Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: Phase I/II clinical trial data.

BACKGROUND: This phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood-brain barrier. METHODS: Part A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5-0.8 mg/m2) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8-1.0 mg/m2) for the combination. RESULTS: In Part A, 30 patients received marizomib monotherapy. The most common AEs were fatigue (66.7%), headache (46.7%), hallucination (43.3%), and insomnia (43.3%). One patient (3.3%) achieved a partial response. In Part B, the recommended phase II dose of marizomib was 0.8 mg/m2 when combined with bevacizumab 10 mg/kg. In Part C, dose escalation to 1.0 mg/m2 was not tolerated. Pooled analysis of 67 patients treated with marizomib ≤0.8 mg/m2 and bevacizumab showed a nonoverlapping safety profile consistent with the known safety profile of each agent: the most common grade ≥3 AEs were hypertension (16.4%), confusion (13.4%), headache (10.4%), and fatigue (10.4%). The overall response rate was 34.3%, including 2 patients with complete response. Six-month progression-free survival was 29.8%; median overall survival was 9.1 months. CONCLUSIONS: The safety profile of marizomib as monotherapy and in combination with bevacizumab was consistent with previous observations that marizomib crosses the blood-brain barrier. Preliminary efficacy did not demonstrate a meaningful benefit of the addition of marizomib to bevacizumab for the treatment of recurrent GBM.

Multidisciplinary care considerations for gender nonconforming adolescents with eating disorders: A case series.

Gender nonconforming youth are at risk for body dissatisfaction and disordered eating. Currently, only a small body of literature addresses this high-risk group. The five cases in this series highlight important themes for this patient population from an interdisciplinary perspective. Identified themes include increased risk for self-harm/suicide, complex psychiatric, and medical implications of delay to treatment for either gender dysphoria or disordered eating, and the importance of collaborative management to maximize care and facilitate healthy development to adulthood. The purpose of this case series is to expand the interdisciplinary discussion regarding the breadth of presentation and management considerations for gender nonconforming adolescents with disordered eating. An interdisciplinary approach to care might enhance access to comprehensive, collaborative treatment for disordered eating, and gender dysphoria in this unique population.

A phase 1 clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): final study results.

Marizomib (MRZ) is an irreversible, pan-subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low-dose dexamethasone (Lo-DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0·3-0·5 mg/m2 ) was administered over 2 h on days 1, 4, 8, 11; POM (3-4 mg) on days 1-21; and Lo-DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle. Thirty-eight patients were enrolled that had received a median of 4 (range 1-10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose-limiting toxicities (DLTs) were observed and 0·5 mg/m2 MRZ was determined to be the RP2D. The most common treatment-related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre-treated, high-risk RRMM patients.

First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors.

Background The antibody-drug conjugate PF-06263507 targets the cell-surface, tumor-associated antigen 5T4 and consists of a humanized IgG1 conjugated to the microtubule-disrupting agent monomethylauristatin-F by a non-cleavable maleimidocaproyl linker. In this first-in-human, dose-finding trial (NCT01891669), we evaluated safety, pharmacokinetics, and preliminary antitumor activity of PF-06263507 in pretreated patients with advanced solid tumors, unselected for 5T4 expression. starting at 0.05 mg/kg, with 25, 56, and 95% dose increments, depending on observed dose-limiting toxicities (DLTs), applying a modified continual reassessment method. Results Twenty-six patients received PF-06263507 at 0.05 to 6.5 mg/kg. The first DLT, grade 3 photophobia, occurred at 4.34 mg/kg and two additional DLTs, grade 2 keratitis and grade 1 limbal stem cell deficiency (> 2-week dosing delay), at 6.5 mg/kg. The most common adverse events (AEs) were fatigue (38.5%), photophobia (26.9%), and decreased appetite, dry eye, nausea, and thrombocytopenia (23.1% each). No treatment-related grade 4-5 AEs were reported. Systemic exposure of PF-06263507 increased in a dose-related manner. At the maximum tolerated dose (MTD, 4.34 mg/kg), mean terminal half-life for PF-06263507 and unconjugated payload were ~6 and 3 days, respectively. Payload serum concentrations were substantially lower compared with PF-06263507. No objective responses were observed. Conclusions The MTD and recommended phase II dose were determined to be 4.34 mg/kg. Ocular toxicities accounted for the DLTs observed, as previously reported with monomethylauristatin-F payloads. Further studies are warranted to investigate clinical activity of this agent in patients with 5T4-expressing tumors.Trial registration ID: NCT01891669.

