A Study to Evaluate the Effects of ASA404 Alone or in Combination With Taxane-based Chemotherapies on the Pharmacokinetics of Drugs in Patients With Advanced Solid Tumor Malignancies

An Open-label, Multi-center Study to Evaluate the Effects of ASA404 Alone and in Combination With Taxane-based Chemotherapy on the Pharmacokinetics of Simvastatin, Caffeine, Omeprazole, and Diclofenac in Patients With Advanced Solid Tumor Malignancies

The purpose of this study is to evaluate the potential inhibitory effects of ASA404 on CYP1A2, CYP2C9, CYP3A4 and CYP2C19 mediated metabolism on the respective probe drugs caffeine, diclofenac, simvastatin, and omeprazole, respectively. This will be accomplished by the simultaneous administration of four substrates as part of a cocktail in order to characterize the potential for in-vivo drug-drug interactions. This cocktail approach has been proposed per FDA guidance as a screening tool for potential in-vivo drug-drug interactions Compared to the individual administration of specific probes in multiple studies, simultaneous administration of multiple in-vivo probes of drug-metabolizing enzymes offer several distinct advantages such as minimizing the confounding influence of inter-individual and intra-individual variability over time. Substrates for the CYP enzymes were chosen based on the FDA guidance recommendations taking into account that 1. The substrates are specific for the individual CYP enzymes, 2. There are no interactions among these substrates; and 3. The study will be conducted in a sufficient number of subjects.

Study Overview

• Status: Terminated
• Conditions: Solid Tumor Malignancies
• Intervention / Treatment: Drug: ASA404, DMXAA, DXAA

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Science Center at Houston
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin & Paul P. Carbone Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Histologically-proven and radiologically-confirmed diagnosis of advanced or metastatic solid tumors for whom treatment with an investigational agent alone or in combination with docetaxel or placlitaxel +carboplatin is appropriate;

• Body Mass Index (BMI) must be within the range of 18-30;
• A minimum of 4 weeks must have elapsed since the last treatment with other cancer therapies, (i.e. endocrine therapy, immunotherapy, chemotherapy, ect);
• Willing and able to remain in the clinic for at least 2 days (the night before dosing and the night after dosing 24 hours) for the 3 x's receiving the cocktail (on Day 1, Day 8 and Day 15 during the

Exclusion Criteria:

• Patients having CNS metastases. (Patients having any clinical signs of CNS metastases must have a CT or MRI of the brain performed to rule out CNS metastases in order to be eligible for the study participation. Patients who have had brain metastases surgically removed or irradiated with no active residual disease confirmed by imaging are allowed)
• Patients who have not recovered from all acute radiotherapy-related toxicities;
• Prior exposure to Vascular Disrupting Agents (VDAs) or other vascular targeting agents
• Right bundle branch block (RBBB), complete left bundle branch block (LBBB), bifascicular block (right bundle branch block with either left anterior hemiblock or left posterior hemiblock)
• Concomitant use of drugs with a risk of QT prolongation and/or causing torsade de pointes

If patient will be treated with paclitaxel:

• Known allergy or hypersensitivity to platinum-containing drugs, taxanes, other drugs formulated in Cremophor EL (polyoxyethylated castor oil) or any known excipients of these drugs
• Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions while taking paclitaxel and therefore are not considered effective contraceptive methods for this study when used as a single agent. Patients taking oral, implantable, or injectable contraceptives who are not willing or otherwise unable to use a concomitant barrier method will be excluded. The Investigator shall counsel the patient accordingly. For a list of substrates of human liver microsomal P450 enzymes, visit website (http://medicine.iupui.edu/flockhart/)

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ASA 404 + standard chemotherapy; ASA 404 in combination with in combination with standard chemotherapy (paclitaxel + carboplatin or docetaxel) and a cocktail of caffeine, diclofenac, simvastatin and omeprazole	Drug: ASA404, DMXAA, DXAA; ASA404 (5,6-dimethylxantheone-4-acetic acid) DMXAA or DXAA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
evaluate the effects of ASA404 on the pharmacokinetics of a cocktail of simvastatin, caffeine, omeprazole, and diclofenac in patients with advanced malignancies.	12 months
evaluate the effects of ASA404 combined with either paclitaxel + carboplatin or docetaxel on the pharmacokinetics of a cocktail of simvastatin, caffeine, omeprazole, and diclofenac in patients with advanced malignancies.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameters of caffeine, diclofenca, simvastatin, and omeprazole, including AUC (0-tlast), AUC (0-inf), t½,CL/F, Vz/F, Cmax, and tmax.		12 months
Pharmacokinetic parameters of ASA404 including AUC (0-tlast), Cmax, and Tmax		4 Months
assessment of safety based mainly on the frequency and severity of adverse events and the number of laboratory values worsening from baseline based on the CTCAE grade.	Other safety data (e.g. vital signs, electrocardiograms, and ophthalmic assessments) will be considered as appropriate.	4 months
assess the safety and tolerability of ASA404		4 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: January 26, 2011
• First Submitted That Met QC Criteria: February 4, 2011
• First Posted (Estimate): February 7, 2011

Study Record Updates

• Last Update Posted (Estimate): September 2, 2011
• Last Update Submitted That Met QC Criteria: August 31, 2011
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: caffeine,; ASA404,; Solid tumor malignancies,; simvastatin,; omeprazole and diclofenac,; PK data
• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents; Vadimezan
• Other Study ID Numbers: CASA404A2111