Phase I Safety Study of DMXAA in Refractory Tumors

Phase 1

Completed

• Conditions: Refractory Tumors

• Registration Number: NCT00856336
• Lead Sponsor: Antisoma Research

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)

Study Timeline

• Study Start: 2003-05
• Primary Completion: 2004-01
• Study Completion: 2004-01
• Status Verified: 2009-03
• Study First Submitted: 2009-03-04
• Study First Submitted QC: 2009-03-04
• Last Update Submitted: 2009-03-04
• Study First Posted: 2009-03-05
• Last Update Posted: 2009-03-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

1. Evidence of cancer, by histopathology or cytology, which was not amenable to any standard therapy or was refractory to conventional therapy

2. Age ≥ 18 years

3. Life expectancy of at least 12 weeks

4. WHO performance status of 0-2

5. Hematological and biochemical indices at the start of treatment:

   1. Hemoglobin at least 9 g/dl
   2. Leukocyte count at least 3.0 x 109/l
   3. Neutrophils at least 1.5 x 109/l
   4. Platelets at least 100 x 109/l
   5. Serum Creatinine not higher than140 μmol/l
   6. 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
   7. Absolute QTc interval values of less than 470 ms in females and less than 450 ms in males as assessed by the Investigator

6. Presence of a lesion which was amenable to dynamic MRI

7. Written informed consent and the ability of the patient to co-operate with treatment and follow up

Exclusion Criteria

1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks prior to treatment

2. Pregnant or lactating women were excluded

3. Patients who were poor medical risks because of non-malignant systemic disease, as well as those with active uncontrolled infection

4. Current malignancies at other sites

5. Significant history of recreational drug abuse

6. Glucocorticosteroids in doses exceeding those required for physiological replacement within the previous 2 weeks

7. Skin lesions that may prevent long-term ECG acquisition

8. Body mass index above 30 kg/m2

9. Patients who were taking certain medications

10. Patients with clinical evidence of brain metastases

11. Patients with certain cardiac conditions

    1. Advancing or unstable ischemic heart disease
    2. Pacing devices and/or implantable cardiovertor-defibrillator
    3. Significant cardiovascular disease or any unstable cardiovascular disease
    4. Non-sustained or sustained atrial and/or ventricular tachyarrhythmias
    5. Atrial fibrillation (including paroxysmal atrial fibrillation) or atrial flutter
    6. Bundle Branch Block, any stable intra-cardiac conduction abnormality with QRS complex > 120 ms, any unstable intra-cardiac conduction abnormality
    7. Sick sinus syndrome, or sinus pauses > 2 seconds
    8. Known atrial and/or ventricular ectopic beats > 10/hour
    9. Fixed second degree AV block, transient or fixed third degree AV block
    10. History of documented ventricular flutter, ventricular fibrillation, Torsade de Pointes tachycardia
    11. Patients who had previously received anthracyclines or other known cardiotoxic medication

12. Women with breast implants as these may have interfered with the recording of the ECG

13. Patients with severe electrolyte abnormalities and patients in whom transient electrolyte abnormalities may have been expected during any visit of the study

14. 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

15. Ophthalmic conditions where in the opinion of the investigator they might affect the recording of the ERG

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Primary Outcome Measures

Name	Time	Method
To identify a range of doses for DMXAA where there was either no effect or an acceptably small effect on QTc

Secondary Outcome Measures

Name	Time	Method
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