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients.

Proteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly observed. All clinical stage PIs effectively inhibit chymotrypsin-like (CT-L) activity; one possible mechanism of resistance is compensatory hyperactivation of caspase-like (C-L) and trypsin-like (T-L) subunits, in response to CT-L blockade. Marizomib (MRZ), an irreversible PI that potently inhibits all three 20S proteasome subunits with a specificity distinct from other PIs, is currently in development for treatment of MM and malignant glioma. The pan-proteasome pharmacodynamic activity in packed whole blood and peripheral blood mononuclear cells was measured in two studies in patients with advanced solid tumours and haematological malignancies. Functional inhibition of all proteasome subunits was achieved with once- or twice-weekly MRZ dosing; 100% inhibition of CT-L was frequently achieved within one cycle at therapeutic doses. Concomitantly, C-L and T-L activities were either unaffected or increased, suggesting compensatory hyperactivation of these subunits. Importantly, this response was overcome by continued administration of MRZ, with robust inhibition of T-L and C-L (up to 80% and 50%, respectively) by the end of Cycle 2 and maintained thereafter. This enhanced proteasome inhibition was independent of tumour type and may underlie the clinical activity of MRZ in patients resistant to other PIs.

Evaluating imbalances of adverse events during biosimilar development.

Biosimilars are designed to be highly similar to approved or licensed (reference) biologics and are evaluated based on the totality of evidence from extensive analytical, nonclinical and clinical studies. As part of the stepwise approach recommended by regulatory agencies, the first step in the clinical evaluation of biosimilarity is to conduct a pharmacokinetics similarity study in which the potential biosimilar is compared with the reference product. In the context of biosimilar development, a pharmacokinetics similarity study is not necessarily designed for a comparative assessment of safety. Development of PF-05280014, a potential biosimilar to trastuzumab, illustrates how a numerical imbalance in an adverse event in a small pharmacokinetics study can raise questions on safety that may require additional clinical trials.

Phase I Clinical Trial of Marizomib (NPI-0052) in Patients with Advanced Malignancies Including Multiple Myeloma: Study NPI-0052-102 Final Results.

PURPOSE: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors. EXPERIMENTAL DESIGN: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. RESULTS: Forty-two patients with advanced malignancies received Schedule A (0.1-0.9 mg/m(2) over 1-10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075-0.6 mg/m(2) over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m(2) over 10 minutes; Schedule B was 0.5 mg/m(2) over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (∼15-416 L) and clearance (∼0.9-22 L/minutes). CONCLUSIONS: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559-66. ©2016 AACR.

Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 Part 1.

Marizomib (MRZ) is a novel, irreversible proteasome inhibitor in clinical development for the treatment of relapsed or relapsed and refractory multiple myeloma (RRMM). MRZ inhibits the 3 proteolytic activities of the 20S proteasome with specificity distinct from bortezomib and carfilzomib. Study NPI-0052-101 Part 1 enrolled relapsed or RRMM patients into an open-label, dose-escalation design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of MRZ administered intravenously on 2 different schedules: schedule A (0.025-0.7 mg/m(2) once weekly on days 1, 8, and 15 of 4-week cycles) and schedule B (0.15-0.6 mg/m(2) twice weekly on days 1, 4, 8, and 11 of 3-week cycles; concomitant dexamethasone was allowed with schedule B). Patients had received an average of 4.9 and 7.3 prior treatment regimens (schedules A and B, respectively). MRZ schedule A was administered to 32 patients, and the RP2D was established as 0.7 mg/m(2) infused over 10 minutes. Schedule B was administered to 36 patients, and the RP2D was determined to be 0.5 mg/m(2) infused over 2 hours. The most common (>20% of patients) related adverse events were fatigue, headache, nausea, diarrhea, dizziness, and vomiting. Six patients achieved clinical benefit responses (defined as minimal response or better), including 5 partial responses (1 patient on schedule A and 4 on schedule B; 3 of these 4 patients received concomitant dexamethasone). MRZ was generally well tolerated, and results suggest activity in previously treated RRMM patients. Combination studies using pomalidomide and dexamethasone are now underway. The trial was registered at www.clinicaltrials.gov as #NCT00461045.

