A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors

BackgroundAxitinib and bevacizumab are targeted therapies against the vascular endothelial growth factor pathway.MethodsPatients with previously treated solid tumors received axitinib (starting dose 5 mg twice daily) combined with FOLFOX plus bevacizumab (1, 2, or 5 mg/kg, cohorts 1–3, respectively), FOLFIRI (cohort 4), or FOLFOX (cohort 5). Safety and pharmacokinetics were assessed.ResultsThirty patients were enrolled (n = 16, 8, and 6 for cohorts 1–3, 4, and 5, respectively). Plasma concentrations and pharmacokinetic (PK) parameters were similar when drugs were administered alone and in various combinations. Most treatment-emergent adverse events (AEs) were mild to moderate and clinically manageable (most common: nausea, fatigue, diarrhea, anorexia, hypertension). Two of the four patients receiving axitinib with FOLFOX plus 5 mg/kg bevacizumab experienced dose-limiting toxicity (DLT) of inability to resume treatment for 14 days following treatment interruption (associated AE: hypertension); the maximum tolerated dose of bevacizumab in this combination was 2 mg/kg. No DLTs occurred with axitinib plus FOLFIRI or FOLFOX. Ten patients had RECIST-confirmed partial tumor responses (objective response rate: 33.3%).ConclusionAxitinib is well tolerated in combination with FOLFOX, FOLFIRI, or FOLFOX plus 2 mg/kg bevacizumab. PK interactions appear to be absent.     

A phase I/II,open-label,randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients

BackgroundThis randomised, open-label, phase I/II study evaluated the efficacy and safety of nintedanib, an oral, triple angiokinase inhibitor, combined with chemotherapy, relative to bevacizumab plus chemotherapy as first-line therapy in patients with metastatic colorectal cancer (mCRC).Patients and methodsPatients with histologically confirmed mCRC (adenocarcinoma), an Eastern Cooperative Oncology Group performance status ≤2 and adequate organ function were included. Patients were randomised 2:1 to receive nintedanib 150 mg or 200 mg b.i.d. plus mFOLFOX6 (oxaliplatin 85 mg/m², l-leucovorin 200 mg/m² or d,l-leucovorin 400 mg/m², 5-fluoruracil bolus 400 mg/m² followed by 2400 mg/m², every 2 weeks) or bevacizumab (5 mg/kg every 2 weeks) plus mFOLFOX6. During phase I, patients underwent a 3 + 3 dose-escalation schema to determine the maximum tolerated dose (MTD) of nintedanib in combination with mFOLFOX6. The primary end point was progression-free survival (PFS) rate at 9 months. Objective response (OR) was a secondary end point.ResultsThe nintedanib recommended phase II dose was 200 mg b.i.d. plus mFOLFOX6 based on safety data from phase I (n = 12). Of 128 patients randomised in the phase II part, 126 received treatment (nintedanib plus mFOLFOX6, n = 85; bevacizumab plus mFOLFOX6, n = 41). PFS at 9 months was 62.1% with nintedanib and 70.2% with bevacizumab [difference: -8.1% (95% confidence interval -27.8 to 11.5)]. Confirmed ORs were recorded in 63.5% and 56.1% of patients in the nintedanib and bevacizumab groups, respectively. The incidence of adverse events (AEs) considered related to treatment was 98.8% with nintedanib and 97.6% with bevacizumab; the incidence of serious AEs was 37.6% with nintedanib and 53.7% with bevacizumab. The pharmacokinetics of nintedanib and the components of mFOLFOX6 were unaffected by their combination.ConclusionsNintedanib in combination with mFOLFOX6 showed efficacy as first-line therapy in patients with mCRC with a manageable safety profile and further studies in this population are warranted.     

