Anti-angiogenic therapies for metastatic colorectal cancer: Current and future perspectives

doi:10.3748/wjg.v19.i44.7955

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World Journal of Gastroenterology

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World J Gastroenterol. Nov 28, 2013; 19(44): 7955-7971
Published online Nov 28, 2013. doi: 10.3748/wjg.v19.i44.7955

Table 1 Clinical trials and main anti-angiogenic drugs in metastatic disease

Clinical trial	Phase	Line	Regimen	Median PFS (mo)	Median OS (mo)	ORR (%)
Aflibercept
VELOUR NCT00561470[87]	III	2^nd	FOLFIRI + aflibercept vs FOLFIRI + placebo	6.90 vs 4.67 HR = 0.758, P = 0.0001	13.50 vs 12.06 HR = 0.817, P = 0.0032	19.8 vs 11.1 P = 0.001
AFFIRM NCT00851084[86]	II	1^st	mFOLFOX6 + aflibercept vs mFOLFOX6	8.48 vs 8.77		49.1 vs 45.9
Brivanib
NCT00640471[90]	III	3^rd	Cetuximab + brivanib vs cetuximab + placebo	5.0 vs 3.4 HR = 0.72, P < 0.001	8.8 vs 8.1 HR = 0.88, P = 0.12	13.6 vs 7.2 P = 0.004
Regorafenib
CORRECT NCT01103323[99]	III	2^nd	Regorafenib vs placebo	1.9 vs 1.7 HR = 0.49, P < 0.000001	6.4 vs 5.0 HR = 0.77, P = 0.0052
Sorafenib
RESPECT NCT00865709[107]	II	1^st	mFOLFOX6 + sorafenib vs mFOLFOX6 + placebo	9.1 vs 8.7 HR = 0.88, P = 0.46	17.6 vs 18.1 HR = 1.13, P = 0.51
Sunitinib
NCT00668863	II	1^st
NCT00457691[108]	III	1^st	FOLFIRI + sunitinib vs FOLFIRI + placebo	7.8 vs 8.4 HR = 1.095, P = 0.807	20.3 vs 19.8 HR = 1.171, P = 0.916	32 vs 34 P = 0.683
Valatanib
CONFIRM1 NCT00056459[110]	III	1^st	FOLFOX4 + vatalanib vs FOLFOX4 + placebo	7.7 vs 7.6 HR = 0.88, P = 0.118	21.4 vs 20.5 HR = 1.08, P = 0.260	P > 0.05
CONFIRM 2 NCT00056446[111]	III	2^nd	FOLFOX4 + vatalanib vs FOLFOX4 + placebo	5.6 vs 4.2HR = 0.83, P = 0.013	13.1 vs 11.9HR = 1.00, P = 0.957

mCRC: Metastatic colorectal cancer; PFS: Progression-free-survival; OS: Overall survival; ORR: Overall response rate; FOLFIRI: 5-fluorouacil + leucovorin + irinotecan; mFOLFOX6: 5-fluoroaucil + leucovorin + oxaliplatin; HR: Harzard ratio.

Table 2 Current clinical trials considering anti-angiogenic therapies for colorectal cancer

