NIVACOR: Phase II study of nivolumab in combination with FOLFOXIRI/bevacizumab in first-line chemotherapy for advanced colorectal cancer RASm/BRAFm patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4118-TPS4118
Author(s):  
Angela Damato ◽  
Francesco Iachetta ◽  
Nicola Normanno ◽  
Francesca Bergamo ◽  
Evaristo Maiello ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
First Line ◽  
Flat Dose ◽  
Braf Mutant ◽  
Clinical Trial Information

TPS4118 Background: FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has been shown to be one of the therapeutic regimens in first line with the highest activity profile in patients (pts) with metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Tumors co-opt the PD-1/PD-L1 signaling pathway as one key mechanism to evade immune destruction. Anti-PD-1 monoclonal antibodies are FDA approved only for DNA mismatch repair deficient/microsatellite instability-high (MMRd/MSI-H), which are only about 5% among all mCRC. Nowadays, there are no data demonstrating anti-PD1 activity in stable and proficient (MMRp/MSS) disease. Another critical therapeutic target is the Vascular Endothelial Growth Factor A (VEGF-A), which acts on endothelial cells to stimulate angiogenesis; his inhibition with bevacizumab increase immune cell infiltration, giving a strong rationale for combining VEGF targeted agents with immune checkpoint inhibitors. Based on evidence, we explore the combination of triplet chemotherapy (FOLFOXIRI) with bevacizumab and nivolumab in pts with mCRC all- RAS/BRAF mutant regardless of microsatellite status. Methods: This is a prospective, open-label, multicentric phase II trial where pts with mCRC RAS/BRAF mutant in first line will receive nivolumab in combination with FOLFOXIRI/Bevacizumab every 2 weeks for 8 cycles followed by maintenance with bevacizumab plus nivolumab every 2 weeks. Bevacizumab will be administered intravenously at dose of 5 mg/kg every 2 weeks and nivolumab intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint is the overall response rate (ORR) and our hypothesis is that the treatment is able to improve the ORR from 66% to 80%. Secondary endpoints include overall survival, safety, time to progression, duration of response. Collateral translational studies evaluate the tumor mutational burden, and genetic alterations by circulating free DNA (cfDNA) obtained from plasma samples. The trial is open to enrollment, 4 of planned 70 pts have been enrolled. Clinical trial information: EudraCT Number: 2018-002893-38. Clinical trial information: NCT04072198 .

A phase II study of bevacizumab in combination with irinotecan plus S-1 as first-line treatment in patients with KRAS mutant-type metastatic colorectal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 676-676
Author(s):  
Tetsuya Eto ◽  
Toshiki Masuishi ◽  
Kohei Suzuki ◽  
Isamu Shibata ◽  
Yuichi Fukami ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Primary Tumor ◽  
Phase Ii Study ◽  
Line Treatment ◽  
First Line ◽  
Mutant Type ◽  
Clinical Trial Information ◽  
Line Chemotherapy ◽  
First Line Treatment

676 Background: FOLFIRI+bevacizumab (BV) is considered as a first-line treatment in patients (pts) with metastatic colorectal cancer (mCRC). The FIRIS study showed the non-inferiority of irinotecan plus S-1 (IRIS) to FOLFIRI. Therefore, we conducted a phase II study to evaluate the efficacy and safety of BV in combination with IRIS as first-line chemotherapy for KRAS mutant-type (mt) mCRC (clinical trial information: UMIN000004630). Methods: Eligibility criteria included histologically confirmed mCRC, KRAS mt, no previous chemotherapy, ECOG performance status (PS) of 0/1, and adequate organ function. S-1 was administered at 80 mg/m2 on days 1–14 and irinotecan at 100 mg/m2 on days 1 and 15 every 28 days. BV was administered at 5 mg/kg on days 1 and 15 every 28 days. The primary endpoint was response rate (RR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. The sample size was calculated to reject a RR of 25% in favor of a target RR of 50% with a significance level of 0.05 and a statistical power of 80%. Results: Of 26 patients enrolled for the study between December 2010 and September 2015, 23 met the inclusion criteria. The patient characteristics were as follows: median age, 66 (range, 46–77) years; male/female, 15/8; PS 0/1, 9/14; number of metastatic tumors 1/ ≥ 2, 8/15; colon/rectum as the primary tumor site, 13/10; primary tumor +/−, 15/8; and unresectable/recurrent, 15/8. The RR was 60.9% (95% confidence interval (CI): 40.8%–77.8%) with complete response, 0; partial response, 14; stable disease, 8; progressive disease, 0; and not evaluable, 1. With a median follow-up period of 58.1 months, the median PFS and OS were 10.7 (95% CI: 4.7–16.8) and 28.5 (95% CI: 17.6–39.3) months, respectively. The most common grade 3 or 4 adverse events were neutropenia (35%), diarrhea (22%), leukopenia (17%), febrile neutropenia (13%), anemia (13%), and hypoalbuminemia (13%). Conclusions: BV in combination with IRIS as first-line chemotherapy showed promising anti-tumor effects and manageable toxicities for KRAS mt mCRC. Clinical trial information: UMIN000004630.

