Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: a Gynecologic Oncology Group study.

1997 ◽  
Vol 15 (1) ◽  
pp. 177-186 ◽  
Author(s):  
S O'Reilly ◽  
G F Fleming ◽  
S D Barker ◽  
J R Walczak ◽  
M A Bookman ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Gynecologic Oncology ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Gynecologic Oncology Group ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Stimulating Factor ◽  
Pharmacologic Study

PURPOSE A phase I and pharmacologic study to evaluate the feasibility of administering paclitaxel (PTX) in combination with topotecan (TPT) without and with granulocyte colony-stimulating factor (G-CSF) in women with recurrent or refractory ovarian cancer. PATIENTS AND METHODS TPT was administered as a 30-minute infusion daily for 5 days and PTX was given as a 24-hour infusion (PTX-24) either before TPT on day 1 or after TPT on day 5. Each patient received both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or PTX-24 without and with G-CSF resulted in five dosage permutations of TPT/PTX (mg/ m2): 0.75/135 without G-CSF and 0.75/135, 1.25/135, 1.50/135, and 1.25/170 with G-CSF. RESULTS Twenty-two patients received 109 courses of therapy. Dose-limiting myelosuppression consistently occurred at the first TPT/PTX-24 dose level (0.75/135 mg/m2) in the absence of G-CSF support. Although the addition of G-CSF resulted in reduced rates of complicated neutropenia, the incidences of dose-limiting neutropenia and thrombocytopenia were unacceptably high after the doses of either TPT or PTX-24 were increased. Paired analysis showed similar hematologic toxicities between the two sequences of drug administration. The pharmacologic behavior of both TPT and PTX-24 was not altered by drug sequencing. Major antitumor responses occurred in 40% of patients with measurable and assessable disease, including 45% and 9% of patients with potentially cisplatin-sensitive and -resistant tumors, respectively. CONCLUSION The recommended doses of TPT on a daily times-five schedule combined with PTX-24 in these patients were 0.75 mg/m2/d and 135 mg/m2, respectively, with G-CSF support. Although this dose of PTX has significant single-agent activity in ovarian cancer, the dose of TPT is much lower than the TPT dose at which single-agent activity has been observed. Due to the inability to administer near relevant single-agent doses of both drugs in combination, as well as the requirement for G-CSF support, further evaluations of this regimen in women with refractory or recurrent ovarian cancer are necessary before it can be recommended for previously treated patients in this setting.

VTX-2337, a TLR8 agonist, plus chemotherapy in recurrent ovarian cancer: Preclinical and phase I data by the Gynecologic Oncology Group.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3077-3077 ◽  
Author(s):  
Bradley J. Monk ◽  
William E. Brady ◽  
Heather A. Lankes ◽  
Andrea Facciabene ◽  
Kristi Manjarrez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mouse Model ◽  
Phase I ◽  
Gynecologic Oncology ◽  
Single Agent ◽  
Injection Site Reaction ◽  
Pegylated Liposomal Doxorubicin ◽  
Recurrent Ovarian Cancer ◽  
Preclinical Model ◽  
Gynecologic Oncology Group

3077 Background: Given the absence of clear molecular drivers in high-grade serous ovarian cancer, targeting the tumor micro-environment with immunotherapy is an emerging approach. VTX-2337 is a potent, small molecule agonist of TLR8 which stimulates the innate immune response, and was previously evaluated as a single agent in cancer patients. We report data combining VTX-2337 with chemotherapy in recurrent ovarian cancer. Methods: VTX-2337 was tested in an ovarian cancer mouse model with an intact human immune system. Additionally, an open-label phase I study of VTX-2337 + pegylated liposomal doxorubicin (PLD) in recurrent ovarian cancer (NCT01294293, N=13) was performed. PLD (40 mg/m2) was given on day 1 of a 28-day cycle. Three dose levels of VTX-2337 (2.5, 3.0, 3.5 mg/m2, N=13) were serially tested and given by SC injection on days 3, 10, and 17. VTX-2337 (3.0 mg/m2) was also tested with paclitaxel (80 mg/m2; N=7) given on days 1, 8, and 15 of a 28 day cycle. Responses were evaluated using RECIST1.1. PK and serum immune cytokines were measured. Patients remained on therapy until toxicity or progression. Results: In the mouse model, clinical responses to PLD were increased. Innate immunity along with CD8+ T cell responses were also induced. In humans, treatment with PLD + VTX-2337 increased various cytokines and chemokines (G-CSF, MCP-1, MIP-1β, TNF-α). The PK of PLD was not affected by VTXE2337. The combination was well tolerated with no DLTs. AEs consisted of those seen with single-agent PLD (Gr 3/4 toxicities, N=6) or VTXE2337 (Gr 1/2 injection site reaction, transient fever, flu-like symptoms). There was 1 partial response (13%) and 63% had stable disease. Paclitaxel + VTX-2337 was also well tolerated. Conclusions: VTX-2337 enhances the effect of PLD in a preclinical model of ovarian cancer, and the combination is well-tolerated in patients. Clinical data and biomarkers consistent with immunostimulation, provide rationale for the on-going randomized, placebo-controlled, phase II trial comparing PLD vs PLD + VTX-2337 (GOG-3003, NCT01666444). Clinical trial information: NCT01666444.

