Herbert L. Kotz

Combination Targeted Therapy With Sorafenib and Bevacizumab Results in Enhanced Toxicity and Antitumor Activity

PURPOSE Sorafenib inhibits Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab is a monoclonal antibody targeted against VEGF. We hypothesized that the complementary inhibition of VEGF signaling would have synergistic therapeutic effects. PATIENTS AND METHODS Patients had advanced solid tumors, Eastern Cooperative Oncology Group performance status of 0 to 1, and good end-organ function. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level [DL] 1) or 10 mg/kg (DL2) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD). RESULTS Thirty-nine patients were treated. DL1 was the MTD and administered in cohort 2 (N = 27). Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization >or= 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/d at a median of four cycles (range, one to 12 cycles). CONCLUSION Combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

Pilot Study of Vaccination with Recombinant CEA-MUC-1-TRICOM Poxviral-Based Vaccines in Patients with Metastatic Carcinoma

Purpose: Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1 are overexpressed in a substantial proportion of common solid carcinomas. The primary end point of this study was vaccine safety, with immunologic and clinical responses as secondary end points. Experimental Design: We report here a pilot study of 25 patients treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-1, along with a triad of costimulatory molecules (TRICOM; composed of B7.1, intercellular adhesion molecule 1, and lymphocyte function–associated antigen 3) engineered into vaccinia (PANVAC-V) as a prime vaccination and into fowlpox (PANVAC-F) as a booster vaccination. Results: The vaccine was well tolerated. Apart from injection-site reaction, no grade ≥2 toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1 and/or CEA were seen following vaccination in 9 of 16 patients tested. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of >20% in the size of large liver metastasis. Conclusions: This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted.

Phase I Clinical Trial of Oral 2-Methoxyestradiol, an Antiangiogenic and Apoptotic Agent, in Patients with Solid Tumors

Purpose: To determine the maximum-tolerated dose (MTD) and toxicity profile of the novel anticancer agent, 2-methoxyestradiol (2ME2) administered orally, in patients with solid tumors. Patients and Methods: Twenty patients with refractory solid tumors were enrolled. 2ME2 was given orally starting at 400 mg bid with dose escalation until 3000 mg bid. Tumor biopsies were taken before and after starting the drug to assess for microvessel density by CD 31 and cell proliferation by Ki67 immunohistochemistry. Serial plasma samples collected up to 50 hours after first single oral dose for characterization of pharmacokinetics, were analyzed using liquid chromatography tandem mass-spectrometry. Results: Eleven men and nine women received 2ME2 at dose levels of 400 mg bid (n=3), 800 mg bid (n=3), 1600 mg bid (n=6), 2200 mg bid (n=5) and 3000 mg bid (n=3). There were no dose limiting toxicities, therefore the MTD was not defined. There was one episode of grade 4 angioedema in the 1600 mg bid dose level 38 days into 2ME2 treatment. Other toxicities were mild to moderate. A patient with clear cell carcinoma of the ovary had a partial response at 1600 mg bid dose level lasting over 3 years. Conclusion: MTD for 2ME2 was not reached at dose of 3000 mg bid. The trial was closed due to extremely low plasma concentrations of 2ME2 relative to the doses administered. 2ME2 treatment had no effect on microvessel density (CD31 immunostaining) and cell proliferation (Ki-67 immunostaining). A new formulation of 2ME2 with improved bioavailability is currently being developed.

Vandetanib, Designed to Inhibit VEGFR2 and EGFR Signaling, Had No Clinical Activity as Monotherapy for Recurrent Ovarian Cancer and No Detectable Modulation of VEGFR2

Purpose: To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer. Experimental Design: A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma samples. Results: Twelve patients entered the study, and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and prolonged QT interval corrected for heart rate, but not hypertension. Exploratory analyses showed that epidermal growth factor receptor (EGFR) phosphorylation was reduced in the eight paired biopsy sets obtained; vascular endothelial growth factor (VEGF) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed. Conclusions: Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue, but only phosphorylated-EGFR was measurably inhibited by vandetanib. Clin Cancer Res; 16(2); 664–72

Phase II trial of carboxyamidotriazole in patients with relapsed epithelial ovarian cancer.