A randomized, double-blinded, placebo-controlled multicenter phase II trial of adjuvant immunotherapy with tecemotide (L-BLP25) after R0/R1 hepatic colorectal cancer metastasectomy (LICC): Final results.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 480-480
Author(s):  
Carl Christoph Schimanski ◽  
Stefan Kasper ◽  
Susanna Hegewisch-Becker ◽  
Jan Schroeder ◽  
Friedrich Overkamp ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Cox Regression ◽  
Phase Ii Trial ◽  
Stage Iv ◽  
High Recurrence Rate ◽  
Muc1 Expression ◽  
Double Blinded ◽  
Clinical Trial Information

480 Background: Hepatic metastasectomy is the only potential curative treatment option for stage IV colorectal cancer (CRC) limited to liver metastases (LM). After R0 resection of LM the high recurrence rate remains a major challenge. L-BLP25 is an antigen-specific cancer vaccine targeting mucin 1 (MUC1). The LICC trial aimed to improve survival outcome in mCRC patients (pts) after R0/R1 LM resection. Methods: This LICC trial, a binational, multicenter, double-blinded, placebo controlled phase II trial, included pts with stage IV LM limited CRC after resection of primary tumor and LM (R0/R1) within the last 8 weeks, ECOG 0/1 and adequate organ function. Pts were 2:1 randomized to receive L-BLP25 or placebo. L-BLP25 930 µg was administered as 8 weekly subcutaneous doses followed by 6 week maintenance intervals until recurrence or a maximum of 2 years. Cyclophosphamide 300 mg/m2 (CP) or matching saline (NS) was given intravenously 3 days prior to first L-BLP25/placebo. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS), secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. Differences in RFS and OS were analyzed with exploratory log-rank tests on the intention-to-treat population. Results: Of 121 pts enrolled between Oct 2011 and Dec 2014, 79 pts received L-BLP25+CP, 42 placebo+NS. Baseline characteristics were well balanced. Median age was 60 years. Median RFS was 6.1 (90% CI: 5.8-8.8) vs. 11.4 months (90% CI: 5.0-20.3) and estimated 3-year OS rate 69.1% vs. 79.1% for L-BLP25 and placebo, respectively. Two-factorial Cox regression models showed no impact of MUC1 expression or treatment on RFS or OS. The most common L-BLP25-related grade 3/4 adverse events were diarrhea, anemia and back pain. There was one death in the L-BLP25 arm due to Merkel cell carcinoma assessed by the investigator as being potentially related to vaccination. Conclusions: The LICC trial failed to meet its primary endpoint of significantly improving RFS and OS with L-BLP25. MUC1 expression was not associated with outcome. Clinical trial information: NCT01462513 . Clinical trial information: NCT01462513.

Encorafenib and binimetinib with or without nivolumab in treating patients with metastatic radioiodine refractory BRAF V600 mutant thyroid cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS6085-TPS6085
Author(s):  
Matthew H. Taylor ◽  
Rom S. Leidner ◽  
Richard Bryan Bell ◽  
Bernard Fox ◽  
Hong Xiao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Thyroid Cancer ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Multikinase Inhibitors ◽  
Braf Mutant

