Population pharmacokinetics, efficacy, and safety of moxetumomab pasudotox in patients with relapsed or refractory hairy cell leukaemia.

AIMS: To characterize the pharmacokinetics (PK) of moxetumomab pasudotox, an anti-CD22 recombinant immunotoxin, in adults with relapsed or refractory hairy cell leukaemia, we examined data from a phase 1 study (Study 1001; n = 49) and from the pivotal clinical study (Study 1053; n = 74). METHODS: Data from both studies were pooled (n = 123) to develop a population PK model. Covariates included demographics, disease state, liver and kidney function, prior treatment, and antidrug antibodies (ADAs). Exposure-response and exposure-safety were analysed separately by study. A 1-compartment model with linear elimination from the central compartment and 2 clearance (CL) rates was developed. RESULTS: Moxetumomab pasudotox was cleared more rapidly after cycle 1, day 1 (CL1 = 24.7 L/h) than subsequently (CL2 = 3.76 L/h), with high interindividual variability (116 and 109%, respectively). In Study 1053, patients with ADA titres >10 240 showed ~4-fold increase in CL. Higher exposures (≥median) were related to higher response rates, capillary leak syndrome and increased creatinine (Study 1053 only), or grade ≥3 adverse events (Study 1001 only). Clinical benefits were still observed in patients with lower exposure or high ADA titres. CONCLUSION: Despite a high incidence of immunogenicity with increased clearance, moxetumomab pasudotox demonstrated efficacy in hairy cell leukaemia.

Results from an international phase 2 study of the anti-CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B-lineage acute lymphoblastic leukemia.

BACKGROUND: In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti-CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy. PROCEDURE: This international, multicenter, phase 2 study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21-day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations. RESULTS: Thirty-two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment-related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment-related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS. CONCLUSIONS: Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted.

Administration of gemcitabine and cisplatin in cancer patients with renal failure under hemodialysis.

PURPOSE: There is no optimal dosing schedule of gemcitabine (GEM) and cisplatin (CDDP) combination for cancer patients with renal failure (RF) on hemodialysis (HD). The purpose of this study was to share our experience of using GEM and CDDP in such patients. METHODS: The starting dose of GEM was defined based on single-agent treatment of two cancer patients with RF. Between November 2006 and June 2009, 4 RF cancer patients on HD received a GEM and CDDP combination chemotherapy (CDDP 30mg/m(2) on days 1, 8, 15 and GEM 600mg/m(2) on day 15; repeated every 28 days). The HD was conducted within 24 hours after the completion of GEM and/or CDDP administration. RESULTS: Reduced-dose GEM and CDDP combination showed efficacy and good tolerability for cancer patients with RF under HD.

Preliminary experience of cetuximab in the treatment of advanced-stage biliary tract cancer.

BACKGROUND: Cetuximab has been proved to be effective alone or in combination with other chemotherapeutic agents in the treatment of various malignancies. The aim of this report was to describe our experience of using cetuximab with chemotherapeutics agents to treat advanced-stage biliary tract cancer. CASE REPORTS: We retrospectively analyzed the outcomes of 5 biliary tract cancer patients receiving cetuximab-containing therapy. Four of them had stage IV disease, and 1 patient had incomplete resection at the time of diagnosis. Epidermal growth factor receptor (EGFR) expression and K-ras status were assessed when a specimen was available. After cetuximab treatment, complete response was achieved in 1 patient, partial response in 3 patients, and stable disease in 1 patient. Three surgical specimens were available, and all revealed positive EGFR expression. Only 1 surgical specimen was adequate for K-ras mutation test, and the wild type was confirmed. Complete response was found in the patient who had wild type K-ras. The progression-free survival of these patients varied from 4 to 16 months. CONCLUSIONS: Cetuximab-containing therapy might be an effective treatment for advanced biliary tract cancer.

Lung cancer metastatic to the masticator space.

