Increased hemoglobin associated with VEGF inhibitors in advanced renal cell carcinoma.

We retrospectively analyzed whether increased hemoglobin is a surrogate biomarker of efficacy for vascular endothelial growth factor (VEGF) inhibitors in advanced renal cell carcinoma (RCC) patients. Twelve patients were identified who had received bevacizumab alone or as combination therapy. Eleven patients experienced a rise in hemoglobin. Median change was 1.6 g/dL (0-4.0). Degree of peak increase correlated with longer progression-free survival (PFS) in metastatic patients: increase of < 15% yielded a 3.1-month median PFS compared to 8.2 months with rises > 15%. This study identifies increased hemoglobin as a possible consequence of VEGF inhibitors. The correlation with longer PFS suggests that rise in hemoglobin may be a surrogate biomarker of efficacy.

De novo maintenance therapy with denileukin diftitox (Ontak) in a patient with peripheral T-cell lymphoma is associated with prolonged remission.

Peripheral T-cell lymphoma (PTCL) is an aggressive form of non-Hodgkin's lymphoma (NHL), associated with poor prognosis and without standard approach to treatment. Denileukin diftitox (Ontak) is a synthetic fusion protein combining the receptor-binding domain of interleukin-2 to the enzymatically active portion of diphtheria toxin. While approved for the treatment of cutaneous T-cell lymphoma, it has demonstrated activity in non-Hodgkin's lymphomas of both T-cell and B-cell origin. This report documents the first case of de novo maintenance therapy with denileukin diftitox sustaining an ongoing complete response at the molecular level for 2 years in a patient with PTCL.

Phase I studies of CBP501, a G2 checkpoint abrogator, as monotherapy and in combination with cisplatin in patients with advanced solid tumors.

PURPOSE: Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G(2) checkpoint abrogator CBP501, as a single agent and in combination with cisplatin. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/D15, q4w, from 0.9 mg/m(2)), or with cisplatin (both on D1, q3w, from 3.6 mg/m(2) CBP501, 50 mg/m(2) cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles. RESULTS: In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine, and loratadine. The MTD was 25 mg/m(2) CBP501 and 75 mg/m(2) cisplatin, with two patients at the highest dose (36.4 mg/m(2) CBP501, 75 mg/m(2) cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G(3) rise of troponin in one patient. Grade 3 to 4 treatment-related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease. CONCLUSIONS: CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with prophylaxis. Evidence of antitumor activity was observed in platinum-resistant patients.

Inotuzumab ozogamicin as novel therapy in lymphomas.

IMPORTANCE OF THE FIELD: More than 65,000 cases of non-Hodgkin's lymphoma are estimated to have been diagnosed in 2009; the majority are of B-cell lineage, and diffuse large cell lymphoma and follicular together account for nearly half of cases. Despite advances in treatment, most patients are not cured. AREAS COVERED IN THIS REVIEW: The antigen CD22 is a transmembrane glycoprotein found on mature B-cells, and on up to 90% of B-cell malignancies. Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 monoclonal antibody conjugated with calicheamicin. Preclinical data indicate activity against B-cell tumors, and early results from clinical trials indicate activity against B-cell lymphomas including follicular lymphoma and diffuse large cell lymphoma. This paper reviews the design, pharmacokinetic and pharmacodynamic characteristics, and preclinical and clinical experience of this promising novel targeted therapy, with data derived from abstracts and published reports from 2002 to the present. WHAT THE READER WILL GAIN: This review will serve as an introduction to and overview of inotuzumab ozogamicin, and describe the rationale guiding advances in development. TAKE HOME MESSAGE: The data thus far confirm the tolerability and clinical activity of inotuzumab ozogamicin in B-cell malignancies, and further investigation as a single agent as well as in combination therapy is warranted.

A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer.

PURPOSE: Histone deacetylase inhibitors have demonstrated anticancer activity against a range of tumors. We aimed to define the maximum tolerated dose, toxicity, activity, and pharmacokinetics of oral panobinostat, a pan-deacetylase inhibitor, alone and in combination with docetaxel for the treatment of castration-resistant prostate cancer (CRPC). METHODS: Sixteen patients were enrolled, eight in each arm. Eligible patients had CRPC and adequate organ function. In arm I, oral panobinostat (20 mg) was administered on days 1, 3, and 5 for 2 consecutive weeks followed by a 1-week break. In arm II, oral panobinostat (15 mg) was administered on the same schedule in combination with docetaxel 75 mg/m(2) every 21 days. RESULTS: Dose-limiting toxicities were grade 3 dyspnea (arm I) and grade 3 neutropenia >7 days (arm II). In arm I, all patients developed progressive disease despite accumulation of acetylated histones in peripheral blood mononuclear cells. In arm II, five of eight patients (63%) had a >or=50% decline in prostate-specific antigen (PSA), including one patient whose disease had previously progressed on docetaxel. CONCLUSIONS: Oral panobinostat with and without docetaxel is feasible, and docetaxel had no apparent effect on the pharmacokinetics of panobinostat. Since preclinical studies suggest a dose-dependent effect of panobinostat on PSA expression, and other phase I data demonstrate that intravenous panobinostat produces higher peak concentrations (>20- to 30-fold) and area under the curve (3.5x-5x), a decision was made to focus the development of panobinostat on the intravenous formulation to treat CRPC.

Denileukin diftitox as novel targeted therapy for lymphoid malignancies.

Denileukin diftitox (DAB(389)IL-2; Ontak) is a cytotoxic fusion protein designed to target cells expressing the receptor for interleukin-2 (IL-2). It has been approved for treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor, but more recent data indicate activity in the setting of not only T-cell but also B-cell malignancies. This review will update the experience to date of denileukin diftitox in T- and B-cell malignancies.