TABLE 1

Combretastatin-based phase I–III clinical trials

Compound/(s)Patients EnrolledTumor Type/ PathologyRegimenMain OutcomesReference
Phase I
CA-4Pn = 25Refractory solid tumorsSingle-dose CA-4P 18–90 mg/m(2) repeated 3-week intervalcr = 1, 60 mg/m(2) upper boundary MTD, 6/7 decline in gradient peak tumor blood flow.Dowlati et al., 2002
CA-4Pn = 34Refractory solid tumorsCA-4P 5–114 mg/m(2)Well tolerated 14/16 patients at 52 or 68 mg/m(2). Improvement liver metastases n = 1.Rustin et al., 2003
CA-4Pn = 13Refractory solid tumorsCA-4P 5–114 mg/m(2)Significant dose-dependent reductions in tumor perfusion 30 min post–CA-4PAnderson et al., 2003
CA-4Pn = 37Refractory solid tumorsCA-4P 6–75 mg/m(2) daily for 5 days repeated on 3-week intervalspr = 1 (metastatic soft tissue carcinoma), sd = 14 52–65 mg/m(2), well-tolerated antitumor efficacy was observedStevenson et al., 2003
CA-4Pn = 25Refractory solid tumorsSingle-dose CA-4P 18–90 mg/m(2) repeated every 3 weeksCA4P prolongs QTc interval.
Advisable to limit patients with known coronary heart disease or risk factors from future trials.Cooney et al., 2004
CA-4P + carboplatinn = 16Refractory solid tumors40 cycles of carboplatin (AUC 4) and 5 mg min/mL; 60 min later CA-4P 27–36 mg/m(2) repeated on 3-week cyclesd = 6, dose-limiting
thrombocytopeniaBilenker et al., 2005
CA4P + bevacizumabn = 16Refractory solid tumorsBevacizumab (10 mg/kg) given 4 h after 2nd dose CA-4P 45–63 mg/m(2)Apparent diffusion coefficient measurements were reproducible in a two-center clinical trial settingKoh et al., 2009
CA-4P + (131)I-A5B7 anti-CEA antibodyn = 12Refractory colon/rectum or pancreatic tumors1800 MBq/m(2) (113)I-A5B7 on day 1, and 2–3 days later 45 mg/m(2) CA-4P repeated weeklymr = 1, sd = 3, pd = 7Meyer et al., 2009
CA-4Pn = 25Refractory solid tumorsCA-4P single-dose 5–85 mg/m(2)Well tolerated in Chinese patients at ≤65 mg/m(2), n = 7 dose-limiting toxicities at doses ≥65 mg/m(2), n = 1 obvious clinical responseHe et al., 2011
CA4P + bevacizumabn = 15Refractory solid tumorsCA-4P 45–63 mg/m(2) on days 1, 8 repeated every 2 weeks. Bevacizumab 10 mg/kg day 8 of subsequent cycles 4 h after CA-4P.CA-4P and bevacizumab combinations are well tolerated. sd = 3.Nathan et al., 2012
CA-1Pn = 43Refractory solid tumorsCA-1P 0.06–15.4 mg/m(2)MTD 8.5 mg/m(2). MTD can be raised to 14 mg/m(2) by excluding hypertension patients. Tumor response at 14 mg/m(2). Antivascular effects at ≥11 mg/m(2).Patterson et al., 2012
CA-4Pn = 8Age-related macular degenerationCA-4P 27 or 36 mg/m(2) weekly for 4 cyclesResults suggest potential efficacy. Transient hypertension.Ibrahim et al., 2013
AVE8062 + docetaxeln = 58Advanced solid tumorsAVE8062 11.5–42 mg/m(2) followed by docetaxel 75–100 mg/m(2) in 3-week cycles until disease progression or unacceptable toxicitypr = 10Eskens et al., 2014
CA-4Pn = 25Refractory solid tumorsCA-4P 20–85 mg/m(2)MTD = 65 mg/m(2). CA-4P is well tolerated with mild adverse events.Liu et al., 2014
CA-1Pn = 20Hepatic tumor burdenCA-1P on days 1, 8, and 15 of 28-day cycleCompleted. No results posted.https://clinicaltrials.gov
CA-1Pn = 16Hepatic tumor burdenCA-1P on days 1, 8, and 15 of 28-day cycle.Completed. No results posted.https://clinicaltrials.gov
AVE8062n = 15Advanced solid tumorsAVE8062 15–50 mg/m(2) once every 3 weeksRecommended dose is 50 mg/m(2).Murakami et al., 2014
