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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01290380
First received: January 26, 2011
Last updated: August 31, 2011
Last verified: August 2011
  Purpose

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.


Condition Intervention Phase
Solid Tumor Malignancies
Drug: ASA404, DMXAA, DXAA
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • evaluate the effects of ASA404 on the pharmacokinetics of a cocktail of simvastatin, caffeine, omeprazole, and diclofenac in patients with advanced malignancies. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • 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. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacokinetic parameters of caffeine, diclofenca, simvastatin, and omeprazole, including AUC (0-tlast), AUC (0-inf), t½,CL/F, Vz/F, Cmax, and tmax. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Pharmacokinetic parameters of ASA404 including AUC (0-tlast), Cmax, and Tmax [ Time Frame: 4 Months ] [ Designated as safety issue: Yes ]
  • 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. [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]
    Other safety data (e.g. vital signs, electrocardiograms, and ophthalmic assessments) will be considered as appropriate.

  • assess the safety and tolerability of ASA404 [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]

Enrollment: 54
Study Start Date: February 2010
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01290380

Locations
United States, Texas
The University of Texas Science Center at Houston
Houston, Texas, United States, 77030
United States, Wisconsin
University of Wisconsin & Paul P. Carbone Comprehensive Cancer Center
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01290380     History of Changes
Other Study ID Numbers: CASA404A2111
Study First Received: January 26, 2011
Last Updated: August 31, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Solid tumor malignancies,
simvastatin,
caffeine,
omeprazole and diclofenac,
ASA404,
PK data

Additional relevant MeSH terms:
Neoplasms
Diclofenac
Omeprazole
Simvastatin
Vadimezan
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Anti-Ulcer Agents
Anticholesteremic Agents
Antimetabolites
Antineoplastic Agents
Antirheumatic Agents
Central Nervous System Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Gastrointestinal Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Proton Pump Inhibitors
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014