A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: the AIO KRK 0110 trial/ML22011 trial.
ABSTRACT: Several randomized trials have indicated that combination chemotherapy applied in metastatic colorectal cancer (mCRC) does not significantly improve overall survival when compared to the sequential use of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present study investigates the question whether this statement holds true also for bevacizumab-based first-line treatment including escalation- and de-escalation strategies.The AIO KRK 0110/ML22011 trial is a two-arm, multicenter, open-label randomized phase III trial comparing the efficacy and safety of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in the first-line treatment of metastatic colorectal cancer. Patients with unresectable metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, will be assigned in a 1:1 ratio to receive either capecitabine 1250 mg/m(2) bid for 14d (d1-14) plus bevacizumab 7.5 mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m(2) BID for 14d (d1-14), irinotecan 200 mg/m(2) (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). Patients included into this trial are required to consent to the analysis of tumour tissue and blood for translational investigations. In Arm A, treatment escalation from Cape-Bev to CAPIRI-Bev is recommended in case of progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to Cape-Bev is possible after 6 months of treatment or in case of irinotecan-associated toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The primary endpoint is time to failure of strategy (TFS). Secondary endpoints are overall response rate (ORR), overall survival, progression-free survival, safety and quality of life.The AIO KRK 0110 trial is designed for patients with disseminated, but asymptomatic mCRC who are not potential candidates for surgical resection of metastasis. Two bevacizumab-based strategies are compared: one starting as single-agent chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and another starting with combination chemotherapy (CAPIRI-Bev) and allowing de-escalation to Cape-Bev and subsequent re-escalation if necessary.ClinicalTrials.gov Identifier NCT01249638 EudraCT-No.: 2009-013099-38.
Project description:<h4>Purpose</h4>The aim of this randomized, multicenter, noncomparative, phase II trial was to investigate the efficacy and safety of two potential first-line treatments, capecitabine and oxaliplatin (CapOX) plus bevacizumab (BEV) and capecitabine and irinotecan (CapIRI) plus bevacizumab, in Japanese patients with metastatic colorectal cancer (mCRC).<h4>Patients and methods</h4>Patients with untreated mCRC were randomly assigned to receive either CapOX plus bevacizumab (CapOX/BEV arm: bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m<sup>2</sup> on day 1 and oral capecitabine 2,000 mg/m<sup>2</sup> on days 1-14, every 3 weeks) or CapIRI plus bevacizumab (CapIRI/BEV arm: bevacizumab 7.5 mg/kg and irinotecan 200 mg/m<sup>2</sup> on day 1 and capecitabine 1,600 mg/m<sup>2</sup> on days 1-14, every 3 weeks). The primary endpoint was overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.<h4>Results</h4>A total of 107 patients were enrolled. The intent-to-treat population comprised 54 patients in the CapOX/BEV arm and 53 patients in the CapIRI/BEV arm. The median follow-up period was 35.5 months. ORR was 56% in the CapOX/BEV arm and 55% in the CapIRI/BEV arm. Median PFS and OS were 12.4 and 26.7 months in the CapOX/BEV arm and 11.5 and 28.7 months in the CapIRI/BEV arm, respectively. The frequencies of hematological and nonhematological adverse events above grade 3 were 13% and 30% in the CapOX/BEV arm and 25% and 23% in the CapIRI/BEV arm, respectively.<h4>Conclusion</h4>CapOX plus bevacizumab and CapIRI plus bevacizumab are equally effective and feasible as the first-line treatments in Japanese patients with mCRC.<h4>Implications for practice</h4>The CCOG-1201 study was designed to evaluate the efficacy and safety of capecitabine and oxaliplatin plus bevacizumab and capecitabine and irinotecan plus bevacizumab as a first-line treatment in Japanese patients with metastatic colorectal cancer. This article reports on the trial and efforts to define the role of these regimens, including the effect of <i>KRAS</i> status and <i>UGT1A1</i> polymorphisms in metastatic colorectal cancer.
Project description:OBJECTIVES:We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer. METHODS:We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage I disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6?cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12?cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL). RESULTS:The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59?months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p?=?0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p?=?0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 0.36 (p?=?0.14); PFS HR?=?0.62 (p?=?0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms. CONCLUSION:mEOC/GOG0241 represents an example of a randomized rare tumor trial. Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. Clinical trial registry number: ISRCTN83438782.