PURPOSE Carboxyamidotriazole (CAI) is a cytostatic inhibitor of nonvoltage-operated calcium channels and calcium channel-mediated signaling pathways. It inhibits angiogenesis, tumor growth, invasion, and metastasis. We hypothesized that CAI would promote disease stabilization lasting >/= 6 months in patients with relapsed ovarian cancer. PATIENTS AND METHODS Patients with epithelial ovarian cancer, good end-organ function, measurable disease, and three or fewer prior regimens were eligible. Oral CAI was given daily using a pharmacokinetic-dosing approach to maintain plasma concentrations between 2 and 4 microg/mL. Radiographic imaging to assess response was performed every 8 weeks. Positive outcome included stabilization or improvement of disease lasting >/= 6 months. Plasma vascular endothelial growth factor (VEGF), interleukin (IL)-8, and matrix metalloproteinase (MMP)-2 were measured. RESULTS Thirty-six patients were assessable for primary end point analysis, and 38 were assessable for toxicity. Forty-four percent of patients had three prior regimens, more than 50% had four or more disease sites, and 48% had liver metastases. Thirty-three patients reached the targeted concentration range during the first cycle. Eleven patients (31%) attained the >/= 6-month outcome end point, with one partial response (8 months) and three minor responses (8, 12+, and 13 months). Median time to progression was 3.6 months (range, 1.6 to 13.3 months). CAI was well tolerated, with mostly grade 1 to 2 toxicity. Grade 3 events included fatigue (5%), vomiting (2%), neutropenic fever (2%), and neutropenia (2%). There were no grade 4 adverse events. No associations between VEGF, IL-8, and MMP-2 with CAI concentration or clinical outcome were observed. CONCLUSION CAI is a potential agent for additional study in the stabilization of relapsed ovarian cancer. Given a limited toxicity profile, it may have utility as a maintenance therapeutic agent for this disease.

A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer: a phase II clinical study with proteomic profiling.

c‐Kit and platelet‐derived growth factor receptor (PDGFR) are potential molecular targets in epithelial ovarian cancer (EOC). Imatinib inhibits the kinase domain and subsequent downstream signaling of these receptor tyrosine kinases. The objective of this study was to investigate biochemical and biologic effects of imatinib on EOC.

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity

Background:We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing.Methods:Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1–5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg−1. DL5 alternated between bevacizumab 10 mg kg−1-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg−1 (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1–5 were analysed.Results:Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand–foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation ⩾4 months (53%; median 6 (4–26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4–37 months.Conclusion:Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.

Lack of reliability of CA125 response criteria with anti-VEGF molecularly targeted therapy

CA125 is an accepted indicator of epithelial ovarian cancer (EOC) response and is used to monitor patients treated with cytotoxic chemotherapy. It is uncertain how CA125 is affected by molecularly targeted drugs. In this pilot study, the authors analyzed the utility of CA125 to predict disease behavior in patients who were receiving sorafenib, a Raf‐kinase/VEGFR2 inhibitor, and bevacizumab, an anti‐VEGF monoclonal antibody.

A Phase I study of paclitaxel and continuous daily CAI in patients with refractory solid tumors

Background: Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active. Patients and Methods: Eligible patients with solid tumors received micronized CAI daily (150-250mg PO) and paclitaxel intravenously q3weeks (175-250mg/m2), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. Patients were assessed for toxicity, pharmacokinetics, and disease outcome. Results: Twenty-nine heavily pretreated patients (median 3 [0-7]) were enrolled on 5 dose levels. No additive or cumulative toxicity was observed, and grade 3 nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m2 q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p

Uterine Papillary Serous Carcinoma: A New Paradigm for Treatment?

The uterine corpus gives rise to cancers of several tissue types. Malignancies of the uterine epithelial lining can appear as glandular endometrioid, papillary serous, or clear cell histologies. Uterine papillary serous carcinoma (UPSC) comprises 20% of uterine cancerspecific deaths. This less-common histologic variant is characterized by its aggressive nature and shorter overall survival compared with uterine cancer of endometrioid histology. Thus, UPSC dictates a more comprehensive approach to treatment than its endometrioid counterpart, requiring complete surgical staging and adjuvant therapy, even in patients with early-stage disease. The study by Nickels Fader et al was a retrospective analysis of outcome in 142 patients with stage I UPSC who were treated with surgery followed by observation, radiotherapy, or chemotherapy radiotherapy. The authors reported better outcomes when adjuvant chemotherapy was used, but raised the question of whether radiation is necessary. The 142 cases were collected from 9 institutions, allowing for meaningful statistical comparisons to be made between the 3 postsurgical treatment options. Patients who were treated postoperatively with chemotherapy were found to have a lower risk of disease recurrence when compared with those treated with observation or radiotherapy alone. This analysis builds on previously published work describing the utility of adjuvant treatment for all patients with stage I UPSC, except those without residual uterine disease after complete surgical staging. To our knowledge, Kelly et al were the first to suggest that chemotherapy was not necessary for patients with stage I UPSC who were found to have no residual disease at the time of definitive surgery. The formal stage of a patient’s uterine carcinoma is defined surgically, based on pathologic assessment of the pelvic and para-aortic lymph nodes as well a full evaluation of the omentum. Patients at low risk of disease recurrence (ie, those who have stage I, grade 1/2 uterine carcinoma of endometrioid histology) may undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) alone, with a reported recurrence rate of only 2%. However, the presence of papillary serous histology places the patient at high risk of disease recurrence, and requires comprehensive surgical resection such as that performed for ovarian cancer, including TAH-BSO, pelvic and para-aortic lymphadenectomy, and omentectomy. The necessity