Phase II study of irinotecan in combination with bevacizumab in recurrent ovarian cancer

Objectives

To evaluate the efficacy and safety of irinotecan and bevacizumab in recurrent ovarian cancer. The primary objective was to estimate the progression free survival (PFS) rate at 6 months. Secondary objectives included estimation of overall survival (OS), objective response rate (ORR), duration of response, and an evaluation of toxicity.

Phase II trial of paclitaxel and nedaplatin in patients with advanced/recurrent uterine cervical cancer: a Kansai Clinical Oncology Group study

Objective

A multicenter phase II trial was conducted to evaluate the activity and toxicity of paclitaxel and nedaplatin (cis-diammineglycolatoplatonum) in patients with advanced/recurrent uterine cervical cancer.

Methods

Patients were required to have measurable disease. Histologic confirmation of the primary diagnosis as uterine cervical cancer was mandatory. The treatment consisted of paclitaxel 175 mg/m² over 3 hours and nedaplatin 80 mg/m² intravenously over 1 hour on day 1 every 28 days until progressive disease or adverse effects prohibited further therapy.

Results

Fifty patients were enrolled into the study protocol from October 2007 to February 2010. 45 patients(90%) were eligible for assessment of response (RECIST version 1.0) to treatment; 31 patients (62%) received prior radiotherapy and 23 patients (46%) received prior chemotherapy. The overall response rate was 44.4% (11 complete responses and 8 partial responses) with 22.2% of patients having stable disease. Grades 3 or 4 adverse events (NCI-CTCAE ver 3) included neutropenia (n = 16, 32.7%), febrile neutropenia (n = 1, 2.0%), anemia (n = 9, 18.4%), but there was no significant thrombocytopenia. Non-hematologic toxicity was generally not serious and without a dominant pattern. The median progression-free survival was 7.5 months (95% C.I., 5.7, 9.4) and overall survival was 15.7 months (95% C.I., 9.4, 21.9).

Conclusions

Paclitaxel 175 mg/m² and nedaplatin 80 mg/m² intravenously on day 1 every 28 days in patients with advanced/recurrence uterine cervical cancer demonstrated easy administration, favorable antitumor activity, and the toxicity profile of this regimen would be decreased compared with cisplatin-containing combinations. Evaluation of this regimen in phase III trials is warranted.     

Predictive value of serum CA-125 levels in patients with persistent or recurrent epithelial ovarian cancer or peritoneal cancer treated with bevacizumab on a Gynecologic Oncology Group phase II trial

Objective

To compare two methods of determining therapeutic response and disease progression — modified Gynecologic Cancer Intergroup (GCIG) criteria based on CA-125 and Radiographic Evaluation Criteria in Solid Tumors (RECIST), in a phase II trial of bevacizumab for patients with recurrent or persistent epithelial ovarian and peritoneal carcinoma.

Methods

Patients were treated with bevacizumab 15 mg/kg every 21 days. Modified GCIG definitions of progression and response were retrospectively applied and compared to RECIST-defined progression and response. The prognostic significance of CA-125- and RECIST-defined responses and progressions were explored.

Results

Sixty-two patients were evaluable by RECIST, 59 for progression by CA-125, and 45 for response by CA-125. Median progression-free survival (PFS) by RECIST and progression-free interval (PFI) by CA-125 were 4.7 and 5.2 months respectively. However, 12.9% of those with CA-125 defined progression remained progression-free according to RECIST for at least 8 months. Thirteen of 62 patients (21%) had response by RECIST and 14/45 (31%) by CA-125. Time dependent analyses indicated that progression by CA-125 was associated with a 5.2 fold increased risk of progression by RECIST, and response by CA-125 had a 5 fold decrease in risk of progression by RECIST. Landmark and time dependent analyses showed prognostic value of responses by CA-125 and RECIST.

Conclusions

In this study, disease assessment by RECIST and CA-125 appears to correlate in general. However, approximately 10% of patients might demonstrate progression earlier by CA-125.     

Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study

OBJECTIVE: To evaluate the activity of single agent weekly paclitaxel in patients with both platinum and paclitaxel (delivered every 3 weeks)-resistant ovarian cancer. METHODS: Forty-eight patients with platinum and paclitaxel-resistant ovarian cancer (defined as progression during, or recurrence < 6 months following, their prior treatment with both agents) received single agent weekly paclitaxel (80 mg/m2/week) until disease progression (assuming acceptable toxicity). Following the initial 12 weekly doses, treatment could be given for 3 weeks, with a 1 week break. RESULTS: In this chemoresistant population, the objective response rate was 20.9%. Serious adverse events were relatively uncommon (neuropathy-grade 2: 21%; grade 3: 4%; and grade 3 fatigue: 8%). CONCLUSION: The weekly administration of paclitaxel can be a useful management approach in women with both platinum and paclitaxel (given every 3 weeks)-resistant ovarian cancer. It would be appropriate to directly compare weekly to every 3-week paclitaxel delivery in the setting of primary chemotherapy of advanced ovarian cancer.     