A case of myelopathy because of enchondromas from Maffucci syndrome with successful surgical treatment.

BACKGROUND CONTEXT: Maffucci syndrome is a rare disorder comprising multiple enchondromas associated with multiple hemangiomas. Less than 200 cases have been reported in the literature. Most reported cases comprised lesions of the long bone metaphyses, hands, and feet. No previous case of myelopathy due to enchondroma from Maffucci syndrome has been reported. PURPOSE: To highlight an interesting and rare presentation of thoracic myelopathy because of enchondromas from Maffucci syndrome. STUDY DESIGN: This is a case report of a single patient presenting with myelopathy in whom enchondromas from Maffucci syndrome were removed from the spinal canal with the return of normal function. METHODS: Clinical examination, magnetic resonance imaging, surgical resection, and histologic analysis. RESULTS: The patient experiencing myelopathy symptoms underwent a surgical resection of the offending lesions that resulted in return to normal function. CONCLUSIONS: Maffucci syndrome is a rare condition; however, in affected patients the possibility of structural spinal abnormalities causing cord compression must be considered, as discrete surgical resection can result in a good outcome.

A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01).

AIMS: The pharmacokinetic (PK) similarity between PF-05280014, a proposed trastuzumab biosimilar, trastuzumab sourced from European Union (trastuzumab-EU) or from United States (trastuzumab-US) was evaluated. Safety and immunogenicity were also assessed. METHODS: In this phase 1, double-blind trial (NCT01603264), 105 healthy male volunteers were randomized 1:1:1 to receive a single 6 mg kg(-1) intravenous dose of PF-05280014, trastuzumab-EU, or trastuzumab-US, and evaluated for 70 days. Drug concentration-time data were analyzed by non-compartmental methods. PK similarity for the comparisons of PF-05280014 to each of trastuzumab-EU and trastuzumab-US, and trastuzumab-EU to trastuzumab-US were determined using the standard 80.00% to 125.00% bioequivalence criteria. RESULTS: Baseline demographics for the 101 subjects evaluable for PK were similar across all arms. The three products exhibited similar PK profiles with target-mediated disposition. The 90% CIs for the ratios of Cmax , AUC (0 , t last) and AUC(0,∞) were within 80.00% to 125.00% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms with treatment-related AEs reported by 71.4%, 68.6% and 65.7% subjects in the PF-05280014, trastuzumab-EU, and trastuzumab-US arms, respectively. The most common AEs were infusion-related reactions, headache, chills, pyrexia and nausea. The AE term 'pyrexia' was numerically greater in the PF-05280014 arm. All post-dose samples, except 1, tested negative for anti-drug antibodies (ADA). CONCLUSIONS: This study demonstrates PK similarity among PF-05280014, trastuzumab-EU and trastuzumab-US. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab.

Lumbar hemangioma masking a plasma cell tumor--case report and review of the literature.

BACKGROUND CONTEXT: Vertebral hemangiomata are ubiquitous bone tumors. Often multiple, they are generally benign in nature and slow growing. They typically have a predictable radiographic appearance. Occasionally, hemangiomata may behave in a more aggressive manner, causing pathologic fracture or even symptoms/signs of nerve compression. In such cases, one must be careful not to assume that an atypical hemangioma is responsible. Coexisting, more malignant processes may be present and sometimes may be radiographically undetectable in the setting of acute fracture. This was the case in our patient. STUDY DESIGN: Case report/university spine surgery center. METHODS: The patient underwent a corpectomy of her affected vertebra with conversion to a total spondylectomy when intraoperative frozen section was consistent with plasma cell neoplasm. A reconstruction with vertebral body replacement and fusion through anterior and posterior approaches was completed. Subsequently, the literature was reviewed for other cases of atypical hemangiomata to investigate the incidence of coexistent lesions. RESULTS: This patient presented with pain secondary to an unstable pathologic vertebral body fracture. Surgery to stabilize her spine was elected. Intraoperative recognition of abnormal-appearing tissue led to the diagnosis of a plasma cell neoplasm that was not seen on imaging. Coexistent in the same vertebra was hemangiomatous tissue that was visible on preoperative imaging. CONCLUSIONS: There are rare reports of aggressively behaving hemangiomata that mainly have occurred in the thoracic spine. There have been no reports of the coexistence of a hemangioma and a plasma cell tumor in the same vertebral level in the setting of acute compression fracture.

