Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270-360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90-18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life-threatening hematologic disease characterized by chronic complement-mediated hemolysis and thrombosis. Despite treatment with eculizumab, a C5 inhibitor, 72% of individuals remain anemic. Pegcetacoplan (APL-2), a PEGylated C3 inhibitor, has the potential to provide more complete hemolysis control in patients with PNH. This open-label, phase Ib study was designed to assess the safety, tolerability, and pharmacokinetics of pegcetacoplan in subjects with PNH who remained anemic during treatment with eculizumab. Pharmacodynamic endpoints were also assessed as an exploratory objective of this study. Data are presented for six subjects in cohort 4 who received treatment for up to 2 years. In total, 427 treatment-emergent adverse events (TEAEs) were reported, 68 of which were possibly related to the study drug. Eight serious TEAEs occurred in two subjects; three of these events were considered possibly related to the study drug. Pegcetacoplan pharmacokinetic concentrations accumulated with repeated dosing, and steady state was reached at approximately 6-8 weeks. Lactate dehydrogenase levels were well controlled by eculizumab at baseline. Pegcetacoplan increased hemoglobin levels and decreased both reticulocyte count and total bilirubin in all six subjects. Improvements were observed in Functional Assessment of Chronic Illness Therapy Fatigue scores. Two subjects discontinued for reasons unrelated to pegcetacoplan. All four subjects who completed the study transitioned to pegcetacoplan monotherapy following eculizumab discontinuation and avoided transfusions. In this small study, pegcetacoplan therapy was generally well-tolerated, and resulted in an improved hematological response by achieving broad hemolysis control, enabling eculizumab discontinuation.

A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia.

Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside (also known as ferric derisomaltose) and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open­label, comparative, multi­center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase ≥2 g/dL from baseline at any time between weeks 1­5. Both non­inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.

New targets for non-small-cell lung cancer therapy.

Lung cancer remains the leading cause of malignancy-related deaths in the USA, regardless of advances in therapeutic agents. Non-small-cell lung cancer demonstrates great molecular heterogeneity in which several pathways are simultaneously active leading to tumorigenesis. Novel agents targeting specific pathways associated with apoptosis, cell proliferation, angiogenesis and other mechanisms have emerged as a separate and unique therapeutic class delivering promising results in a vast number of malignancies. This innovative class of agents has been studied in advanced-stage non-small-cell lung cancer and, although some agents have demonstrated a clinical benefit, the overall course of the disease remains relatively unchanged, still holding a poor overall prognosis. Most of these agents have been shown to be 'cytostatic', inducing more stable disease rather than objective responses. Thus, the entrance of these novel agents into our drug armamentarium seems to be more attractive in combination with conventional chemotherapy agents based on additive or synergistic response seen with this combined approach. Herein, we review the most relevant clinical data using these novel targeted agents either alone or in combination with chemotherapy in non-small-cell lung cancer.

Intensity-modulated radiotherapy with concurrent chemotherapy for previously irradiated, recurrent head and neck cancer.

PURPOSE: Primary treatment fails in >70% of locally advanced head and neck cancer patients. Salvage therapy has a 30-40% response rate, but few long-term survivors. Intensity-modulated radiotherapy (IMRT) has recently emerged as a new modality for salvage therapy. This retrospective study evaluated our experience using every-other-week IMRT with concurrent chemotherapy. METHODS AND MATERIALS: Between 2001 and 2006, 41 patients underwent IMRT as repeat RT with concurrent chemotherapy. All but 6 patients received 60 Gy at 2 Gy/fraction. RT was delivered on an alternating week schedule. RESULTS: With a median follow-up time of 14 months, the overall response rate was 75.6%, with a complete response and partial response rate of 58.5% and 17.1%, respectively. The Kaplan-Meier estimate of overall survival, disease-free survival, and progression-free survival at 24 months was 48.7%, 48.1%, and 38%, respectively. Patients who underwent surgery as a part of their salvage therapy had a mean estimated survival of 30.9 months compared with 22.8 months for patients who received only chemoradiotherapy (p = 0.126). Grade 3 or 4 acute toxicities occurred in 31.7% of patients, but all had resolved within 2 months of therapy completion. No deaths occurred during treatment, except for 1 patient, who died shortly after discontinuing treatment early because of previously undiagnosed metastatic disease; 6 patients had long-term complications. CONCLUSIONS: Concurrent chemotherapy with repeat radiotherapy with IMRT given every other week appears to be both well tolerated and feasible in patients treated with previous radiotherapy for recurrent head and neck cancer. IMRT represents a reasonable modality for reducing treatment-related toxicities in a repeat RT setting.

Induction chemotherapy in the management of squamous cell carcinoma of the head and neck.

Platinum-based chemotherapy administered concurrently with radiation has been adopted as the standard treatment for locally advanced head and neck squamous cell carcinoma. Historically, randomized trials using induction chemotherapy prior to radiation therapy alone have failed to demonstrate a clear survival advantage, and concurrent chemoradiation has delivered better results than previously obtained with radiation therapy alone, establishing the benefit of adding chemotherapy. This method of treatment, together with new modalities of therapy and novel agents, has reintroduced the question of induction chemotherapy before definitive chemoradiation. Systemic chemotherapy offers a better possibility of reducing systemic metastasis and improving cosmetic appearance. This article reviews developing trends using induction chemotherapy followed by chemoradiation in patients with head and neck squamous cell carcinoma.

Efficacy and safety of oxaliplatin and docetaxel in patients with locally advanced and metastatic non-small-cell lung cancer (NSCLC).

BACKGROUND AND AIMS: Platinum-based doublets are recommended as treatment for advanced or metastatic non-small-cell lung cancer (NSCLC); however, chemotherapy must be tailored to limit side effects. A phase II study was conducted to evaluate the efficacy and safety of oxaliplatin combined with docetaxel for NSCLC. METHODS: Patients with stage IIIB or IV, chemotherapy-naive NSCLC received docetaxel 70 mg/m(2), oxaliplatin 130 mg/m(2), and pegfilgrastim 6 mg every 21 days for up to six cycles. Primary endpoint was overall response rate (ORR), secondary endpoints were progression-free (PFS) and overall survival (OS), and safety. RESULTS: Twenty-nine patients were treated; 93% had stage IV disease and 28% had brain metastases. In 27 evaluable patients with follow-up, there were 10 partial responses for an ORR of 37% (90% confidence interval [CI], 22-55%). Median PFS was 4.6 months (95% CI, 2.6-6.5 months); 12-month PFS was 14.8% (95% CI, 3.4-34.0%). Median OS was 10.9 months (95% CI, 8.9-16.8 months); 12-month OS was 40% (95% CI, 19-61%) and 18-month OS was 16% (95% CI, 1-46%). In 29 treated patients, there were no unusual or unexpected adverse events. The most common grade 3 and 4 toxicities were anemia (14% of patients) and hyperglycemia (10%); there were only two reports of neutropenia; both were grade 1 or 2. CONCLUSION: These phase II findings suggest that the combination of oxaliplatin and docetaxel is active and well tolerated, and should be further investigated as a feasible treatment alternative for patients with advanced or metastatic NSCLC.