Bevacizumab combined with chemotherapy in the second-line treatment of metastatic colorectal cancer: results from the phase II BEVACOLOR study

BackgroundThis prospective phase II study assessed the efficacy and safety of bevacizumab plus chemotherapy regimens commonly used in the second-line treatment of metastatic colorectal cancer (mCRC).MethodsPatients with mCRC who progressed or relapsed after first-line oxaliplatin-based or irinotecan-based treatment received bevacizumab 2.5 mg/kg/week plus chemotherapy until disease progression. The primary endpoint was disease-control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety.ResultsFifty-three patients (66% men; median age, 62 years old) received second-line bevacizumab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI; 57%), folinic acid, fluorouracil, oxaliplatin (FOLFOX; 26%), irinotecan (15%), or capecitabine plus irinotecan (XELIRI; 2%). The DCR was 87% (95% CI, 77%-97%); ORR was 32% (95% CI, 19%-46%). Median PFS was 6.5 months (95% CI, 5.8-7.8 months) and median OS 19.3 months, (95% CI, 14.2-25.1 months).The most frequent grade 3/4 adverse events included neutropenia (21%), diarrhea (15%), asthenia, and vomiting (9% each). Five patients (9%) had grade 3/4 targeted toxicities: grade 3 hypertension (n = 2), grade 3 venous thromboembolism (n = 2), and grade 4 arterial thromboembolism (n = 1). None of these events led to death during the study.ConclusionBevacizumab plus standard second-line chemotherapy is highly active in patients with mCRC and has an acceptable safety profile.     

Phase I trial of oxaliplatin, infusional 5-fluorouracil, and leucovorin (FOLFOX4) with erlotinib and bevacizumab in colorectal cancer

RationaleThis phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD.Patients and MethodsPatients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously. Bevacizumab 5 mg/kg days 1 and 15 was added at the MTD upon Food and Drug Administration approval. Correlative studies included pharmacokinetics, pharmacodynamics was assessed in paired skin biopsies, and fluorodeoxyglucose positron emission tomography scans.ResultsFifteen patients received 60 cycles (120 FOLFOX treatments). Two dose-limiting toxicities (DLTs) were seen at DL 3: intolerable grade 2 rash (Common Terminology Criteria for Adverse Events version 2) lasting > 1 week, and grade 4 neutropenia. Dose level 2 was expanded to 6 more patients, this time adding bevacizumab, and 1 DLT of grade 3 mucositis occurred. As expected, the primary toxicities were cytopenias, diarrhea, rash, and fatigue. There were 2 occurrences of pneumatosis. One patient experienced an unrelated grade 4 myocardial infarction before starting chemotherapy. No pharmacokinetic drug interactions were observed. The Response Evaluation Criteria in Solid Tumors response rate was 11 of 14 (78%), median progression-free survival was 9.5 months, and median overall survival was 30 months. Three patients are currently alive > 3 years, with 1 having no evidence of disease.ConclusionThe MTD of erlotinib with FOLFOX4 with or without bevacizumab is 100 mg daily. The regimen appeared to increase toxicity but showed activity in patients with CRC.     

Axitinib or Bevacizumab Plus FOLFIRI or Modified FOLFOX-6 After Failure of First-Line Therapy for Metastatic Colorectal Cancer: A Randomized Phase II Study

ObjectiveAxitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, shows activity in multiple tumor types, including those refractory to previous antiangiogenic therapy. This randomized, multicenter, parallel-group, open-label phase II trial compared axitinib with bevacizumab each in combination with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) for second-line treatment of metastatic colorectal cancer.MethodsPatients were randomized 1:1 to axitinib 5 mg twice daily or bevacizumab 5 mg/kg every 2 weeks plus modified FOLFOX-6 (if previously treated with irinotecan) or FOLFIRI (if previously treated with oxaliplatin) and were stratified by performance status and prior bevacizumab therapy. Primary endpoint was progression-free survival.ResultsIn 171 patients, progression-free survival was 7.6 months with axitinib/FOLFOX vs. 6.4 months with bevacizumab/FOLFOX (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.55-1.96; 1-sided P = .55) and 5.7 months with axitinib/FOLFIRI vs. 6.9 months with bevacizumab/FOLFIRI (HR, 1.27; 95% CI, 0.77-2.11; 1-sided P = .83). Overall survival was 17.1 vs. 14.1 months with axitinib/FOLFOX and bevacizumab/FOLFOX (HR, 0.69; 95% CI, 0.37-1.27; 1-sided P = .12) and 12.9 vs. 15.7 months with axitinib/FOLFIRI and bevacizumab/FOLFIRI (HR, 1.36; 95% CI, 0.82-2.24; 1-sided P = .88). More grade ≥ 3 adverse events (eg, diarrhea, fatigue, decreased appetite) and treatment discontinuations due to adverse events occurred with axitinib.ConclusionsCompared with bevacizumab, axitinib did not improve outcomes when added to second-line chemotherapy for metastatic colorectal cancer. With current dosing regimens, axitinib plus FOLFOX or FOLFIRI seems to be less well tolerated than bevacizumab-based regimens.     

Mechanism of action of everolimus in renal cell carcinoma

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown clinical activity in metastatic colorectal cancer patients when used as either a first-line or second-line treatment. Here, we evaluated the efficacy and safety of bevacizumab plus FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) or FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) in metastatic colorectal cancer cases after failure to FOLFIRI and FOLFOX. Between October 2004 and February 2007, the data on 42 patients with metastatic colorectal cancer after failure of FOLFIRI and FOLFOX were reviewed retrospectively. All patients were treated with bevacizumab plus FOLFIRI or FOLFOX. The median patient age was 57.0 years. The ECOG performance status was 0 or 1 in 27 patients (64.3%). The number of previous chemotherapy regimens was ≥3 in 35 patients (83.3%). Thirty-nine patients were evaluable for response. Four patients had partial responses (PRs) and no patient had a complete response (CR), giving an overall response rate of 9.5%. Twenty-two patients (52.4%) had stable disease and 13 patients (31.0%) showed progressive disease. With a median follow-up time of 12.9 months (range 1.0–30.0 months), the median progression-free survival time and the median overall survival time were 5.3 and 9.5 months, respectively. Grade 3 or 4 neutropenia developed in 18 patients (42.9%), including febrile neutropenia in 4 patients (9.5%). Common non-hematologic toxicities were fatigue (21.4%), neuropathy (21.4%), and mucositis (21.4%). Grade 2 or 3 hypertension occurred in 4 patients (9.6%), and grade 1 or 2 proteinuria was seen in 16 patients (38.1%). The frequencies of adverse events related BV, such as bleeding, thrombosis, and gastrointestinal perforation, were within the ranges of previous reports. However, there were no treatment-related deaths. The combination of bevacizumab plus FOLFIRI or FOLFOX showed modest activity and was relatively tolerable in patients with metastatic colorectal cancer refractory to both FOLFIRI and FOLFOX.     

A phase II,multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer

BackgroundThis phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel–carboplatin (CP) plus motesanib or bevacizumab.Patients and methodsChemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs).ResultsORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma C_max and C_min values were consistent with its pharmacokinetic properties observed in previous studies.ConclusionsThe efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study.     

XELOX and bevacizumab followed by single-agent bevacizumab as maintenance therapy as first-line treatment in elderly patients with advanced colorectal cancer: the boxe study

Purpose

The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved progression-free survival (PFS) in patients with metastatic colorectal cancer (CRC). An increased risk of arterial thromboembolic events has been observed in some trials in older patients, and the potential benefit of a maintenance therapy with bevacizumab alone has not been clearly demonstrated. This phase II study was designed to evaluate the efficacy and safety of XELOX (capecitabine plus oxaliplatin) plus bevacizumab followed by bevacizumab alone in elderly patients with advanced CRC.

