Anne Stähle

A phase 3 trial of bevacizumab in ovarian cancer.

BACKGROUND Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. METHODS We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival. RESULTS A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months. CONCLUSIONS Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

Gemcitabine Plus Carboplatin Compared With Carboplatin in Patients With Platinum-Sensitive Recurrent Ovarian Cancer: An Intergroup Trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG

PURPOSE Most patients with advanced ovarian cancer develop recurrent disease. For those patients who recur at least 6 months after initial therapy, paclitaxel platinum has shown a modest survival advantage over platinum without paclitaxel; however, many patients develop clinically relevant neurotoxicity, frequently resulting in treatment discontinuation. Thus, an alternative regimen without significant neurotoxicity was evaluated by comparing gemcitabine plus carboplatin with single-agent carboplatin in platinum-sensitive recurrent ovarian cancer patients. METHODS Patients with platinum-sensitive recurrent ovarian cancer were randomly assigned to receive either gemcitabine plus carboplatin or carboplatin alone, every 21 days. The primary objective was to compare progression-free survival (PFS). RESULTS Three hundred fifty-six patients (178 gemcitabine plus carboplatin; 178 carboplatin) were randomly assigned. Patients received a median of six cycles in both arms. With a median follow-up of 17 months, median PFS was 8.6 months (95% CI, 7.9 to 9.7 months) for gemcitabine plus carboplatin and 5.8 months (95% CI, 5.2 to 7.1 months) for carboplatin. The hazard ration (HR) for PFS was 0.72 (95% CI, 0.58 to 0.90; P = .0031). Response rate was 47.2% (95% CI, 39.9% to 54.5%) for gemcitabine plus carboplatin and 30.9% (95% CI, 24.1% to 37.7%) for carboplatin (P = .0016). The HR for overall survival was 0.96 (95% CI, 0.75 to1.23; P = .7349). While myelosuppression was significantly more common in the combination, sequelae such as febrile neutropenia or infections were uncommon. No statistically significant differences in quality of life scores between arms were noted. CONCLUSION Gemcitabine plus carboplatin significantly improves PFS and response rate without worsening quality of life for patients with platinum-sensitive recurrent ovarian cancer.

Gemcitabine/carboplatin (GC) vs. carboplatin (C) in platinum sensitive recurrent ovarian cancer (OVCA). Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVAR, the NCIC CTG and the EORTC GCG

5005 Background: Most patients (pts) with OVCA relapse. ICON 4 - AGO OVAR 2.2 results suggest combination C-based therapy may be superior to single agent C. GC is a feasible less neurotoxic regimen and thus of interest to evaluate in this setting. METHODS In this phase III trial pts with platinum sensitive recurrent OVCA (≥ 6 months after the end of primary therapy) were randomized to receive C (AUC 4 d1) plus G (1000 mg/m2 d1 and 8) or C (AUC 5 d1) every 3 weeks. The primary objective compared progression free survival (PFS) in both arms. Secondary objectives were response rate (RR) and duration, overall survival (OS), toxicity and quality of life (QoL). RESULTS From 09/99 and 04/02, 356 pts (178 GC, 178 C) were randomized. Both study arms were well balanced for baseline disease characteristics. Median number of cycles was 6 for GC (0-10) and C (0-9). The weekly dose intensity was 98.2% for C (C arm) and 96.2% for C and 75.6% (92.8% for d 1 and 63.4% for d8) for G (GC arm). Grade 3/4 hematologic toxicities were significant higher in the GC arm (anemia 27.4% of pts. vs. 8.0%, neutropenia 70.3% vs. 12.0%, thrombocytopenia 34.9% vs. 11.4%). G-CSF or GM-CSF was more often used in GC (23.6% of pts. vs. 10.1%) as well as red cell transfusions (37.1% vs. 14.6%). Clinical sequelae were similar between arms: febrile neutropenia (1.1% GC vs. 0% C) and infections (0.6% for both arms). Grade 3/4 non-hematologic toxicities were infrequent in both arms (< 5%), especially for sensory neuropathy (1.1% GC vs. 1.7% C). Overall RR for GC was 47.2% (95% CI: 39.9-54.5%) and 30.9% (95% CI: 24.1-37.7) for C (p= 0.0016). GC pts reported significantly faster palliation of abdominal symptoms as well as significantly improved global QoL. With a median follow up of 13 months, median PFS was 8.6 mo (95%CI: 8.0-9.7) for GC and 5.8 mo (95% CI: 5.2-7.1) for C (HR 0.72 [95% CI: 0.57-0.90], p= 0.0038, e= 311). OS data are immature and this study was not powered to detect differences in OS. CONCLUSION The combination of G plus C improves PFS and QoL in platinum sensitive recurrent OVCA patients with acceptable toxicity. [Table: see text].

Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubicin) in women with advanced or recurrent endometrial cancer expressing LHRH receptors: a multicenter phase 2 trial (AGO-GYN5).