BACKGROUND: Distant metastasis from lung cancer occurs most frequently to the brain, bone, adrenal gland, liver, lymph nodes, and spinal cord. However, masticator space metastasis is rarely found among lung cancer patients. CASE REPORT: We report a case of large cell neuroendocrine carcinoma of the lung with metastasis to the masticator space diagnosed by imaging and histopathological examinations. CONCLUSION: The present case highlights the fact that large cell neuroendocrine carcinoma of the lung can result in an uncommon isolated masticator space metastasis. Clinicians should carefully evaluate cancer patients who report a painful sensation in the cheek. Thorough dental and physical examination, and imaging studies could provide early diagnosis and treatment.

Gemcitabine plus vinorelbine as an effective salvage chemotherapeutic regimen in cisplatin-refractory germ cell tumor.

Germ cell tumors (GCT) are the most common malignancies among male adolescents. Approximately 5% of GCTs are of extragonadal origin. Cisplatin-based chemotherapy is the standard first-line treatment for GCT. Patients who fail to respond to first-line treatment usually have poor outcomes. High-dose chemotherapy with stem cell support, paclitaxel, gemcitabine, and oxaliplatin are reported as effective salvage treatment. We report two patients with cisplatin-refractory, metastatic, nonseminomatous, and extragonadal GCT treated successfully with gemcitabine plus vinorelbine (GV). One patient achieved good partial remission and had a five-month progression-free period. Another patient is still alive with stable disease after 4 cycles of treatment. In heavily treated, cisplatin-refractory GCT patients, GV could be considered an effective chemotherapeutic regimen.

Antibody-Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index.

Since the first approval of gemtuzumab ozogamicin (Mylotarg; Pfizer; CD33 targeted), two additional antibody-drug conjugates (ADC), brentuximab vedotin (Adcetris; Seattle Genetics, Inc.; CD30 targeted) and inotuzumab ozogamicin (Besponsa; Pfizer; CD22 targeted), have been approved for hematologic cancers and 1 ADC, trastuzumab emtansine (Kadcyla; Genentech; HER2 targeted), has been approved to treat breast cancer. Despite a clear clinical benefit being demonstrated for all 4 approved ADCs, the toxicity profiles are comparable with those of standard-of-care chemotherapeutics, with dose-limiting toxicities associated with the mechanism of activity of the cytotoxic warhead. However, the enthusiasm to develop ADCs has not been dampened; approximately 80 ADCs are in clinical development in nearly 600 clinical trials, and 2 to 3 novel ADCs are likely to be approved within the next few years. While the promise of a more targeted chemotherapy with less toxicity has not yet been realized with ADCs, improvements in technology combined with a wealth of clinical data are helping to shape the future development of ADCs. In this review, we discuss the clinical and translational strategies associated with improving the therapeutic index for ADCs.

Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia.

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

Ectopic ACTH syndrome associated with large-cell neuroendocrine carcinoma of the lung.

Although ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a well-known paraneoplastic phenomenon, an association with large-cell neuroendocrine carcinoma of the lung (LCNEC) has not been reported. We describe a 63-year-old man with metastatic LCNEC to the left temporomandibular joint (TMJ) who presented with progressive muscle weakness and bilateral lower leg edema for 2 weeks. He did not have a typical Cushingoid appearance nor used diuretics. His newly noted hypertension, hypokalemia (plasma potassium (K) concentration 1.8 mEq/L) with renal K wasting, and metabolic alkalosis suggested a state of mineralocorticoid excess. His plasma renin activity and aldosterone concentrations were low, but cortisol and ACTH levels were extremely elevated, consistent with ACTH-dependent Cushing's syndrome. Nonsuppressible plasma cortisol level and normal sella turcica on magnetic resonance imaging pointed to EAS. A strongly positive stain for ACTH from the metastatic left TMJ mass supported LCNEC-related EAS. His hypokalemia and hypertension were controlled with spironolactone and K supplementation. This is the first reported case of EAS in LCNEC and should be kept in mind as a cause of hypokalemia in lung cancer patients.

Management of adverse events associated with idelalisib treatment: expert panel opinion.

Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of idelalisib treatment-emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade ≥ 3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy.

Detection of reactivation and genetic mutations of the hepatitis B virus in patients with chronic hepatitis B infections receiving hematopoietic stem cell transplantation.