Methods

Treatment consisted of bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m² on day 1, plus capecitabine 1,000 mg/m² twice daily on days 1–14, every 3 weeks up to a maximum of 8 cycles. Patients then received maintenance therapy consisting of bevacizumab alone (7.5 mg/kg) once every 3 weeks up to disease progression. The primary study end-points were safety and response rate.

Results

A total of 44 patients were recruited. In an intention-to-treat analysis, the overall response rate was 52 % [95 % confidence interval (CI) 37 to 68 %], with 86 % of patients achieving disease control. Median PFS and overall survival were 11.5 months (95 % CI 10.0–12.9 months) and 19.3 months (95 % CI 16.5–22.1 months), respectively. In all, 10 patients (23 %) had grade 3/4 adverse events (AEs), the most common being diarrhea (9 %), neutropenia (7 %), peripheral neuropathy (7 %), and stomatitis (7 %). No patients died because of treatment-related AEs. The rate of bevacizumab-related AEs (hypertension, thromboembolic events, and gastrointestinal perforation) was consistent with that reported earlier in the general CRC population.

Conclusion

The combination of XELOX and bevacizumab is effective and has a manageable tolerability profile when administered to elderly patients with advanced CRC. Maintenance therapy with single-agent bevacizumab may be considered to extend PFS in this setting of patients.     

A Phase II Trial of Docetaxel With Bevacizumab as First-line Therapy for HER2-Negative Metastatic Breast Cancer (TORI B01)

IntroductionAddition of the antiangiogenic agent bevacizumab to paclitaxel significantly improves response rates and progression-free survival for metastatic breast cancer (MBC). To assess the activity of docetaxel plus bevacizumab, a multicenter phase II trial was conducted.Patients and MethodsPatients with measurable first-line HER2/neu—negative MBC were eligible. This trial began as a 2-arm study with a docetaxel-alone arm. When bevacizumab became widely available, it was converted to a 1-arm open-label trial of docetaxel/bevacizumab. Patients enrolled in the docetaxel-alone arm were permitted to cross over to docetaxel/bevacizumab. Patients received bevacizumab 15 mg/kg and docetaxel 75 mg/m² intravenously (I.V.) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal.ResultsFrom March 2005 to September 2006, 76 patients were enrolled. Of the 7 patients who were randomized to docetaxel alone, 6 crossed over to docetaxel/bevacizumab (included in the safety analysis only). Two patients were found to be ineligible before receiving drug. Efficacy data are based on the 67 patients who were originally enrolled in the docetaxel/bevacizumab arm and received at least 1 dose of study medication. The confirmed objective response rate is 51% (34 of 67) with 9% complete responses (6 of 67) and 42% partial responses (28 of 67). Nine additional patients (13%) had stable disease lasting ≥ 6 months. With a median follow-up of 21.7 months, the median time to progression is 9.3 months, and median overall survival is 26.3 months. Common grade 3/4 adverse events included neutropenia (33%), leukopenia/lymphopenia (25%), fatigue (22%), infection (17%), pain (16%), and hypertension (9%).ConclusionDocetaxel/bevacizumab was generally well tolerated with manageable toxicity and promising efficacy results.     

RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma

BackgroundThe open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/BEV) in patients with metastatic renal cell carcinoma.Patients and methodsPreviously untreated patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with either everolimus 10 mg/day (EVE/BEV) or interferon (9 MIU 3 times/week, if tolerated) (IFN/BEV). Tumor assessments occurred every 12 weeks. The primary objective was the assessment of treatment effect on progression-free survival (PFS), based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success).ResultsBaseline characteristics were balanced between the EVE/BEV (n = 182) and IFN/BEV (n = 183) arms. The median PFS was 9.3 and 10.0 months in the EVE/BEV and IFN/BEV arms, respectively (P = 0.485). The predicted probability of phase III success was 5.05% (hazard ratio = 0.91; 95% confidence interval 0.69–1.19). The median duration of exposure was 8.5 and 8.3 months for EVE/BEV and IFN/BEV, respectively. The percentage of patients discontinuing because of adverse events (AEs) was 23.4% for EVE/BEV and 26.9% for IFN/BEV. Common grade 3/4 AEs included proteinuria (24.4%), stomatitis (10.6%), and anemia (10.6%) for EVE/BEV and fatigue (17.1%), asthenia (14.4%), and proteinuria (10.5%) for IFN/BEV. The median overall survival was 27.1 months in both arms.ConclusionsThe efficacy of EVE/BEV and IFN/BEV appears similar. No new or unexpected safety findings were identified and, with the exception of proteinuria in about one-fourth of the population, EVE/BEV was generally well tolerated.Clinical trial registry and trial registration numberClinicalTrials.gov: NCT00719264.     

Phase I study of every 2- or 3-week dosing of ramucirumab,a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors

BackgroundRamucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics.Patients and methodsPatients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed.ResultsTwenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2–81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ∼110–160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2–18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers.ConclusionRamucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors.ClinicalTrials.govNCT00786383.     

西妥昔单抗联合化疗治疗转移性结直肠癌的临床观察

目的：观察西妥昔单抗联合含伊立替康或奥沙利铂化疗方案治疗转移性结直肠癌的近期疗效及毒副反应。方法：１０例经病理组织学确诊的转移性结直肠癌患者,给予西妥苷单抗联合ＦＯＬＦＩＲＩ方案或ＦＯＬＦＯＸ方案治疗,西妥昔单抗首次给予负荷剂量４００ｍｇ／ｍ^２,每周给予维持剂量为２５０ｍｇ／ｍ^２。结果：全组１０例患者中,完全缓解（ＣＲ）１例,部分缓解（ＰＲ）４例,稳定（ＳＤ）２例,进展（ＰＤ）３例,有效率为５０％,疾病控制率为７０％,中位肿瘤进展时间（ＴＴＰ）为６.４个月。主要毒副反应为痤疮样皮疹和腹泻。结论：西妥昔单抗联合ＦＯＬＦＩＲＩ方案或ＦＯＬＦＯＸ方案治疗转移性结直肠癌疗效较好,毒副反应可耐受。     

A Dose-finding Study of Metronomic Oral Vinorelbine in Combination With Oral Cyclophosphamide and Bevacizumab in Patients With Advanced Breast Cancer

BackgroundMetronomic chemotherapy can induce disease control in patients with metastatic breast cancer (MBC) and has better safety profiles than conventional chemotherapy. Evidence suggests that cytotoxics can be anti-angiogenic in pre-clinical models and may have synergistic effects when combined with anti-vascular endothelial growth factor therapies.Patients and MethodsPatients pretreated with ≥ 1 prior line of therapy for MBC received oral cyclophosphamide 50 mg daily in combination with oral vinorelbine at escalating doses of 20 mg (V20), 30 mg (V30), and 40 mg (V40) 3 times per week, and intravenous bevacizumab 15 mg/kg every 3 weeks. Patients with human epidermal growth factor receptor 2-positive disease were given the same regimen plus standard trastuzumab. Doses were escalated when 3 patients completed 3 treatment cycles of V20 and V30, without experiencing dose-limiting toxicities. The recommended dose was then tested in a further 6 patients. Circulating tumour cells and circulating endothelial cells (CEC) were measured in 30 mL of whole blood samples at baseline, after cycle 1, and at the disease progression.ResultsFifteen patients were recruited from June 2013 to October 2015. The median age was 61 years (range, 29-72 years); 80% had estrogen receptor-positive and 33% had human epidermal growth factor receptor 2-positive disease. At least 67% had visceral metastases, and 80% had received ≥ 2 lines of prior treatment. No dose-limiting toxicities were observed at the 3 dose-levels, making V40 the recommended dose. Overall 8 (53%) patients developed grade 2 adverse events (arthralgia, n = 3 [20%]; asthenia, n = 2 [13%]; diarrhea, n = 2 [13%]; leukopenia, n = 2 [13%]). Bevacizumab was associated with grade 3 hypertension (n = 3 [20%]). Stable disease as best response was observed in 11 (73.3%) patients. The clinical benefit rate was 66.6% (10/15 patients). The median time to progression was 6.9 months. At baseline, CECs were more commonly detectable than circulating tumor cells; however, no statistical correlation was found between CEC kinetics and response.ConclusionA metronomic vinorelbine dose of 40 mg combined with cyclophosphamide and bevacizumab is a promising treatment regimen in pretreated patients with MBC.     