Objective Advanced or recurrent endometrial cancer (EC) no longer amenable to surgery or radiotherapy is a life-threatening disease with limited therapeutic options left. Eighty percent of ECs express receptors for luteinizing hormone–releasing hormone (LHRH), which can be targeted by AEZS-108 (zoptarelin doxorubicin acetate). This phase 2 trial was performed to assess the efficacy and safety of AEZS-108 in this group of patients. Methods Patients had FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) III or IV or recurrent EC, LHRH receptor–positive tumor status, and at least had 1 measurable lesion (Response Evaluation Criteria in Solid Tumors). Prior anthracycline therapy was not allowed. Patients received AEZS-108 as a 2-hour infusion on day 1 of a 21-day cycle. The treatment was continued for a maximum of 6 to 8 cycles. The primary end point was the response rate determined by the Response Evaluation Criteria in Solid Tumors. Results From April 2008 to November 2009, 44 patients were included in the study at 8 centers in Germany (AGO) and 3 centers in Bulgaria. Forty-three of these patients were eligible. Two (5%) patients had a complete remission, and 8 (18%) achieved a partial remission. Stable disease for at least 6 weeks was observed in 44%. The median time to progression was 7 months, and the median overall survival was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%). Conclusions AEZS-108, an LHRH-agonist coupled to doxorubicin, has significant activity and low toxicity in women with advanced or recurrent LHRH receptor–positive EC, supporting the principle of receptor-mediated targeted chemotherapy.

Efficacy and safety of AEZS-108 (INN: zoptarelin doxorubicin acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors: a multicenter phase II trial of the ago-study group (AGO GYN 5).

OBJECTIVES To evaluate the activity and toxicity of AEZS-108 (Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors. METHODS Women with epithelial ovarian, fallopian tube or primary peritoneal cancer, expressing LHRH receptors were eligible for this trial, when they had progression during treatment with a platinum based regimen or within 6months after receiving a platinum based regimen and a previous taxane treatment. At least one measurable target lesion (RECIST) or CA-125 levels higher than twice the upper limit of normal range (GCIG-criteria) were required. Patients received AEZS-108 (267mg/m(2) equimolar to 76.8mg/m(2) of free doxorubicin) every 3weeks as a two hour i.v. infusion. RESULTS Fifty-five of 59 (93%) of ovarian cancer samples screened expressed LHRH receptors. 42 patients were enrolled in this study and received at least 1 infusion of AEZS-108 (ITT population). Of these 42 patients 6 (14.3%) had a partial response, 16 (38%) stable disease, 16 (38%) progressive disease and 4 patients were not evaluable. Median time to progression was 12weeks (95% CI: 8-20weeks), and median overall survival was 53weeks (95% CI: 39-73weeks). Toxicity profile was favorable. CONCLUSION AEZS-108 has a clinical activity in platinum refractory/resistant ovarian cancer which seems to be comparable to that of pegylated liposomal doxorubicin or to topotecan. Toxicity was comparably low. These data support the concept of a targeted chemotherapy for tumors expressing LHRH receptors.

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/m(2)) in primary advanced OC with or without lonafarnib (L). Lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg 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 1cm: 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 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.

A randomized, phase III study (AGO-OVAR-9, GINECO-TCG, NSGO-OC-0102): Gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer (OC): Survival of FIGO stage I-IIA patients

LBA5510 Background: One option to increase the efficacy of TC in pts with first diagnosis of ovarian cancer is to add a not cross-resistant drug. METHODS We conducted a randomized, prospective, stratified, phase III study comparing therapy with TC to TC plus gemcitabine. From 7/02 to 4/04, pts with a histological verified first diagnosis of epithelial OC, FIGO IC-IV were randomized to either TC (paclitaxel [T] 175 mg/m2 3h iv d1 + carboplatin [C] AUC 5 iv d1) or TCG (TC + gemcitabine [G] 800 mg/m2 iv d1+8) for at least 6 cycles every 21 days starting within 6 weeks post-operatively. The randomization was balanced within three strata: 1) FIGO I-IIA, 2) FIGO IIB-IIIC with residual tumor ≤ 10mm, 3) FIGO IIB-IIIC with residual tumor > 10 mm or FIGO IV. Primary endpoint is overall survival. RESULTS We enrolled 1,742 pts and administered 5,268 cycles TC and 5,129 cycles TCG. All baseline characteristics of the patients in both arms were well balanced. Most pts received 6+ cycles (87.2% TC, 86.2% TCG). Previous interim analyses has shown that TCG was tolerable but induced more hematological toxicity and final analysis has shown that addition of gemcitabine did not improve overall survival in patients with FIGO stage IIB-IV disease. Approximately 11% of the patients (n = 175) had FIGO stage I-IIA disease (stratum I). Most patients received 6+ cycles (93.3% TC, 86.9% TCG). With a median follow-up of 53.8 (range 0 -75) months, and using the log rank test and Cox regression analysis, no relevant differences in progression free survival (first quartile about 57 months and median ≥ 75 months in both groups, HR = 0.90 [95% CI: 0.47-1.72], p = 0.7500) and a negative trend in overall survival (first quartile ≥ 75 months in both groups, HR = 2.19 [95% CI: 0.75-6.41], p = 0.1419) were seen. CONCLUSIONS Addition of G to TC did not improve efficacy in patients with stage I-IIA ovarian cancer. This was also the case for stratum II-III patients (previously reported). The addition of G to TC in patients with first diagnosis of ovarian cancer cannot be recommended. [Table: see text].