Project description:BACKGROUND:First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPIRI+BEV [capecitabine (CAP: 1600?mg/m2), irinotecan (IRI: 200?mg/m2), and BEV (7.5?mg/m2)] was non-inferior to FOLFIRI+BEV as a second-line therapy for mCRC patients and was associated with a lower incidence of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible than FOLFOXIRI+BEV, without compromising efficacy. METHODS:QUATTRO-II is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses of OX and IRI will be investigated as a safety lead-in. In Step 2, patients will be randomized to the recommended dose of either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV treatments will be administered for up to 4?months followed by fluoropyrimidine plus BEV maintenance. The primary endpoint is progression-free survival (PFS). The similarity in PFS between the two arms will be evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and 1.25. Ensuring a 70% probability that the observed HR will be "0.8?<?HR?<?1.25" under the assumption of the true HR of 1.0, and 100 patients will be evaluated during the 3-year study period. Secondary endpoints include overall survival, overall response rate, safety, and patient reported outcome (PRO) (FACT/GOG-Ntx4). DISCUSSION:Considering the lower incidence of hematologic toxicities with modified CAPIRI+BEV than with FOLFIRI+BEV, CAPOXIRI+BEV may be a promising treatment option if sufficient efficacy and lower hematologic toxicities are indicated in this study. Additionally, a lower incidence of peripheral sensory neuropathy (PSN) reported following CAPEOX treatment compared to that after FOLFOX in ACHIEVE, an adjuvant phase III trial, suggest that CAPOXIRI+BEV can mitigate OX-induced PSN. TRIAL REGISTRATION:Clinicaltrials.gov NCT04097444 . Registered September 20, 2019, https://clinicaltrials.gov/ct2/show/study/NCT04097444 / Japan Registry of Clinical Trials jRCTs041190072. Registered October 9, 2019.
Project description:Selected patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) benefit from cytoreductive surgery (CRS) combined with intraperitoneal chemoperfusion (IPC). However, even after optimal cytoreduction, systemic and locoregional recurrence are common. Perioperative chemotherapy with bevacizumab (BEV) may improve the outcome of these patients.The BEV-IP study is a phase II, single-arm, open-label study aimed at patients with colorectal or appendiceal adenocarcinoma with synchronous or metachronous PC. This study evaluates whether perioperative chemotherapy including BEV in combination with CRS and oxaliplatin-based IPC results in acceptable morbidity and mortality (primary composite endpoint). Secondary endpoints are treatment completion rate, chemotherapy-related toxicity, pathological response, progression free survival, and overall survival.The BEV-IP trial is the first prospective assessment of the safety and efficacy of perioperative chemotherapy combined with anti-angiogenic treatment in patients undergoing CRS and IPC for colorectal peritoneal metastases.ClinicalTrials.gov Identifier: NCT02399410 EudraCT number: 2015-001187-19 (registered March 9, 2015).
Project description:The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen.Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg(-1) days 1 and 15 plus paclitaxel 90 mg m(-2) days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg(-1) day 1 plus capecitabine 1000 mg m(-2) bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs.The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP.A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340).
Project description:Perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging.Patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m(2) twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0).Ninety pts were included in arm A (44) or arm B (46). Grade 3-4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02).The addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies.Clinicaltrials.gov identifier NCT01043484. Trial registration date: 12/30/2009.
Project description:Stimulation of vascular endothelial growth factor (VEGF) has been observed following transarterial chemoembolization (TACE) in hepatocellular cancer (HCC) and may contribute to tumor regrowth. This pilot study examined whether intravenous (IV) bevacizumab, a monoclonal antibody against VEGF, could inhibit neovessel formation after TACE.30 subjects with HCC undergoing TACE at a single academic institution were randomized with a computer-generated allocation in a one to one ratio to either bevacizumab at a dose of 10 mg/kg IV every 14 days beginning 1 week prior to TACE (TACE-BEV arm) or observation (TACE-O arm). Angiography was performed with TACE at day 8, and again at weeks 10 and 14. Repeat TACE was performed at week 14 if indicated. TACE-BEV subjects were allowed to continue bevacizumab beyond week 16. TACE-O subjects were allowed to cross-over to bevacizumab at week 16 in the setting of progressive disease. The main outcome measure was a comparison of neovessel formation by serial angiography. Secondary outcome measures were progression free survival (PFS) at 16 weeks, overall survival (OS), bevacizumab safety, and an analysis of VEGF levels before and after TACE with and without bevacizumab.Among the 30 subjects enrolled, 9 of 15 randomized to the TACE-O arm and 14 of 15 randomized to the TACE-BEV arm completed all 3 angiograms. At week 14, 3 of 9 (33%) TACE-O subjects and 2 of 14 (14%) TACE-BEV subjects demonstrated neovascularity. The PFS at 16 weeks was 0.19 in the TACE-O arm and 0.79 in the TACE-BEV arm (p = 0.021). The median OS was 61 months in the TACE-O arm and 49 months in the TACE-BEV arm (p = 0.21). No life-threatening bevacizumab-related toxicities were observed. There were no substantial differences in bevacizumab pharmacokinetics compared to historical controls. Bevacizumab attenuated the increase in VEGF observed post-TACE.IV bevacizumab was well tolerated in selected HCC subjects undergoing TACE, and appeared to diminish neovessel formation at week 14.ClinicalTrials.gov NCT00049322.
