A phase 1 trial of recombinant human IL-21 in combination with cetuximab in patients with metastatic colorectal cancer

Abstract Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

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Phase 1 studies assessing the safety and clinical activity of autologous and allogeneic NKG2D-based CAR-T therapy in metastatic colorectal cancer

Annals of Oncology ◽

10.1093/annonc/mdz157.008 ◽

2019 ◽

Vol 30 ◽

pp. iv124-iv125 ◽

Cited By ~ 3

Author(s):

E. Van Cutsem ◽

J. Machiels ◽

M. Van den Eynde ◽

H. Prenen ◽

A. Hendlisz ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Phase 1 ◽

Clinical Activity ◽

Car T

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Phase 1/2 study of KRN330, a fully human anti-A33 monoclonal antibody, plus irinotecan as second-line treatment for patients with metastatic colorectal cancer

Investigational New Drugs ◽

10.1007/s10637-014-0088-3 ◽

2014 ◽

Vol 32 (4) ◽

pp. 682-690 ◽

Cited By ~ 6

Author(s):

Johanna C. Bendell ◽

Heinz-Josef Lenz ◽

Theresa Ryan ◽

Bassel F. El-Rayes ◽

John L. Marshall ◽

...

Keyword(s):

Colorectal Cancer ◽

Monoclonal Antibody ◽

Metastatic Colorectal Cancer ◽

Phase 1 ◽

Line Treatment ◽

Second Line

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A triplet combination with irinotecan, oxaliplatin, continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in RAS wild-type, metastatic colorectal cancer: A phase 1 dose finding study.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.856 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 856-856 ◽

Cited By ~ 1

Author(s):

Shigenori Kadowaki ◽

Toshiki Masuishi ◽

Takashi Ura ◽

Seiichiro Mitani ◽

Yukiya Narita ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Continuous Infusion ◽

Response Rate ◽

Group Performance ◽

Phase 1 ◽

Eastern Cooperative Oncology Group ◽

Fixed Dose ◽

Wild Type ◽

Dose Levels

856 Background: The FOLFOXIRI regimen (irinotecan, oxaliplatin, 5-fluorouracil and leucovorin) improves the response rate and overall survival compared to FOLFIRI in pts with metastatic colorectal cancer (mCRC), and addition of cetuximab to chemotherapy increases efficacy in pts with RAS wild-type mCRC. We conducted a phase 1 study of FOLFOXIRI plus cetuximab to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety and efficacy in Japanese pts with RAS wild-type mCRC. Methods: Main eligibility criteria were: histologically confirmed colorectal adenocarcinoma; KRAS and NRAS wild-type status; measurable metastatic disease according to Response Evaluation Criteria in Solid Tumors version 1.1; age 20-74 years; Eastern Cooperative Oncology Group performance status 0 or 1. Pts with UDP-glucuronosyltransferase 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded. Pts received an escalating dose of intravenous irinotecan (100, 120, and 150 mg/m2 in the dose levels 0, 1, and 2, respectively) and a fixed dose of intravenous oxaliplatin (85 mg/m2), continuous infusion 5-fluorouracil (2400 mg/m2) plus l-leucovorin (200 mg/m2), and cetuximab (an initial dose of 400 mg/m2 followed by 250 mg/m2 per week). Results: A total of 9 Japanese pts were treated (3 and 9 in the dose levels 1 and 2, respectively). No patients experienced a dose-limiting toxicity (the MTD was not reached), and the dose level 2 (irinotecan 150 mg/m2) was established as the RD. With a median 8 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (44%), paronychia (22%), and acne-like rash (11%). No febrile neutropenia and treatment-related death were observed. Among 9 pts, 1 pt had complete response, 7 pts had partial response, and 1 pt had progressive disease, for an overall response rate of 89%. As of September 24, 2017, median progression free survival was 14.0 (95% CI 7.2-20.7) months. Conclusions: The combination of cetuximab and FOLFOXIRI has shown a favorable toxicity profile and promising antitumor activity in pts with RAS wild-type mCRC. Clinical trial information: UMIN000018217.

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Ramucirumab plus merestinib in previously treated metastatic colorectal cancer: safety, pharmacokinetic, and preliminary efficacy findings from a Phase 1 study

Annals of Oncology ◽

10.1093/annonc/mdz157.007 ◽

2019 ◽

Vol 30 ◽

pp. iv124

Author(s):

M. Saleh ◽

P. Cassier ◽

L. Eberst ◽

G. Naik ◽

V. Morris II ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Phase 1 ◽

Phase 1 Study ◽

Previously Treated

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Exceptional responses in patients with metastatic colorectal cancer enrolled in first-in-man studies from 2002 through 2012.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.687 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 687-687

Author(s):

