Table Selected Clinical Trials of Anti-Angiogenesis Therapy in Gynecologic Malignancies

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1 Table Selected Clinical Trials of Anti-Angiogenesis Therapy in Gynecologic Malignancies Uterus Study N Eligibility Regimen RR (No. of Responses) Median OS Grade 3/4 Toxicities Nimeiri et al[42] Total: 56 Carcinoma: 40 CS: 16 Simpkins et al[36] Advanced 15 Advanced GOG 229E[37] 52 Recurrent GOG 229F[38] 44 Recurrent or persistent GOG 229G[39] 49 Recurrent or persistent PO sorafenib (400 mg) twice daily 5% (2) Paclitaxel (175 mg/m 2 ), carboplatin (AUC=5) and bevacizumab (15 mg/kg) q21d 6 8 cycles, plus maintenance bevacizumab 16 cycles if complete response Bevacizumab (15 mg/kg) 11.4 mo HTN (13%), PPE (13%) 0 5 mo 73% (11) 58 mo Hematologic (66%), GI (13%); 1 case each of: anorexia, diarrhea, fatigue, pain, tinnitus 13.5% (7) 10.5 mo HTN (8%) Aflibercept (4 mg/kg) q2wk 7% (3) 14.6 mo Cardiovascular (28%), constitutional (7%), hemorrhage (7%), metabolic (9%), pain (18%): 2 deaths: GI perforation, arterial rupture Bevacizumab (10 mg/kg) every other week, with temsirolimus (25 mg) IV weekly 24.5% (12) 16.9 mo Metabolic (37%), GI (37%) RTOG 0921[40] 30 Primary adjuvant treatment for high-risk carcinoma after surgical resection RTOG 0921[40] 15 Recurrent Castonguay et al[43] 34 Advanced GOG229I[44] 43 Advanced GOG 229K[45] 32 Advanced Pelvic IMRT (45 Gy/25 fx) with cisplatin (50 mg/m 2 weekly 2 wks) and bevacizumab (5 mg/kg weekly 3 wks), followed by adjuvant carboplatin (AUC=5) and paclitaxel (135 mg/m 2 ) 4 cycles Bevacizumab (10 mg/kg) q2wk for 3 doses during external beam radiation PO sunitinib malate (50 mg) daily; 4 wks on/2 wks off PO brivanib alaninate (800 mg) daily PO nintedanib (200 mg) twice daily 1-yr OS: 93%, 3-yr OS: 80% 1 case each of: fatigue, electrolyte imbalance, HA, hot flashes, tinnitus, epistaxis, pain, neuralgia 1 case of portal venous thrombus 18.1% 19.4 mo Fatigue (50%), HTN (23%), PPE (17%), diarrhea (13%) 18.6% 10.7 mo (90% CI: ) HTN (25%), GI (16%), metabolic (13%), nausea (10%); 1 case each of: death (multi-organ failure), intestinal fistula 9.4% 10.1 mo GI (25%), transaminitis (16%); 1 case each of: edema, HTN, neutropenia, nausea 230 Oncology May 2015 cancernetwork.com

2 Table continued Selected Clinical Trials of Anti-Angiogenesis Therapy in Gynecologic Malignancies Ovary Study N Eligibility Regimen Median PFS GOG 218[50] 1,873 Incompletely and completely resected FIGO III or any FIGO IV ICON-7[51] 1,528 FIGO I IIA (clear cell, grade 3); FIGO IIB-IV OCEANS[52] 484 Platinumsensitive recurrence AURELIA[53] 361 Platinumresistant recurrence; 2 prior chemo regimens; no e/o rectosigmoid involvement (175 mg/m 2 ) + placebo; followed by placebo maintenance (175 mg/m 2 ) + bevacizumab (15 mg/kg); placebo maintenance (175 mg/m 2 ) + bevacizumab (15 mg/kg); bevacizumab (15 mg/kg) maintenance (175 mg/m 2 ) (175 mg/m 2 ), bevacizumab (7.5 mg/kg); bevacizumab (7.5 mg/kg) maintenance Carboplatin (AUC=4), gemcitabine (1,000 mg/m 2 ), placebo Carboplatin (AUC=4), gemcitabine (1,000 mg/m 2 ), bevacizumab (15 mg/kg) Paclitaxel (80 mg/m 2 ) on days 1, 8, 15, 22 q4wk or Topotecan (4 mg/m 2 ) on days 1, 8, 15 q4wk or Liposomal doxorubicin (40 mg/m 2 ) q4wk Chemotherapy as above plus bevacizumab (15 mg/kg) 10.3 mo 11.2 mo 14.1 mo HR: 0.72; ; 17.3 mo 19.0 mo HR: 0.81; ; P = mo 12.4 mo HR: 0.48; ; 3.4 mo 6.7 mo HR: 0.48; ; Median OS 39.3 mo 38.7 mo 39.7 mo HR: 0.92: 95% CI: ; P = mo 58 mo HR: 0.99; 95% CI: ; P = mo 16.6 mo HR: 0.85; 95% CI: ; P =.17 Toxicities HTN (22.9%), GI (2.6%), proteinuria (1.6%), VTE (6.7%) Bleeding (1%), HTN (6%), VTE (4%), GI (1%), neutropenia (17%) HTN (17.4%), proteinuria (8.5%), bleeding (5.7%), F/A (1.6%), VTE (4%) HTN (20.1%), proteinuria (12.8%), F/A (2.2%), GI (1.7%), VTE (3.4%) cancernetwork.com Oncology May

