Arizona City, AZ, United States
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Rini B.I.,Cleveland Clinic | Stein M.,Cancer Institute of New Jersey | Shannon P.,Premiere Oncology of Arizona | Eddy S.,Cancer Institute of New Jersey | And 5 more authors.
Cancer | Year: 2011

BACKGROUND: On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. METHODS: Adult patients with mRCC who had received ≤1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. RESULTS: Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. CONCLUSIONS: In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses >6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity.© 2010 American Cancer Society.


Camidge D.R.,University of Colorado at Denver | Herbst R.S.,University of Texas M. D. Anderson Cancer Center | Gordon M.S.,Premiere Oncology of Arizona | Eckhardt S.G.,University of Colorado at Denver | And 8 more authors.
Clinical Cancer Research | Year: 2010

Purpose: PRO95780 is a fully human IgG1 monoclonal antibody that triggers the extrinsic apoptosis pathway through death receptor 5. This first-in-human study assessed the safety, tolerability, pharmacokinetics, and any early evidence of efficacy of PRO95780 in patients with advanced malignancies. Experimental Design: Target concentrations were predicted to occur at 10 mg/kg. Patients received up to eight cycles of PRO95780 i.v. using a 3+3 dose escalation design at 1 to 20 mg/kg every 14 days (every 28 days in cycle 1; stage 1), with cohort expansion at either the maximum tolerated dose or 10 mg/kg, whichever was lower (stage 2). Patients were evaluated for response every other cycle. Results: The maximum tolerated dose was not reached within this study. Four (8%) of 50 patients reported adverse events of greater than grade 2 at least possibly related to PRO95780, including 2 patients with reversible grade 3 transaminase elevation. The mean terminal half-life was 8.8 to 19.3 days, with dose-dependent increases in exposure (peak plasma concentration and area under the concentration) across 1 to 15 mg/kg. Most patients treated with 10 mg/kg or above achieved trough concentration above the target efficacious concentration at day 15 with moderate accumulation after multiple doses. No objective responses occurred, although three minor responses were observed in patients with colorectal and granulosa cell ovarian cancers (each treated with 4 mg/kg) and chondrosarcoma (10 mg/kg). Conclusions: PRO95780 is safe and well tolerated at doses up to 20 mg/kg. Evidence of activity was noted in several different tumor types at 4 and 10 mg/kg. Pharmacokinetic analysis supports a dosing regimen of 10 to 15 mg/kg every 2 to 3 weeks. ©2010 AACR.


Hersh E.M.,Arizona Cancer Center | O'Day S.J.,Melanoma Program | Ribas A.,University of California at Los Angeles | Samlowski W.E.,Nevada Cancer Institute | And 4 more authors.
Cancer | Year: 2010

BACKGROUND: nab-Paclitaxel (ABI-007, Abraxane), a 130-nM, albumin-bound (nab) particle form of Cremophor-free paclitaxel, is approved for metastatic breast cancer. In the current study, the efficacy and safety of nab-paclitaxel were evaluated in previously treated and chemotherapy-naive patients with metastatic melanoma (MM). METHODS: Patients with histologically or cytologically confirmed, measurable MM were enrolled. nab-Paclitaxel was administered intravenously weekly for 3 of 4 weeks at a dose of 100 mg/m2 (in previously treated patients) or 150 mg/m2 (in chemotherapy-naive patients). RESULTS: Thirty-seven patients were treated in each cohort. The response rate was 2.7% in the previously treated cohort and 21.6% in the chemotherapy-naive cohort; the response plus stable disease rate was 37.8% and 48.6% in the previously treated and chemotherapy-naive cohorts, respectively. The median progressionfree survival (PFS) was 3.5 months and 4.5 months, and the median survival was 12.1 months and 9.6 months, respectively. The probability of being alive and free of disease progression at 6 months was 27% for the previously treated cohort and 34% for the chemotherapy-naive cohort; the probability of surviving 1 year was 49% and 41%, respectively, for the previously treated and chemotherapy-naive cohorts. Approximately 78% of the previously treated patients and 49% of the chemotherapy-naive patients were treated without dose reduction. Eight (22%) chemotherapy-naive patients discontinued therapy because of toxicities. Drug-related toxicities included grade 3 to 4 (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neuropathy, alopecia, neutropenia, and fatigue. CONCLUSIONS: nab-Paclitaxel was found to be well tolerated and demonstrated activity in both previously treated and chemotherapy-naive patients with MM. The response rate, PFS, and survival compared favorably with current standard dacarbazine therapy and combination therapies for melanoma. nab-Paclitaxel therapy of MM should be investigated further in controlled clinical trials. © 2010 American Cancer Society.


