Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) and determination of a threshold score for moderate symptoms.

Background: The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (©Blueprint Medicines Corporation), a 12-item daily diary that assesses 11 signs and symptoms of indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM), was psychometrically evaluated among patients with ISM. Additionally, thresholds of the ISM-SAF total symptom score (TSS) to distinguish patients with moderate to severe symptoms from those with mild symptoms were evaluated.

Methods: The ISM-SAF was completed daily as an electronic diary in a prospective, observational study utilizing an online survey of patients with ISM in the United States.

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) in a phase 2 clinical study.

Background: Indolent systemic mastocytosis (ISM) is a rare, clonal mast cell neoplasm characterized by severe, unpredictable symptoms. The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) items compose a Total Symptom Score (TSS), Gastrointestinal Symptom Score (GSS), and Skin Symptom Score (SSS) to assess symptom severity. This study evaluated the psychometric performance of ISM-SAF among ISM patients.

Development of symptom-focused outcome measures for advanced and indolent systemic mastocytosis: the AdvSM-SAF and ISM-SAF.

Background: Advanced systemic mastocytosis (AdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM) are rare diseases characterized by neoplastic mast cell infiltration of more than one organ. A content-valid patient-reported outcome (PRO) questionnaire that assesses relevant signs and symptoms that are important and understandable to individuals with a condition is critical for assessing new treatment benefit as well as supporting product labeling claims. Notably, no such PRO questionnaire has been developed in accordance with regulatory and scientific guidelines for use in AdvSM, ISM, and SSM patient populations.

Psychometric evaluation of the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF).

Background: The Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) was developed to evaluate symptoms of advanced systemic mastocytosis (AdvSM). This study aimed to psychometrically evaluate AdvSM-SAF scores and provide score interpretation guidelines.

Methods: The 10-item AdvSM-SAF was administered daily (scored as a seven-day average) in EXPLORER, an open-label Phase 1 study in AdvSM.

Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors.

Introduction: Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies.

Methods: This phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy.

Ceritinib in ALK-rearranged non-small-cell lung cancer.

Background: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.

Methods: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK.

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.

Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion.

Potential biomarkers of bortezomib activity in mantle cell lymphoma from the phase 2 PINNACLE trial.

Immunohistochemical analyses of archival tumor specimens were used for pre-planned exploratory analyses of protocol-specified candidate biomarkers of bortezomib activity in 73 patients with relapsed/refractory mantle cell lymphoma in the phase 2 PINNACLE study. Consistent with other studies, elevated Ki-67 was a marker of poor prognosis, demonstrating significant associations with shorter time to progression and overall survival. Elevated NF-kappaB p65 and low PSMA5 expression demonstrated a trend for better response and were significantly associated with longer time to progression; elevated NF-kappaB p65 demonstrated a trend toward longer overall survival.

Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma.

Purpose: To determine overall response rate (ORR), time to progression (TTP), and duration of response (DOR) with twice-weekly/weekly bortezomib plus rituximab, and evaluate safety/tolerability, in patients with relapsed or refractory CD20(+) follicular lymphoma (FL) or marginal-zone lymphoma.

Patients And Methods: Patients were randomly assigned (minimization method) to bortezomib 1.3 mg/m(2) twice weekly (days 1, 4, 8, and 11; 21-day cycle, five cycles; arm A) or bortezomib 1.

Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma.

This subgroup analysis of the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial examined whether prior exposure to specific therapies affected the relative efficacy of bortezomib versus dexamethasone in relapsed/refractory myeloma. Time to progression and overall survival were superior with bortezomib in all subgroups, with no evidence of interaction between any prior therapies and assignment to study therapy. Patients with prior thalidomide exposure had worse outcomes overall, but neither prior thalidomide nor prior autologous stem cell transplantation affected the relative efficacy of bortezomib versus dexamethasone.

Phase I study of the c-raf-1 antisense oligonucleotide ISIS 5132 in combination with carboplatin and paclitaxel in patients with previously untreated, advanced non-small cell lung cancer.

Background: A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c-raf-1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC).

Patients And Methods: Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days.

Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline.

The frequency, characteristics and reversibility of bortezomib-associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose-modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11, eight 21-d cycles, then days 1, 8, 15, 22, three 35-d cycles); bortezomib was held, dose-reduced or discontinued depending on peripheral neuropathy severity, according to a protocol-specified dose-modification guideline.

The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma.

Quality of response is associated with prolonged overall survival (OS) in newly diagnosed multiple myeloma patients. This cohort study within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone in relapsed myeloma assessed the relationship between quality of response to bortezomib (n = 315) and clinical benefit. Treatment-free interval (TFI), time to alternative therapy (TTAT), time to progression (TTP) and OS were assessed in response-evaluable patients in the bortezomib arm in cohorts defined by achievement of complete response (CR; n = 27), very good partial response (VGPR; n = 31), partial response (PR; n = 77), minimal response (MR; n = 21) or non-response (NR, including stable and progressive disease; n = 159).

Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial.

Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.

Bortezomib-induced tumor lysis syndrome in multiple myeloma.

Tumor lysis syndrome (TLS) is exceedingly rare in multiple myeloma because of the relatively slow proliferation and response of the malignant cells. Bortezomib is a novel agent that inhibits proteasome and has shown activity against multiple myeloma. We report 8 episodes of TLS seen in 7 patients with bortezomib therapy, with or without dexamethasone, among 496 patients treated on 3 phase II multicenter studies.

Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib.

The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays.

Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma.

Purpose: Evaluate response rate, duration of response (DOR), time-to-progression (TTP), overall survival (OS), and safety of bortezomib treatment in patients with relapsed or refractory mantle cell lymphoma (MCL).

Patients And Methods: Bortezomib 1.3 mg/m(2) was administered on days 1, 4, 8, and 11 of a 21-day cycle, for up to 17 cycles.

Drug-induced cutaneous vasculitis in patients with non-Hodgkin lymphoma treated with the novel proteasome inhibitor bortezomib: a possible surrogate marker of response?

Bortezomib is the first proteasome inhibitor to be approved for use in haematological malignancies. Although a rash has been described as a common adverse event associated with the drug, it has not been well characterised. Based on three phase II studies of bortezomib in patients with non-Hodgkin lymphoma (140 assessable patients), we identified 26 patients who developed a unique erythematous maculopapular rash during treatment, six of whom underwent cutaneous biopsy.

Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity.

Purpose: To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures.

Patients And Methods: Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle.

Bortezomib or high-dose dexamethasone for relapsed multiple myeloma.

Background: This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies.

Methods: We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3 mg per square meter of body-surface area) on days 1, 4, 8, and 11 for eight three-week cycles, followed by treatment on days 1, 8, 15, and 22 for three five-week cycles, or high-dose dexamethasone (40 mg orally) on days 1 through 4, 9 through 12, and 17 through 20 for four five-week cycles, followed by treatment on days 1 through 4 for five four-week cycles.