Project description:AIM: The treatment of recurrent glioblastoma remains an open issue and the role of BEV has been largely debated since only few data compared this agent with the standard agents. METHODS: A multicenter, open-label, randomized (2:1), non-comparative phase II study (EudraCT:2011-001363-46; AVAREG-ML25739) with BEV 10 mg/m2 iv every 2 weeks or FTM 75 mg/m2 iv day 1-8-15 followed, after a 35 days interval, by FTM 100 mg/m2 every 3 weeks, was conducted. Primary endpoint was overall survival at 6 months (OS6). RESULTS: 91 pts with recurrent GBM were enrolled among 10 Italian centers between 11/2011 and 9/2012. Median age was 57 years (range:28-78), PS was 0/1/2 in 42/35/14 pts. All pts were treated with RT/TMZ accordingly with EORTC 26981-22981/NCIC-CE3. Time from diagnosis to 1st recurrence was 331 days in the BEV arm and 460 days in the FTM arm. At time of recurrence, 21 pts (23.1%) received re-resection before the study inclusion (13/8 pts in BEV/FTM arms). Fifty-nine pts were enrolled in the BEV arm and 32 pts in the FTM arm. OS6 was 62.1% (95%CI:48.4-74.5) and 73.3% (95%CI:54.1-87.7), OS9 was 37.9% (95%CI:25.5-51.6) and 46.7% (95%CI:28.3-65.7) in the BEV and FTM arms, respectively. Median OS was 7.3 months (95%CI:5.8-9.2) in the BEV arm and 8.7 months (95%CI:6.3-15.4) in the FTM arm. PFS6 was 26.3% and 10.7%, respectively. In the BEV arm, OS6 and OS9 were 77.8% (95%CI:57.7-91.4) and 59.3% (95%CI:38.8-77.6) in pts =55 yrs, and were 48.4% (95%CI:30.1-66.9) and 19.3% (95%CI:7.4-37.5) in pts >55 yrs. HR for OS in BEV group for pts >55 yrs compared with pts =55 yrs was 2.0 (95%CI:1.0-4.1, p = 0.05). G3-4 toxicity: thrombocytopenia 0% vs 21.9%, neutropenia 1.7% vs 12.5%, intestinal perforation and cerebral ischaemia/hemorrhage 3.4% vs 0%, pulmonary thromboembolism 1.7% vs 0%, and acute myocardial infarction 1.7% vs 0%, in the Bev and FTM arms respectively. CONCLUSIONS: BEV in recurrent GBM showed survival rates superimposable with FTM.
Project description:BACKGROUND: RANO criteria were applied to evaluate differences in response between the 2 arms: TMZ or TMZ + BEV in a randomized study. We evaluate here the RANO sub-criterion (PI) to evaluate response. METHODS: Between December 2009 and April 2013, p with unresectable GBM, PS < 3 and MMS ?25 were randomly assigned to receive eitherTMZ (200 mg/m2, days 1–5,for 2 28-day cycles), followed by standard TMZ with concomitant radiotherapy (60Gy) and then adjuvant TMZ for 6 cycles (TMZ Arm), or the same regimen but with the addition of BEV (10mg/kg /15 days) during pre-radiotherapy and concomitant treatment (BEV Arm). The primary endpoint was response according to RANO criteria after the 2 pre-radiotherapy cycles. The study was powered to detect a 30% difference between arms. A centralized revision of MRI's blinded to clinical status of p is ongoing. (ClinicalTrials.gov NCT01102595). RESULTS:103 p were registered and 93 randomized – 45 to the TMZ Arm and 48 to the BEV Arm. All p who received at least one dose of treatment were included in the analysis. Overall response rate (ORR) was evaluated after the 2-pre-radiotherapy cycles. Patients completed pre-radiotherapy treatment in 48.9% (TMZ Arm) vs 66.7% (BEV Arm), p = 0.08. Response was not evaluable in 3p (TMZ arm) and 5p (BEV arm) because of previous toxicity or refuse to continue. ORR by RANO criteria for evaluable p was: Arm TMZ: PR 3 (7.1%) SD 8 (19%) PD 31 (73.8%)., Arm B: PR 11 (25.6%) SD 17 (39.5%) 15 (34.9%) P = 0.001. Response by individual RANO sub criterion (Arm TMZ% vs Arm BEV%).1- MRI IP: PR (8.3 vs 26.2), SD (22.2 vs 42.8), P (69.4 vs 31) (P = 0.003), 2-Neurological status: SD (54.8 vs 79.5), No SD (45.2 vs 20.5) (P = 0.014), 3-Dexametasone dose: stable (60.5 vs 51.2), increase (28.9 vs 4.7), reduction (10.5 vs 44.2) (P < 0.001). CONCLUSION: ORR was significantly higher in the BEV Arm for both for general RANO criteria as for each individual criterion (MRI, clinical stability and dexametasone doses.
Project description:BACKGROUND:In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. METHODS:Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5?mg PO daily plus bevacizumab 15?mg/kg IV every 3?weeks (Let/Bev) and letrozole 2.5?mg PO daily (Let) for 24?weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. RESULTS:Seventy-five patients were randomized (Let/Bev n?=?50, Let n?=?25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7-24.1%) achieved pCR and 4 (9%; 95% CI, 2.5-21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0-14.2%). The rates of downstaging were 44.4% (95% CI, 29.6-60.0%) and 37.5% (95% CI, 18.8-59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. CONCLUSION:In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. TRIAL REGISTRATION:This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.