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Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer.

ABSTRACT: The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPK-targeted agents such as pimasertib.Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. The primary objective of the safety run-in phase was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose of pimasertib combined with FOLFIRI.Sixteen patients were enrolled in the trial. Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI, respectively. The MTD was considered to be 45 mg per day. The most common treatment-emergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated.Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45 mg per day, pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns were identified.

SUBMITTER: Macarulla T

PROVIDER: S-EPMC4580393 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Folfiri-Aflibercept vs. Folfiri-Bevacizumab as Second Line Treatment of RAS Mutated Metastatic Colorectal Cancer in Real Practice.

Project description:Background: There are no clinical studies comparing the efficacy of bevacizumab vs.aflibercept in association with folfiri in RAS mutated (RAS-M) metastatic colorectal cancer patients (mCRC) pretreated with folfox and bevacizumab. Patients and Methods: Consecutive RAS-M unresectable mCRC patients progressing to first-line folfox/bevacizumab were treated with 12 cycles of folfiri/bevacizumab (arm A) or folfiri/aflibercept (arm B) at Oncologist discretion. Differences in overall survival between the two schedules were analyzed. Responses and toxicities were described with RECIST and NCI-CTC v4.0, respectively. Results: Seventy-four patients were treated from January 2014 to January 2018; 31 with arm A, 43 with arm B. Among clinical factors there was a predominance of more extended disease (>2 metastatic sites) in arm B (26/43 [60.5%] vs. 10/31 [32.2%] arm A; p = 0.0414). Fifty-nine patients were evaluable for response: arm A, 5 PR (Partial Response), 15 SD (Stable Disease), 8 PD (Progressive Disease); arm B, 5 PR, 16 SD, 10 PD. There were no grade 4 toxic events. Duration of first-line chemotherapy was significantly shorter in patients treated in arm B (12 pts <6 months, 16 pts ≥6, and <12, 15 pts ≥12) vs. arm A (1 pts <6 months, 14 pts ≥6, and <12, 16 pts ≥12) (p = 0.0210); these patients were excluded from survival analysis to avoid prognostic interferences. No maintenance treatment with aflibercept was done in arm B while in arm A bevacizumab with or without fluorouracil and folinic acid were allowed. Median OS were 8.9 months in arm A vs. 12.1 months in arm B (+3.2 months; p = 0.9331, HR: 1.02; 95% CI: 0.57-1.84). Six-months survivals were 65% in arm A and 80% in arm B. Conclusions: Folfiri/bevacizumab and folfiri/aflibercept are equally effective second-line therapies in RAS-M mCRC patients. Although not significant, folfiri/aflibercept was associated with a lower risk of death particularly during the 6-months induction phase.

| S-EPMC6700318 | biostudies-literature

Aflibercept Plus FOLFIRI as Second-Line Treatment for Metastatic Colorectal Cancer: A Single-Institution Real-Life Experience.

Project description:The addition of aflibercept to FOLFIRI has been demonstrated to improve survival in patients with metastatic colorectal cancer (mCRC) who progressed after receiving a standard oxaliplatin-based regimen. In this retrospective, single-institution, observational study we collected clinical data from mCRC patients who received aflibercept in combination with FOLFIRI in routine clinical practice from October 2012 to March 2021 to describe feasibility and efficacy of this regimen in a real-world population. Forty-nine patients receiving aflibercept-FOLFIRI as second-line treatment were identified, 40.8% of whom were aged over 65 years. The majority of patients had multi-organ metastases (73.5%), and had previously received bevacizumab in combination with chemotherapy (CT) as first-line treatment (79.6%). Median overall survival (OS) and progression-free survival (PFS) were 13 and 6 months, respectively; overall response rate (ORR) and disease control rate (DCR) were 12.3% and 49.1%, respectively. Several factors were associated with survival in univariate analysis, including PFS in first-line therapy, number of metastatic sites, bone metastases and others. However, in multivariate analysis, only PFS in first-line CT over 12 months was significantly associated with better OS (HR 0.32; 95% CI 0.13-0.79; p = 0.01). Hypertension was the most commonly reported grade (G) 3-4 adverse event (AE), affecting 18.4% of the overall population. Thromboembolic events were observed in 16.3% of patients, hemorrhagic events in 10.2%, and proteinuria in 8.2%. Neutropenia was the most frequently observed hematological G3-4 AE with an incidence of 10.2%. Aflibercept-FOLFIRI has been confirmed as a feasible second-line treatment for mCRC in a re-al-life setting, and PFS in first-line therapy >12 months resulted as the only predictive marker of better survival.

| S-EPMC8345481 | biostudies-literature

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.

