Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572.

BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

A phase II open-label trial of bortezomib in patients with multiple myeloma who have undergone an autologous peripheral blood stem cell transplant and failed to achieve a complete response.

BACKGROUND: A majority of multiple myeloma (MM) patients fail to achieve complete response (CR) to peripheral blood stem cell transplantation (PBSCT); effective options following autologous transplantation are needed. Bortezomib (B) is active against MM. This study was conducted to determine the feasibility, safety, tolerability, and efficacy of B following high-dose melphalan therapy and PBSCT. Methods Fifty patients enrolled (48 evaluable) and 49 were treated (safety population). TREATMENT: 4 cycles B 1.3 mg/m(2) Days 1, 4, 8, and 11/21-days; 4 additional cycles were permitted for stable or responding patients. Results Median age was 55 years (range, 38-73), 68% male, 64% ECOG PS = 0, 44% Durie-Salmon Stage IIIA prior to induction, 42% had symptomatic IgG MM; 74% had prior single transplant (26% tandem). Responses post-transplant: 70% PRs, 18% MRs. A median of 4 cycles (range, 2-8) of B were administered. Responses: CR 8%, uCR 2%, PR 23%, uPR 19%, MR 10%, and no change 35%; median time-to-treatment failure (TTF) was 6.2 months (range, 1.0-19.4). Three deaths occurred (n = 1 sepsis, n = 2 disease progression). Grade 3-4 treatment-related toxicities included: thrombocytopenia, neuropathy (14%, each); asthenia, neutropenia (10%, each); and nausea (4%). Twelve patients (24%) discontinued treatment due to toxicity and 30 patients (60%) completed the study; 20 patients started new treatment (median 5.8 months [range, 1.5-20.3]). CONCLUSIONS: The study closed early due to widespread availability of B, and the lack of B-naïve patients. Bortezomib monotherapy after melphalan and autologous PBSCT was feasible, safe and well-tolerated (toxicities were manageable), but failed to produce the hypothesized response rates.

Phase II study of denileukin diftitox for previously treated indolent non-Hodgkin lymphoma: final results of E1497.

Denileukin diftitox (DD) is approved for treatment of CD-25 expressing cutaneous T-cell lymphomas (CTCL). Initial studies of DD demonstrated responses in patients with B-cell non-Hodgkin lymphoma (NHL). This phase II trial evaluated response rate (RR) and tolerability of DD in this population. Patients were stratified into two arms: those with NHL expressing > or =20% IL-2R (IL-2R+) or <20% IL-2R (IL-2R-). DD was dosed at 18 microg/kg/day for 5 days every 21 days. Corticosteroid pre-medication was not allowed. Thirty-five patients of a planned 77 accrued due to closure for slow accrual. This report is on 29 patients (18 males) with indolent B-cell NHL (11 IL-2R+ and 18 IL-2R-). Histologic subtypes included small lymphocytic (SLL) (8 patients) and follicular grade I/II lymphoma (21 patients). Patients received a median of three prior regimens, including rituximab in 76%. Three partial responses were observed (RR 10%). The RR for the IL-2R- and IL-2R+ patients was 11% and 9%, respectively. Of 8 patients with SLL, 2 responded. Toxicities were generally grade I - II and transient but 1 patient experienced a fatal thrombo-embolism. Therapy with DD is tolerable and modest efficacy was observed in SLL subtype. Measured IL-2R status did not correlate with efficacy.

Phase II trial of gemcitabine and docetaxel in patients with advanced carcinoma of the urothelium: a trial of the Eastern Cooperative Oncology Group.

BACKGROUND: Gemcitabine and docetaxel are active agents in advanced urothelial carcinoma. A Phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multiinstitutional setting in patients previously treated with one prior chemotherapy regimen. METHODS: Twenty-nine eligible patients with advanced urothelial carcinoma were treated with docetaxel at a dose of 40 mg/m(2) over 1 hour followed by gemcitabine, 800 mg/m(2), over 30 minutes, both intravenously (i.v.) on Days 1 and 8. Cycles were repeated every 21 days until disease progression or a maximum of 6 cycles. RESULTS: Five patients obtained an objective response for an overall response rate of 17% (90% confidence interval, 7-33%). One patient achieved a complete clinical response. The median overall survival of the group was 7.7 months. Toxicity was moderate with granulocytopenia, anorexia, and fatigue being the most commonly noted side effects. CONCLUSIONS: Gemcitabine and docetaxel is an active second-line combination in patients with advanced urothelial carcinoma. Responses in visceral, lymph node, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and anorexia was common. Thromboembolic symptoms were reported and are of concern. The combination of gemcitabine and docetaxel has the potential to palliate a subset of previously treated patients with an adequate performance status.