The impact of short term synaptic depression and stochastic vesicle dynamics on neuronal variability.

Neuronal variability plays a central role in neural coding and impacts the dynamics of neuronal networks. Unreliability of synaptic transmission is a major source of neural variability: synaptic neurotransmitter vesicles are released probabilistically in response to presynaptic action potentials and are recovered stochastically in time. The dynamics of this process of vesicle release and recovery interacts with variability in the arrival times of presynaptic spikes to shape the variability of the postsynaptic response. We use continuous time Markov chain methods to analyze a model of short term synaptic depression with stochastic vesicle dynamics coupled with three different models of presynaptic spiking: one model in which the timing of presynaptic action potentials are modeled as a Poisson process, one in which action potentials occur more regularly than a Poisson process (sub-Poisson) and one in which action potentials occur more irregularly (super-Poisson). We use this analysis to investigate how variability in a presynaptic spike train is transformed by short term depression and stochastic vesicle dynamics to determine the variability of the postsynaptic response. We find that sub-Poisson presynaptic spiking increases the average rate at which vesicles are released, that the number of vesicles released over a time window is more variable for smaller time windows than larger time windows and that fast presynaptic spiking gives rise to Poisson-like variability of the postsynaptic response even when presynaptic spike times are non-Poisson. Our results complement and extend previously reported theoretical results and provide possible explanations for some trends observed in recorded data.

A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer.

OBJECTIVE: ATN-224 (choline tetrathiomolybdate) is an oral Cu(2+)/Zn(2+)-superoxide dismutase 1 (SOD1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose-levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naïve prostate cancer. METHODS: Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) < 12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels > 150 ng/dl) were eligible. ATN-224 was administered at 2 dose-levels, 300 mg (n = 23) or 30 mg (n = 24) daily, by way of randomization. PSA progression was defined as a ≥ 50% increase (and >5 ng/ml) in PSA from baseline or post-treatment nadir. Endpoints included the proportion of patients who were free of PSA progression at 24 weeks, changes in PSA slope/PSADT, and safety. The study was not powered to detect differences between the 2 treatment groups. RESULTS: At 24 weeks, 59% (95% CI 33%-82%) of men in the low-dose arm and 45% (95% CI 17%-77%) in the high-dose arm were PSA progression-free. Median PSA progression-free survival was 30 weeks (95% CI 21-40(+)) and 26 weeks (95% CI 24-39(+)) in the low-dose and high-dose groups, respectively. Pre- and on-treatment PSA kinetics analyses showed a significant mean PSA slope decrease (P = 0.006) and a significant mean PSADT increase (P = 0.032) in the low-dose arm only. Serum ceruloplasmin levels, a biomarker for ATN-224 activity, were lowered in the high-dose group, but did not correlate with PSA changes. CONCLUSIONS: Low-dose ATN-224 (30 mg daily) may have biologic activity in men with biochemically-recurrent prostate cancer, as suggested by an improvement in PSA kinetics. However, the clinical significance of PSA kinetics changes in this patient population remains uncertain. The absence of a dose-response effect also reduces enthusiasm, and there are currently no plans to further develop this agent in prostate cancer.

Splenic artery embolization: a single center experience on the safety, efficacy, and clinical outcomes.

