Michael S. Huie

Vorinostat (NSC# 701852) in Patients with Relapsed Non-small Cell Lung Cancer: A Wisconsin Oncology Network Phase II Study

Introduction: Vorinostat is a small molecule inhibitor of histone deacetylase, and has shown preclinical activity in non-small cell lung cancer (NSCLC). Methods: Patients with relapsed NSCLC were eligible. Patients received oral vorinostat, 400 mg daily. The primary objective was response rate, with the goal of at least one responder in the first 14 evaluable patients, according to the two-stage minimax design. Secondary objectives included time to progression (TTP), overall survival (OS), and safety. Results: Sixteen patients enrolled from January 2006 to April 2007. The median age was 59.5 years. Thirteen patients were female. Two patients were not evaluable for response due to progressive disease within Cycle 1. No objective antitumor responses were seen in the 14 evaluable patients. Eight patients experienced stable disease (median 3.7 months, range 1.4–19.4). Median TTP was 2.3 months (range 0.9–19.4 months), median OS was 7.1 months (range 1.4–30.0+ months), and estimated 1 year OS rate was 19% (SE 10%). One patient died on study from an acute ischemic stroke; this event was deemed possibly related to treatment. Grade 3/4 adverse events possibly related to vorinostat included neutropenia, lymphopenia, fatigue, pulmonary embolus/deep vein thrombosis, dehydration, elevated alkaline phosphatase, and hypokalemia. Conclusions: No objective antitumor activity was detected with single agent vorinostat in this setting; however, it yields TTP in relapsed NSCLC similar to that of other targeted agents. Further studies in NSCLC should focus on combining vorinostat with other antitumor agents.

VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study.

Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non‐intensive regimen, modified R‐hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR‐CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR‐CVAD chemotherapy every 21 d for six cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression‐free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow‐up of 42 months, the 3‐year PFS and OS were 63% and 86%, respectively. The observed 3‐year PFS and OS with VcR‐CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.

VcR-CVAD Induction Chemotherapy Followed by Maintenance Rituximab Produces Durable Remissions in Mantle Cell Lymphoma: A Wisconsin Oncology Network Study

Introduction VcR‐CVAD was developed as an intermediate‐intensity induction regimen with maintenance rituximab (MR) to improve remission durations after first‐line therapy for mantle cell lymphoma (MCL) in older and younger patients with MCL. Patients and Methods Patients with previously untreated MCL received VcR‐CVAD induction chemotherapy for 6 cycles (21‐day cycles). Patients achieving at least a partial response received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary endpoints were overall and complete response (CR), and the secondary endpoints were progression‐free survival (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. There was an even distribution of patients < 60 years and ≥ 60 years. Mantle cell lymphoma international prognostic index medium‐ or high‐risk disease was present in 60%. The overall response rate observed was 90% (77% CR/unconfirmed CR). After a median follow‐up of 7.8 years, the 6‐year PFS and OS were 53% and 70%, respectively. There was no difference in 6‐year PFS or OS between the younger (age < 60 years) and older (age ≥ 60 years) subgroups. In a univariate analysis, lactate dehydrogenase, when analyzed for interaction with age, had a significant effect on PFS outcomes at 6 years. There were no pretreatment variables determined to have a significant effect on OS outcomes at 6 years. Conclusions Long‐term outcomes with VcR‐CVAD are comparable with more intensive inductions and consolidation approaches. MCL is biologically heterogeneous, and durable remission can be achieved with intermediate intensity therapy. MR appears to contribute to these excellent outcomes. Micro‐Abstract VcR‐CVAD with maintenance rituximab is an intermediate‐intensity regimen for older and younger patients with mantle cell lymphoma (MCL). Thirty patients were treated, with a primary endpoint of response and secondary endpoints of progression‐free and overall survival. After a median follow‐up of 7.8 years, no relapses were observed beyond 6 years. VcR‐CVAD has long‐term outcomes comparable with more intensive chemotherapy regimens.

Phase I study of piritrexim and gemcitabine in patients with advanced solid tumors

Objectives:In this phase I study, the combination of piritrexim and gemcitabine was given to establish the maximum tolerated dose and the recommended phase II dose, and to determine a toxicity and efficacy profile. Methods:Fifty-two patients with normal and impaired renal function were enrolled on this phase I study. The starting dose was piritrexim 10 mg 3 times daily (5 days of the week for 3 weeks and 1 week off each 28-day cycle) and gemcitabine 1000 mg/m2 on days 1, 8, and 15. The piritrexim was escalated in a stepwise fashion with this dose of gemcitabine and then with gemcitabine 1000 mg/m2 for days 1 and 15. Results:The recommended phase II dose of this combination was felt to be piritrexim 50 mg/day (10 mg every morning, 20 mg every noon, and 20 mg every evening) with gemcitabine 1000 mg/m2 on days 1, 8, and 15, and piritrexim 75 mg/day (25 mg thrice daily) with gemcitabine 1000 mg/m2 on days 1 and 15. Neutropenia and thrombocytopenia were the most often reported toxicity. Dose-limiting toxicity was thrombocytopenia in both groups. The number of renal-impaired patients enrolled was too small to establish a maximum tolerated dose for this group (piritrexim became unavailable), but the combination was tolerated in the patients with impaired renal dysfunction. There was 1 complete response, 1 partial response, and 1 minimal response. Conclusion:The combination of piritrexim and gemcitabine was determined to be tolerable in heavily pretreated patients for use in solid tumors.