Project description: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.

| S-EPMC4478977 | biostudies-literature

Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer.

Project description:Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

| S-EPMC6398889 | biostudies-literature

XELIRI compared with FOLFIRI as a second-line treatment in patients with metastatic colorectal cancer.

Project description:The aim of this study was to compare the efficacy, safety and survival rate of a treatment regimen comprising capecitabine plus irinotecan (XELIRI) to those of a standard regimen comprising leucovorin, fluorouracil and irinotecan (FOLFIRI), to determine the correlation among the inherited genetic variations in UGT1A1, UGT1A7 and UGT1A9. A total of 84 consecutive patients with histologically confirmed metastatic colorectal cancer (mCRC) were included in the study. All patients were treated with FOLFIRI or XELIRI. The median progression-free survival time was 4.4 months for FOLFIRI and 5.7 months for XELIRI (hazard ratio=1.35; 95% confidence interval, 0.83-2.21; P=0.22). When compared with FOLFIRI (6.34%), XELIRI was associated with lower rates of severe toxicity (3.29) (P=0.026) and similar disease control rates (69.57% for FOLFIRI and 61.11% for XELIRI; P=0.49). In total, 17 single nucleotide polymorphisms were identified, five of which revealed an association with grade 3/4 neutropenia, including UGT1A7*4; however, UGT1A1*28 and UGT1A1*6, which have been previously reported, were not significant. Additionally, H2 haplotypes, which include UGT1A9*22, and H5 and H7 haplotypes, which include UGT1A7*2, UGT1A7*3 and UGT1A7*4, were associated with a higher risk of severe neutropenia. In conclusion, XELIRI is an effective treatment regimen with acceptable response rates and tolerability for mCRC patients as a second-line treatment. Furthermore, inherited genetic variations in UGT1A1, UGT1A7 and UGT1A9 are associated with grade 3/4 neutropenia.

| S-EPMC4156196 | biostudies-literature

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic <i>KRAS</i> Mutant Colorectal Adenocarcinoma.

Project description:Lessons learnedThe safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.BackgroundSimtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.MethodsPatients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.ResultsIn total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.ConclusionThe addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC. The Oncologist 2017;22:243-e8.

| S-EPMC5344646 | biostudies-literature

First-line sunitinib plus FOLFIRI in Japanese patients with unresectable/metastatic colorectal cancer: a phase II study.

Project description:This phase II, open-label, single-arm study investigated sunitinib + FOLFIRI in Japanese patients with treatment-naïve unresectable/metastatic colorectal cancer. Patients received i.v. FOLFIRI (levo-leucovorin 200 mg/m(2) + irinotecan 180 mg/m(2), followed by 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) 46-h infusion) every 2 weeks, and oral sunitinib 37.5 mg/day on Schedule 4/2 (4 weeks on, 2 weeks off), until disease progression or treatment withdrawal. Progression-free survival (PFS) was the primary endpoint, with a target median of 10.8 months (35% improvement over FOLFIRI alone). Seventy-one patients started a median of 3 (range 1-11) sunitinib cycles (median relative dose intensity, <60%). The median PFS was 6.7 months (95% confidence interval, 4.7-9.2) by independent review, 7.2 months (95% confidence interval, 5.4-9.5) by investigator assessment. Objective response rate (complete responses + partial responses) was 36.6% (independent review) and 42.3% (investigator assessment). Clinical benefit rate (complete responses + partial responses + stable disease) was 83.1% (independent review) and 88.7% (investigator assessment). Common all-causality, any-grade, adverse events were: neutropenia and leukopenia (both 97.2%); thrombocytopenia (84.5%); diarrhea and nausea (both 78.9%); decreased appetite (74.6%); and fatigue (66.2%). Neutropenia (96%) was the most frequent grade 3/4 adverse event. This study was closed early due to findings from a concurrent phase III study of sunitinib + FOLFIRI in non-Japanese patients with metastatic colorectal cancer. In conclusion, the median PFS for sunitinib + FOLFIRI in Japanese patients was shorter than the 10.8 month target, indicating that sunitinib did not add to the antitumor activity of FOLFIRI. This study was registered with www.ClinicalTrials.gov (NCT00668863).

| S-EPMC7659192 | biostudies-literature

Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre Phase I/II trial.

