Avastin: Package Insert and Label Information (Page 5 of 6)

14.8 Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study MO22224

The safety and efficacy of Avastin were evaluated in a multicenter, open-label, randomized study [MO22224 (NCT00976911)] comparing Avastin with chemotherapy versus chemotherapy alone in patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within <6 months from the most recent platinum-based therapy (N=361). Patients had received no more than 2 prior chemotherapy regimens. Patients received one of the following chemotherapy regimens at the discretion of the investigator: paclitaxel (80 mg/m2 on days 1, 8, 15 and 22 every 4 weeks; pegylated liposomal doxorubicin 40 mg/m2 on day 1 every 4 weeks; or topotecan 4 mg/m2 on days 1, 8 and 15 every 4 weeks or 1.25 mg/m2 on days 1-5 every 3 weeks). Patients were treated until disease progression, unacceptable toxicity, or withdrawal. Forty percent of patients on the chemotherapy alone arm received Avastin alone upon progression. The main outcome measure was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 61 years (25 to 84 years) and 37% of patients were ≥65 years. Seventy-nine percent had measurable disease at baseline, 87% had baseline CA-125 levels ≥2 times ULN and 31% had ascites at baseline. Seventy-three percent had a platinum-free interval (PFI) of 3 months to 6 months and 27% had PFI of <3 months. ECOG performance status was 0 for 59%, 1 for 34% and 2 for 7% of the patients.

The addition of Avastin to chemotherapy demonstrated a statistically significant improvement in investigator-assessed PFS, which was supported by a retrospective independent review analysis. Results for the ITT population are presented in Table 14 and Figure 7. Results for the separate chemotherapy cohorts are presented in Table 15.

Table 14: Efficacy Results in Study MO22224
Efficacy ParameterAvastin with Chemotherapy(N=179)Chemotherapy(N=182)
*
per stratified Cox proportional hazards model
per stratified log-rank test
Progression-Free Survival per Investigator
Median (95% CI), in months6.8 (5.6, 7.8)3.4 (2.1, 3.8)
HR (95% CI)*0.38 (0.30, 0.49)
p-value <0.0001
Overall Survival
Median (95% CI), in months16.6 (13.7, 19.0)13.3 (11.9, 16.4)
HR (95% CI)*0.89 (0.69, 1.14)
Overall Response Rate
Number of Patients with Measurable Disease at Baseline142144
Rate, % (95% CI)28% (21%, 36%)13% (7%, 18%)
Duration of Response
Median, in months9.45.4
Figure 7: Kaplan-Meier Curves for Investigator-Assessed Progression-Free Survival in Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study MO22224

Figure 7
(click image for full-size original)

Table 15: Efficacy Results in Study MO22224 by Chemotherapy
Efficacy ParameterPaclitaxelTopotecanPegylated Liposomal Doxorubicin
Avastin with ChemotherapyChemotherapyAvastin with ChemotherapyChemotherapyAvastin with ChemotherapyChemotherapy
(N=60)(N=55)(N=57)(N=63)(N=62)(N=64)
NE=Not Estimable
*
per stratified Cox proportional hazards model
Progression-Free Survival per Investigator
Median, in months(95% CI)9.6(7.8, 11.5)3.9(3.5, 5.5)6.2(5.3, 7.6)2.1(1.9, 2.3)5.1(3.9, 6.3)3.5(1.9, 3.9)
Hazard ratio *(95% CI)0.47(0.31, 0.72)0.24(0.15, 0.38)0.47(0.32, 0.71)
Overall Survival
Median, in months(95% CI)22.4(16.7, 26.7)13.2(8.2, 19.7)13.8(11.0, 18.3)13.3(10.4, 18.3)13.7(11.0, 18.3)14.1(9.9, 17.8)
Hazard ratio *(95% CI)0.64(0.41, 1.01)1.12(0.73, 1.73)0.94(0.63, 1.42)
Overall Response Rate
Number of patients with measurable disease at baseline454346505151
Rate, %(95% CI)53(39, 68)30(17, 44)17(6, 28)2(0, 6)16(6, 26)8(0, 15)
Duration of Response
Median, in months11.66.85.2NE8.04.6

14.9 Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study AVF4095g

The safety and efficacy of Avastin were evaluated in a randomized, double-blind, placebo-controlled study [AVF4095g (NCT00434642)] studying Avastin with chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment (N=484). Patients were randomized (1:1) to receive Avastin (15 mg/kg day 1) or placebo every 3 weeks with carboplatin (AUC 4, day 1) and gemcitabine (1000 mg/m2 on days 1 and 8) a for 6 to 10 cycles followed by Avastin or placebo alone until disease progression or unacceptable toxicity. The main outcome measures were investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 61 years (28 to 87 years) and 37% of patients were ≥65 years. All patients had measurable disease at baseline, 74% had baseline CA-125 levels >ULN (35 U/mL). The platinum-free interval (PFI) was 6 months to 12 months in 42 % of patients and >12 months in 58% of patients. The ECOG performance status was 0 or 1 for 99.8% of patients.

A statistically significant prolongation in PFS was demonstrated among patients receiving Avastin with chemotherapy compared to those receiving placebo with chemotherapy (Table 16 and Figure 8). Independent radiology review of PFS was consistent with investigator assessment [HR 0.45 (95% CI: 0.35, 0.58)]. OS was not significantly improved with the addition of Avastin to chemotherapy [HR 0.95 (95% CI: 0.77, 1.17)].

Table 16: Efficacy Results in Study AVF4095g
Efficacy ParameterAvastin with Gemcitabine and Carboplatin(N=242)Placebo with Gemcitabine and Carboplatin(N=242)
Progression-Free Survival
Median, in months12.48.4
Hazard ratio (95% CI)0.46(0.37, 0.58)
p-value< 0.0001
Overall Response Rate
% patients with overall response78%57%
p-value< 0.0001
Figure 8: Kaplan-Meier Curves for Progression-Free Survival in Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study AVF4095g

Figure 8
(click image for full-size original)

Study GOG-0213

The safety and efficacy of Avastin were evaluated in a randomized, controlled, open-label study [Study GOG-0213 (NCT00565851)] of Avastin with chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy (N=673). Patients were randomized (1:1) to receive carboplatin (AUC 5) and paclitaxel (175 mg/m2 IV over 3 hours) every 3 weeks for 6 to 8 cycles (N=336) or Avastin (15 mg/kg) every 3 weeks with carboplatin (AUC 5) and paclitaxel (175 mg/m2 IV over 3 hours) for 6 to 8 cycles followed by Avastin (15 mg/kg every 3 weeks) as a single agent until disease progression or unacceptable toxicity. The main outcome measure was OS. Other outcome measures were investigator-assessed PFS, and ORR.

The median age was 60 years (23 to 85 years) and 33% of patients were ≥ 65 years. Eighty-three percent had measurable disease at baseline and 74% had abnormal CA-125 levels at baseline. Ten percent of patients had received prior bevacizumab. Twenty-six percent had a PFI of 6 months to 12 months and 74% had a PFI of >12 months. GOG performance status was 0 or 1 for 99% of patients.

Results are presented in Table 17 and Figure 9.

Table 17: Efficacy Results in Study GOG-0213
Efficacy ParameterAvastin with Carboplatin and Paclitaxel(N=337)Carboplatin and Paclitaxel(N=336)
*
HR was estimated from Cox proportional hazards models stratified by the duration of treatment free-interval prior to enrolling onto this study per IVRS (interactive voice response system) and secondary surgical debulking status.
HR was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status.
Overall Survival
Median, in months42.637.3
Hazard ratio (95% CI) (IVRS)*0.84 (0.69, 1.01)
Hazard ratio (95% CI) (eCRF)0.82 (0.68, 0.996)
Progression-Free Survival
Median, in months13.810.4
Hazard ratio (95% CI) (IVRS)*0.61 (0.51, 0.72)
Overall Response Rate
Number of patients with measurable disease at baseline274286
Rate, %213 (78%)159 (56%)
Figure 9: Kaplan Meier Curves for Overall Survival in Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study GOG-0213

Figure 9
(click image for full-size original)

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