A phase II study investigating cabozantinib in patients with refractory metastatic colorectal cancer (AGICC 17CRC01).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 103-103
Author(s):  
Aaron James Scott ◽  
Steven J. Cohen ◽  
Atrayee Basu Mallick ◽  
Efrat Dotan ◽  
Philip Jordan Gold ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Alternative Hypothesis ◽  
Pik3ca Mutation ◽  
Phase Iii ◽  
Type I ◽  
Primary Tumors

103 Background: Therapeutic resistance to antiangiogenics in metastatic colorectal cancer (mCRC) inevitably develops via multiple mechanisms including upregulation of the MET kinase pathway. Cabozantinib, an oral multityrosine kinase inhibitor targeting MET, AXL, and VEGFR, demonstrated significant anti-tumor activity in CRC xenograft and cell line models. Methods: A single-arm, two-stage phase II study was conducted at 7 AGICC centers nationwide. 44 patients (pts) with mCRC who had progressed on or were intolerant of standard of care agents were treated with cabozantinib 60 mg daily in q3 wk cycles. The primary endpoint was 12-wk PFS rate. Based on the control arm of phase III CORRECT study, the Kaplan-Meier 12-wk PFS rate estimate was 13% and served as the null hypothesis. This study was powered at 0.906 to detect the alternative hypothesis of 12-wk PFS rate of 33% with a type I error rate of 0.044. Secondary endpoints were safety, RR, OS, and retrospective analysis of PFS and RR based on RAS, BRAF, and PIK3CA mutation status. Results: 44 pts were enrolled and 34 pts were response-evaluable as having undergone at least the first 6-wk restaging scan. 10 pts discontinued treatment prior to the first 6-wk scan due to clinical disease progression. Median number of cycles was 4 and median follow-up was 2.5 months. As of data-cutoff 8/23/2019, 55 Grade 3/4 AEs were reported with the most common being hypertension, fatigue, diarrhea, pain, HFS, nausea, vomiting, and proteinuria. 32 SAEs occurred in 18 pts. 5 Grade 5 AEs were reported: disease progression (3), disseminated intravascular coagulopathy, and bowel perforation. 15 pts (34%) achieved ≥ 12-wk PFS and 8 patients remain on treatment. Best response was 1 PR and 31 SD with a DCR at 6 wks of 72.7%. Of the pts who achieved ≥ 12-wk PFS, 12 had left-sided primary tumors, 5 had a RAS mutation, 1 had a PIK3CA mutation, and all pts were BRAF WT and MSI stable. Conclusions: Cabozantinib was deemed safe and demonstrates encouraging efficacy in a heavily pretreated mCRC pt population. These results support further investigation of cabozantinib in mCRC. Clinical trial information: NCT03542877.

scholarly journals Bevacizumab Maintenance Versus No Maintenance During Chemotherapy-Free Intervals in Metastatic Colorectal Cancer: A Randomized Phase III Trial (PRODIGE 9)

2018 ◽  
Vol 36 (7) ◽  
pp. 674-681 ◽  
Author(s):  
Thomas Aparicio ◽  
Francois Ghiringhelli ◽  
Valérie Boige ◽  
Karine Le Malicot ◽  
Julien Taieb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Induction Chemotherapy ◽  
Controlled Trial ◽  
Performance Status ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Tumor Control ◽  
Primary Tumors

Purpose Conflicting results are reported for maintenance treatment with bevacizumab during chemotherapy-free intervals (CFI) in metastatic colorectal cancer after induction chemotherapy. Patients and Methods In this open-label, phase III, randomized controlled trial, we compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during CFI subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. After disease progression, the induction regimen was repeated for eight cycles, followed by a new CFI. Results From March 2010 to July 2013, 491 patients were randomly assigned. Disease progression or death occurred during induction chemotherapy in 85 patients (17%); 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups; the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses of the trial. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. In the per-protocol population, defined as patients with at least one reinduction after the first progression, the median duration of the first CFI was 4.3 months in both arms; the median TCD was 17.8 and 23.3 months ( P = .339), the median PFS was 9.9 and 9.5 months, and the median OS was 27.6 and 28.5 months in the maintenance and observation groups, respectively. Multivariable analysis revealed that female gender, WHO performance status ≥ 2, and unresected primary tumors were associated with a shorter TCD. Conclusion Bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.