3 Table continued Selected Clinical Trials of Anti-Angiogenesis Therapy in Gynecologic Malignancies Ovary continued Study N Eligibility Regimen Median PFS Median OS Toxicities AGO- OVAR16[54] 940 FIGO II IV, no evidence of progression after surgery and 5 cycles platinum-taxane therapy PO pazopanib (800 mg) once daily for up to 24 mos Placebo once daily for up to 24 mos 17.9 mo 12.3 mo HR: 0.77; 95% CI: ; P =.002 Pazopanib 27% vs placebo 11%: HTN, diarrhea, nausea, headache, fatigue, neutropenia ICON-6[55] 456 Platinumsensitive recurrence Chemotherapy (choice of platinum + paclitaxel, platinum + gemcitabine, carboplatin alone; ), PO placebo; maintenance PO placebo Chemotherapy as above, PO cediranib (20 mg) daily; maintenance PO cediranib (20 mg) Chemotherapy as above, PO cediranib (20 mg) daily; maintenance PO placebo 9.4 mo 12.5 mo HR: 0.57; 95% CI: ; P = mo 20.3 mo HR: 0.70; 95% CI: ; P =.04 HTN (7%), diarrhea (5%), fatigue (20%), voice change (21%), bleeding (25%) TRINOVA-1[10] 919 FIGO IIB IV PO nintenanib (200 mg) BID, paclitaxel (175 mg/m 2 ), carboplatin (AUC=5 or 6) ; nintenanib (200 mg) PO BID for up to 120 wks PO placebo BID, paclitaxel (175 mg/m 2 ), carboplatin (AUC=5 or 6) ; placebo PO BID for up to 120 wks 17.3 mo 16.6 mo HR: 0.84; 95% CI: ; P = mo 17.7 mo Neutropenia (44%), anemia (14%), thrombocytopenia (18%), GI (20%), transaminitis (15%), HTN and fatigue (4%) Liu et al[70] 100 Recurrent platinumsensitive germline BRCA 1/2 mutation PO olaparib (400 mg) BID PO cediranib (30 mg) daily, PO olaparib (200 mg) BID HR: 0.42; 95% CI: ; P =.005 Nonbevacizumab: 14 vs 10 mos; HR: 0.60; 95% CI: Bevacizumab: 15 mos for both; HR: 1.06; Conventional vs dose-dense paclitaxel: HR: 0.97; 95% CI: HTN (39%), diarrhea (23%), fatigue (27%), nausea (5%), headache (5%) GOG FIGO II-IV and suboptimal residual (> 1 cm) after surgery Carboplatin (AUC=6), paclitaxel (175 mg/m 2 ) or (80 mg/m 2 on days 1, 8, 15) plus bevacizumab (15 mg/ kg) on day 1 beginning with cycle 2, administered, followed by maintenance bevacizumab until progression or toxicity (provider choice) 232 Oncology May 2015 cancernetwork.com

4 Table continued Selected Clinical Trials of Anti-Angiogenesis Therapy in Gynecologic Malignancies Ovary continued Study N Eligibility Regimen Median PFS Median OS Toxicities GOG Recurrent platinum-sensitive EOC, after randomization to secondary cytoreductive surgery Paclitaxel over 3 hrs or docetaxel over 1 hr and carboplatin IV over 60 min on day 1; 6 8 cycles Paclitaxel over 3 hrs or docetaxel over 1 hr and carboplatin IV over 60 min on day 1; 6 8 cycles; plus bevacizumab Bevacizumab (15 mg/kg) on day 1 beginning on cycle 2 for 21 cycles plus: IV paclitaxel (80 mg/m 2 ) on days 1, 8, and 15, plus IV carboplatin (AUC=6) on day 1; 6 cycles vs IV paclitaxel (80 mg/m 2 ) on days 1, 8, and 15 plus IP carboplatin (AUC=6) on day 1; 6 cycles vs IV paclitaxel (135 mg/m 2 ) on day 1 plus IP cisplatin (75mg/ m 2 ) on day 2 plus IP paclitaxel (60 mg/m 2 ) on day 8; 6 cycles 10.4 mo 13.8 mo HR: 0.61; 95% CI: ; P < mo 42.2 mo HR: 0.83; 95% CI: ; P =.06 Neutropenia (84%), GI perforation/abscess (15%), infection (13%), HTN (12%), proteinuria (8%), VTE (4%) GOG 252 1,500 FIGO II IV EOC, fallopian tube, or primary peritoneal carcinoma, either optimal residual ( 1 cm) or suboptimal residual (closed to accrual) GOG 0186I 107 Recurrent EOC Bevacizumab (15 mg/kg) vs Bevacizumab (15 mg/kg), fosbretabulin tromethamine IV 4.8 mo 7.3 mo HR: 0.69; 90% CI: HTN (35% combo vs 16% bevacizumab alone). 1 case each of: grade 3 VTE (combo), GI perforation (bevacizumab alone) TRINOVA-3 1,015 FIGO III IV EOC, primary peritoneal, or fallopian tube carcinoma Paclitaxel (175 mg/m 2 ), carboplatin (AUC=5 or 6) 6 cycles plus: AMG 386 (15 mg/kg) IV weekly (until progression or unacceptable toxicity develops) or Placebo AMG 386 IV weekly (closed to accrual) cancernetwork.com Oncology May

