Phase Ib trial of Combretastatin A4 Phosphate (CA4P) in combination with radiotherapy (RT): Initial clinical results

Abstract

3117 Background: CA4P, a vascular targeting agent, may act synergistically with radiation. This is an ongoing Phase Ib trial of CA4P in combination with external beam RT. Methods: Patients with inoperable, advanced non-small cell lung cancer (NSCLC), or prostate adenocarcinoma, who are to receive RT, were eligible. The first two cohorts had NSCLC, and received RT over 3 weeks (27Gy in 6 fractions). Patients in the 3rd and 4th cohorts had prostate cancer, and received RT over 4 weeks (55Gy in 20 fractions). Patients in the 1st and 3rd cohorts received a single dose of CA4P; patients in the 2nd and 4th cohorts received weekly CA4P for the duration of their RT. All patients received 50mg/m2 of CA4P. Results: 20 patients have been treated. 1hr post CA4P, systolic blood pressure (SBP) and diastolic blood pressure (DBP) increased from baseline by a mean of 17mmHg (paired t-test, p=0.00001), and 10mmHg (p=0.000003), with a fall in pulse rate (PR) of 7bpm (p=0.00001). BP recovered by 5hrs, but PR increased by 9bpm at 3hrs, sustained to 6hrs (p=0.00001). All BP changes were CTC grade 1. QTc increased 4hrs after CA4P by 13msec (p=0.001); this remained increased at 6hrs by 8msec (p=0.03). No QTc exceeded 480msec. No significant ECG changes were seen. One patient had grade 3 postural syncope 4hrs after his 1st dose of CA4P, with spontaneous recovery. He received further doses without complications. All NSCLC patients developed lymphopenia (grade 3 in 5), 2 patients had grade 2 leucopenia, and 1 had neutropenia. None suffered significant infections. Lymphopenia had been reported after thoracic RT, however in a Phase I study of CA4P, 27% of patients had lymphopenia, suggesting a drug effect. 9 patients with NSCLC had tumour pain (grade 4 in 1), 7 required opioids. No patients with prostate cancer had tumour pain. Conclusions: CA4P is well tolerated when combined with RT. There was no increase in acute or late RT reaction, and no accumulation of toxicity with repeated doses. Cardiovascular drug effects were mild and self-limiting. Further evaluation of this novel combination is ongoing. No significant financial relationships to disclose.