Oxaliplatin plus continuous infusion topotecan: First stage of an ongoing phase II study for recurrent ovarian cancer: A New York Cancer Consortium study (#N01-CM62204)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5556-5556
Author(s):  
N. LaNatra ◽  
H. Hochster ◽  
F. Muggia ◽  
S. V. Blank ◽  
J. Curtin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
New York ◽  
Phase I ◽  
Continuous Infusion ◽  
Stable Disease ◽  
Response Duration ◽  
Recurrent Ovarian Cancer ◽  
Good Tolerability ◽  
Median Response ◽  
Grade 3

5556 Background: Topoisomerase-1 inhibitors and platinums are active in ovarian cancer. Our prior series described infusional topotecan as less myelosuppressive than bolus and more easily combined with oxaliplatin than cisplatin. An NYU phase I study of the combination in previously treated ovarian cancer patients (pts) showed promising activity and good tolerability (Hochster H, Gynecol Oncol 2008). Methods: Ovarian cancer pts treated with 1–2 prior regimens (1 platinum/taxane regimen, no topotecan) were treated with oxaliplatin 85 mg/m2 day 1, 15 and topotecan (0.4 mg/m2/day) continuous infusion x 14 days every 4 weeks (wks). Platinum resistant (stratum I = 10) and sensitive (stratum II = 17) pts are included in this two-stage trial (n = 52) to evaluate overall response rate (ORR) and toxicities. Results: From January 2006 to November 2008, 27 pts entered. Median age was 61 (37–79). Fifteen pts had 1 prior regimen and 12 pts had 2. Five pts discontinued before 2 cycles (3 for predefined toxicity, 2 by pt/physician choice). 102 cycles of chemotherapy were given (median 4, [1–6]). Grade 3/4 toxicities included thrombocytopenia (37% grade 3, 19% grade 4), neutropenia (37% grade 3, 11% grade 4), anemia (15% grade 3), neuropathy (7% grade 3), diarrhea (4% grade 3), transaminitis (4% grade 3), and fatigue (7% grade 3). Twenty-one pts had day 15 oxaliplatin held, 10 pts required dose reductions, and 21 pts had treatment delays mainly from thrombocytopenia. No pts had neutropenic fever. Twenty-one pts are now evaluable. Stratum I had 1 complete and no partial responses, 5 pts with stable disease and 2 with progressive disease. Stratum II had 3 complete and 6 partial responses, 4 pts with stable disease and none progressed. Median response duration is 41 wks (17–62); median duration of stable disease is 17 wks (4–70). Conclusions: Excluding thrombocytopenia, tolerance to this regimen confirms phase I results. In pts with creatinine clearances (CrCl) < 60 ml/min, the incidence of grade 3/4 thrombocytopenia was 75% versus 35 % for pts with CrCl > 60 ml/min. Pts with CrCl of 40–60 ml/min will now start topotecan 0.3 mg/m2/day x 14 days. Reaching our predefined ORR of at least 30% for stratum II and 20% for stratum I, the second stage of accrual has begun. [Table: see text]

Topotecan Has Substantial Antitumor Activity as First-Line Salvage Therapy in Platinum-Sensitive Epithelial Ovarian Carcinoma: A Gynecologic Oncology Group Study

2000 ◽  
Vol 18 (5) ◽  
pp. 1062-1062 ◽  
Author(s):  
William P. McGuire ◽  
John A. Blessing ◽  
Michael A. Bookman ◽  
Samuel S. Lentz ◽  
Charles J. Dunton
Keyword(s):  
Ovarian Cancer ◽  
Active Drug ◽  
Response Rate ◽  
Gynecologic Oncology ◽  
Response Duration ◽  
Recurrent Ovarian Cancer ◽  
Hematologic Toxicity ◽  
Gynecologic Oncology Group ◽  
Median Response ◽  
Platinum Sensitive