A phase II trial of oral capecitabine in patients with platinum--and taxane--refractory ovarian, fallopian tube, or peritoneal cancer

PURPOSE: To determine the efficacy, toxicity, and quality of life of capecitabine (Xeloda), an oral 5-fluorouracil derivative, in patients with chemorefractory recurrent mullerian cancers. PATIENTS AND METHODS: Patients with chemorefractory persistent or recurrent ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled. Capecitabine was administered beginning at 2000 mg/m2/day orally in two divided doses with meals on a 21-day cycle: 14 days of capecitabine followed by a 7-day rest period. One dose escalation or reduction was allowed. Response was assessed after cycle 2 and cycle 4 and every third cycle thereafter. Standard evaluation included two-dimensional measurement of evaluable disease. Standard criteria for response were used. Therapy was discontinued if progression occurred after at least two cycles of therapy. Quality of life and symptoms were assessed. RESULTS: Forty-one patients were enrolled. Ninety-two percent of patients had >2 previous chemotherapy regimens. All patients had platinum- and taxane-resistant disease. Thirty-six patients were evaluable for response. Three patients had a partial response, with a median response duration of five cycles. Twenty-two patients had stable disease for 3 to 11 cycles (median, 6 cycles). Eleven had progressive disease. The only grade 4 toxicity was abdominal pain (n = 2). The most common grade 3 toxicities were fatigue (n = 19), hand-foot syndrome (n = 11), abdominal pain (n = 7), and diarrhea (n = 4). One patient had a grade 3 hematologic toxicity (anemia). CONCLUSION: Capecitabine at the dosages used in this study is well tolerated and has minimal hematologic toxicity.     

A phase I study with an expanded cohort to assess the feasibility of intraperitoneal carboplatin and intravenous paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A Gynecologic Oncology Group study

Objective

This study aimed to determine the first-cycle maximum tolerated dose (MTD) of intraperitoneal carboplatin in combination with intravenous paclitaxel and then assess the feasibility of this dose over multiple cycles.

Methods

Beginning at an intraperitoneal (IP) carboplatin dose area under the curve (AUC) of 5 and a fixed intravenous dose of 175 mg/m² paclitaxel, patients were entered on a dose-escalating phase evaluating first-cycle dose-limiting toxicity (DLT). After estimating the MTD, cohorts of 20 patients were then entered in an expanded phase to evaluate DLT over four cycles.

Results

Twenty-one patients were entered on the dose-escalating phase. A first-cycle MTD of carboplatin at AUC 8 was tolerated although thrombocytopenia was dose-limiting over multiple cycles. An additional 69 patients were treated in expanded cohorts. Only 5/90 (5.6%) patients discontinued treatment because of a port problem. Four-cycle DLT required de-escalation to a carboplatin AUC of 6, and even at that dose, there were 14 dose-limiting toxic effects in 40 patients (35%). Seven dose-limiting toxicities were due to neutropenia, and 6 were due to grade 3/4 thrombocytopenia. Six cycles of therapy were completed in 75% of eligible patients, but dose adjustments were required.

Conclusions

The first-cycle MTD did not predict the tolerability of this regimen over multiple cycles. Using an IP carboplatin dose of AUC 6 in combination with paclitaxel, the regimen can be administered with a high completion rate over multiple cycles. Because neutropenia is a frequent DLT, the addition of hematopoietic growth factors may permit a high completion rate while maintaining this dose.     

Paclitaxel (Taxol) treatment for refractory ovarian cancer: Phase II clinical trial

OBJECTIVE: Our aim was to determine the efficacy and toxicity of paclitaxel in the treatment of refractory and platinum-resistant epithelial ovarian cancer. STUDY DESIGN: Eligibility required three prior failed chemotherapy regimens and documented platinum resistance. One hundred patients with advanced ovarian cancer received paclitaxel 135 mg/m² over 24 hours every 21 days with optional granulocyte colony-stimulating factor support. RESULTS: Paclitaxel was generally well tolerated. In four patients bowel perforation or fistula developed. After three cycles 34% of patients had stable disease and 25% of patients demonstrated a response, either partial or complete. After six cycles 24% of patients continued to respond. To date, six patients have achieved a complete response. CONCLUSION: A 25% response rate in patients with refractory ovarian cancer was observed, which was durable to six cycles. (AM J Obstet Gynecol 1994;170:1666-71.)     