Phase I Trial of Escalating Doses of Paclitaxel Combined With Fixed Doses of Cisplatin and Doxorubicin in Advanced Endometrial Cancer and Other Gynecologic Malignancies: A Gynecologic Oncology Group Study

2001 ◽  
Vol 19 (4) ◽  
pp. 1021-1029 ◽  
Author(s):  
Gini F. Fleming ◽  
Jeffrey M. Fowler ◽  
Steven E. Waggoner ◽  
Larry J. Copeland ◽  
Benjamin E. Greer ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Gynecologic Oncology ◽  
Single Agent ◽  
Primary Objective ◽  
Gynecologic Oncology Group ◽  
Pelvic Radiotherapy ◽  
Starting Dose ◽  
Dose Levels ◽  
Stimulating Factor

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m2 and 45 mg/m2, whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m2. Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m2, doxorubicin 45 mg/m2, and paclitaxel 160 mg/m2 with G-CSF support is recommended for further testing.

Phase II multicenter open-label study of karenitecin in previously treated epithelial ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study

2008 ◽  
Vol 18 (3) ◽  
pp. 460-464 ◽  
Author(s):  
J. J. KAVANAGH ◽  
M. W. SILL ◽  
P. T. RAMIREZ ◽  
D. WARSHAL ◽  
M. L. PEARL ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Topoisomerase I ◽  
Response Rate ◽  
Gynecologic Oncology ◽  
Complete Response ◽  
Gynecologic Oncology Group ◽  
Open Label ◽  
Peritoneal Cancer ◽  
Previously Treated

The topoisomerase I agents are established as a therapy in recurrent ovarian cancer. Karenitecin, an analog of topotecan with solubility and pharmacologic advantages, was tested in a phase II trial in previously treated patients with recurrent or persistent ovarian cancer. The drug was administered intravenously over 1 h at a dose of 1.0 mg/m2 daily for 5 days every 21 days. Patients were treated until disease progression, intolerable toxicity, or voluntary withdrawal. Response was evaluated according to modified RECIST criteria. Twenty-seven patients were entered into the study. One patient was inevaluable for not receiving any treatment. Of the 26 evaluable patients, there were two partial responses and one complete response for a total response rate of 12%. This response rate was insufficient to justify accrual to the second stage. The most common grade 3 or 4 toxicities were neutropenia (19%) and gastrointestinal (15%). Karenitecin is a well-tolerated topoisomerase compound but has minimal activity in extensively pretreated ovarian cancer with the dose-schedule employed.

Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors.

1998 ◽  
Vol 16 (12) ◽  
pp. 3858-3865 ◽  
Author(s):  
L B Saltz ◽  
D Spriggs ◽  
L J Schaaf ◽  
G K Schwartz ◽  
D Ilson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Irinotecan Dose ◽  
Pharmacologic Study

PURPOSE In vitro synergy between cisplatin and irinotecan (CPT-11) has been reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. PATIENTS AND METHODS To maximize the opportunity for synergy, we divided the cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotecan. The dose of cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50 mg/m2/wk and this was escalated by 30% increments in successive cohorts of three to six patients to establish the maximum-tolerated dose (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were analyzed. RESULTS Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50 mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (DLT) encountered in this trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30 assessable patients achieved a partial response. No alteration in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the administration of cisplatin with irinotecan. CONCLUSION The administration of cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the potential to maximize any clinical synergy between the two agents. Evidence of substantial clinical activity was seen in this phase I study.

Phase I feasibility and pharmacologic study of weekly intraperitoneal paclitaxel: a Gynecologic Oncology Group pilot Study.

1995 ◽  
Vol 13 (12) ◽  
pp. 2961-2967 ◽  
Author(s):  
P Francis ◽  
E Rowinsky ◽  
J Schneider ◽  
T Hakes ◽  
W Hoskins ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Gynecologic Oncology ◽  
Maximum Tolerated Dose ◽  
Gynecologic Oncology Group ◽  
Continuous Exposure ◽  
Weekly Schedule ◽  
Partial Small Bowel Obstruction ◽  
Dose Levels ◽  
Pharmacologic Study

PURPOSE This study was designed to define the maximum-tolerated dose (MTD) and pharmacology of paclitaxel administered by the intraperitoneal (IP) route on a weekly schedule. PATIENTS AND METHODS Thirty-three patients with residual ovarian cancer following standard chemotherapy were entered onto this phase I trial. Patients were treated weekly with IP paclitaxel administered in 2 L of normal saline following premedication. Patients with nonassessable disease received 16 weekly courses. The initial dose level was 20 mg/m2/wk. There was no intrapatient dose escalation. RESULTS Multiple grade 2 toxicities were observed at the 75-mg/m2/wk dose level. These toxicities included abdominal pain, nausea, vomiting, leukopenia, and fatigue. One episode of grade 4 vomiting thought to be secondary to a transient partial small-bowel obstruction occurred at this dose level. At dose levels > or = 60 to 65 mg/m2, pharmacology studies documented the persistence of significant IP paclitaxel levels 1 week after drug administration, suggesting very slow peritoneal clearance and continuous exposure of the peritoneal cavity to active concentrations of paclitaxel. Low plasma paclitaxel concentrations were detected in the majority of patients treated at dose levels > or = 55 mg/m2. CONCLUSION Paclitaxel can be delivered by the IP route on a weekly schedule with both an acceptable toxicity profile and a major pharmacokinetic advantage for cavity exposure. The recommended dose and schedule for phase II study of IP paclitaxel is 60 to 65 mg/m2 weekly.

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