Abstract 5381
Background
Ineffective chemotherapy may partly be caused by subtherapeutic intratumoral drug levels. Nanomedicines are developed to improve the therapeutic index, by increasing intratumoral drug exposure and preserving healthy tissue. CPC634 is a new nanoparticle entrapping docetaxel. Here, we hypothesized that CPC634 increases intratumoral docetaxel level and overall duration of exposure.
Methods
In this randomized cross-over study we assessed both plasma and intratumoral pharmacokinetics (PK) of docetaxel after intravenous administration of 75 mg/m2 conventional docetaxel (Cd) and CPC634. We aimed to identify a 25% increase of intratumoral docetaxel exposure after CPC634 infusion compared to Cd. Adult patients were randomized to receive Cd in cycle 1 and CPC634 in cycle 2 or vice versa. Tumor biopsies were taken 24, 48, 72, 96, 168 or 336 hours after infusion during both cycles. Total docetaxel concentration (TDC) was determined for both drugs and released docetaxel for CPC634 in tumor tissue and plasma. PK data were analyzed using mixed modeling.
Results
In total, 21 evaluable patients were included. In plasma, the area under the curve (AUCinf) of released docetaxel was higher (+27%, 95% CI: 11-44%, P = 0.001) while peak plasma concentration (Cmax) (-91%, 95% CI: -92:-89%, P < 0.001) and clearance (-21%, 95% CI: -31;-10%, P = 0.001) decreased during CPC634 administration versus Cd. Intratumoral TDC was 375% higher (95% CI: 187-686%, P < 0.001) after CPC634 administration, while released docetaxel was comparable to Cd (+8%, 95% CI: -30-+69%, P = 0.71).
Conclusions
The plasma PK profile of CPC634 is favorable compared to Cd since a lower Cmax, lower clearance and prolonged higher systemic exposure is seen. Higher intratumoral TDC levels were reached with CPC634, while released docetaxel levels were comparable to Cd. The almost 4-fold increased tumor accumulation for prolonged period of time of TDC supports the expectation that CPC634 will exhibit beneficial efficacy/safety balance. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in platinum resistant ovarian cancer patients (NCT03742713) are currently ongoing.
Clinical trial identification
Netherlands Trial Registry NL6299 (NTR6474).
Editorial acknowledgement
Legal entity responsible for the study
Prof. Dr. A.H.J. Mathijssen as principle investigator.
Funding
Cristal Therapeutics.
Disclosure
C.J.F. Rijcken: Officer / Board of Directors: Cristal Therapeutics; Leadership role: Cristal Therapeutics; Shareholder / Stockholder / Stock options: Cristal Therapeutics; Full / Part-time employment: Cristal Therapeutics. R. Hanssen: Full / Part-time employment: Cristal Therapeutics. R.H.J. Mathijssen: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier; Honoraria (institution): Novartis; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Astellas. S.L. Koolen: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.
Resources from the same session
3909 - Spectrum of pathogenic germline mutations in Chinese lung cancer patients through next-generation sequencing
Presenter: Ying Huang
Session: Poster Display session 1
Resources:
Abstract
3061 - Poor prognostic impact of NTRK2 gene variation in Esophageal Squamous Cell Carcinoma
Presenter: Ye Chen
Session: Poster Display session 1
Resources:
Abstract
4735 - Mutation profile of Tibetan lung cancer revealed by Whole Exome Sequencing
Presenter: Xin Wang
Session: Poster Display session 1
Resources:
Abstract
5236 - Synergistic activity between niraparib and chemotherapy in colorectal cancer: molecular determinants from a preclinical model
Presenter: Pietro Paolo Vitiello
Session: Poster Display session 1
Resources:
Abstract
4051 - cRGDfK (cRGD) conjugated Pyropheophor¬bide-a (Pyro), a new tumor photodynamic agent, is highly accumulated and specific in tumor cell killing
Presenter: Fengwei Wang
Session: Poster Display session 1
Resources:
Abstract
859 - The expression of MMR, CD133 and the presence of p53 wt predict the response to Cabazitaxel in malignant neural tumors cell lines.
Presenter: Kevin Doello
Session: Poster Display session 1
Resources:
Abstract
2497 - IKS01, a next generation antibody drug conjugate (ADC) designed to be efficacious in tumors with low and moderate levels of folate receptor expression
Presenter: Jenny Thirlway
Session: Poster Display session 1
Resources:
Abstract
1636 - Novel Non-Camptothecin Compounds with Antiproliferative Activities against Breast Cancer Cells
Presenter: Wen-shan Li
Session: Poster Display session 1
Resources:
Abstract
3443 - Sensitization of estrogen receptor-positive breast cancer cells to tamoxifen by novel epi-oligomycin A
Presenter: Margarita Yastrebova
Session: Poster Display session 1
Resources:
Abstract
840 - Autophagy inhibition enhances leflunomide-induced cytotoxicity in human bladder cancer cells
Presenter: Li Cheng
Session: Poster Display session 1
Resources:
Abstract