Randomized phase II trial of carboplatin and paclitaxel with or without lonafarnib in first-line treatment of epithelial ovarian cancer stage IIB-IV

Objectives

This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS).

Patients and Methods

We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175 mg/m²) in primary advanced OC with or without lonafarnib (L). Lonafarnib was given in a dose of 100 mg orally twice a day during chemotherapy and was increased afterwards to 200 mg up to six months as a maintenance therapy.

Results

105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p = 0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1 cm: median PFS was 11.5 months (95% CI: 7.4-14.2) compared with 16.4 (95% CI: 10.3-40.4) for TC (p = 0.0141; HR = 0.36 (95% CI: 0.15-0.84)) with median OS 20.6 months (95% CI: 13.1-31.0) and 43.4 months (95% CI: 15.7-) for the TC arm (p = 0.012; HR = 0.32 (95% CI: 0.13-0.8)).

Conclusion

The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1 cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.     

Phase II trial of amonafide in previously treated patients with advanced ovarian cancer: a Southwest Oncology Group study.

Twenty-three patients with metastatic or recurrent Stage III or IV epithelial ovarian cancer who were refractory to or relapsed following previous chemotherapy with cisplatin or a cisplatin analog were entered into a phase II study of amonafide. The starting dose of amonafide was 300 mg/m2 delivered daily over 1 hr by intravenous infusion. In the absence of myelosuppression, the dose of amonafide was escalated by increments of 75 mg/m2 to a maximum of 450 mg/m2. There were 19 eligible and 17 fully evaluable patients. Grade 3 or 4 leukopenia occurred in 14 (74%) patients and grade 3 or 4 thrombocytopenia in 6 (32%) patients. No objective complete or partial responses were observed. Four patients had stable disease for 3, 4, 4.5, and 6 months, respectively. Therefore, amonafide in the doses used in the present trial does not have significant activity in previously treated patients with ovarian cancer.     

Phase II trial of vinblastine in previously treated patients with ovarian cancer: a Southwest Oncology Group Study

Sixty-eight patients with relapsing, epithelial type ovarian carcinoma were entered into a Phase II study of vinblastine. Vinblastine was administered as a continuous intravenous infusion over five days at a starting dose of 1.7 mg/m2/day every 3 weeks. There were 44 fully evaluable and 6 partially evaluable patients. Forty-one of these patients had had only one prior treatment regimen. Grade 3 or 4 leukopenia occurred in 12 patients (24%), but Grade 3 or 4 thrombocytopenia occurred in only 2 patients. There were two clinical complete responses of 18 and 36 weeks duration and one partial response of 6 weeks for an overall response rate of 7%. We conclude that vinblastine, administered in optimal dose and schedule, has little clinical activity in previously treated patients with ovarian cancer.     

Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer

OBJECTIVE: To determine the activity and tolerability of gemcitabine in the palliative treatment of ovarian cancer. METHODS: Patients affected by ovarian cancer, and with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, were enrolled into this phase II study. Gemcitabine, 1000 mg/m(2), was administered on days 1, 8, and 15, by 30-min intravenous infusion. Cycles were repeated every 28 days. RESULTS: Fifty patients were enrolled. All the patients were platinum and/or paclitaxel resistant (median number of previous regimens, 2; range, 1-5). Median platinum-free interval was 3 (range, 1-11) months and median paclitaxel-free interval was 6 (range, 1-36) months. A total of 210 courses were evaluable for toxicity, with a median number of four cycles administered per patient (range, 1-10). A grade 3 or 4 hematological toxicity was observed in 27 patients (54%) (anemia grade 3, 16%; grade 4, 2%; neutropenia grade 3, 24%; grade 4, 18%; thrombocytopenia grade 3, 8%; grade 4, 0%). A 20-50% dose reduction was required for 36 patients (72%, 55% of cycles). Blood transfusions were necessary for 15 patients (30%), while 2 (4%) were treated with erythropoetin. Granulocyte colony-stimulating factor was necessary in 4 patients (8%). Nonhematological toxicity was mild and manageable. Only 4 patients (8%) experienced a grade 3 hepatic toxicity (elevated liver enzymes). Forty-one patients (82%) are, so far, evaluable for response. Among them, 7 partial responses (17%; 95% confidence interval [CI], 6-29), 15 disease stabilizations (>16 weeks) (36.6%; 95% CI, 21.9-51.3), and 19 progressions (46.3%; 95% CI, 31.0-61.6) have been registered. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks. CONCLUSIONS: This study confirms the activity and safety of gemcitabine in heavily pretreated patients with recurrent ovarian cancer.     

