-1.
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Cohen
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Cohen
Lally
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Lee Y, Eton O, Pappas J, Chen S, Paton M, Dees EC, Jones S, Cohen RB, Cervantes A, Tabernero J. Dosing strategies for MLN8054, a selective Aurora A kinase inhibitor, based on pharmacokinetic modeling and simulations. 2008;:130-1.
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Cohen
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Lewis N, Cohen RB, Nishida Y, Hurwitz HI, Arrowwood C, Uronis HE, Gamza F, Longley C, Buchbinder A, Figueroa J. Phase I, pharmacokinetic (PK), dose-escalation study of EZN-2968, a novel hypoxia-inducible factor-1 alpha (HIF-1a) antagonist, administered weekly in patients (pts) with solid tumours. EJC Supplements. 2008;6(12):125.
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Cohen
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Cohen
Martin
Olszanski
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Mehra R, Cohen RB. New Agents in the Treatment for Malignancies of the Salivary and Thyroid Glands. Hematology-Oncology Clinics of North America. 2008 Dec;22(6):1279-95.
The treatment of relatively rare malignancies, such as those of the salivary glands and iodine refractory thyroid cancer, has been invigorated by the development of novel molecular targeting agents. Accrual to clinical trials for these disease sites continues to be limited by their relatively low incidence. Nonetheless, multicenter collaborations have contributed greatly to the development of a number of emerging systemic therapies. This article briefly summarizes the epidemiology and pathogenesis of salivary gland and thyroid cancer, and then describes some of the new drugs under evaluation for these malignancies.
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Cohen
Mehra
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von Mehren M, Schilder RJ, Cheng JD, Temmer E, Cardoso TM, Renshaw FG, Bayever E, Zannikos P, Yuan Z, Cohen RB. A phase I study of the safety and pharmacokinetics of trabectedin in combination with pegylated liposomal doxorubicin in patients with advanced malignancies. Ann Oncol. 2008 Oct;19(10):1802-9.
BACKGROUND: To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies. PATIENTS AND METHODS: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m(2), and normal cardiac function. A 1-h PLD (30 mg/m(2)) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m(2)) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles. RESULTS: The MTD of trabectedin was 1.1 mg/m(2). Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent. CONCLUSION: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
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Schilder
Cohen
von Mehren
Cheng
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Mehra R, Cohen RB. New agents in the treatment for malignancies of the salivary and thyroid glands. Hematol Oncol Clin North Am. 2008 Dec;22(6):1279-95, xi.
The treatment of relatively rare malignancies, such as those of the salivary glands and iodine refractory thyroid cancer, has been invigorated by the development of novel molecular targeting agents. Accrual to clinical trials for these disease sites continues to be limited by their relatively low incidence. Nonetheless, multicenter collaborations have contributed greatly to the development of a number of emerging systemic therapies. This article briefly summarizes the epidemiology and pathogenesis of salivary gland and thyroid cancer, and then describes some of the new drugs under evaluation for these malignancies.
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Cohen
Mehra
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Cohen
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Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: Results from a phase II study. J Clin Oncol. 2008 Oct;26(29):4708-13.
Purpose Patients with advanced, incurable thyroid cancer not amenable to surgery or radioactive iodine (I-131) therapy have few satisfactory therapeutic options. This multi-institutional study assessed the activity and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 in patients with advanced thyroid cancer. Patients and Methods Patients with thyroid cancer of any histology that was resistant or not appropriate for I-131 were enrolled onto a single-arm phase II trial to receive axitinib orally (starting dose, 5 mg twice daily). Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors was the primary end point. Secondary end points included duration of response, progression-free survival (PFS), overall survival, safety, and modulation of soluble (s) VEGFR. Results Sixty patients were enrolled. Partial responses were observed in 18 patients, yielding an ORR of 30% (95% CI, 18.9 to 43.2). Stable disease lasting >= 16 weeks was reported in another 23 patients (38%). Objective responses were noted in all histologic subtypes. Median PFS was 18.1 months (95% CI, 12.1 to not estimable). Axitinib was generally well tolerated, with the most common grade >= 3 treatment-related adverse event being hypertension (n = 7; 12%). Eight patients (13%) discontinued treatment because of adverse events. Axitinib selectively decreased sVEGFR-2 and sVEGFR-3 plasma concentrations versus sKIT, demonstrating its targeting of VEGFR. Conclusion Axitinib is a selective inhibitor of VEGFR with compelling antitumor activity in all histologic subtypes of advanced thyroid cancer.
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Cohen
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Cohen
Anderson
Freedman
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Mehra R, Cohen RB, Burtness BA. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol. 2008 Oct;6(10):742-50.