Ribas A.,University of California at Los Angeles | Chesney J.A.,University of Louisville | Gordon M.S.,Premiere Oncology of Arizona | Abernethy A.P.,Duke University | And 12 more authors.
Journal of Translational Medicine | Year: 2012

Background: CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time.Methods: A phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab.Results: No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies.Conclusions: This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000). © 2012 Ribas et al.; licensee BioMed Central Ltd.


Hwang J.J.,Lombardi Cancer Center | Kuruvilla J.,Princess Margaret Hospital | Mendelson D.,Premiere Oncology of Arizona | Pishvaian M.J.,Lombardi Cancer Center | And 5 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Two phase I, single-agent studies were conducted to determine the dose and regimen of obatoclax, an antagonist of all BCL-2 antiapoptotic proteins, for evaluation in phase II trials. The two studies, GX001 and GX005, evaluated the safety and tolerability of weekly 1-hour and 3-hour infusions of obatoclax, respectively. Experimental Design: Eligible patients in both studies were adults with solid tumor or lymphoma and performance status 0-1 for whom standard therapies were not appropriate. In the GX001 study an accelerated dose titration design was initially used with subsequent cohorts of three to six patients with 40% dose increments between levels. In the GX005 study three to six patients entered at each dose level with 40% dose increments between levels. Results: Thirty-five patients were enrolled in studies GX001 (n = 8) and GX005 (n = 27). Clinically significant central nervous system (CNS) toxicity was observed using the 1-hour infusion schedule. The obatoclax maximum tolerated dose (MTD) in GX001 was 1.25 mg/m2 due to these infusional CNS events. The 3-hour infusion schedule studied in GX005 had improved tolerability, and the obatoclax MTD was 20 mg/m2. One patient in GX005 with relapsed non-Hodgkin's lymphoma achieved partial response of 2 months' duration, and one patient with relapsed non-Hodgkin's lymphoma had stable disease for 18 months. Conclusions: The 1-hour infusion schedule of obatoclax was associated with neuropsychiatric doselimiting toxicities at relatively low doses (MTD, 1.25 mg/m2). The 3-hour i.v. infusion of obatoclax administered once weekly to patients with solid tumors was better tolerated (MTD, 20 mg/m 2), and evidence of clinical activity was observed. ©2010 AACR.


Gordon M.S.,Premiere Oncology of Arizona | Sweeney C.S.,Indiana University | Mendelson D.S.,Premiere Oncology of Arizona | Eckhardt S.G.,Aurora University | And 12 more authors.
Clinical Cancer Research | Year: 2010

Purpose: The aims were to assess the safety, pharmacokinetics, maximum tolerated dose, and antitumor activity of AMG 102, a fully human hepatocyte growth factor/scatter factor (HGF/SF)-neutralizing monoclonal antibody, in patients with solid tumors. Experimental Design: Patients (N = 40) with refractory advanced solid tumors were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10, or 20 mg/kg AMG 102 i.v. every 2 weeks) and a doseexpansion cohort (20 mg/kg AMG 102 every 2 weeks). Safety, anti-AMG 102 antibody formation, pharmacokinetics, tumor response, and exploratory biomarkers were assessed. Results: AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia (5%), myalgia (5%), and hypertension (5%). Two patients experienced dose-limiting toxicities: one patient (0.5 mg/kg cohort) experienced grade 3 hypoxia and grade 3 dyspnea and one patient (1 mg/kg cohort) experienced grade 3 upper gastrointestinal hemorrhage. No anti-AMG 102 antibodies were detected, and AMG 102 had linear pharmacokinetics within the dose range investigated. Sixteen of 23 (70%) evaluable patients had a best response of stable disease with progression-free survival ranging from 7.9 to 40 weeks. Circulating levels of the biomarker HGF/SF (bound and unbound) increased in a dose-dependent manner, whereas soluble c-Met concentrations were generally similar across doses. Conclusions: AMG 102 is safe and well tolerated, has a favorable pharmacokinetic profile, and will be further investigated as a monotherapy and in combination with other agents. ©2010 AACR.