Quattro-II study: A multicenter randomized phase II study comparing capoxiri plus bevacizumab with FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer as the first-line treatment.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS267-TPS267
Author(s):  
Akihito Tsuji ◽  
Takayuki Yoshino ◽  
Takeharu Yamanaka ◽  
Hideaki Bando ◽  
Hironaga Satake ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Recommended Dose ◽  
Hematologic Toxicity ◽  
First Line ◽  
Randomized Phase Ii ◽  
Patient Reported

TPS267 Background: The first-line FOLFOXIRI with Bevacizumab (BEV) is highly effective and regarded as one of standard-of-care treatments in patients (pts) with metastatic colorectal cancer (mCRC) despite a high incidence of adverse events (AEs) such as neutropenia and diarrhea. The AXEPT, Asian Phase III study showed CAPIRI+BEV [Capecitabine (CAP: 1600 mg/m2), Irinotecan (IRI: 200 mg/m2) and BEV (7.5 mg/m2)] q3wk was non-inferior to FOLFIRI+BEV in pts with the second-line mCRC, with a lower incidence hematologic toxicity favoring CAPIRI+BEV over FOLFIRI+BEV. Based on these, a reduced dose of 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. Key eligibility criteria are as follows; age ≥20 years, ECOG performance status (PS) 0-1 (≥71 years age: PS 0), adequate organ function, and UGT1A1 single-heterozygous (UGT1A1*1/*6 or *1/*28) or wild-type (*1/*1) genotype. Pts are randomized to either the recommended dose of CAPOXIRI+BEV or FOLFOXIRI+BEV (OX: 85 mg/m2, IRI: 165 mg/m2, l-leucovorin: 200 mg/m2, 5-FU: 3200 mg/m2), with the strata of RAS/ BRAF status, previous adjuvant OX, tumor sidedness, and UGT1A1 status. Induction triplet chemotherapy plus BEV treatments are administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The recommended dose of CAPOXIRI+BEV will be determined as a safety-lead-in before moving forward to the phase II main part. The primary endpoint is progression-free survival (PFS). The similarity of PFS between the two arms is evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls in between 0.80 and 1.25. Ensuring 70% probability that the observed HR will be “0.8<HR<1.25” under the assumption of the true HR of 1.0, a total of 100 patients will be needed with 3-year study period. Secondary endpoints included overall survival, overall response rate, safety, and patient-reported outcome (FACT/GOG-Ntx4). The enrollment started in October 2019. Clinical trial information: NCT04097444.

Cetuximab metastatic colorectal cancer strategy (ERMES) study: A phase III randomized two arm study with FOLFIRI + cetuximab until disease progression compared to FOLFIRI + cetuximab for 8 cycles followed by cetuximab alone until disease progression in first-line treatment of patients with RAS and BRAF wild type metastatic colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS810-TPS810 ◽  
Author(s):  
Carmine Pinto ◽  
Nicola Normanno ◽  
Armando Orlandi ◽  
Evaristo Maiello ◽  
Domenico Bilancia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Objective Response ◽  
Phase Iii ◽  
Type I ◽  
Line Treatment ◽  
First Line ◽  
Primary Endpoints ◽  
First Line Treatment

TPS810 Background: The optimal duration and content of first-line therapy in mCRC pts once they have achieved objective response is controversial. In the FIRE-3 trial, ETS was significantly associated with PFS and OS. Based on this evidence it can be hypothesized that once this goal has been achieved, further exposure to combined antineoplastic treatment may not result in improvement or preservation of such result but only in an increase of toxicity. We designed a strategy study to compare FOLFIRI + cetuximab until PD to FOLFIRI + cetuximab for 8 cycles followed by cetuximab alone until PD in first line treatment of RAS/BRAF WT mCRC pts. Methods: This is a multicenter, open-label, randomized phase III trial. Untreated and unresecteble RAS/BRAF WT mCRC pts were randomized 1:1 to receive Cetuximab (400 mg/mq w1 and then 250 mg/mq weekly) + FOLFIRI until PD (standard arm) or Cetuximab (400 mg/mq week 1 and then 250 mg/mq weekly) + FOLFIRI for 8 cycles followed by Cetuximab monotherapy until PD (experimental arm). Tumor assessment is planned every 8 weeks. The objective of the study is to demonstrate a not inferior efficacy and a better toxicity profile for the experimental treatment compared to the standard treatment. The co-primary endpoints are PFS and incidence of G 3-4 AEs. Secondary endpoints are OS, ORR, ETS (8 weeks) and safety. A prospective multiple gene mutation analysis by NGS of both tumor tissue and blood will be performed to find potential predictive factors and surrogate markers of treatment efficacy. The two co-primary endpoints will be compared between the two arms using a fixed-sequence testing procedure to control for the family-wise type I error rate of 0.05 in a strong sense. This sequence considers that a reduction of grade 3-4 AEs is only of relevance, if non-inferiority is shown regarding PFS. 600 evaluable pts will be enrolled and randomized. Study recruitment started on January 2015, currently 139 pts have been randomized. Clinical trial information: NCT02484833.