PURPOSE: Topotecan is known to be active in recurrent ovarian cancer, but most prior studies have focused on platinum-resistant or refractory populations. This study was undertaken to define the response rate and progression-free interval in platinum-sensitive patients. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after one or two prior chemotherapy regimens and in whom the interval between prior platinum therapy and the initiation of protocol therapy was greater than 6 months were treated with topotecan 1.5 mg/m2 intravenously over 30 minutes daily for 5 days, with this cycle repeated every 21 days. RESULTS: Forty-eight patients were entered onto the study; 47 were assessable for toxicity and 46 for response. The response rate was 33% (two complete responses and 13 partial responses), with a median response duration of 11.2 months. Hematologic toxicity predominated but was manageable in most patients with frequent incorporation of cytokines and RBC and platelet transfusions. Fatigue was reported in 15 patients and resulted in the discontinuation of therapy in five responding patients. CONCLUSION: Topotecan is an active drug in platinum-sensitive ovarian cancer, with significant but manageable hematologic toxicity. Fatigue is also a common problem that may be dose-limiting in some patients.

Gemcitabine and Vinorelbine Combination in Platinum-Sensitive Recurrent Ovarian Cancer

2009 ◽  
Vol 19 (9) ◽  
pp. 1529-1534 ◽  
Author(s):  
Annamaria Ferrero ◽  
Vilma Logrippo ◽  
Pier Giorgio Spanu ◽  
Luca Fuso ◽  
Stefania Perotto ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Response Rate ◽  
Response Duration ◽  
Recurrent Ovarian Cancer ◽  
Ca 125 ◽  
Cancer Antigen 125 ◽  
Median Response ◽  
Platinum Sensitive ◽  
Free Interval ◽  
Platinum Based Chemotherapy

Objectives:Most patients with ovarian cancer are candidates for second-line or salvage treatments often for prolonged periods. Patients with platinum-sensitive disease can benefit from a platinum retreatment with a likelihood of response dependents on the treatment-free interval. Alternative agents and combination chemotherapy are potential therapeutic approaches. At our institution, we carried out a phase II trial to evaluate feasibility, efficacy, and toxicity of gemcitabine and vinorelbine combination in recurrent ovarian carcinoma. The aim of the present study was to evaluate the role of this combination in patients with platinum-sensitive disease.Patients and Methods:Patients with platinum-sensitive disease recurring after 1 or more lines of platinum-based chemotherapy were included. Vinorelbine at 25 mg/m2followed by gemcitabine at 1000 mg/m2was administered intravenously on days 1 and 8 every 3 weeks. Response Evaluation Criteria in Solid Tumors and cancer antigen 125 test (CA-125 Kinetics [Rustin criteria]) were adopted to classify responses. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria.Results:Thirty-nine patients were eligible. Platinum-free interval (PFI) was 6 to 12 months in 13 patients (33.3%; PFI 6-12) and more than 12 months in 26 patients (66.7%; PFI > 12). The overall response rate was 48.7%, with 6 complete responses. Median response duration was 38 weeks. The response rate was 23% in PFI 6-12 and 62% in PFI >12. The most frequently observed toxicity was hematological, with 23% of the patients having grade 3 or 4 neutropenia.Conclusions:Gemcitabine and vinorelbine combination is effective and well tolerated in recurrent platinum-sensitive ovarian cancer. It may represent an option in the management of these patients because the chronic nature of the disease.

A phase I trial of the proteosome inhibitor PS-341 in combination with carboplatin in platinum and taxane resistant ovarian cancer patinets

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5558-5558
Author(s):  
C. N. Landen ◽  
R. Coleman ◽  
M. R. Milam ◽  
T. Johnston ◽  
R. Iyer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Stable Disease ◽  
Performance Status ◽  
Single Agent ◽  
Optimal Dose ◽  
Recurrent Ovarian Cancer ◽  
Cytotoxic Agents ◽  
Pharmacokinetic Data ◽  
Resistant Disease