	Trial	Phase	Line	Therapy/arms	Status of trial
Bevacizumab	NCT01321957	II	1^st	FOLFOX + bevacizumab vs FOLFOX + bevacizumab + irinotecan	Currently recruiting participants
	NCT00819780	II	1^st	Panitumumab + mFOLFOX6 vs bevacizumab + mFOLFOX6	Ongoing, but not recruiting participants
	NCT01531595	II	1^st	3 cycles of XELOX + bevacizumab alternating with 3 cycles of XELIRI + bevacizumab	Currently recruiting participants
	NCT01067053	II	1^st	Bevacizumab + capecitabine + oxaliplatin - 6 cycles; after the first 6 cycles of treatment, continuing only with bevacizumab and capecitabine	Ongoing, but not recruiting participants
	NCT01765582	II	1^st	FOLFOXIRI + bevacizumab vs Sequential FOLFOXIRI + bevacizumab vs FOLFOX + bevacizumab	Currently recruiting participants
	NCT01006369	II	-	FOLFOX6 + bevacizumab + hydroxychloroquine vs XELOX + bevacizumab + hydroxychloroquine	Currently recruiting participants
	NCT01417494	II	1^st	Chemotherapy (FOLFIRI, FOLFOX, LV5FU2) + bevacizumab vs Chemotherapy (FOLFIRI, FOLFOX, LV5FU2)	Currently recruiting participants
	NCT01532804	II	2^nd	FOLFOX6 + bevacizumab (day 1 = day 15, 12 cycles) vs Raltitrexed + oxaliplatin + bevacizumab ( day 1 = day 21, 8 cycles)	Currently recruiting participants
	NCT00952029	II/III	1^st	FOLFIRI + bevacizumab and during the chemotherapy-free interval maintenance with bevacizumab vs FOLFIRI + bevacizumab and during the chemotherapy-free interval NO maintenance	Currently recruiting participants
Cetuximab	NCT01640405	III	1^st	mFOLFOX6 + bevacizumab vs FOLFOXIRI + bevacizumab	Currently recruiting participants
	NCT00444678	II	-	Cetuximab + capecitabine + oxaliplatin	Ongoing, but not recruiting participants
	NCT01251536	II	1^st	Cetuximab (standard dose: 250 mg/m² weekly) vs Cetuximab (dose escalation: days 22 and 29-350 mg/m², from day 36 onwards - 500 mg/m² weekly)	Currently recruiting participants
	NCT01718808	II	1^st	Cetuximab + capecitabine vs Cetuximab	Currently recruiting participants
	NCT01867697	II	1^st	Cetuximab (biweekly) + FOLFIRI (continuously) vs Cetuximab (biweekly) + alternating FOLFIRI and mFOLFOX6	Currently recruiting participants
	NCT00640081	II	1^st	Intermittent chemotherapy plus intermittent cetuximab treatment (12 wk), plus cetuximab followed by a period off all therapy; reintroduction of the same chemotherapy and cetuximab regimen (12 wk after initial progression off treatment) vs Intermittent chemotherapy plus continuous cetuximab treatment (12 wk), plus cetuximab followed by a period of withdrawal of the chemotherapy, but continued weekly cetuximab monotherapy with reintroduction of the same chemotherapy regimen to the cetuximab (12 wk after initial progression off chemotherapy treatment)	Ongoing, but not recruiting participants
	NCT00479752	II	1^st	FOLFOX4 + cetuximab (initial dose: 400 mg/m² in week 1, followed by weekly doses of 250 mg/m²) vs FOLFOX4 + cetuximab (500 mg/m² every 2 wk)	Ongoing, but not recruiting participants
	NCT00482222	III	1^st	Oxaliplatin/fluoropyrimidine vs oxaliplatin/fluoropyrimidine + cetuximab pre and post surgery	Currently recruiting participants
	NCT00433927	III	1^st	FOLFIRI + cetuximab vs FOLFIRI + bevacizumab	Ongoing, but not recruiting participants
Panitumumab	NCT01228734	III	1^st	Cetuximab + FOLFOX4 vs FOLFOX4	Ongoing, but not recruiting participants
	NCT01030042	III	2^nd	FOLFOX4 followed, after progression, by irinotecan + cetuximab vs Cetuximab + irinotecan	Currently recruiting participants
	NCT00885885	II	-	Panitumumab + FOLFOX4 vs Panitumumab + FOLFOX4	Ongoing, but not recruiting participants
	NCT01215539	II	1^st	Panitumumab + capecitabine + oxaliplatin	Currently recruiting participants
	NCT01126112	II	1^st	Panitumumab (6 mg/kg every 2 wk )	Ongoing, but not recruiting participants
	NCT00819780	II	1^st	Panitumumab + mFOLFOX 6 vs bevacizumab + mFOLFOX 6	Ongoing, but not recruiting participants
	NCT01328171	II	1^st	FOLFOXIRI + panitumumab vs FOLFOXIRI	Currently recruiting participants
	NCT01508000	II	1^st	mFOLFOX6 (6 cycles after and before surgery) + surgery vs mFOLFOX6 + bevacizumab (6 cycles after and before surgery) + surgery vs mFOLFOX6 + panitumumab (6 cycles after and before surgery) + surgery	Not yet open for participant recruitment
