Allan Lipton

The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study

Background:This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel.Methods:Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m–2 docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated.Results:In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of ⩾6 months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of ⩾3 mg kg–1. Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had ⩾5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from ⩾5 to <5 CTCs and 9 out of 10 (90%) had a ⩾30% decline in CTCs after therapy.Conclusions:Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted.

Serial serum c-erbB-2 levels in patients with breast carcinoma.

Recently, the extracellular domain of the c‐erbB‐2 oncogene product (HER‐2/neu) has been reported to be elevated in the serum of one‐fourth of patients with metastatic breast carcinoma. The role of serum c‐erbB‐2 as a tumor marker, however, is still poorly defined. The purpose of this study was to evaluate the utility of serial serum c‐erbB‐2 levels as a tumor marker in patients with metastatic breast carcinoma.

Mitogenic Stimulation of Tumor Cells by Platelet Derived Growth Factors

There is evidence that platelets are involved in the hematogenous spread of malignant tumors. Certain tumor cells aggregate platelet in vitro (1–4) and an intimate relationship between platelets and tumor cells is further suggested by ultrastructural studies in vivo which show arrested tumor emboli surrounded by platelets (5–8). Certain tumor lines also induce thrombocytopenia in vivo (1,5,9). The reasons for this close platelet-tumor cell relationship are speculative at present. Possibilities include: 1) protection by platelets of the tumor cell against immune destruction, 2) enhanced tumor cell transit of the vascular endothelium via platelet adherence or 3) tumor cell survival and multiplication due to release of platelet mitogenic factors.

Obesity, patient characteristics, and TIMP-1: Effects on non-bone RFS in NCIC CTG MA.14.

562 Background: High TIMP-1 levels have been associated with decreased benefit from chemotherapy in premenopausal N+ women (Shrohl, et al., SABCS 2008, Abstract # 6054) and response to aromatase inhibitors in breast metastatic setting (Lipton, et al., JCO, 2008). In the adjuvant setting,we postulated that pretrial chemotherapy altered TIMP-1 levels, or lead to sensitivity to adjuvant hormonal therapy. Observations in rats offers a different possibility, that obesity is associated with high TIMP-1 levels. Methods: NCIC CTG MA.14 is a trial where 667 postmenopausal patients were randomized to receive adjuvant tamoxifen ± octreotide LAR with a stratification factor of no, concurrent or sequential chemotherapy. Serum TIMP-1 was assessed on 621 of 667 (93.1%) of the trial patients. We used exact Fisher tests to examine associations of baseline obesity and other patient characteristics with TIMP-1, categorized as = 454 ng/mL, based on 95% non-parametric cut-point for healthy post-menopausal females. St...