A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer

2021 ◽  
Author(s):  
Hyehyun Jeong ◽  
Yong Sang Hong ◽  
Jeong Eun Kim ◽  
Hyeong-Seok Lim ◽  
Joong Bae Ahn ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Vascular Disrupting Agent ◽  
Safety And Efficacy ◽  
Previously Treated ◽  
Vascular Disrupting

scholarly journals Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study

2021 ◽  
Author(s):  
Takeshi Kato ◽  
Yoshinori Kagawa ◽  
Yasutoshi Kuboki ◽  
Makio Gamoh ◽  
Yoshito Komatsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Wild Type ◽  
Open Label ◽  
Safety And Efficacy ◽  
Multicentre Phase

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.

A phase 1 dynamic accelerated titration dose escalation study of the vascular disrupting agent NPI-2358

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14097-14097 ◽  
Author(s):  
M. A. Spear ◽  
P. LoRusso ◽  
A. W. Tolcher ◽  
C. Lin ◽  
D. Wang ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Troponin I ◽  
Tumor Regression ◽  
Phase 1 ◽  
Chemotherapeutic Agents ◽  
Drug Accumulation ◽  
Weekly Schedule ◽  
Dose Escalation Study ◽  
Vascular Disrupting Agent ◽  
Vascular Disrupting

14097 Background: NPI-2358 is a novel tumor vascular disrupting agent acting on β-tubulin that destabilizes tumor vascular endothelial cells with an additional direct cytotoxic activity. NPI-2358 selectively induces tumor vascular collapse and tumor regression in multiple murine tumor models and also potentiates the effects of chemotherapeutic agents. Preclinical data indicate NPI-2358 may have advantages in terms of safety profile and activity (tumor blood flow remains markedly reduced after 24 hours). Methods: A Phase 1 study of NPI-2358 is being conducted in patients with solid tumors and lymphomas. Patients in this study were treated with NPI-2358 administered as a weekly IV infusion for 3 weeks in 4-week cycles. Eight subjects have been enrolled. The dose of NPI-2358 was escalated in cohorts of 1–3 patients dependent on observed adverse events (any cohort may consist of 1 patient provided no =Grade 2 AE is reported in the prior cohort). A cohort is expanded to 6 patients if a DLT is reported. Escalation was conducted in 100% intervals, and decreased to 50% intervals once a Grade 2 adverse event was reported. In addition to weekly safety monitoring (including ECGs, Troponin I, and blood pressure), echocardiography and pharmacokinetics were performed on Days 1 and 15 (D1 & D15), and a DCE-MRI obtained 4 hours after the first dose was compared to baseline. Results: The dose has been escalated from 2 mg/m2 to 9 mg/m2 (predicted minimum efficacious dose = 7.5 mg/m2) without evidence of dose-limiting toxicity or other significant toxicities including cardiovascular or neurotoxicity. Intrapatient values for Ktrans from DCE-MRIs appear highly reproducible. No responses have been reported, however, one patient with pancreatic adenocarcinoma has had stable disease (SD) for 3 cycles and continues to receive NPI-2358. Average Cmax and AUClast have increased from 16.2 ng/ml to 147 ng/ml, and from 101 to 360 ng/ml*hr respectively. No drug accumulation was observed; T1/2 was 4.2 ±1.9 h, clearance was 45 ±12 L/h and distributive volume was 251±57 L. Conclusions: NPI-2358 is well tolerated at doses above the minimum predicted efficacious dose. PK data show increasing Cmax and AUC with dose escalation and no drug accumulation on a weekly schedule. No significant financial relationships to disclose.

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

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3626-TPS3626 ◽  
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.

scholarly journals Dose-escalation of REgorafenib for patients with previously treated metastatic colorectal cancer - DEREGULATE study

2015 ◽  
Vol 26 ◽  
pp. vii129
Author(s):  
Ryuta Nishitai ◽  
Dai Manaka ◽  
Hisashi Amaike ◽  
Akira Nozaki ◽  
Masashi Kanai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Previously Treated

42 POSTER NPI-2358 (a novel vascular disrupting agent) Phase 1 dose escalation trial with an RP2D cohort

2008 ◽  
Vol 6 (12) ◽  
pp. 17
Author(s):  
M. Mita ◽  
M.A. Spear ◽  
L.K. Yee ◽  
K.P. Papadopoulos ◽  
E.I. Heath ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Vascular Disrupting Agent ◽  
Vascular Disrupting

Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients

2015 ◽  
Vol 26 (8) ◽  
pp. 872-877 ◽  
Author(s):  
Jara M. Baas ◽  
Lisanne L. Krens ◽  
Monique M. Bos ◽  
Johanneke E.A. Portielje ◽  
Erdogan Batman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Safety And Efficacy ◽  
Previously Treated ◽  
Colorectal Cancer Patients

Targeted chemoradiation for metastatic colorectal cancer: A phase I trial of oral capecitabine combined with 131I- huA33

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4078-4078
Author(s):  
R. A. Herbertson ◽  
N. Tebbutt ◽  
S. Gill ◽  
F. T. Lee ◽  
B. Chappell ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Tumor Targeting ◽  
Tumor Response ◽  
Single Photon ◽  
Phase 1 ◽  
Photon Emission ◽  
Good Tolerability ◽  
Imaging Results

4078 Background: HuA33 is a humanized antibody that targets the A33 antigen, which is highly expressed in intestinal epithelium and >95% of human colon cancers, but not other normal tissues. Previous studies have shown huA33 can target and be retained in a metastatic tumor for 6 weeks, but eliminated from normal colonocytes within days. This phase 1 study used radio-labeled huA33 in combination with capecitabine chemotherapy to target chemoradiation to metastatic colorectal cancer. Methods: The primary objective was safety and tolerability of the combination of capecitabine and 131I-huA33. Pharmacokinetics, biodistribution, immunogenicity, and tumor response were also assessed. Eligibility included measurable metastatic colorectal cancer, adequate hematological and biochemical function, and informed consent. An outpatient scout 131I-huA33 dose was followed by a single therapy infusion one week later, when capecitabine was commenced. Dose escalation occurred over 5 dose levels. Patients were evaluated weekly, with tumor response assessment at the end of the12 week trial. Tumor targeting was assessed using gamma camera and single photon emission computerized tomography (SPECT) imaging. Results: 16 patients have enrolled with 2 currently on treatment, including one in the final dose cohort. Accrual will be completed by March 2007. The dose escalation protocol was amended following 2 dose limiting toxicities in the second cohort, but subsequent cohorts demonstrated good tolerability. Biodistribution analysis demonstrated excellent tumor targeting of the known tumor sites, expected transient bowel uptake, but no other normal tissue uptake. Maximal duration of stable disease is currently 3 years. Conclusions: 131I-huA33 achieves specific targeting of radiotherapy to sites of metastasis and can be safely combined with chemotherapy. This provides an opportunity to deliver chemoradiation specifically to metastatic disease in colorectal cancer patients. [Table: see text] No significant financial relationships to disclose.

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