AVE8062 + platinum salts + taxanesn = 71Advanced solid tumorsAVE8062 + platinum salts + taxanes every 3 weeksCompleted. No results posted.https://clinicaltrials.gov
AVE8062 + bevacizumabn = 39Advanced solid tumorsAVE8062 on day 1 Bevacizumab on day 2 every 3-week cycleCompleted. No results posted.https://clinicaltrials.gov
AVE8062 + cisplatinn = 12Advanced solid tumorsAVE8062 combined with 75 mg/m(2) cisplatin once every 3 weeksCompleted. No results posted.https://clinicaltrials.gov
AVE8062 + docetaxel + cisplatinn = 11Advanced solid tumorsAVE8062 + docetaxel + cisplatin once every 3 weeksCompleted. No results posted.https://clinicaltrials.gov
AVE8062 + paclitaxel + carboplatinn = 18Advanced solid tumorsAVE8062 + paclitaxel + carboplatin once every 3 weeksCompleted. No results posted.https://clinicaltrials.gov
CA-1PRecruitingRelapsed and refractory AML and MDSCA-1P [5 mg/m(2) ± 25% until MTD reached] given days 1, 8, 15, and 22 of a 28-day cycleTo determine safety and MTD.https://clinicaltrials.gov
BNC105Pn = 21Advanced solid tumorsBNC105P 2.1–18.9 mg/m(2)Recommended dose 16 mg/m(2).Rischin et al., 2011
Everolimus + BNC105Pn = 15Advanced RCCEverolimus 10 mg + BNC105P 4.2–16 mg/m(2); 21-day cycleEverolimus 10 mg + BNC105P 16 mg/m(2) daily identified as recommended dose to enter Phase IIPal et al., 2015
Phase Ib
CA4P + carboplatin or paclitaxeln = 21Refractory solid tumorsCA-4P 27–60 mg/m(2), 18–22 h later carboplatin (AUC 4–5) or paclitaxel 135–175 mg/m(2) every 3 weekspr = 6/9 ovarian cancer patients. Combinations are well tolerated with antitumor activity observed.Rustin et al., 2005
CA4P + carboplatin + paclitaxeln = 48Refractory solid tumorsCA-4P 27–72 mg/m2 (10-min infusion), 20 h later carboplatin AUC 4–5 paclitaxel 135–175 mg/m(2)Combinations were well tolerated. pr = 10 (22%).Rustin et al., 2010
CA-4P + radiotherapyn = 39NSCLC prostate adenocarcinoma SCCHN27–66 Gy in 6–33 fractions over 3–6 weeks, CA-4P 50–63 mg/m(2) 1, 3, or 6 doses. Patients with SCCHN also received cetuximab.Combinations were well tolerated. Responses were seen in 7/18 NSCLC patients.Ng et al., 2012
Pazopanib ± CA-4PRecruitingAdvanced recurrent ovarian cancerPazopanib 600 or 800 mg each day of 28-day cycle until disease progression. ±CA-4P 45–60 mg/m(2) every week for 3 weeks of a 4-week cycle. Max 6 cycles.Ongoing. Results will determine doses for Phase II.https://clinicaltrials.gov
Phase II
CA-4Pn = 26Anaplastic thyroid cancerCA-4P 45 mg/m(2) on days 1, 8, and 15 over 2 cycles and end of therapy sd = 7; 1/3 survived more than 6 months. Low baseline sICAM predictive of event-free survival.Mooney et al., 2009
Carboplatin + paclitaxel ± CA-4Pn = 18Relapsed ovarian cancerCA-4P 63 mg/m(2), 18 h later paclitaxel 175 mg/m(2) and carbopatin AUC 5 repeated every 3 weeksCombination is well tolerated. Addition of CA-4P to carboplatin and paclitaxel gave a higher response rate.Zweifel et al., 2011
CA-4P ± carboplatin/paclitaxeln = 80Anaplastic thyroid cancerCA-4P 60 mg/m(2) on days 1, 8, and 15. Carboplatin AUC 6 and paclitaxel 200 mg/m(2) day 2 every 3 weeks for 6 cycles. Then CA-4P days 1, 8 every 3 weeks or similar doses carboplatin and paclitaxel every 3 weeks for 6 cycles.Thyroidectomy followed by CA-4P showed a nonsignificant improvement in patient survival.Sosa et al., 2012
