Phase I and pharmacokinetic study of the oral tris-(8-quinolinolato)gallium(III) complex (FFC11, KP46) in patients with solid tumors - a study of the CESAR Central European Society for Anticancer Drug Research - EWIV

Abstract

3205 Background: FFC11 is an orally bioavailable gallium complex, which exerts its antitumoral activity via inhibition of ribonucleotide reductase, induction of S phase arrest and apoptosis. In preclinical models FFC11 proved to be a stronger anticancer agent than gallium nitrate and it was effective against a model of tumor-associated hypercalcemia. Methods: FFC 11 is administered orally for 14 days followed by a 14-days recovery period representing one cycle of therapy. The phase I trial is started at 30 mg/m2. Dose escalation (DE) is performed acc. to an accelerated dose titration design with escalation steps of 100%. The accelerated phase is finished when 1 pt exhibits dose limiting toxicity (DLT) or 2 pts experience toxicities ≥ grade (G) 2 NCI-CTC. Further DE will be done acc. to a modified Fibonacci scheme. Tumor response is assessed using the RECIST criteria. PK parameters were estimated assuming a one compartment model. Results: 7 pts were entered at the following dose levels (DL): 30 mg/m2, 60 mg/m2, 120 mg/m2, 240 mg/m2 and 480 mg/m2. Patient’s profile comprised the following tumor entities: parotid gland, stomach, renal cell (4) and ovarian cancer. Most pts were heavily pretreated. The adverse events for which a relationship to the study medication could not definitely be ruled out were neutropenia (G2 at DL1) (1pt) and anemia (G2 at DL1) (2pts), stomatitis and conjunctivitis (G1 at DL2) (1pt), dizziness, headache and acne (G1 at DL4) (1pt), fatigue (G1) and diarrhoea (G3) both at DL5 (1pt); the latter represented a DLT. Further enrolment on this DL was terminated due to feasibility reasons. In one out of the 4 pts with renal cell carcinoma (RCC) an unconfirmed partial response (PR) has been observed after 8 weeks and in a second pt with RCC the disease was stabilized for 29 weeks. Peak plasma levels were reached 5–7 h after intake. PK analysis revealed a long terminal half-life (28 h), a high CL/F (42 L/h) and a large V/F (1700 L). Conclusions: FFC11 has been well tolerated with some preliminary evidence of efficacy in RCC. FFC11 will be developed further after the production of higher dosed tablets. Supported by Faustus Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Faustus Cie