PURPOSE: We aimed to assess the safety, efficacy, and clinical outcomes of splenic artery embolization (SAE). MATERIALS AND METHODS: A total of 50 patients (male:female, 33:17; mean age, 49 years) who underwent 50 SAEs between 1998 and 2011 were retrospectively studied. The procedure indications included aneurysm or pseudoaneurysm (n=15), gastric variceal hemorrhage (n=15), preoperative reduction of surgical blood loss (n=9), or other (n=11). In total, 22 procedures were elective, and 28 procedures were urgent or emergent. The embolic agents included coils (n=50), gelatin sponges (n=15), and particles (n=4). The measured outcomes were the technical success of the procedure, efficacy, side effects, and the 30-day morbidity and mortality rates. RESULTS: All embolizations were technically successful. The procedure efficacy was 90%; five patients (10%) had a recurrent hemorrhage requiring a secondary intervention. Side effects included hydrothorax (n=26, 52%), thrombocytosis (n=16, 32%), thrombocytopenia (n=13, 26%), and postembolization syndrome (n=11, 22%). Splenic infarcts occurred in 13 patients (26%). The overall and procedure-specific 30-day morbidity rates were 38% (19/50) and 14% (splenoportal thrombosis, 3/50; encapsulated bacterial infection, 1/50; splenic abscess, 1/50; femoral hematoma requiring surgery, 1/50; hydrothorax requiring drainage, 1/50). The overall and procedure-specific 30-day mortality rates were 8% (4/50) and 0%. The multivariate analysis showed that advanced patient age (P = 0.037), postprocedure thrombocytopenia (P = 0.008), postprocedure hydrothorax (P = 0.009), and the need for a secondary intervention (P = 0.004) predicted the 30-day morbidity, while renal insufficiency (P < 0.0001), preprocedure hemodynamic instability (P = 0.044), and preprocedure leukocytosis (P < 0.0001) were prognostic factors for the 30-day mortality. CONCLUSION: SAE was performed with high technical success and efficacy, but the outcomes showed nontrivial morbidity rates. Elderly patients with thrombocytopenia and hydrothorax after SAE, and patients who require secondary interventions, should be monitored for complications.

Phase 1 first-in-human trial of the vascular disrupting agent plinabulin(NPI-2358) in patients with solid tumors or lymphomas.

PURPOSE: Plinabulin (NPI-2358) is a vascular disrupting agent that elicits tumor vascular endothelial architectural destabilization leading to selective collapse of established tumor vasculature. Preclinical data indicated plinabulin has favorable safety and antitumor activity profiles, leading to initiation of this clinical trial to determine the recommended phase 2 dose (RP2D) and assess the safety, pharmacokinetics, and biologic activity of plinabulin in patients with advanced malignancies. EXPERIMENTAL DESIGN: Patients received a weekly infusion of plinabulin for 3 of every 4 weeks. A dynamic accelerated dose titration method was used to escalate the dose from 2 mg/m² to the RP2D, followed by enrollment of an RP2D cohort. Safety, pharmacokinetic, and cardiovascular assessments were conducted, and Dynamic contrast-enhanced MRI (DCE-MRI) scans were performed to estimate changes in tumor blood flow. RESULTS: Thirty-eight patients were enrolled. A dose of 30 mg/m² was selected as the RP2D based on the adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient blood pressure elevations, with DCE-MRI indicating decreases in tumor blood flow (Ktrans) from 13.5 mg/m² (defining a biologically effective dose) with a 16% to 82% decrease in patients evaluated at 30 mg/m². Half-life was 6.06 ± 3.03 hours, clearance was 30.50 ± 22.88 L/h, and distributive volume was 211 ± 67.9 L. CONCLUSIONS: At the RP2D of 30 mg/m², plinabulin showed a favorable safety profile, while eliciting biological effects as evidenced by decreases in tumor blood flow, tumor pain, and other mechanistically relevant adverse events. On the basis of these results additional clinical trials were initiated with plinabulin in combination with standard chemotherapy agents.

Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors.