Project description:This trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy.In Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m(-2) every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity.Phase I included 10 patients (median age 63 (49-73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43-80) years) received irinotecan 180 mg m(-)(2) every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51-77). Median PFS and OS were 3.7 (95% CI, 3.2-4.7) and 8.0 (95% CI, 4.8-9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%).The NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov NCT00989469).

| S-EPMC3950852 | biostudies-literature

A phase 2 randomised study of veliparib plus FOLFIRI±bevacizumab versus placebo plus FOLFIRI±bevacizumab in metastatic colorectal cancer.

Project description:BackgroundMetastatic colorectal cancer (mCRC) has low survival rates. We assessed if addition of veliparib, concurrent to FOLFIRI, improves survival in patients with previously untreated mCRC.MethodsThis study compared veliparib (200 mg BID for 7 days of each 14-day cycle) to placebo, each with FOLFIRI. Bevacizumab was allowed in both arms. The primary endpoint was progression-free survival (PFS).ResultsPatients were randomised to receive veliparib (n = 65) or placebo (n = 65) in combination with FOLFIRI. Median PFS was 12 vs 11 months (veliparib vs placebo) [HR = 0.94 (95% CI: 0.60, 1.48)]. Median OS was 25 vs 27 months [HR = 1.26 (95% CI: 0.74, 2.16)]. Response rate was 57% vs 62%. Median DOR was 11 vs 9 months [HR = 0.73 (95% CI: 0.38, 1.40)]. AEs with significantly higher frequency (p < 0.05) in the veliparib group were anaemia (39% vs 19%, p = 0.019) and neutropenia (66% vs 37%, p = 0.001) for common AEs (≥20%); neutropenia (59% vs 22%, p < 0.001) for common Grade 3/4 AEs (≥5%); none in serious AEs. Haematopoietic cytopenias were more common with veliparib (79% vs 52%, p = 0.003). Fourteen percent of patients on veliparib and 15% on placebo discontinued treatment due to AEs.ConclusionVeliparib added to FOLFIRI ± bevacizumab demonstrated similar efficacy as FOLFIRI ± bevacizumab in frontline mCRC patients. No unexpected safety concerns occurred.

| S-EPMC6342906 | biostudies-literature

Suvemcitug as second-line treatment of advanced or metastatic solid tumors and with FOLFIRI for pretreated metastatic colorectal cancer: phase Ia/Ib open label, dose-escalation trials.

Project description:BackgroundSuvemcitug (BD0801), a novel humanized rabbit monoclonal antibody against vascular endothelial growth factor, has demonstrated promising antitumor activities in preclinical studies.Patients and methodsThe phase Ia/b trials investigated the safety and tolerability and antitumor activities of suvemcitug for pretreated advanced solid tumors and in combination with FOLFIRI (leucovorin and fluorouracil plus irinotecan) in second-line treatment of metastatic colorectal cancer using a 3 + 3 dose-escalation design. Patients received escalating doses of suvemcitug (phase Ia: 2, 4, 5, 6, and 7.5 mg/kg; phase Ib: 1, 2, 3, 4, and 5 mg/kg plus FOLFIRI). The primary endpoint was safety and tolerability in both trials.ResultsAll patients in the phase Ia trial had at least one adverse event (AE). Dose-limiting toxicities included grade 3 hyperbilirubinemia (one patient), hypertension and proteinuria (one patient), and proteinuria (one patient). The maximum tolerated dose was 5 mg/kg. The most common grade 3 and above AEs were proteinuria (9/25, 36%) and hypertension (8/25, 32%). Forty-eight patients (85.7%) in phase Ib had grade 3 and above AEs, including neutropenia (25/56, 44.6%), reduced leucocyte count (12/56, 21.4%), proteinuria (10/56, 17.9%), and elevated blood pressure (9/56, 16.1%). Only 1 patient in the phase Ia trial showed partial response, [objective response rate 4.0%, 95% confidence interval (CI) 0.1% to 20.4%] whereas 18/53 patients in the phase Ib trial exhibited partial response (objective response rate 34.0%, 95% CI 21.5% to 48.3%). The median progression-free survival was 7.2 months (95% CI 5.1-8.7 months).ConclusionsSuvemcitug has an acceptable toxicity profile and exhibits antitumor activities in pretreated patients with advanced solid tumors or metastatic colorectal cancer.

| S-EPMC10265603 | biostudies-literature

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