Phase I Safety Study of DMXAA in Refractory Tumors

Study Overview
=================
Brief Summary
-----------------
This was a phase I study aimed at identifying safe doses of DMXAA (now known as ASA404) to be used in future combination studies with chemotherapy.

Detailed Description
-----------------
This was a multi-centre randomized, double blind study to further characterize the effect of DMXAA on QTc interval, ophthalmic safety and pharmacodynamic effects on tumour blood flow. Patients with refractory tumors were to each undergo six doses of treatment at weekly intervals, receiving each of six doses of DMXAA (300, 600, 1200, 1800, 2400 and 3000 mg/m2)

Official Title
-----------------
5,6-Dimethylxanthenone-4-Acetic Acid (DMXAA) in the Treatment of Refractory Tumors: A Phase I Multicentre Doubleblind Randomized Six-Way Intrapatient Dose-Ranging Crossover Safety Study.

Conditions
-----------------
Refractory Tumors

Intervention / Treatment
-----------------
* Drug: DMXAA


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Evidence of cancer, by histopathology or cytology, which was not amenable to any standard therapy or was refractory to conventional therapy Age ≥ 18 years Life expectancy of at least 12 weeks WHO performance status of 0-2 Hematological and biochemical indices at the start of treatment: Hemoglobin at least 9 g/dl Leukocyte count at least 3.0 x 109/l Neutrophils at least 1.5 x 109/l Platelets at least 100 x 109/l Serum Creatinine not higher than140 μmol/l Liver function tests (ALT, AST, ALK PHOS) no higher than thrice the upper limit of the reference range, if no demonstrable liver metastases or no more than 5 x upper limit of the normal range in the presence of liver or bone metastases Absolute QTc interval values of less than 470 ms in females and less than 450 ms in males as assessed by the Investigator Presence of a lesion which was amenable to dynamic MRI Written informed consent and the ability of the patient to co-operate with treatment and follow up Exclusion Criteria: Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks prior to treatment Pregnant or lactating women were excluded Patients who were poor medical risks because of non-malignant systemic disease, as well as those with active uncontrolled infection Current malignancies at other sites Significant history of recreational drug abuse Glucocorticosteroids in doses exceeding those required for physiological replacement within the previous 2 weeks Skin lesions that may prevent long-term ECG acquisition Body mass index above 30 kg/m2 Patients who were taking certain medications Patients with clinical evidence of brain metastases Patients with certain cardiac conditions Advancing or unstable ischemic heart disease Pacing devices and/or implantable cardiovertor-defibrillator Significant cardiovascular disease or any unstable cardiovascular disease Non-sustained or sustained atrial and/or ventricular tachyarrhythmias Atrial fibrillation (including paroxysmal atrial fibrillation) or atrial flutter Bundle Branch Block, any stable intra-cardiac conduction abnormality with QRS complex > 120 ms, any unstable intra-cardiac conduction abnormality Sick sinus syndrome, or sinus pauses > 2 seconds Known atrial and/or ventricular ectopic beats > 10/hour Fixed second degree AV block, transient or fixed third degree AV block History of documented ventricular flutter, ventricular fibrillation, Torsade de Pointes tachycardia Patients who had previously received anthracyclines or other known cardiotoxic medication Women with breast implants as these may have interfered with the recording of the ECG Patients with severe electrolyte abnormalities and patients in whom transient electrolyte abnormalities may have been expected during any visit of the study Patients in whom concomitant neurotropic drug therapy was known to change or was likely to change during the course of the study, where such therapy was likely to affect the patients ERG measurement Ophthalmic conditions where in the opinion of the investigator they might affect the recording of the ERG

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: DMXAA|DMXAA, given intravenously over 20 minutes. Patients were to each undergo six doses of treatment at weekly intervals, receiving each of six doses (300, 600, 1200, 1800, 2400 and 3000 mg/m2)|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To identify a range of doses for DMXAA where there was either no effect or an acceptably small effect on QTc |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate and describe the relationship between QTc prolongation, plasma levels of DMXAA and time from start of infusion. |  |  | 
| To further investigate the safety profile of DMXAA |  |  | 
| To further investigate the pharmacokinetic behaviour of DMXAA |  |  | 
| To further characterise the ophthalmic effects of DMXAA |  |  | 
| To document anti-tumour activity and/or clinical signs of efficacy in patients |  |  | 
| To assess the effects of DMXAA on tumour blood flow using dynamic MRI |  |  |