Phase II trial of vinblastine in previously treated patients with ovarian cancer: a Southwest Oncology Group Study

Sixty-eight patients with relapsing, epithelial type ovarian carcinoma were entered into a Phase II study of vinblastine. Vinblastine was administered as a continuous intravenous infusion over 5 days at a starting dose of 1.7 mg/m2/day every 3 weeks. There were 44 fully evaluable and 6 partially evaluable patients. Forty-one of these patients had had only one prior treatment regimen. Grade 3 or 4 leukopenia occurred in 12 patients (24%), but Grade 3 or 4 thrombocytopenia occurred in only 2 patients. There were two clinical complete responses of 18- and 36-week durations and one partial response of 6 weeks for an overall response rate of 7%. We conclude that vinblastine, administered in optimal dose and schedule, has little clinical activity in previously treated patients with ovarian cancer.     

Phase II trial of adjuvant pelvic radiation "sandwiched" between combination paclitaxel and carboplatin in women with uterine papillary serous carcinoma

Objective

To evaluate the safety and survival in women treated with adjuvant pelvic radiation “sandwiched” between six cycles of paclitaxel and carboplatin chemotherapy with completely resected UPSC.

Methods

Surgically staged women with UPSC (FIGO stage 1-4) and no visible residual disease were enrolled. Treatment involved paclitaxel (175 mg/m²) and carboplatin (AUC = 6.0-7.5) every 21 days for 3 doses, followed by radiation therapy (RT), followed by an additional 3 cycles of paclitaxel and carboplatin (AUC = 5-6). Survival analysis, using Kaplan-Meier methods, was performed on patients who completed at least 3 cycles of chemotherapy and RT.

Results

A total of 81 patients were enrolled, of which 72 patients completed the first 3 cycles of chemotherapy followed by prescribed RT. Median age was 67 years (range: 43-82 years). 59/72 (82%) had disease confined to the uterus and 13/72 (18%) had completely resected extra-uterine disease (stage 3 and 4). 65 (83%) completed the protocol. Overall PFS and OS for combined stage 1 and 2 patients was 65.5 ± 3.6 months and 76.5 ± 4.3 months, respectively. PFS and OS for combined stage 3 and 4 patients was 25.8 ± 3.0 and 35.9 ± 5.3 months, respectively. Three-year % survival probability for stage 1 and 2 patients was 84% and for stage 3 and 4 patients was 50%. Of the 435 chemotherapy cycles administered, there were 11(2.5%) G3/G4 non-hematologic toxicities. 26(6.0%) cycles had dose reductions and 37(8.5%) had dose delays.

Conclusions

Compared to prior studies of single modality adjuvant therapy, RT “sandwiched” between paclitaxel and carboplatin chemotherapy is well-tolerated and highly efficacious in women with completely resected UPSC.     

Phase I trial of concomitant vinorelbine, cisplatin, and pelvic irradiation in cervical carcinoma and other advanced pelvic malignancies

OBJECTIVE: To determine the maximum tolerated dose (MTD) of vinorelbine in combination with weekly cisplatin and pelvic radiation therapy (RT). METHODS: Eligible patients included those with bulky or locally advanced cervical cancer. Women with other advanced gynecologic malignancies were also eligible. All patients received cisplatin 40 mg/m(-2)/week (maximum dose, 70 mg) during pelvic RT. Vinorelbine was administered on the same day as cisplatin at a starting dose of 10 mg/m(-2)/week and escalated in 5 mg/m(-2)/week increments. Dose-limiting toxicity (DLT) was defined as: grade 3-4 non-hematologic toxicity, grade 4 hematologic toxicity, or any toxicity which required > or =1 week delay in RT or an omission of >1 dose of chemotherapy. RESULTS: Between April 2001 and September 2002, 12 women with pelvic malignancies (11 cervical, 1 recurrent ovarian) were enrolled. Cohorts of 3, 6, and 3 patients were treated at 10, 15, and 20 mg/m(-2)/week dose levels of vinorelbine. At the 20 mg/m2 level, DLT was observed. Two of three patients missed >1 cycle of chemotherapy secondary to predominantly hematologic toxicity. One patient at the 20 mg level developed a creatinine clearance <50 ml/min and missed 1 dose of cisplatin. Another developed transient grade 3 diarrhea. No grade 4 toxicities were observed. CONCLUSIONS: The MTD of vinorelbine in combination with cisplatin and pelvic RT in patients with cervical cancer is 15 mg/m(-2)/week.     

Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol S0211)

Platinum-resistant ovarian cancer continues to be a difficult therapeutic problem. Clearly, molecularly targeted agents should be evaluated in this patient population. Patients were eligible for this phase II study with stage III or IV ovarian cancer, whose tumor expressed Kit (CD117) or platelet-derived growth factor receptor (PDGFR) and with relapse of measurable disease within 6 months of completing frontline, platinum- and taxane-based chemotherapy. Patients were treated daily with 400 mg of imatinib mesylate orally. It was assumed that the agent would be of no further interest if the population response rate was less than 10%. A two-stage design was used for patient accrual. A total of 34 patients were registered to the study. Of these, 15 were found to be ineligible or not evaluable (8 because their tumor samples were negative for both DC117 and PDGFR). Of 19 evaluable patients, 2 (11%) tested positively for c-Kit and 17 (89%) tested positively for PDGFR. There were no objective responders. Thirteen patients (68%) had increasing disease or symptomatic deterioration, and six (32%) went off protocol during the first month due to adverse events. Median progression-free survival was 2 months (95% CI 1-3 months) and median overall survival was 10 months (95% CI 6-18 months). Eleven percent of patients experienced grade 4 hematologic/metabolic toxicity and 37% experienced grade 3 nonhematologic toxicity. We conclude that imatinib mesylate as a single agent does not appear to have useful clinical activity in c-Kit and/or PDGFR positive, recurrent ovarian cancer in heavily pretreated patients with ovarian cancer.     

Phase II study of fulvestrant in recurrent/metastatic endometrial carcinoma: a Gynecologic Oncology Group study

Objectives.

To evaluate the activity and toxicity of fulvestrant in advanced, recurrent, or persistent endometrial carcinoma.

Methods.

Eligible patients with advanced, recurrent or persistent endometrial carcinoma not amenable to curative therapy were treated with fulvestrant at a dose of 250 mg by IM injection every 4 weeks for at least 8 weeks. Therapy was continued until evidence of progressive disease, or adverse effects prohibited further therapy. Response was assessed in patients with at least one target lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Immunohistochemical analysis of tumor tissue (histology or cytology) for estrogen and progesterone receptors was required from the metastatic or recurrent site.

Results.

Sixty-seven patients were enrolled in this study. Upon review, 14 patients were excluded. In the 22 estrogen receptor (ER) negative patients, no patients demonstrated either a complete or partial response, and 4 (18%) demonstrated stable disease (as best response). In the 31 ER positive patients, 1 (3%), 4 (13%) and 9 (29%) patients demonstrated a complete, partial response, and stable disease (as best response), respectively. The median progression free survival and overall survival in the ER negative patients were 2 and 3 months and in the ER positive patients 10 and 26 months. Treatment was well tolerated, and no patient discontinued therapy due to toxicity.

Conclusions.

Fulvestrant has minimal activity in advanced, recurrent, or persistent endometrial carcinoma.     

Phase 2 trial of single agent docetaxel in platinum and paclitaxel-refractory ovarian cancer, fallopian tube cancer, and primary carcinoma of the peritoneum

OBJECTIVE: Previously reported data have suggested the lack of complete cross-resistance between docetaxel and paclitaxel in ovarian cancer. We wished to evaluate the biological and clinical activity of docetaxel in a patient population with well-characterized platinum and paclitaxel-refractory ovarian cancer. METHODS: In this single-institution phase 2 trial, 30 women with advanced ovarian cancer whose disease had either failed to respond to primary platinum-paclitaxel chemotherapy or where the cancer had progressed within 3 months of their last treatment with both a platinum agent and paclitaxel were treated with single agent docetaxel (75 mg/m(2) q 3 weeks). Due to a prior history of excessive chemotherapy-induced neutropenia, 3 patients initiated treatment at a dose of 60 mg/m(2). RESULTS: The median number of courses of docetaxel delivered on this protocol was 3 (range 1-7), with 7 patients requiring dose reductions due to treatment-related side effects. The most common toxicities included grade 4 neutropenia, neutropenic fever, and grade >/=2 fatigue experienced by 9 (30%), 2 (7%), 5 (17%) patients, respectively. Three patients (10%) achieved both an objective response (by CA-125 criteria) and symptomatic improvement (e.g., decrease in pain and ascites). The durations of responses were 3, 4, and 6 months. CONCLUSION: Single-agent docetaxel has modest, but definite activity in patients with well-characterized platinum and paclitaxel-resistant ovarian cancer. Use of this drug should be considered a rational management approach in appropriately selected patients in this clinical setting.