5 Table continued Selected Clinical Trials of Anti-Angiogenesis Therapy in Gynecologic Malignancies Cervix continued Study N Eligibility Regimen RR Median OS Toxicities Kudelka et al[71] GOG 227C [59] VEG [72] 18 Recurrent or 46 Recurrent 152 Recurrent, CIRCCa[73] 69 Recurrent, RTOG 0417[74] 49 Locally advanced GOG 240[60] 452 Recurrent, TNP-470 ( mg/m 2 ) every other day (phase I) 22% Grade 2 4 AEs: GI (33%), neurologic (28%) Bevacizumab (15 mg/kg) PR: 10.9% 7.3 mo (range: mo) Pazopanib (800 mg) daily Lapatinib (1,500 mg) daily Combination therapy (discontinued for futility and unacceptable toxic effects) (175 mg/m 2 ) ; cediranib (20 mg) daily (175 mg/m 2 ), placebo Definitive radiation therapy plus cisplatin (40 mg/m 2 ) q1wk plus bevacizumab (10 mg/kg) q2wk Cisplatin (50 mg/m 2 ) plus paclitaxel (135 or 175 mg/m 2 ) Topotecan (0.75 mg/m 2, days 1 3) plus paclitaxel (175 mg/m 2 ) Cisplatin (50 mg/m 2 ) plus paclitaxel (135 or 175 mg/m 2 ) plus bevacizumab (15 mg/kg) Topotecan (0.75 mg/m 2, days 1 3) plus paclitaxel (175 mg/m 2 ) plus bevacizumab (15 mg/kg) 9% 5% 66% 42% 12.7 mo 9.8 mo HR: 0.67; 90% CI: ; P = mo 15.8 mo P =.03 HR: 0.93; 95% CI: ; P =.41 3-yr OS: 81.3% 45% 50% P = mo 17 mo HR: 0.71; 95% CI: ; P =.004 Common grade 3/4 AEs: HTN (15%), VTE (11%), and GI (9%); grade 5 infection (1%) Common AEs for pazopanib vs lapatinib arms: diarrhea (54% vs 58%), nausea (36% vs 33%), HTN (30% vs 3%), anorexia (28% vs 32%), any grade 4 (12% vs 9%) Grade 2 4 AEs for cediranib vs placebo arms: diarrhea (50% vs 18%), HTN (34% vs 12%); any grade (19% vs 9%) Grade 3/4 AEs: hematologic (29%), GI (6%), neurologic (4%), renal (4%) Grade 3/4 AEs in bevacizumab arm: VTE (8%), GI or genitourinary fistulas (6%), and HTN (25%) AE = adverse event; AUC = area under the curve; AVO-OVAR = Arbeitgemeinschaft Gynäkologische Onkologie Studiengruppe Ovarialkarzinom; CI = confidence interval; CIRCCa = Cediranib in Recurrent Cervical Cancer; CS = carcinosarcoma; EOC = epithelial ovarian carcinoma; F/A = fistula/abscess; FIGO = International Federation of Gynecology and Obstetrics; GI = gastrointestinal; GOG = Gynecologic Oncology Group; H/A = headache; HTN = hypertension; HR = hazard ratio; ICON = International Collaborative Ovarian Neoplasm; IMRT = intensity-modulated radiation therapy; = not available; OS = overall survival; PFS = progression-free survival; PPE = palmar-plantar erythrodysesthesia; PR = partial response; RR = response rate; RTOG = Radiation Therapy Oncology Group; TRINOVA = Trebananib in Ovarian Cancer; VTE = venous thromboembolism. 234 Oncology May 2015 cancernetwork.com