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. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents.     

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/m² (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. Overall, 124/331 patients (37%) had treatment-emergent peripheral neuropathy, including 30 (9%) with grade ≥3; incidence and severity were not affected by age, number/type of prior therapies, baseline glycosylated haemoglobin level, or diabetes history. Grade ≥3 incidence appeared lower versus phase II trials (13%) that did not specifically provide dose-modification guidelines. Of patients with grade ≥2 peripheral neuropathy, 58/91 (64%) experienced improvement or resolution to baseline at a median of 110 d, including 49/72 (68%) who had dose modification versus 9/19 (47%) who did not. Efficacy did not appear adversely affected by dose modification for grade ≥2 peripheral neuropathy. Bortezomib-associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma. Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome.     

Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies. PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m(2), followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity. RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m(2) MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease. CONCLUSION: PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma in this study, and merits further investigation in these populations.     

An electrodiagnostic evaluation of the effect of pre-existing peripheral nervous system disorders in patients treated with the novel proteasome inhibitor bortezomib

AimsBortezomib (Velcade^®), a novel proteasome inhibitor, has shown promise in the treatment of malignancies, including multiple myeloma and non-Hodgkin's lymphoma. Several studies have identified neuropathy as a potentially dose-limiting side effect of treatment with bortezomib. We report the clinical and electrodiagnostic data from four patients who developed signs and symptoms of peripheral neuropathy from treatment with bortezomib.Materials and methodsPatients were included if they were enrolled in active phase 2 trials of bortezomib for non-Hodgkin's lymphoma or prostate cancer, developed signs and symptoms of peripheral neuropathy, and were referred for electrodiagnostic evaluation.ResultsFour patients, including two with non-Hodgkin's lymphoma and two with prostate cancer, underwent electrodiagnostic testing. Electrodiagnostic evaluation showed pre-existing peripheral nervous system disorders in three out of four patients. Multiple peripheral nervous system disorders were present in two out of four patients.ConclusionsBortezomib can cause a predominately sensory axonal polyneuropathy. Pre-existing peripheral nervous system disorders, such as neuropathy and radiculopathy, are common in patients with cancer, and may pre-dispose to the development of symptomatic neuronal toxicity when treated with bortezomib. Baseline electrodiagnostic evaluation may identify patients with pre-existing peripheral nervous system disorders at risk for additive neuronal toxicity from neurotoxic chemotherapeutic agents.     

Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia

Therapeutic options are limited and the prognosis is poor for patients with fludarabine-refractory B-cell chronic lymphocytic leukemia (CLL). Bortezomib induces apoptosis in vitro in CLL cells, both alone and in combination, including in cells resistant to fludarabine or other agents. The aim of the current randomized, open-label, Phase II study was to investigate the clinical activity of bortezomib in patients with fludarabine-refractory B-cell CLL. Twenty-two patients with histologically confirmed B-cell CLL were treated with bortezomib at doses of 1.0 mg/m2, 1.3 mg/m2, or 1.5 mg/m2 on Days 1, 4, 8, and 11 of a 21-day treatment cycle for a maximum of 9 cycles. None of 19 patients evaluable for response achieved complete remission or partial response; however, signs of biologic activity based on disease site responses (e.g., reduction in lymphocytosis, splenomegaly, and lymphadenopathy) were observed. In the 1.5 mg/m2 dose group, a higher proportion of patients had stable disease, and a lower proportion had progressive disease compared with the 2 lower-dose groups. Eleven patients, all in the 2 higher dose groups, experienced Grade 3/4 adverse events (AEs) (according to National Cancer Institute Common Toxicity Criteria [version 2.0]); 2 patients experienced Grade 4 neutropenia. Grade 3 hematologic AEs included anemia, neutropenia, thrombocytopenia, and hemolytic anemia; Grade 3 nervous system AEs included aphasia; peripheral neuropathy, not otherwise specified; and peripheral sensory neuropathy. Although no objective responses were achieved in patients with fludarabine-refractory B-cell CLL, single-agent bortezomib demonstrated biologic activity. In view of the evidence for its activity, further exploration of bortezomib in combination with other agents is warranted.     

Renal metastases from neuroblastoma

Neuroblastoma is one of the pediatric cancers that has the most unpredictable evolution. It can metastasize to almost any organ, but intrarenal metastases have never been reported. We report 2 such cases: the first patient had a left adrenal neuroblastoma completely resected 10 months before routine follow up ultrasound and CT scan demonstrated 3 right intrarenal metastases. The second patient was being investigated for a left abdominal mass when one left intrarenal metastasis was found during the same CT scan. An intrarenal mass found during investigation for staging or follow up of neuroblastoma should then be considered as a metastase until proven otherwise.     

Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer.

PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa). PATIENTS AND METHODS: Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2)). RESULTS: A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at >/= 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes. CONCLUSION: The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.     

Response to bortezomib and activation of osteoblasts in multiple myeloma

Histomorphometry and biochemical markers of bone turnover have shown that, although osteoclast activity is increased in multiple myeloma (MM), mostly through the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin axis, the key element in vivo to determine the presence or absence of osteolytic lesions resides on the presence and activity of osteoblasts. The loss of bone observed in MM is the result of an uncoupling of bone formation and bone resorption. Bortezomib is a first-in-class proteasome inhibitor developed as an antineoplastic agent with marked activity in relapsed/refractory MM. Response to bortezomib has been related to a significant increase in alkaline phosphatase (ALP). Increased ALP in patients responding to bortezomib was associated with a parallel increase in bone-specific ALP and parathyroid hormone, suggesting that response to bortezomib in MM is closely associated with osteoblastic activation. Variation in markers of osteoblastic activation (such as ALP) have also predicted response and response duration in patients with myeloma treated with bortezomib (P < 0.0001). This clinical observation has been confirmed in an experimental mouse model for primary human myeloma. The consequences of increased bone anabolism on myeloma growth need to be closely evaluated in prospective trials.