5558 Background. PS-341 (Millenium Pharmaceuticals, Inc.), a proteosome inhibitor, affects p53, NFκB, cell adhesion molecules, and sensitivity to cytotoxic agents to promote apoptosis and inhibit metastasis in cancer cells. PS-341 alone rarely causes myelosupression or renal toxicity, and therefore is an attractive agent to use in combination with cytotoxic chemotherapy. This phase I study evaluates the safety, dose-limiting toxicities (DLTs), and optimal dose of PS-341 when combined with carboplatin in ovarian cancer patients with recurrent, platinum- and taxane-resistant disease. Methods: After IRB approval, patients with recurrent ovarian cancer, platinum and taxane resistant (progression on platinum and/or taxane therapy or recurrence within 6 months of completing platinum and/or taxane therapy), measurable disease, and performance status 0–2 were eligible and enrolled after giving informed consent. As guided by toxicity and pharmacokinetic data from single-agent phase I trials, PS-341 was administered on days 1, 4, 8, and 11 by IV push every 28 days with carboplatin (AUC 5) on day 1. Four dose levels were evaluated: 0.8, 1.0, 1.3, and 1.5 mg/m2. Dose was escalated if 0 of 3 or 1 of 6 patients had a DLT. The MTD was defined as 2 or more patients out of 6 with a DLT. Results: 21 women (median age 63, range 43–83), were treated with carboplatin and PS-341 at 0.8mg/ m2 (n=6), 1.0 mg/m2 (n=3), 1.3 mg/m2 (n=6), or 1.5 mg/m2. (n=6). At each level, respectively, there were 1, 0, 1, and 3 DLT’s attributable to PS- 341; all were grade 3, consisting of fatigue (n=3), nausea/vomiting/dehydration (n=1), and anorexia/dehydration/syncope (n=1). There were no Grade 4 toxicities. Common grade 2 toxicities included fatigue (n=12), nausea (n=10), anorexia, anemia, and dyspnea (n=7 each). 18 patients evaluable for response had stable disease (SD) or progression of disease (PD): at 0.8 mg/m2, SD=2, PD=3; at 1.0 mg/m2, PD=3; at 1.3 mg/m2, SD=3, PD=3; at 1.5 mg/m2, SD=3, PD=1. Median duration of stable disease was 4 months (range 3–10). Conclusions: The recommended dose of PS-341 in combination is 1.3 mg/m2. Treatment was well-tolerated with reversible side effects and no grade 4 toxicities, and at the optimal dose, there was a 50% rate of stable disease. No significant financial relationships to disclose.

A pharmacodynamic study of JI-101, an orally active inhibitor of VEGF-2, PDGF-β, and EphB4 receptors, in patients with refractory/recurrent ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13548-e13548
Author(s):  
Theresa Louise Werner ◽  
Aaron Lynn Luebke ◽  
Mark Wade ◽  
Nuggehally R Srinivas ◽  
Dhiraj J. Abhyankar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mechanism Of Action ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Active Inhibitor ◽  
Common Grade ◽  
Grade 3

e13548 Background: JI-101 is an oral multi-kinase inhibitor, which targets VEGFR-2, PDGF-β, and EphB4. By targeting multiple angiogenesis signaling pathways, JI-101 has the potential advantage of inhibiting all vital stages of tumor angiogenesis, reducing tumor resistance, and enhancing anti-tumor efficacy. None of the currently approved angiogenesis inhibitors have any appreciable inhibition of EphB4, and therefore, this represents a novel mechanism of action. JI-101 has preclinical activity in various tumor models and has been well tolerated in phase 1 trials. Methods: Eleven women with refractory/recurrent ovarian cancer were enrolled with a median age of 54 yrs (range 52-76). All patients had adequate organ function and ECOG performance status ≤ 2. Each patient received single agent JI-101 at 200mg BID for 28 day treatment cycles. Toxicity and response were evaluated at two month intervals. Results: Eight of 11 patients were evaluable for response (3 were unevaluable due to inability to complete two cycles). A median of 3 cycles (range 2-6) was given. No grade 4 adverse events (AEs) were seen. The most common grade 2/3 hematological AEs were grade 2 anemia (1) and lymphopenia (1). The most common grade 2/3 non-hematological AEs were grade 3 hypertension (7), grade 3 bowel obstruction (2), grade 3 transaminitis (2), and abdominal pain (2). Six patients had stable disease (SD) at two months and two had progressive disease. Best response was SD at four months. Two-month progression free survival was 71% (90% CI 52-99%). Conclusions: JI-101 is well tolerated in refractory/recurrent ovarian cancer patients with the majority of patients with stable disease at two months. The most common toxicity was hypertension, which was easily controlled with anti-hypertensives. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent could be pursued in a less refractory patient population.