Squamous cell carcinoma of the head and neck (HNSCC), while curable in many cases with surgery, radiation, and chemotherapy, remains a disease that is associated with significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated beneficial effects in this disease. The Food and Drug Administration approved cetuximab-a monoclonal antibody-in conjunction with radiation, for locally advanced, potentially curable disease, and also as a single agent for incurable recurrent/metastatic disease. In addition, there are more recent data showing a survival benefit for patients with recurrent/metastatic disease who were treated with a first-line regimen of platinum, fluorouracil and cetuximab. These promising results have had a significant impact on the standard of care for HNSCC, and have prompted further research on the role of EGFR inhibitors in the treatment of HNSCC. In the following review, we will discuss the history, mechanism, and clinical trials that pertain to the role of cetuximab in the treatment of HNSCC.
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Cohen
Burtness
Mehra
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Cohen
Anderson
Freedman
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Cohen
Astsaturov
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von Mehren M, Schilder RJ, Cheng JD, Temmer E, Cardoso TM, Renshaw FG, Bayever E, Zannikos P, Yuan Z, Cohen RB. A phase I study of the safety and pharmacokinetics of trabectedin in combination with pegylated liposomal doxorubicin in patients with advanced malignancies. Ann Oncol. 2008 Oct;19(10):1802-9.
BACKGROUND: To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies. PATIENTS AND METHODS: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m(2), and normal cardiac function. A 1-h PLD (30 mg/m(2)) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m(2)) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles. RESULTS: The MTD of trabectedin was 1.1 mg/m(2). Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent. CONCLUSION: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
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Schilder
Cohen
von Mehren
Cheng
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Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, Maloney L, Gordon G, Simmons H, Marlow A, Litwiler K, Brown S, Poch G, Kane K, Haney J, Eckhardt SG. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008 May;26(13):2139-46.
Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogenactivated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type ( melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD ( 100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation ( geometric mean, 79%). Five of 20 patients demonstrated >= 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for >= 5 months, including two patients with SD for 19 ( thyroid cancer) and 22 ( uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.
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Cohen
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Mehra R, Cohen RB, Harari P. Targeted therapies in head and neck cancer. In: Small W, editor. Combining targeted biological agents with radiotherapy : current status and future directions. New York: Demos Medical Pub.; 2008. p. 107-38.
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Cohen
Mehra
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Borghaei H, Langer CJ, Millenson M, Ruth KJ, Litwin S, Tuttle H, Seldomridge JS, Rovito M, Mintzer D, Cohen R, Treat J. Phase II study of paclitaxel, carboplatin, and cetuximab as first line treatment, for patients with advanced non-small cell lung cancer (NSCLC): results of OPN-017. J Thorac Oncol. 2008 Nov;3(11):1286-92.
BACKGROUND: Cetuximab has demonstrated synergy with taxanes in preclinical models; as well as single agent activity. We assessed the activity of cetuximab with carboplatin and paclitaxel given on a 4-week schedule, in advanced, chemo-naive non-small cell lung cancer. PATIENTS AND METHODS: This phase II, single arm, multi-institution study featured standard dosage of cetuximab 400 mg/m day 1, then 250 mg/m with paclitaxel (100 mg/m/wk, for 3 weeks), and carboplatin (area under curve = 6) day 1 of each 28 day cycle. After 4 to 6 cycles, in the absence of disease progression or excess toxicity, cetuximab was continued weekly. Primary end point was response rate. RESULTS: Fifty-three patients (median age 63, 51% male) participated. Response rate was 57% (3 complete response and 27 partial response). At a median follow-up of 12.5 months, the estimated overall survival is 13.8 months (95% CI: 9.08-16.02) with an event-free survival rate of 5.53 months (95% CI: 4.77-7.99), 18.9% remain free from progression at 1 year. Improved survival was associated with female gender, absence of prior radiation, PS 0 and epidermal growth factor receptor expression. Toxicities included rash (28% grade 3), nail changes (3.7% grade 3), hypomagnesemia (7.5% grade 3 and 3.7% grade 4), and neutropenia (25% grade 3 and 13% grade 4) in addition to other typical side effects anticipated with paclitaxel/carboplatin. There were no grade 5 toxicities. CONCLUSION: Combination of cetuximab/paclitaxel/carboplatin in non-small cell lung cancer was well tolerated and clinically active with manageable toxicities. This unique schedule, integrating weekly paclitaxel and cetuximab has not yet been tested in a randomized trial.
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Cohen
Litwin
Borghaei
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Dees E, Infante JR, Cohen RB, O'Neil B, Burris H, von Mehren M, Gray G, Galvin K, Manfredi M, Eton O. Phase I and pharmacokinetic study of MLN8054, a selective inhibitor of Aurora A kinase. 2008;:91.
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Cohen
von Mehren
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