phase 1 - A Open-Label, Multiple Ascending Dose Study of DS-3078a, an Oral TORC1/2 Kinase Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas - Full Text View - ClinicalTrials.gov

A Open-Label, Multiple Ascending Dose Study of DS-3078a, an Oral TORC1/2 Kinase Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas - Full Text View - ClinicalTrials.gov

 This study is currently recruiting participants.

Verified April 2012 by Daiichi Sankyo Inc.

First Received on April 26, 2012.   Last Updated on April 27, 2012   History of Changes

UK: Advanced Solid Tumours Clinical Trial: Phase I Study of AT13148, a Novel AGC Kinase Inhibitor [Conditions: Advanced Solid Tumours; Interventions: AT13148]

Advanced Solid Tumours Clinical Trial: Phase I Study of AT13148, a Novel AGC Kinase Inhibitor [Conditions: Advanced Solid Tumours; Interventions: AT13148]

Verified by: Cancer Research UK, April 2012

First Received: April 25, 2012 | Last Updated: April 25, 2012 | Phase: Phase 1 | Start Date: April 2012

Overall Status: Not yet recruiting | Estimated Enrollment: 40

The purpose of this first clinical study of the noval multiple AGC kinase inhibitor, AT13148, is to identify the recommended dose for future studies in cancer patients by exploring the safety and maximum tolerated dose and biological effects in patients with advanced solid tumours...

Brief Summary

Official Title: “A Cancer Research UK Phase I First in Man Study of the Novel AGC Kinase Inhibitor AT13148 Given Orally in Patients With Advanced Solid Tumours.”

The purpose of this first clinical study of the noval multiple AGC kinase inhibitor, AT13148, is to identify the recommended dose for future studies in cancer patients by exploring the safety and maximum tolerated dose and biological effects in patients with advanced solid tumours.

• Study Type: Interventional
• Study Design: Masking: Open Label, Primary Purpose: Treatment
• Study Primary Completion Date: October 2015

Detailed Clinical Trial Description

AT13148 is a new drug which looks promising in laboratory studies. We now wish to find out if it will be useful in treating patients with cancer. AT13148 is a type of drug called a protein kinase inhibitor. It blocks several different chemical messengers (enzymes) called AGC kinase proteins. These chemical messengers are part of the signaling process within cells which can make cells produce chemicals that trigger and control cell growth and cell death. In some types of cancer these chemical messengers are 'switched on' or 'switched off' permanently due to changes in the genes of cells called "gene mutations" leading to uncontrolled cancer cell growth. AT13148 targets multiple protein kinases from three families of kinases unlike many of the other protein kinase inhibitors currently being tested which target just one or two kinases. This may mean that it will work better and in a wider group of cancer patients. Patients will not be selected to take part based on having these gene mutations for this first trial because we want to learn more about which mutations are most important but this would be the hope for future trials. The patient population anticipated to benefit from this drug includes certain types of breast, prostate and ovarian cancer which more commonly have these gene mutations.

abstract: Phase 1 Dose-Escalation Study of Aflibercept Plus Docetaxel

Phase 1 Dose-Escalation Study of Aflibercept Plus Docetaxel:

Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors.

Materials and Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m²) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated.

Results: Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data.
Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (>3 months in 18 patients).

Conclusion: On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development. Clin Cancer Res; 18(6); 1743–50. ©2012 AACR.