TPS6085 Background: Differentiated thyroid cancer is the most common endocrine malignancy and has a high frequency of actionable molecular aberrations including BRAF V600E mutations (45%), RET fusions (10%), and NTRK fusions ( < 2%). FDA approved systemic therapies for metastatic radioiodine refractory differentiated thyroid cancer (RR-DTC) include multikinase inhibitors (Lenvatinib and sorafenib), NTRK inhibitors (larotrectinib and entrectinib for NTRK fusion+ cancers), and RET inhibitors (selpercatinib and pralsetinib for RET fusion+ cancers). Previous phase II clinical trials showed clinical efficacy with first and second generation BRAF inhibitors in patients with BRAF mutant RR-DTC. BRAF inhibitors have not yet been FDA approved for treatment of BRAF mutant RR-DTC. Effective therapeutic options for patients with BRAF mutant RR-DTC remains an important unmet clinical need. BRAF mutant thyroid cancers often show elevated expression of PD-L1. Additionally, BRAF inhibition results in increased expression of PD-L1 in thyroid cancer. This clinical trial seeks to evaluate the safety and efficacy of encorafenib plus binimetinib with or without nivolumab in patients with BRAF mutant metastatic RR-DTC. Encorafenib and binimetinib are highly selective and potent oral inhibitors of BRAF and MEK, respectively. Nivolumab is a potent inhibitor of the immune co-inhibitory receptor programmed cell death protein 1 (PD-1). Methods: This is a phase II, single institution, open-label, randomized clinical trial evaluating the combinations of (Arm 1) encorafenib 450 mg/day + binimetinib 45 mg twice daily and (Arm 2) encorafenib 450 mg/day + binimetinib 45 mg twice daily + nivolumab 480 mg I.V. every 4 weeks in patients with metastatic BRAF mutant RR-DTC. The trial will enroll 20 patients in each arm and treatment will be given in 28 day cycles for up to 2 years. Eligible patients must have metastatic/unresectable BRAF mutant RR-DTC, an ECOG performance status of 0-1 and adequate bone marrow, liver and kidney function. Patients with CNS metastases are included if the metastases have been treated and remained stable or are asymptomatic and ≤10 mm in diameter. Patients may be systemic therapy naïve or have previously been treated with multikinase inhibitors. Prior therapy with BRAF, MEK or immune checkpoint inhibitors is exclusionary. The primary endpoint is confirmed objective response rate (ORR) determined by RECIST v1.1 with restaging imaging every 12 weeks. Secondary endpoints include progression free survival, overall survival, and safety/tolerability (CTCAE v5.0). Arms 1 and 2 will be evaluated independently and are not powered for direct comparison. The trial design includes continuous toxicity monitoring with a Pocock-type stopping boundary. This clinical trial is in progress and 3 patients have been enrolled. Clinical trial information: NCT04061980.

The randomized phase II study of FOLFOXIRI plus cetuximab versus FOLFOXIRI plus bevacizumab as the first-line treatment in metastatic colorectal cancer with RAS wild-type tumors: The DEEPER trial (JACCRO CC-13).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3501-3501
Author(s):  
Akihito Tsuji ◽  
Hisatsugu Ohori ◽  
Tatsuro Yamaguchi ◽  
Masato Matsuura ◽  
Atsujiro Nishioka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Primary Endpoint ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
Randomized Phase Ii ◽  
Secondary Endpoints ◽  
Clinical Trial Information ◽  
First Line Treatment

3501 Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or the VOLFI trial ( J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150mg/m2, oxaliplatin 85mg/m2, 5-FU 2400mg/m2) plus cet vs. bev as first-line treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05. Secondary endpoints included ETS rate at week 8, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full analysis set (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively. On the cutoff date of September 2020, the median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. Safety data was already reported at the ASCO GI symposium 2021 (J Clin Oncol 39, 2021 suppl 3; abstr 86). The primary endpoint was met (p =.001); 57.4%（-15.0̃100）for the cet arm versus 46.0% （-0.6̃100）for the bev arm. As for primary tumor sidedness, median DpR were 60.3% versus 46.1% (p =.0007) in the left-side and 50.0% versus 41.2% (p =.46) in the right-side. The ETS rate and ORR as the secondary endpoints were 77.8% and 69.1% in the cet arm versus 74.6% and 71.7% in the bev arm, respectively, with no statistical significance. Although the survival data were immature, PFS and OS of both arms were 12.7 months (95%CI 11.5-14.0) and 37.6 months (95%CI 30.8 to 43.0), respectively. Conclusion: The mFOLFOXIRI plus cet has been shown to be significantly superior to the mFOLFOXIRI plus bev in terms of DpR as the primary endpoint in first-line treatment for RAS wild-type mCRC. Clinical trial information: NCT02515734. Clinical trial information: UMIN000018217.