First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant or refractory ovarian cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 1-1
Author(s):  
Christopher Browning Cole ◽  
Christina M. Annunziata
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Interferon Gamma ◽  
Phase I Study ◽  
Immune Cell ◽  
Human Study ◽  
Good Tolerability ◽  
Platinum Resistant ◽  
Grade 3 ◽  
Peginterferon Alfa

1 Background: This phase I study evaluated the safety and tolerability of autologous intraperitoneal monocytes treated with SYLATRON (Peginterferon alfa-2b) and ACTIMMUNE (Interferon gamma-1b). Methods: For the dose escalation portion, 3-6 patients with platinum-resistant or refractory ovarian cancer were enrolled into 4 cohorts and treated intraperitoneally (IP) with Peginterferon alfa-2b (25-250 mcg) and Interferon gamma-1b (5-50 mcg), with or without autologous monocytes (75-750 x 106 cells), in order to determine the recommended phase II dose (RP2D). A total of six patients were treated at the RP2D. Patients received the combination of interferons+/- monocytes via IP catheter once every 28 days. Results: 18 patients were enrolled (median age, 61 years; median 5 prior therapies). 1 of 3 patients at the second dose level experienced a dose-limiting toxicity (DLT, grade 3 anemia) and so this cohort was expanded to 6 patients; no subsequent DLTs were observed. The RP2D was defined as 250 mcg/50/mcg/750 x 106 cells on the basis of overall safety and tolerability. The only treatment–related grade 3 or higher adverse events occurring in more than one patient were lymphocyte decrease (33.3%) and abdominal pain (11.1%). Preliminary assessment of efficacy is ongoing. The best response observed has been partial response (PR) in 2/11 evaluable patients, with one patient having a 61% reduction in target lesion size. An additional 4/11 patients had stable disease, and 3 patients remained on treatment for >6 cycles. Exploratory biomarker analyses are ongoing to to further elucidate changes in the immune cell population and correlate with response. An expansion cohort of 10 patients at the RP2D is currently enrolling. Conclusions: This is the first-in-human study of the combination of IP peginterferon alfa-2b, interferon gamma-1b, and autologous monocytes, and the combination displays good tolerability and antitumor activity in a heavily pretreated population, supporting further investigation. Clinical trial information: NCT02948426.

The use of continuous infusion topotecan in persistent and recurrent ovarian cancer

2003 ◽  
Vol 13 (2) ◽  
pp. 138-141 ◽  
Author(s):  
J. C. Elkas ◽  
C. H. Holschneider ◽  
B. Katz ◽  
A. J. Li ◽  
R. Louie ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Los Angeles ◽  
Continuous Infusion ◽  
Medical Center ◽  
Recurrent Ovarian Cancer ◽  
Response To Treatment ◽  
Hematologic Toxicity ◽  
Severe Toxicity ◽  
Platinum Refractory ◽  
Grade 3