Shiven B. Patel ◽

Danielle Tometich ◽

Zachary L Reese ◽

Sunil Sharma ◽

Ignacio Garrido-Laguna

Keyword(s):

Colorectal Cancer ◽

Clinical Trials ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitor ◽

Phase 1 ◽

Complete Response ◽

Response To Therapy ◽

Search Term ◽

Tumor Type ◽

Gamma Secretase

687 Background: Understanding exceptional responses to therapy at the molecular level may open new venues for the treatment of patients with metastatic colorectal cancer (mCRC). Responses in first-in-man (FIM) studies with targeted therapies are rare and may indicate that actionable genetic aberrations are present in these patients. Methods: We utilized Scopus using the search term “phase 1 and solid tumors” to collect all FIM studies published between 2002 and 2012. We identified patients with mCRC who attained an exceptional response to therapy defined as a complete response (CR) or a partial response (PR) lasting > 6 months (m). Results: We identified 118 FIM studies enrolling 5,369 patients with advanced malignancies. mCRC was the most common tumor type, totaling 1,055 (19.6%) patients. Of these, two patients enrolled in protocols with MDX-1106 (anti PD-1) and RG7180 (mAb EGFR) attained a complete response (CR). Five patients had PR lasting > 6 m. These patients were treated with RG7180 (time on study 7.8 m), Apatinib, a VEGFR tyrosine kinase inhibitor (8.5 and 7.1 m), PV701, a replication-competent oncolytic virus (10 m) and RO4929097, a gamma-secretase inhibitor (7 m). In addition two patients had PR lasting < 6 m with regorafenib (5.3 m) and RG7180 (5.6 m). This database of exceptional responders to therapy will be publicly available at Huntsman Cancer Institute website. Currently, regorafenib and EGFR mAbs (cetuximab and panitumumab) are approved for use in mCRC. EGFR mAbs have shown improvement in survival in RAS wild-type mCRC. Clinical trials are underway evaluating apatinib. Anti-PD1s have shown limited activity as single agents in mCRC and are currently undergoing testing in combination with chemotherapy. Conclusions: We identified exceptional responses among patients with mCRC enrolled in FIM in the last decade. Ongoing efforts are directed to conduct next generation sequencing (NGS) in archived tissue from these patients. Ultimately, this initiative may facilitate the identification of biomarkers of response to be tested in clinical trials with these or novel drugs sharing similar mechanisms of action.

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A phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps3626 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS3626-TPS3626 ◽

Cited By ~ 1

Author(s):

Antoine Hollebecque ◽

Guillem Argiles ◽

Thierry Andre ◽

Andres Cervantes ◽

Catherine Leger ◽

...

Keyword(s):

Colorectal Cancer ◽

Antitumor Activity ◽

Metastatic Colorectal Cancer ◽

Dose Escalation ◽

Phase 1 ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Dose Escalation Study ◽

Nude Mouse Model

TPS3626 Background: Trifluridine/tipiracil, also known as TAS‐102, is a combination of an antineoplastic thymidine‐based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride). The antitumor activity of combined trifluridine/tipiracil and oxaliplatin has been studied in gastrointestinal tumor xenografts, including a 5‐FU resistant subline, using a nude mouse model. This study demonstrated increased antitumor activity for the combination compared to trifluridine/tipiracil or oxaliplatin alone (p < 0.001) (Nukatsuka et al., Anticancer Res 2015). These data support the rationale for clinical use of the combination. We describe a phase 1, international, dose-escalation study of the combination in metastatic colorectal cancer (mCRC). Methods: This trial includes mCRC patients pretreated with at least one line of standard chemotherapy. The 14‐day administration schedule of trifluridine/tipiracil differs from current clinical practice to avoid overlapping toxicity, notably decreased neutrophils due to oxaliplatin or trifluridine/tipiracil. Trifluridine/tipiracil is administered orally (cohort 1: 25 mg/m² bid; cohort 2: 30 mg/m² bid; cohort 3: 35 mg/m² bid) from day 1 to 5; and oxaliplatin at 85 mg/m² (with a possibility to reduce to 65 mg/m²) on day 1. The primary objective is to determine the maximum tolerated dose (MTD) through a 3+3 design. Secondary objectives include safety, pharmacokinetics, and preliminary efficacy (overall survival, progression‐free survival, overall response rate and biomarkers). As of December 2016, no dose‐limiting toxicities had been reported in cohorts 1 or 2. The MTD has not yet been reached and dose‐escalation continues with enrollment in cohort 3 at full dose for both drugs (trifluridine/tipiracil 35 mg/m² bid and oxaliplatin 85 mg/m²). Once established, the MTD will be confirmed in 6 additional patients to define the recommended dose to be used in the expansion part of the study planned in the same patient population. The results of the dose‐escalation part are expected in 2017. (NCT02848443). Clinical trial information: NCT02848443.

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