scholarly journals Randomized phase II study of valproic acid in combination with bevacizumab and oxaliplatin/fluoropyrimidine regimens in patients with RAS-mutated metastatic colorectal cancer: the REVOLUTION study protocol

2020 ◽  
Vol 12 ◽  
pp. 175883592092958
Author(s):  
Antonio Avallone ◽  
Maria Carmela Piccirillo ◽  
Elena Di Gennaro ◽  
Carmela Romano ◽  
Filomena Calabrese ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Valproic Acid ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Histone Deacetylase Inhibitors ◽  
Phase Ii Study ◽  
Objective Response ◽  
Antitumor Effects ◽  
Primary Tumors ◽  
The Revolution

Background: Despite effective treatments, metastatic colorectal cancer (mCRC) prognosis is still poor, mostly in RAS-mutated tumors, thus suggesting the need for novel combinatorial therapies. Epigenetic alterations play an important role in initiation and progression of cancers, including CRC. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with chemotherapy in the treatment of solid tumors. Owing to its HDACi activity and its safe use for epileptic disorders, valproic acid (VPA) is a good candidate for anticancer therapy that we have largely explored preclinically translating our findings in currently ongoing clinical studies. We have shown in CRC models that HDACi, including VPA, induces synergistic antitumor effects in combination with fluoropyrimidines. Furthermore, unpublished results from our group demonstrated that VPA induces differentiation and sensitization of CRC stem cells to oxaliplatin. Moreover, preclinical and clinical data suggest that HDACi may prevent/reverse anti-angiogenic resistance. Methods/Design: A randomized, open-label, two-arm, multicenter phase-II study will be performed to explore whether the addition of VPA to first line bevacizumab/oxaliplatin/fluoropyrimidine regimens (mFOLFOX-6/mOXXEL) might improve progression-free survival (PFS) in RAS-mutated mCRC patients. A sample size of 200 patients was calculated under the hypothesis that the addition of VPA to chemotherapy/bevacizumab can improve PFS from 9 to 12 months, with one-sided alpha of 0.20 and a power of 0.80. Secondary endpoints are overall survival, objective response rate, metastases resection rate, toxicity, and quality of life. Moreover, the study will explore several prognostic and predictive biomarkers on blood samples, primary tumors, and on resected metastases. Discussion: The “Revolution” study aims to improve the treatment efficacy of RAS-mutated mCRC through an attractive strategy evaluating the combination of VPA with standard cancer treatment. Correlative studies could identify novel biomarkers and could add new insight in the mechanism of interaction between VPA, fluoropyrimidine, oxaliplatin, and bevacizumab. Trial Registration: EudraCT: 2018-001414-15; ClinicalTrials.gov identifier: NCT04310176

A phase II study of lenvatinib in patients with metastatic colorectal cancer refractory to standard chemotherapy: LEMON study (NCCH1503).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3538-3538
Author(s):  
Hirokazu Shoji ◽  
Satoru Iwasa ◽  
Aya Kuchiba ◽  
Gakuto Ogawa ◽  
Mamiko Kawasaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Elevated Serum ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Correct Trial