	NCT01814501	II	2^nd	5-FU + irinotecan + panitumumab	Currently recruiting participants
	NCT00940316	II	2^nd	Erlotinib + panitumumab + irinotecan (treatment repeats every 2 wk) vs Erlotinib + panitumumab (treatment repeats every 2 wk) vs Erlotinib + panitumumab	Currently recruiting participants
	NCT00364013	III	1^st	FOLFOX + panitumumab vs FOLFOX	Ongoing, but not recruiting participants
	NCT01910610	III	1^st	FOLFIRI + cetuximab, followed by oxaliplatin-based chemotherapy + bevacizumab vs OPTIMOX + bevacizumab, followed by irinotecan-based chemotherapy + bevacizumab, followed by an anti-EGFR agent (cetuximab +/- irinotecan or panitumumab) with or without irinotecan	Not yet open for participant recruitment
Aflibercept	NCT01669720	II	2^nd	Aflibercept iv (4 mg/kg every 2 wk)	Currently recruiting participants
	NCT01652196	II	1^st	Aflibercept iv + mFOLFOX 6 iv (days 1 and 15; repeats every 28 d)	Currently recruiting participants
	NCT01802684	II	1^st	Induction therapy (sequence #1)Regimen: Aflibercept + mFOLFOX7 - 6 cycles (3 mo) Maintenance after induction (sequence #2) First phase (sequence #2A); Regimen: Aflibercept + fluoropyrimidine (simplifed LV5FU2 or capecitabine) - 6 cycles (3 mo) Second phase (sequence #2B); Regimen: Aflibercept +/- fluoropyrimidine (simplifed LV5FU2 or capecitabine) - until PD or limiting toxicity Reintroduction (sequence #3); Regimen: Aflibercept + mFOLFOX7 - 6 cycles (3 mo) Maintenance after reintroduction (sequence #4); Regimen: Aflibercept + fluoropyrimidine - until PD or limiting toxicity	Not yet open for participant recruitment
	NCT01882868	II	2^nd	Aflibercept iv + FOLFIRI Aflibercept + FOLFIRI (every 2 wk)	Currently recruiting participants
	NCT01889680	II	1^st	mFOLFOX6 + aflibercept (every 14 d for 6 cycles) plus 5-FU/LV (every 14 d) vs mFOLFOX6 + aflibercept (every 14 d for 6 cycles) plus 5-FU/LV + aflibercept (every 14 d)	Not yet open for participant recruitment
	NCT01646554	II/III	1^st	mFOLFOX6 and SURGERY 6 cycles before and 6 cycles after surgery consisting in: Hour 0: Oxaliplatin 85 mg/m²iv 2-h infusion; Hour 0: Folinic acid 400 mg/m² (DL form) or 200 mg/m² (L form) iv 2-h infusion; Hour 2: 5-FU 400 mg/m²iv bolus over 2-4 min; Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46 h; On day 1 of a 14 d cycle vs mFOLFOX6 + aflibercept and surgery; 6 cycles before and 6 cycles after surgery consisting in: Hour 0: Aflibercept 4 mg/kg intravenous infusion 1-h; Hour 1: Oxaliplatin 85 mg/m² 2-h infusion; Hour 1: Folinic acid 400 mg/m² (DL form) or 200 mg/m² (L form) 2-h infusion; Hour 3: 5-FU bolus 400 mg/m²iv bolus over 2-4 min; Hour 3: 5-FU 2400 mg/m² given as a continuous infusion over 46 h; Day 1 of a 14 day cycle	Not yet open for participant recruitment
	NCT01661270	III	2^nd	Aflibercept iv (day 1 of each cycle, every 2 wk) + FOLFIRI vs Placebo iv (day 1 of each cycle, every 2 wk) + FOLFIRI	Currently recruiting participants
	NCT01571284	III	2^nd	Aflibercept IV (every 2 wk ) + FOLFIRI	Currently recruiting participants
	NCT01670721	III	2^nd	Aflibercept IV (on day 1) + FOLFIRI administered as follows: dI-leucovorin infusion over 2 h on day 1; Irinotecan: infusion over 90-min infusion, on day 1, followed by bolus 5-FU and 5-FU continuous infusion over 46 h or as individualized by physician's clinical judgment; Treatment cycle to be administered every 2 wk	Currently recruiting participants
Brivanib	NCT01367275	II	2^nd	Brivanib (800 mg orally daily days 1-14) + Irinotecan iv (180 mg/m² on day 1)	Ongoing, but not recruiting participants
Cediranib	NCT00588900	II	2^nd	Irinotecan iv (days 1 and 8) + Cediranib oral (days 1-21)	The recruitment status of this study is unknown because the information has not been verified recently
Ramucirumab	NCT01111604	II	2^nd	mFOLFOX-6 vs mFOLFOX-6 + ramucirumab ( 8 mg/kg iv infusion, administered every 2 wk) vs mFOLFOX-6 + icrucumab ( 15 mg/kg iv infusion, administered every 2 wk)	Ongoing, but not recruiting participants
Ramucirumab	NCT01183780	III	2^nd	FOLFIRI + ramucirumab ( 8 mg/kg administered intravenously every 2 wk) vs FOLFIRI + placebo	Currently recruiting participants