Traynor A.M.,University of Wisconsin - Madison | Gordon M.S.,Premiere Oncology of Arizona | Alberti D.,University of Wisconsin - Madison | Mendelson D.S.,Premiere Oncology of Arizona | And 4 more authors.
Investigational New Drugs | Year: 2010

Purpose: To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of MN-209, a novel vascular disrupting agent, in patients with advanced solid tumors. Study Design: MN-029 was administered weekly for three consecutive weeks out of four; two cycles were planned. Dose escalation proceeded by 100% per toxicity criteria. Intra-patient dose escalation was permitted. Results: Twenty patients received a total of 151 infusions of MN-029. No DLTs or grade 4 toxicities occurred. The most common adverse events were nausea, vomiting, arthralgias, and headache. One patient developed acute substernal chest pain 4 days after his first dose of MN-029 and was removed from the study. An MTD was not determined. The recommended phase II dose was identified as 180 mg/m2/week. One patient with advanced pancreatic cancer attained a partial response lasting 10 weeks. Conclusions: MN-029 was well tolerated in this schedule. Further development of this class of agents is warranted, especially in combination with other anticancer treatments. © Springer Science + Business Media, LLC 2009.


PubMed | Premiere Oncology of Arizona
Type: Clinical Trial, Phase I | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2010

The aims were to assess the safety, pharmacokinetics, maximum tolerated dose, and antitumor activity of AMG 102, a fully human hepatocyte growth factor/scatter factor (HGF/SF)-neutralizing monoclonal antibody, in patients with solid tumors.Patients (N = 40) with refractory advanced solid tumors were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10, or 20 mg/kg AMG 102 i.v. every 2 weeks) and a dose-expansion cohort (20 mg/kg AMG 102 every 2 weeks). Safety, anti-AMG 102 antibody formation, pharmacokinetics, tumor response, and exploratory biomarkers were assessed.AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia (5%), myalgia (5%), and hypertension (5%). Two patients experienced dose-limiting toxicities: one patient (0.5 mg/kg cohort) experienced grade 3 hypoxia and grade 3 dyspnea and one patient (1 mg/kg cohort) experienced grade 3 upper gastrointestinal hemorrhage. No anti-AMG 102 antibodies were detected, and AMG 102 had linear pharmacokinetics within the dose range investigated. Sixteen of 23 (70%) evaluable patients had a best response of stable disease with progression-free survival ranging from 7.9 to 40 weeks. Circulating levels of the biomarker HGF/SF (bound and unbound) increased in a dose-dependent manner, whereas soluble c-Met concentrations were generally similar across doses.AMG 102 is safe and well tolerated, has a favorable pharmacokinetic profile, and will be further investigated as a monotherapy and in combination with other agents.


PubMed | Premiere Oncology of Arizona
Type: Journal Article | Journal: International journal of cancer | Year: 2010

Angiogenesis is essential for the development and growth of tumors. It is a highly regulated process that requires cross-talk between signaling pathways at all stages of blood vessel development and tumor growth, from the recruitment of endothelial cells to vessel maturation. This review summarizes tumor angiogenesis and describes the key signaling pathways governing blood vessel development. The role of angiogenesis in various tumor types is discussed, but the focus is on invasive breast cancer, a disease that will affect approximately 182,000 women in the USA in 2008. Research efforts over the past decade have identified numerous potential, as well as proven therapies with activity in breast cancer. These include chemotherapeutics as well as therapies that inhibit specific angiogenic pathways known as targeted agents. Some of the data from single- and multitargeted antiangiogenic agents are described in this review. Published 2008 Wiley-Liss, Inc. This article is a US Government work, and, as such, is in the public domain in the United States of America.

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