A Phase I,Open-Label Study of Trebananib Combined With Sorafenib or Sunitinib in Patients With Advanced Renal Cell Carcinoma

BackgroundTrebananib, an investigational peptibody, binds to angiopoietin 1 and 2, thereby blocking their interaction with Tie2.Patients and MethodsThis open-label phase I study examined trebananib 3 mg/kg or 10 mg/kg intravenous (I.V.) once weekly plus sorafenib 400 mg twice per day or sunitinib 50 mg once per day in advanced RCC. Primary end points were adverse event incidence and pharmacokinetics.ResultsThirty-seven patients were enrolled. During trebananib plus sorafenib administration (n = 17), the most common treatment-related adverse events (TRAEs) included rash (n = 12; 71%), diarrhea (n = 12; 71%), hypertension (n = 11; 65%), and fatigue (n = 11; 65%); grade ≥ 3 TRAEs (n = 7; 41%); and 2 patients (12%) had peripheral edema. During trebananib plus sunitinib administration (n = 19), the most common TRAEs included diarrhea (n = 14; 74%), fatigue (n = 13; 68%), hypertension (n = 11; 58%), and decreased appetite (n = 11; 58%); grade ≥ 3 TRAEs (n = 13; 68%); and 8 (42%) patients had peripheral edema. Trebananib did not appear to alter the pharmacokinetics of sorafenib or sunitinib. No patient developed anti-trebananib antibodies. Objective response rates were 29% (trebananib plus sorafenib) and 53% (trebananib plus sunitinib).ConclusionThe toxicities of trebananib 3 mg/kg or 10 mg/kg I.V. plus sorafenib or sunitinib in RCC were similar to those of sorafenib or sunitinib monotherapy, with peripheral edema being likely specific to the combinations. Antitumor activity was observed.     

Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma

BackgroundThis phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma.MethodsPatients received voxtalisib 30–90 mg once daily (q.d.) or 20–50 mg twice daily (b.i.d.), in combination with 200 mg/m² TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m² TMZ and RT (n = 5). A standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose. Patients were evaluated for adverse events (AEs), plasma pharmacokinetics, pharmacodynamic effects in skin biopsies, and tumor response.ResultsThe maximum tolerated doses were 90 mg q.d. and 40 mg b.i.d. for voxtalisib in combination with TMZ. The most frequently reported treatment-related AEs were nausea (48%), fatigue (43%), thrombocytopenia (26%), and diarrhea (24%). The most frequently reported treatment-related grade ≥3 AEs were lymphopenia (13%), thrombocytopenia, and decreased platelet count (9% each). Pharmacokinetic parameters were similar to previous studies with voxtalisib monotherapy. Moderate inhibition of PI3K signaling was observed in skin biopsies. Best response was partial response in 4% of evaluable patients, with stable disease observed in 68%.ConclusionsVoxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition.     

Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen.