BNC105Pn = 30Advanced MPMBNC105P 16 mg/m(2) on days 1, 8 of a 21-day cycle. Repeated until progression or toxicity.BNC105P was safe and tolerable, but results were insufficient to warrant use as a single agent. pr = 1; sd = 13.Nowak et al., 2013
Carboplatin + paclitaxel + bevacizumab ± CA-4Pn = 60Chemotherapy naive NSCLCCarboplatin (AUC 6), paclitaxel [200 mg/m(2)], bevacizumab (15 mg/kg) day 1 of 21-day cycle. CA-4P [60 mg/ m(2)] or placebo on days 1, 7, and 14 every 3 weeks until progression or 12 months from randomizationRegimen including CA-4P cr = 0/32, pr = 18/32, sd = 8/32, pd = 1/32.https://clinicaltrials.gov
CA-4Pn = 23Choroidal neovasculariz-ation secondary to pathologic myopiaCA-4P 27–45 mg/m(2) on days 0 and 7 (±2 days) up to 3 additional treatmentsCompleted. No results posted.https://clinicaltrials.gov
CA-4Pn = 20Asian patients with PCVCA-4P single-dose 15–45 mg/m(2)Completed. No results posted.https://clinicaltrials.gov
Bevacizumab ± CA-4Pn = 107Recurrent fallopian tube, ovarian or peritoneal carcinomaBevacizumab ± CA-4P repeated every 21 days in absence of disease progression or unacceptable toxicityOngoing. Not recruiting. No results posted.https://clinicaltrials.gov
CA-4PRecruitingGI-NET with elevated biomarkersCA-4P 60 mg/m(2) on days 1, 8, and 15 of a 3-week cycle until progression or unacceptable toxicityOngoing. No results posted.https://clinicaltrials.gov
Taxane + platinum ± AVE8062n = 176Metastatic NSCLC with no prior treatmentAVE8062 35 mg/m(2) or placebo day 1. Followed by taxane-platinum. Repeated every 3 weeks. Max 6 cycles.Addition of AVE8062 to taxane-platinum did not improve progression- free survival.Von Pawel et al., 2014
Everolimus + BNC105Pn = 139Advanced RCCEverolimus 10 mg ± BNC105P 16 mg/m(2) dailyNo difference in mean PFS observed. Several biomarkers associated with BNC105P outcome.Pal et al., 2015
AVE8062 + paclitaxel + carboplatinn = 157Platinum-sensitive recurrent ovarian cancerAVE8062 or placebo and paclitaxel for min 6 cycles until disease progression or unacceptable toxicityCompleted. No results posted.https://clinicaltrials.gov
Carboplatin + gemcitabine ± BNC105Pn = 134Partially sensitive ovarian cancerCarboplatin AUC 4 on day 1 Gemcitabine 800–1000 mg/m(2) (determined in phase 1) on days 1 and 8, BNC105P (determined in phase 1) on days 2 and 9, 21-day cycle for 6 cycles. Single-agent maintenance BNCP105P 16 mg/m(2) for 6 additional cycles.Completed. No results posted.https://clinicaltrials.gov
Phase III
Cisplatin ± AVE8062n = 355Refractory soft tissue sarcomaAVE8062 25 mg/m(2) or placebo, followed by cisplatin 75 mg every 3 weeksCompleted. No results posted.https://clinicaltrials.gov
  • AML, acute myeloid leukemia; auc, area under the concentration-time curve; AVE8062, AC7700 or ombrabulin; BNC105P, 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan phosphate; CA-1P, combretastatin A-1 phosphate or OXi4503; CA-4P, combretastatin A-4 phosphate or fosbretabulin or fosbretabulin tromethamine or zybrestat; cr, complete response; GI-NET, gastrointestinal neuroendocrine tumors; MDS, myelodysplastic syndromes; MPM, malignant pleural mesothelioma; mr, minor response; MTD, maximum tolerated dose; NSCLC, nonsmall cell lung cancer; PCV, polypoidal choroidal vasculopathy; pd, progressive disease; PFS, progression-free survival; pr, partial response; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; sd, stable disease; sICAM, soluble intracellular adhesion molecule-1.