A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma

173 Background: A phase I study of Cabozantinib (C) in combination with docetaxel (D) and prednisone (P) in patients (pts) with mCRPC determined that 40 mg daily was the maximum tolerated dose of C in combination with D and P (C+DP). We report a pooled analysis of the phase I and randomized phase II study comparing C+DP to DP alone. Methods: Eligible pts had mCRPC without prior chemotherapy in the castrate setting. All pts received a fixed dose of D (75 mg/m2IV day one of each 21 day cycle) and P (5 mg PO twice daily), and in the C+DP group, C at three escalating dose levels: 20 mg, 40 mg, or 60 mg in the phase I cohort (all PO daily) and 40 mg daily in the phase II cohort. Results: A total of 32 pts received C+DP (19 pts in phase I and 13 pts in the phase II cohort). 12 pts received DP alone. Baseline characteristics for C+DP vs DP included median age 69 (45 – 84) vs 69 (50-83) and median PSA 74.8 ng/ml (0.01-4093.7) vs 309.5 ng/ml (94.6 – 2649) respectively. Clinical trial information: NCT01683994. 18/32 C+DP pts had previous enzalutamide or abiraterone, with a median PFS of 13.6 months (95% CI: 5.2 – 21.0). 23/32 pts (72%) treated with C+DP required dose reduction or discontinuation of C, and 10/32 (31%) required C discontinuation. 2/32 patients (6%) in the C+DP group died on protocol, possibly related to study drug (sudden death NOS/venous thromboembolism). Grade 4 adverse events (AEs) in the C+DP group included: neutropenia (28%), leukopenia (6%), pulmonary embolism (3%), and mucositis (3%) and in DP: hyperglycemia (8%). Grade 3 AEs (>10%) in C+DP included: neutropenia (31%), febrile neutropenia (16%), leukopenia (13%), hypophosphatemia (13%) and in DP: anemia (17%). Conclusions: In pts with mCRPC, C+DP is associated with a greater PFS and PSA responses compared to DP alone. Toxicities with the combination were manageable. Further study is required to better define the potential benefits of C+DP in mCRPC.[Table: see text]

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Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma

Neuro-Oncology ◽

10.1093/neuonc/nou160 ◽

2014 ◽

Cited By ~ 21

Author(s):

D. A. Reardon ◽

L. B. Nabors ◽

W. P. Mason ◽

J. R. Perry ◽

W. Shapiro ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Phase Ii Study ◽

Recurrent Glioblastoma ◽

Erbb Family ◽

Randomized Phase Ii ◽

Erbb Family Blocker

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Bevacizumab versus bevacizumab plus vorinostat in adults with recurrent malignant glioma: Results of a phase I part of a phase I/II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2029 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2029-2029

Author(s):

Jing Wu ◽

Morris D. Groves ◽

Mark R. Gilbert ◽

Kenneth R. Hess ◽

Carolyn Sue Loch ◽

...

Keyword(s):

Phase I ◽

Malignant Glioma ◽

Phase Ii ◽

Phase Ii Study ◽

Toxicity Profile ◽

Recurrent Malignant Glioma ◽

Randomized Phase Ii ◽

Starting Dose ◽

Grade 3 ◽

Recurrent Gbm

2029^ Background: Antiangiogenic therapy using b evacizumab (Bev) has shown promising activity against recurrent glioblastoma (GBM). However, most patients have disease progression after striking but transient responses. Salvage therapies have been uniformly ineffective, suggesting development of resistance mechanisms including upregulation of other proangiogenic factors and increased activity of hypoxia inducible factors (HIF)-1a. Vorinostat, a histone deacetylase (HDAC) inhibitor has single agent activity against recurrent GBM and downregulates HIF-1a and other proangiogenic and invasive factors. We hypothesized that HDAC inhibition combined with Bev would result in improved clinical outcome. We report the results of the Phase I portion of the study preceding the initiation of the 2-arm adaptive randomized Phase II study. Methods: Adults with recurrent malignant glioma, KPS ≥ 60, normal hepatic, renal and marrow organ function and no prior exposure to Bev or Vorinostat were enrolled to the combination therapy after the confirmation of recurrent GBM. A conventional 3+3 Phase I design was used to determine the maximum tolerated dose (MTD) and the toxicity profile of the combination of Bev and Vorinostat. The starting dose was Bev at 10mg/kg administered on days 1 and 15 intravenously and Vorinostat 400 mg/day orally on days 1 to 7, and days 15 to 21 with each cycle being 28 days. Results: A total of 6 patients were enrolled and all 6 patients were evaluable. Three patients were enrolled in the first cohort at the starting dose of the combination and completed the first cycle. One patient experienced a grade 3 ALT elevation and grade 3 hyperglycemia, which were designated as possibly related to vorinostat and constituting a dose-limiting toxicity (DLT). No grade 4 toxicities were noted. The cohort was expanded by 3 more patients with none of these patients experienced a DLT in the first cycle. The starting dose level of Bev and v orinostat was declared the Phase II dose. Conclusions: Combination of Bev (10 mg/kg q 2 weeks) and of vorinostat (400 mg on days 1 to 7 and 15 to 21) has tolerable toxicity profile. This will be followed by a multicenter Bayesian adaptive randomized Phase II study.

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