3538 Background: Although regorafenib significantly improved overall survival compared with placebo for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies in the global phase III CORRECT trial, regorafenib is often discontinued due to toxicity. Lenvatinib is an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptors α, RET, and KIT, showing receptor inhibition profile and kinetics different from regorafenib. This phase II study was conducted to evaluate the efficacy and safety of lenvatinib in patients with mCRC refractory to standard chemotherapies. Methods: mCRC patients with measurable lesions, PS 0-1, and refractory to standard chemotherapies including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab (if RAS wild-type), and TAS-102 (trifluridine/tipiracil) were eligible. Prior treatment with regorafenib was not allowed. Patients received lenvatinib orally at a dose of 24 mg once daily in 28-day cycles until unacceptable toxicity or disease progression. The primary endpoint was disease control rate (DCR) assessed by independent central review. Secondary endpoints included safety, response rate, progression-free survival (PFS), and overall survival. The planned sample size was 30 patients to expect a DCR of 60% with a threshold DCR of 35%, one-sided alpha of 5% and power of 80%. Results: Between October 2016 to January 2018, 30 patients were enrolled. All had received prior chemotherapy; 14 (47%) and 16 (53%) had received 3 or ≥ 4 prior lines for advanced disease, respectively. The median number of lenvatinib cycles was 4 (range 1-13). Two patients achieved partial response and 19 patients had stable disease, resulting in a response rate of 6.7% and DCR of 70.0% (95% CI: 50.6-85.3%). Median PFS was 3.6 months (95% CI: 2.6-3.7). The most common grade ≥ 3 adverse events were hypertension (53%), elevated serum aspartate aminotransferase (13%), thrombocytopenia (10%), and anorexia (7%) without unexpected safety signals. Conclusions: Lenvatinib showed promising antitumor activity with acceptable toxicity for patients with mCRC refractory to standard chemotherapies. Clinical trial information: UMIN000023446.

Phase II study of avelumab in combination with cetuximab in pre-treated RAS wild-type metastatic colorectal cancer patients: CAVE (cetuximab-avelumab) Colon.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS731-TPS731 ◽  
Author(s):  
Teresa Troiani ◽  
Erika Martinelli ◽  
Davide Ciardiello ◽  
Nicoletta Zanaletti ◽  
Claudia Cardone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Alternative Hypothesis ◽  
Total Duration ◽  
Drop Out ◽  
Cytotoxic Agents ◽  
Wild Type ◽  
First Line

TPS731 Background: The immune system plays a crucial role in modulating response to monoclonal antibodies therapy in cancer. Novel immunecheckpoint inhibitors have demonstrated potent efficacy alone and in combinations with cytotoxic agents in several cancers. In this regard, avelumab in combination with cetuximab might be a relevant rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients treated in first-line with chemotherapy (CT) in combination with anti-EGFR drugs and who achieved a complete or partial response. Methods: CAVE Colon is a single arm, multi-center phase II study designed to evaluate the efficacy of avelumab and cetuximab in pre-treated RAS WT mCRC patients. Eligible patients: pathologically confirmed RAS WT mCRC treated with a first-line CT in combination with an anti-EGFR agent with a major response achieved (complete or partial), who have progressed to a second line therapy, and received no prior immunotherapy. Primary endpoint is overall survival, secondary endpoint are overall response rate according to RECIST 1.1, progression free survival and safety profile. The current study seeks to demonstrate a median OS of 11 months (alternative hypothesis) by the experimental combination for comparison with historical median OS 8.0 (null hypothesis) with standard third line treatments, which correspond to an improvement of OS at six months from 40% to 57%. It was estimated that it would be needed to enroll 66 patients to achieve a 80% power with a one-sided 5% level test. The accrual period will be 18 months and the total duration of the study will be 36 months. Considering a potential drop-out of approximately 15% of patients, a total of 75 patients will be recruited. Seven patients have been enrolled and started treatment to date (September 15, 2018) with avelumab 10 mg/kg q14 as a one-hour i.v. infusion and cetuximab at 400 mg/m2 over two-hour and subsequently 250 mg/m2 q 14 as one-hour i.v. infusion until disease progression or unacceptable toxicity. EudraCT number: 2017-004392-32. This study is partially supported by Merck KgA, Darmstadt, Germany. Results: N/A. Conclusions: N/A. Clinical trial information: EudraCT number: 2017-004392-32.

Phase II study of a 21-day continuous infusion schedule with epirubicin in metastatic colorectal cancer

1988 ◽  
Vol 24 (4) ◽  
pp. 801-802 ◽  
Author(s):  
Janke Greidanus ◽  
Pax H.B. Willemse ◽  
Dirk Th. Sleijfer ◽  
Nanno H. Mulder ◽  
RenéC.J. Verschueren ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Continuous Infusion ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Infusion Schedule

scholarly journals Phase II Study of Recombinant Antitumor and Antivirus Protein Injection Compared With Placebo in Metastatic Colorectal Cancer After Failure of Standard Treatment

2015 ◽  
Vol 20 (6) ◽  
pp. 619-620
Author(s):  
Ru Jia ◽  
Yan Wang ◽  
Xiao‐Yang Mao ◽  
Shan‐Shan Li ◽  
Nong Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Standard Treatment ◽  
Phase Ii Study
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