PURPOSE: To evaluate the objective tumor response rates and toxicities of leucovorin (LV) plus fluorouracil (5-FU) cancer regimen combined with oxaliplatin (85 mg/m(2)) every 2 weeks on metastatic colorectal cancer patients with documented proof of progression while on bimonthly LV and 5-FU alone. PATIENTS AND METHODS: One hundred patients were enrolled onto this study and 97 received the study drugs between October 1995 and December 1996. Eighty-nine patients were eligible for per-protocol efficacy analysis with documented proof of progression on one of the following two treatments: LV 500 mg/m(2) and continuous 5-FU infusion 1.5 to 2 g/m(2)/22 hours, days 1 through 2 every 2 weeks (FOLFUHD); or LV 200 mg/m(2), bolus 5-FU 400 mg/m(2), and continuous 5-FU infusion 600 mg/m(2)/22 hours, days 1 through 2 every 2 weeks (LV5FU2). In our study, 40 patients received FOLFUHD + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX3) and 57 patients received LV5FU2 + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX4). RESULTS: Of the 97 patients treated, 20 partial responses were observed (FOLFOX3/4: response rate, 20.6%; 95% confidence interval, 13% to 31.1%; FOLFOX3: response rate,18.4%; FOLFOX4: response rate, 23.5%). For patients treated with FOLFOX3/4, the median response duration for was 7.5 months, and the major toxicities were peripheral neuropathy and neutropenia. The incidence of grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy was 20.6%; whereas the overall incidence of grade 3 to 4 neutropenia was 27.8%, 15%, and 36.9% for FOLFOX3/4, FOLFOX3, and FOLFOX4, respectively (P =.02). From the start of treatment, median progression-free survival was 4. 7, 4.6, and 5.1 months for FOLFOX3/4, FOLFOX3, FOLFOX4, respectively, and median overall survival was 10.8, 10.6, and 11.1 months, respectively. CONCLUSION: This phase II study of oxaliplatin at 85 mg/m(2) in combination with bimonthly LV plus 5-FU in patients with colorectal cancer resistant to LV plus 5-FU alone confirms the enhanced antitumor activity of oxaliplatin in combination with 5-FU.     

A phase I trial of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer

Purpose

Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities.

Methods

Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6–bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily.

Results

Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib.

Conclusions

MTD was imatinib 400 mg plus full dose mFOLFOX–bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.     

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study

BackgroundA targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy.Patients and methodsPatients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety.ResultsThree hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75–1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81–1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups.ConclusionBevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment.Clinical trial identifierUMIN000002557.     

Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer

We report the first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for human epidermal growth factor receptor (HER)-2-positive locally recurrent (LR) or metastatic breast cancer (MBC). Patients were aged ≥18 years with confirmed breast adenocarcinoma, measurable LR/MBC and documented HER-2-positive disease. Patients received bevacizumab (15 mg/kg on day 1) plus trastuzumab (8 mg/kg on day 1 of cycle 1, 6 mg/kg on day 1 of each subsequent cycle) plus capecitabine (1,000 mg/m2 twice daily, days 1-14) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. Eighty-eight patients were enrolled; 40 (46%) are still on study treatment. The median follow-up was 8.8 months (range, 0.9-17.1 months). The overall response rate, the primary endpoint, was 73% (95% confidence interval [CI], 62%-82%), comprising 7% complete and 66% partial responses. The median progression-free survival interval was 14.4 months (95% CI, 10.4 months to not reached [NR]), with 35 events. The median time to progression was 14.5 months (95% CI, 10.5 months to NR), with 33 events. Treatment was well tolerated; main side effects were grade 3 hand-foot syndrome (22%), grade ≥3 diarrhea (9%), and grade ≥3 hypertension (7%). Overall, 44% of patients experienced grade ≥3 treatment-related adverse events and 13 patients discontinued capecitabine because of toxicity, but continued with bevacizumab and trastuzumab. Heart failure was seen in two patients. The combination of bevacizumab, trastuzumab, and capecitabine was clinically active as first-line therapy for patients with HER-2-positive MBC, with an acceptable safety profile and no unexpected toxicities.