Regorafenib	NCT01298570	II	2^nd	Regorafenib (160 mg, po, daily, per 7 day cycle) + FOLFIRI (day 1 and day 15 of each 28 d cycle) vs Placebo (oral administration, days 4-10 and days 18-24 of 28 day cycle +)+ FOLFIRI (day 1 and day 15 of each 28 d cycle)	Currently recruiting participants
	NCT01289821	II	1^st	Day 1 and day 15 of each cycle: 85 mg/m² oxaliplatin + folinic acid (either 400 mg/m² D/L-folinic acid or 200 mg/m² L-folinic acid), iv + 400 mg/m² 5 FU iv + 2400 mg/m² 5 iv; Days 4 to 10 and days 18 to 24: regorafenib 160 mg (four 40 mg tablets)	Ongoing, but not recruiting participants
	NCT01875380	II	1^st	Regorafenib (orally, 160 mg per day for 3 wk, followed by 1 wk of rest)	Not yet open for participant recruitment
	NCT01103323	III	2^nd	Regorafenib (160 mg per oral once daily for 3 wk on 1 wk off of every 4 wk cycle) vs Placebo (per oral once daily for 3 wk on 1 wk off of every 4 wk cycle)	Ongoing, but not recruiting participants
	NCT01584830	III	2^nd	Regorafenib [3 wk on/1 wk off (160 mg od po)]Placebo [3 wk on/1 wk off (160 mg od po)]	Ongoing, but not recruiting participants
	NCT01853319	III	2^nd	Regorafenib (160 mg per oral every day for 3 wk of every 4 wk cycle)	Not yet open for participant recruitment
	NCT01538680	III	2^nd	Regorafenib (160 mg po every day for 3 wk on, 1 wk off)	Expanded access is currently available for this treatment
Semaxanib	NCT00021281	III	1^st	Semaxanib iv (on days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36 and 39) + irinotecan iv, leucovorin calcium iv, fluorouracil iv (on days 1, 8, 15, and 22) (every 6 wk) vs Irinotecan iv, leucovorin calcium iv, fluorouracil iv (on days 1, 8, 15, and 22) (every 6 wk) vs Semaxanib iv (on days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36 and 39) + irinotecan iv (days 1, 15 and 29) + leucovorin calcium iv, fluorouracil iv (on days 1, 2, 15, 16, 29 and 30) vs Irinotecan iv, leucovorin calcium iv, fluorouracil iv (on days 1, 8, 15, and 22) (every 6 wk)	The recruitment status of this study is unknown because the information has not been verified recently
Sorafenib	NCT01715441NEXIRI 2	II	2^nd	Irinotecan 180 mg/m²iv with cross over to irinotecan and sorafenib combination at progression vs Sorafenib 400 mg twice daily with cross over to irinotecan and sorafenib combination at progression vs Irinotecan 120 mg/m²iv at cycle 1, 150 mg/m² at cycle 2 and 180 mg/m² at cycle 3 + sorafenib 400 mg twice daily from cycle 1	Currently recruiting participants
	NCT01471353	II	2^nd	Sorafenib 200-400 mg po twice daily on days 1-21 (dose escalation scheme) + capecitabine 1000 mg/m²po twice daily on days 1-14 repeated every 21 d	Currently recruiting participants
	NCT00826540	II	2^nd	Sorafenib twice daily on days 1-5 and 8-12 + bevacizumab iv on day 1	Ongoing, but not recruiting participants
	NCT00839111	II	2^nd	Sorafenib (400 mg twice daily from day 3 to day 14, day 17-28) + FOLFIRI	The recruitment status of this study is unknown because the information has not been verified recently
	NCT01290926	II	2^nd	Sorafenib (200 mg in the morning, 400 mg in the evening) + capecitabine (850 mg/m² twice daily)	The recruitment status of this study is unknown because the information has not been verified recently
	NCT00326495	II	2^nd	Oral sorafenib (400 mg by twice daily) plus cetuximab (400 mg/m², week 1; 250 mg/m²iv, weekly)	Currently recruiting participants
Sunitinib	NCT00936832	II	1^st	FOLFIRI (on days 1, 15, and 29) + oral sunitinib (on days 1-28). (repeats every 6 wk)	The recruitment status of this study is unknown because the information has not been verified recently

Research on July 25, 2013 (http://clinicaltrials.gov.). 5-FU: 5-fluoraucil; FOLFIRI: 5-fluorouacil + leucovorin + irinotecan; mFOLFOX6: 5-fluoroaucil + leucovorin + oxaliplatin; HR: Harzard ratio.

Citation: Marques I, Araújo A, Mello RA. Anti-angiogenic therapies for metastatic colorectal cancer: Current and future perspectives. World J Gastroenterol 2013; 19(44): 7955-7971
URL: https://www.wjgnet.com/1007-9327/full/v19/i44/7955.htm
DOI: https://dx.doi.org/10.3748/wjg.v19.i44.7955