Targeted Therapies

Formerly BioOncology Watch

www.tgt-therapies.com

MAY 2004

LUNG CARCINOMA

Phase I study of G3139 in small-cell lung cancer (SCLC).  G3139 is an antisense oligonucleotide that is complimentary to the first 6 codons of bcl-2 mRNA.  Charles Rudin and colleagues studied the combination of G3139 with standard first-line carboplatin and etoposide chemotherapy in patients with previously untreated SCLC.  A total of 16 patients were treated in the following 3 consecutive dosing cohorts: Cohort 1) G3139 5 mg/kg/day on Days 1 to 8 every 21 days with carboplatin AUC = 6 on Day 6 and etoposide 80 mg/m2/day on Days 6 to 8 (n = 5); Cohort 2) carboplatin AUC reduced to 5 (n = 4); and Cohort 3) G3139 dose increased to 7 mg/kg/day (n = 7).  While 2 of 3 evaluable patients in Cohort 1 experienced grade 4 neutropenia during the first cycle of therapy, no dose-limiting toxicity during Cycle 1 was reported in Cohort-2 or -3 patients.  All 3 regimens were associated with a significant incidence of neutropenia and thrombocytopenia in later cycles; however, 75% of patients were able to complete all 6 planned cycles of therapy.  Partial responses were achieved in 12 (86%) of 14 evaluable patients and 2 patients had stable disease.  The median time to progression was 5.9 months.  These findings demonstrated that the combination of G3139, carboplatin, and etoposide was feasible and resulted in an encouraging response rate.  A randomized phase II trial has been initiated in the Cancer and Leukemia Group B.  (Rudin CM, et al. J Clin Oncol 2004;22:1110 - 1117)

 

Predictors of sensitivity to gefitinib in advanced non-small-cell lung cancer (NSCLC).  Vincent Miller and others analyzed the medical records of 139 NSCLC patients who were treated in 3 consecutive studies with the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib, at Memorial Sloan-Kettering Cancer Center.  Twenty-one patients (15%) achieved a partial response by radiographic measurements. Multivariate analysis identified histology (adenocarcinoma with bronchioloalveolar features) and smoking status (never having smoked) to be independent predictors of response.  These observations suggested that NSCLC may have a different biology in patients with bronchioloalveolar carcinoma and in those who have never smoked.  Further studies to evaluate a molecular phenotype of a patient likely to respond to gefitinib are warranted. (Miller VA, et al. J Clin Oncol 2004;22:1103-1109)

 

NON-HODGKIN'S LYMPHOMA (NHL)

Rituximab-EPOCH salvage therapy. The EPOCH regimen (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) has activity as a salvage regimen, but rarely provides durable remissions. M. Jermann et al added rituximab 375 mg/m2 i.v.on Day 1 to each cycle of EPOCH therapy in a study of 50 patients with relapsed or refractory CD20-positive large B-cell (n = 43) or mantle-cell (n = 7) lymphoma.  The median number of cycles administered was 4 and 68% of patients achieved a response (28% complete and 40% partial responses). Consolidation treatment with high-dose chemotherapy supported by autologous stem cell transplantation was given to 19 patients; median follow-up was 33 months and median event-free and overall survival times were 11.8 and 17.9 months, respectively.  Infusion-related reactions occurred in 14 (28%) patients and febrile neutropenia developed in 7% of 151 treatment cycles with rituximab-EPOCH. Sudden death occurred in 2 patients.  These data indicate that rituximab-EPOCH is effective salvage therapy for patients with relapsed or refractory CD20-positive large B-cell or mantle-cell lymphomas. (Jermann M, et al. Ann Oncol 2004;15:511-516)

 

Antibody-targeted chemotherapy with CMC-544.  Focused delivery to tumor cells of a cytotoxic agent linked to a monoclonal antibody has the potential to maximize antitumor effects and minimize toxicity.  CMC-544 is an anti-CD22 monoclonal antibody covalently linked to calicheamicin, a potent cytotoxic antitumor antibiotic. CD22 is an attractive target because it is uniquely expressed on the surface of mature B lymphocytes and their malignant counterparts and is rapidly internalized when bound to an anti-CD22 antibody.  In the current study, John DiJoseph and associates evaluated the preclinical functional characteristics of CMC-544. CMC-544, but not the unconjugated anti-CD22 monoclonal antibody, exerted potent cytotoxicity against CD22-positive B-cell lymphoma (BCL) cell lines.  CMC-544 prevented the establishment of BCL xenografts and cured small but established BCL xenografts.  In addition, CMC-544 caused the regression of large BCLs.  The strong antitumor profile of CMC-544 exhibited in these studies warrants its clinical evaluation in patients with B-lymphoid malignancies.  (DiJoseph JF, et al. Blood 2004;103:1807-1814)

 

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Early prediction of outcome to alemtuzumab therapy.  Alemtuzumab, an anti-CD52 monoclonal antibody, is effective therapy for some patients with refractory CLL.  Andy Rawstron and colleagues at the Leeds General Infirmary (Leeds, UK) used minimal residual disease (MRD) flow cytometry of peripheral blood and bone marrow to monitor 43 CLL patients undergoing alemtuzumab monotherapy.  It was found that significant depletion of bone marrow tumor occurred only if circulating B-lymphocyte counts were persistently < 0.001 x 109/L.  The following algorithm was then discovered to identify the majority of patients who did not benefit from a full course of alemtuzumab therapy with 100% positive predictive value: peripheral blood B-cell count > 0.001 x 109/L at week 2 of therapy with a < 1 log depletion of circulating B cells between weeks 2 and 4.  Monitoring CLL levels after treatment identified patients at risk for early disease progression.  If validated in larger studies, monitoring the blood B-cell count according to this algorithm has the potential to optimize treatment with alemtuzumab by identifying nonresponders within 2 to 4 weeks of the start of therapy and avoiding further unnecessary exposure to alemtuzumab. Unfortunately the use of MRD flow cytometry is not yet practical in general clinical practice.  (Rawstron AC, et al. Blood 2004;103:2027-2031)

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