BACKGROUND: This study elucidates the profiles for hepatitis B virus (HBV) reactivation and genetic mutation of the core promoter and precore regions for HBV-carriers receiving hematopoietic stem cell transplantation (HSCT). METHODS: Sera from 20 HSCT patients diagnosed with hematological diseases, 13 donors and 36 healthy HBV-carriers, were collected regularly for analysis. The hepatic biochemistry profiles, serological HBV markers, and HBV-DNA titers were checked regularly, and primer-amplification of the HBV core promoter or precore region and sequencing were performed once the mutations were identified. RESULTS: Deteriorated liver function was demonstrated for 13 of 20 post-HSCT patients, compared with none of the 36 controls (P<0.01). The HBV-DNA was detected more frequently for post-HSCT subjects than for controls (P=0.001). Incidence of the HBV precore nucleotide 1896 G-to-A mutation was significantly higher for HSCT patients (P=0.004), and a significant association was demonstrated for carriage of core promoter or precore mutations and the development of hepatitis (P=0.015). Different HBV genotypes were revealed in post-HSCT patients and the respective donors. CONCLUSIONS: Intensive chemotherapy and immunosuppression may cause HBV reactivation in HBV carriers receiving HSCT, and more frequent core promoter or precore mutations could be detected in HBV carriers receiving HSCT than healthy HBV carriers, with the chemotherapy/immunosuppression-induced immunocompromise possibly contributing to this effect. Donor HBV genotype did not interfere with that of the recipient after HSCT. Core promoter or precore region mutations were associated with a higher incidence of liver dysfunction than wild-type HBV carriers in the HSCT patients.

Serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity as a biomarker for bone metastasis in non-small cell lung cancer patients.

BACKGROUND: Diagnosis and follow-up of bone metastasis (BMet) in non-small cell lung cancer (NSCLC) patients usually rely on symptoms and image studies. A serum marker of bone resorption may improve the quality of treatment in such patients. Tartrate-resistant acid phosphatase 5b (TRACP5b) is a specific marker for osteoclasts and we proposed it can be used as a marker of BMet in NSCLC patients. METHODS: In November 2002 till August 2008 serum samples were obtained from 141 newly diagnosed stage IIIA, IIIB or IV NSCLC patients and 41 normal subjects. All patients received baseline bone scintinography examination and evaluation of clinical symptoms as a standard of BMet diagnosis. Patients were divided into 2 groups by having BMet (Group I, n = 72) or not (Group II, n = 69). An in-house immunoassay using a TRACP-specific monoclonal antibody, 14G6, was used to measure the serum TRACP5b activity at pH 6.1. RESULTS: The mean serum TRACP5b activities of Group I, Group II and normal subjects were 3.50 ± 2.2 3U/l, 2.09 ± 0.72 U/l and 2.33 ± 0.52 U/l, respectively. After adjusting for age, stage, gender, and histology in a generalized linear model, Group I has significantly higher TRACP5b activity than Group II (p < 0.001). The receiver operating characteristic analysis established a cutoff value of 2.551 U/l to identify BMet in NSCLC patients with a sensitivity of 63.9% and a specificity of 76.8%. TRACP5b activity declined in patients who responded to treatment (p = 0.047), and elevated in patients who developed new BMet (p = 0.05). CONCLUSIONS: Serum TRACP5b activity test is a potentially useful adjunct in diagnosing and monitoring BMet in NSCLC. Further study is warranted to establish its real value in diagnosis and monitoring of BMet in NSCLC patients.

Ectopic hepatocellular carcinoma of the diaphragm.

Ectopic hepatocellular carcinoma (HCC) is very rarely reported. It may occur at various sites. To the best of our knowledge, only one case of ectopic HCC of the diaphragm has been reported. We present another such case with invasion to the lung. Subtotal resection of the left hemidiaphragm, wedge resection of the lung (left lower lobe), and splenectomy were undertaken. Postoperative course was unremarkable; the patient received two courses of adjuvant chemotherapy with cisplatin, VP-16, and bleomycin 1 month later. Follow-up computed tomography and ultrasound were performed 8 months later; there was no local recurrence or distal metastasis.