Phase II study of irinotecan and bevacizumab plus alternate day S-1 as second-line treatment in patients with metastatic colorectal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 749-749
Author(s):  
Chihiro Tanaka ◽  
Chu Matsuda ◽  
Ken Kondo ◽  
Yukihiko Tokunaga ◽  
Takao Takahashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Grade 3 ◽  
Clinical Trial Information ◽  
First Line Treatment

749 Background: The recommended dose of combination chemotherapy of irinotecan, bevacizumab and oral S-1 is 100mg/m2, 5mg/kg and 80-120mg/body respectively. To evaluate whether the dose of irinotecan could be raised to 150mg/m2 with modified administration of S-1, we have conducted a phase II study of irinotecan and bevacizumab plus alternate day S-1 in patients with metastatic colorectal cancer (UMIN000008947). Methods: Patients with metastatic colorectal cancer after failure with first-line treatment of oxaliplatine and fluoropyrimidine were enrolled. Irinotecan (150 mg/m2) and bevacizumab (5mg/kg) were given intravenously on day 1. Oral S-1was administered on alternate days at a dose of 40-60mg twice a day. Cycles were repeated every two weeks. Results: A total of 51 patients were evaluated in the first fouur cycles. Grade 3 and 4 neutropenia were 10% (10/51) and 13.7%(7/10), grade 3 and 4 thrombocytopenia were 0%(0/51) and 2.0% (1/51). Grade 2 and 3 mucositis were 13.7% (7/51) and 3.9% (2/51). Grade 2 and 3 nausea were 11.8% (6/51) and 2.0% (1/51). Grade 2 and 3 diarrhea were 17.6% (9/51) and 15.7% (8/51). The relative dose intensities were 84.8% for irinotecan, 87.5% for bevacizumab, and 84.8% for S-1 respectively in the first four cycles. Conclusions: Our data suggest that irinotecan (150 mg/m2) and bevacizumab was administered safely with alternate day S-1 as second-line tratment in patients with metastatic colorectal cancer. Clinical trial information: 000008947.

Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3623-TPS3623 ◽  
Author(s):  
Yasutoshi Kuboki ◽  
Akihito Kawazoe ◽  
Yoshito Komatsu ◽  
Tomohiro Nishina ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Sample Size ◽  
Phase Ii ◽  
Alternative Hypothesis ◽  
Objective Response ◽  
Clinical Trial Information ◽  
Egfr Antibody

TPS3623 Background: Immune checkpoint inhibitor (ICI) was reported to show durable responses in patients with MSI-H (Microsatellite Instability-High) metastatic colorectal cancer (mCRC). On the other hand, for patients with MSS (Microsatellite Stable) mCRC, ICI monotherapy achieved no response. Recently, WNT/β-catenin signaling has been reported to be involved in the elimination of tumor-infiltrating lymphocytes and the resistance of anti-PD-L1 antibodies. CRC is representative cancer with WNT/β-catenin pathway activation. Furthermore, STAT3 has also been reported to be a key driver of this immune evasion. Considering these rationales, the blocking of these signaling pathways with ICI may enhance antitumor immune response. Therefore, we initiated phase I/II study to assess efficacy and safety for the combination of BBI608, which blocks STAT3 and WNT/β-catenin signaling, with pembrolizumab in patients with mCRC. Methods: The eligibility criteria were patients with gastrointestinal cancer not responded to or intolerant of standard chemotherapies (SOC) for phase I part, and MSS mCRC refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and anti-EGFR antibody (if wild-type RAS) for Cohort B in phase II part. For Cohort A, MSI-H mCRC refractory or intolerant to the SOC, irrespective of anti-EGFR antibody are investigated. Phase I part was designed to determine the recommended phase II dose in a “3+3” cohort-based dose escalation design of BBI608 (240mg BID every day on level 1 and 480mg BID every day on level 2) with pembrolizumab (200mg/body q3w). Primary endpoint of the phase II part is Immune-related objective response rate (irORR) determined by their Response Evaluation Criteria In Solid Tumors (irRECIST). A null hypothesis and alternative hypothesis for cohort B are irORR = 5% and 20%, respectively. Required sample size for Cohort B was 40 with a one-sided alpha of 5% and power of 90%. Required sample size for Cohort A (10 patients) was determined in an exploratory manner. We also investigate biomarker study using paired samples of both tumor biopsy and blood. The enrollment to phase I part began in November 2016. Clinical trial information: NCT02851004. Clinical trial information: NCT02851004.

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