Retrospective quality control review of FDG scans in the imaging sub-study of PALETTE EORTC 62072/VEG110727: a randomized, double-blind, placebo-controlled phase III trial.

PURPOSE: (18)F-Labelled fluorodeoxyglucose (FDG) can detect early changes in tumour metabolism and may be a useful quantitative imaging biomarker (QIB) for prediction of disease stabilization, response and duration of progression-free survival (PFS). Standardization of imaging procedures is a prerequisite, especially in multicentre clinical trials. In this study we reviewed the quality of FDG scans and compliance with the imaging guideline (IG) in a phase III clinical trial. METHODS: Forty-four cancer patients were enroled in an imaging sub-study of a randomized international multicentre trial. FDG scan had to be performed at baseline and 10-14 days after treatment start. The image transmittal forms (ITFs) and Digital Imaging and Communications in Medicine (DICOM) [1] standard headers were analysed for compliance with the IG. Mean liver standardized uptake values (LSUVmean) were measured as recommended by positron emission tomography (PET) Response Criteria in Solid Tumors 1.0 (PERCIST) [2]. RESULTS: Of 88 scans, 81 were received (44 patients); 36 were properly anonymized; 77/81 serum glucose values submitted, all but one within the IG. In 35/44 patients both scans were of sufficient visual quality. In 22/70 ITFs the reported UT differed by >1 min from the DICOM headers (max. difference 1 h 4 min). Based on the DICOM, UT compliance for both scans was 31.4%. LSUVmean was fairly constant for the 11 patients with UT compliance: 2.30 ± 0.33 at baseline and 2.27 ± 0.48 at follow-up (FU). Variability substantially increased for the subjects with unacceptable UT (11 patients): 2.27 ± 1.04 at baseline and 2.18 ± 0.83 at FU. CONCLUSION: The high attrition number of patients due to low compliance with the IG compromised the quantitative assessment of the predictive value for early response monitoring. This emphasizes the need for better regulated procedures in imaging departments, which may be achieved by education of involved personnel or efforts towards regulations. LSUVmean could be monitored to assess quality and compliance in an FDG PET/CT study.

Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.

PURPOSE: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. EXPERIMENTAL DESIGN: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide x 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. RESULTS: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. CONCLUSIONS: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.

Pazopanib in advanced desmoplastic small round cell tumours: a multi-institutional experience.

BACKGROUND: We retrospectively reviewed data from nine pre-treated metastatic desmoplastic small round cell tumour (DSRCT) patients who received pazopanib. PATIENTS AND METHODS: Three patients received pazopanib within the EORTC phase II 62043, three in the EORTC phase III 62072, and three in the context of UK named patient program. RESULTS: Nine patients were retrieved from the databases, the median age was 30 years (range: 21-47), they were all males. All had received prior chemotherapy. At the time of treatment start, 4 patients (44%) had ECOG PS 0, 4 (44%) PS 1, 1 (11%) PS 2. Best response was partial response (PR) in 2/9 (22%) patients, stable disease (SD) in 5/9 (56%) and progressive disease (PD) in 2/9 (22%) with a clinical benefit rate (PR + SD > 12 weeks) of 78%. Median PFS and OS were 9.2 (95%CI: 0-23.2) and 15.4 (95%CI: 1.5-29.3) months respectively. With a median follow-up of 20 months, 2/9 (22%) patients are still alive, all progressed. The most common toxicities included neutropenia (G1-2 45%; G3-4 11%), anaemia (G1-2 45%), fatigue (G1-2 67%), diarrhoea (G1-2 45%; G3-4 11%), nausea (G1-2 45%), hypertension (G1-2 45%) and increase in liver enzymes (G1-2 34%; G3-4 11%). Three patients (34%) required a dose reduction. One of the patients discontinued treatment because of persistent increase in total bilirubin level, one due to patient's choice. CONCLUSION: In this series, pazopanib showed interesting activity in DSRCT patients who progressed after prior chemotherapy without major toxicity.

A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation.

PURPOSE: poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma. METHODS: Patients with chemotherapy naïve measurable metastatic melanoma, performance status ≤2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored. RESULTS: Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months. CONCLUSIONS: This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.