We retrospectively review our experience with continuous infusion topotecan for the treatment of persistent or recurrent ovarian cancer in this paper. Nine patients were identified who were treated at the University of California Los Angeles Medical Center between January 1997 and December 1999 using a 14–21 day continuous infusion schedule (0.3–0.7 mg/m2/d). Dose adjustments were performed for grade 3–4 toxicities and treatment was discontinued for persistent severe toxicity or progressive disease. Response to treatment was analyzed and stratified by platinum refractory, resistant, and sensitive disease. A total of 41 treatment cycles were given to nine patients with a median of five per patient (range 1–11). Median follow-up was 8 months. There were two partial responses (22%) and four patients had stable disease (44%), which included two patients with platinum-refractory tumors. No grade 3 or 4 hematologic toxicities were observed. However, two patients suffered grade 3 gastrointestinal toxicity during the first cycle leading to discontinuation of topotecan administration. There was no cumulative toxicity. Topotecan administered by continuous infusion demonstrated response rates comparable to other dosing schedules with minimal hematologic toxicity. Treatment of patients with persistent or recurrent ovarian cancer with continuous infusion topotecan warrants further investigation.

A multi-institutional evaluation of the safety and efficacy of bevacizumab for recurrent, platinum-resistant ovarian cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5019-5019 ◽  
Author(s):  
J. D. Wright ◽  
A. Alvarezsecord ◽  
T. M. Numnum ◽  
R. P. Rocconi ◽  
M. A. Powell ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stable Disease ◽  
Bowel Perforation ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Significant Activity ◽  
Recent Trial ◽  
Platinum Resistant ◽  
Heavily Pretreated ◽  
Grade 3

5019 Background: Bevacizumab has shown activity in recurrent ovarian cancer with an acceptable adverse event profile. However, the incidence of bowel perforation in a recent trial of heavily pretreated ovarian cancer patients was higher than expected from prior experience with bevacizumab. Whether the difference in the rate of bowel perforation was due to refractory disease, treatment history, disease burden, or location of tumor is uncertain. We sought to review our multi-institutional experience with bevacizumab in patients with recurrent ovarian cancer. Methods: A retrospective review of patients with recurrent ovarian cancer treated with single agent or combination bevacizumab therapy was undertaken. Toxicity was assessed using standard criteria. Response was determined radiographically and through serial CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. Results: Sixty-two eligible patients were identified. All had failed prior platinum-based therapy and had received a median of 5 prior chemotherapy regimens and 2 prior platinum-containing regimens. Single agent bevacizumab was administered to 12 (19%) women, while 50 (81%) received the drug in combination with a cytotoxic agent. The most common toxicities were myelosuppression (60%), proteinuria (19%) and hypertension (16%). Grade 3–5 toxicities occurred in 15 (24%) patients, including grade 3–4 hypertension in 4 (7%). Gastrointestinal perforations were identified in 4 (7%) subjects. Nine (15%) patients discontinued therapy due to toxicity. Fifty-eight patients were assessable for response. The overall response rate was 36% (4 CR, 17 PR) with stable disease in 40%. Clinical benefit (CR, PR, stable disease) was seen in 83% of patients treated with single agent therapy and 74% of those treated with bevacizumab-combination regimens. Conclusions: Bevacizumab demonstrates significant activity for recurrent, platinum-resistant ovarian cancer. Life threatening bowel perforations were noted in 7% of our subjects. The frequency of perforations in our cohort suggests that this complication is more likely to occur in heavily pretreated patients. No significant financial relationships to disclose.

Phase I Trial of Intraperitoneal Injection of the E1B-55-kd-Gene–Deleted Adenovirus ONYX-015 (dl1520) Given on Days 1 Through 5 Every 3 Weeks in Patients With Recurrent/Refractory Epithelial Ovarian Cancer

2002 ◽  
Vol 20 (6) ◽  
pp. 1562-1569 ◽  
Author(s):  
P. A. Vasey ◽  
L. N. Shulman ◽  
S. Campos ◽  
J. Davis ◽  
M. Gore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Abdominal Pain ◽  
Phase I ◽  
Neutralizing Antibodies ◽  
Phase I Trial ◽  
P53 Gene ◽  
Recurrent Ovarian Cancer ◽  
Maximum Tolerated Dose ◽  
Clear Cut ◽  
Grade 3

PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 × 109 plaque forming units (pfu), 1 × 1010 pfu, 3 × 1010 pfu, and 1 × 1011 pfu. RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 × 1010 pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 1011 pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.

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