PURPOSE: Copper chelation reduces the secretion of many angiogenic factors and reduces tumor growth and microvascular density in animal models. ATN-224 is a second-generation analogue of ammonium tetrathiomolybdate. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin, to 5 to 15 mg/dL (normal 16-60) in 14 to 21 days, to determine the pharmacokinetic profile of ATN-224 and to evaluate dose-limiting toxicities. PATIENTS AND METHODS: Cohorts of patients were treated with escalating oral doses of ATN-224 until copper depletion followed by a titrated maintenance dose. RESULTS: Eighteen patients received 78 cycles of ATN-224. Mean baseline ceruloplasmin was 39.6 mg/dL. The maximum administered dose was 330 mg/d where grade 3 fatigue was dose-limiting. At the maximum tolerated dose of 300 mg/d, the median time to achieve target ceruloplasmin was 21 days, and toxicities included grade 3 anemia, grade 3 neutropenia, fatigue, and sulfur eructation. ATN-224 treatment caused a significant reduction (> 90%) in RBC superoxide dismutase 1 activity and circulating endothelial cells. Pharmacokinetic data indicate greater absorption of ATN-224 and more rapid ceruloplasmin reduction when administered with a proton pump inhibitor. Stable disease of > 6 months was observed in 2 patients. CONCLUSIONS: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/d leads to a reduction of serum ceruloplasmin levels in 80% patients within 21 days. A loading dose of 300 mg/d for 2 weeks followed by a titrated maintenance dose will be the recommended starting dose for phase II study.

Lack of an association between Chlamydia psittaci and ocular adnexal lymphoma.

The objective of this study was to assess whether there is PCR evidence for C. psittaci DNA in ocular adnexal lymphoma specimens collected in an academic institution in the U.S. This was a retrospective, single-center study of patients from 1994 - 2004. We used 28 ocular adnexal lymphoma biopsy specimens from adult patients, 16 control lymphoma specimens from patients with systemic lymphomas not involving the ocular adnexa, and five control benign adnexal tissue samples. The presence of C. psittaci DNA was investigated by polymerase chain reaction (PCR) in each group. Two different assays were utilized: (1) conventional PCR/gel based assay targeting a 111-bp fragment of the 16S gene and (2) a real-time PCR assay amplifying a 148-bp portion of the 16S gene with detection via a specific fluorescent probe. Amplification was carried out to 60 cycles. Positive controls consisted of isolated DNA from C. psittaci strains VS1, CP3, and FP. A human DNA internal control was used to assess sample DNA quality and amplification success. Mean outcome measure was the presence of C. psittaci DNA. Using both assays, all patient samples in all categories yielded negative results. Both assays detected C. psittaci DNA from isolated strains. Internationally, Chlamydia psittaci has been associated with ocular adnexal lymphomas with great variability. Similar to several other recent studies in the USA, our study could not confirm the presence of C. psittaci in ocular adnexal lymphomas. Differences in the prevalence of C. psittaci infection in various geographic regions or technical differences in the application of the assays may underlie the variability in the association between C. psittaci and ocular adnexal lymphoma.

The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

AG-013736 is an oral anti-angiogenesis agent with activity against a variety of receptor tyrosine kinases, including VEGFR-1, VEGFR-2, VEGFR-3, c-kit, and PDGFR-beta. A phase 2 study was conducted in patients with poor prognosis AML or MDS. Twelve patients (six AML; six MDS) were treated with AG-013736 at a dose of 10mg orally daily for a median of 56 days (range, 1-248 days). Median age was 80 years (range, 58-88 years). Grade 3 or 4 drug-related toxicities included hypertension (42%), mucositis (8%) and deep venous thrombosis (8%). No objective responses occurred; two patients with MDS had stable disease for 8.3 and 6.2 months, respectively. Bone marrow expression of VEGFR-1 and VEGFR-2 was observed in 11% and 0% of patients, respectively. Sustained decreases in soluble VEGFR-2 plasma levels with concomitant elevation in plasma VEGF and placental growth factor levels were obtained during the course of therapy with AG-013736. AG-01736 had minimal biologic or clinical activity in this elderly patient population.

Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results.

PURPOSE: We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer. PATIENTS AND METHODS: Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid. RESULTS: Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity. CONCLUSION: In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.

Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study.

PURPOSE: Identifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PATIENTS AND METHODS: Thirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1--day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (K(trans)) and initial area under the curve (IAUC), were calculated to assess the effect of treatment on tumor vascular function. RESULTS: Evaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in K(trans) and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a > or = 50% decrease in K(trans) was indicative of an objective vascular response, a 50% decrease in K(trans) was achieved and corresponded to a plasma AUC(0-24) of > 200 ng . h/mL. CONCLUSION: A sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase II testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.