ABSTRACT
PURPOSE: The aim of this study was to evaluate the tolerability and efficacy of poly(ADP-ribose) polymerase (PARP) inhibition by veliparib during cytotoxic topotecan administration with filgrastim or pegfilgrastim neutrophil support in women with persistent or recurrent uterine cervix cancer. EXPERIMENTAL DESIGN: This phase I-II trial examined twice-daily oral veliparib (10 mg) given during once-daily intravenous topotecan (0.6 mg/m²) on days 1 to 5 of each treatment cycle. Cycles were repeated every 21 days until disease progression or until toxicity prohibited further therapy. Toxicity and objective response rate were primary endpoints. RESULTS: Twenty-seven women were enrolled. Frequently reported grade 3 or higher treatment-related toxicities were anemia (59%), thrombocytopenia (44%), leukopenia (22%), and neutropenia (19%). There were 2 partial responses (7% [90% confidence interval, 1%-22%]). Four patients had a disease progression date more than 6 months after the start of veliparib-topotecan therapy. Patients with low immunohistochemical expression (0-1+) of PARP-1 in their primary uterine cervix cancer were more likely to have a longer progression-free interval (hazard ratio, 0.25; P = 0.02) and survival (hazard ratio, 0.12; P = 0.005) after veliparib-topotecan therapy. CONCLUSIONS: Clinical activity of a veliparib-topotecan combination was minimal in women with persistent or recurrent uterine cervix cancer. Women whose uterine cervix cancers express PARP-1 at low levels may benefit preferentially from PARP inhibitors combined with cytotoxic therapies, suggesting further study of PARP expression as an integral triage biomarker.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Uterine Cervical Neoplasms/drug therapy , Adult , Aged , Anemia/chemically induced , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Carcinoma/chemistry , Cell Cycle Proteins/analysis , Disease Progression , Female , Filgrastim/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Middle Aged , Neoplasm Recurrence, Local/chemistry , Neutropenia/chemically induced , Neutropenia/prevention & control , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/analysis , Polyethylene Glycols , Recombinant Proteins/therapeutic use , Ribonucleotide Reductases/analysis , Thrombocytopenia/chemically induced , Topotecan/administration & dosage , Topotecan/adverse effects , Uterine Cervical Neoplasms/chemistryABSTRACT
PURPOSE: We conducted a phase II trial to evaluate the efficacy and safety of single-agent sorafenib in chemotherapy-naïve patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN). The primary end point was response probability (ie, confirmed complete and partial response [PR]). PATIENTS AND METHODS: Chemotherapy-naïve patients with metastatic, persistent, or recurrent SCCHN who received one induction or fewer or received an adjuvant chemotherapy regimen, who had adequate organ function, and who had a performance status Subject(s)
Antineoplastic Agents/therapeutic use
, Benzenesulfonates/therapeutic use
, Carcinoma, Squamous Cell/drug therapy
, Head and Neck Neoplasms/drug therapy
, Pyridines/therapeutic use
, Adult
, Aged
, Aged, 80 and over
, Benzenesulfonates/adverse effects
, Carcinoma, Squamous Cell/mortality
, Carcinoma, Squamous Cell/pathology
, Disease-Free Survival
, Drug Evaluation
, Female
, Head and Neck Neoplasms/mortality
, Head and Neck Neoplasms/pathology
, Humans
, Male
, Middle Aged
, Neoplasm Metastasis
, Niacinamide/analogs & derivatives
, Phenylurea Compounds
, Pyridines/adverse effects
, Sorafenib
ABSTRACT
BACKGROUND: In preclinical models, the proteasome inhibitor bortezomib (PS-341) inhibits the growth of small cell lung cancer (SCLC) by inhibiting the antiapoptotic Bcl-2 signaling pathway. We conducted a phase II trial of PS-341 in previously treated patients with platinum-sensitive and -refractory extensive stage SCLC to determine response rate, toxicity, and survival. METHODS: Patients with histologically confirmed SCLC, measurable disease, Zubrod performance status 0-1, and previous treatment with platinum-based therapy were enrolled. They were stratified by platinum-sensitivity status: sensitive (relapse >90 days after platinum) or refractory (progression during or < or =90 days after platinum). PS-341 was administered at 1.3 mg/m intravenously on days 1, 4, 8, and 11 every 21 days. RESULTS: Of 56 eligible patients, 28 were platinum sensitive and 28 refractory. Twenty-nine patients (52%) had received two or more previous chemotherapy regimens. One platinum-refractory patient had a confirmed partial response. A majority of assessable patients (91%) progressed. Median progression-free survival and overall survival were 1 month and 3 months, respectively. Ten patients (18%) discontinued treatment due to adverse events or side effects. CONCLUSION: Although PS-341 induced a response in a patient with platinum-refractory disease, it has limited single-agent activity in this heavily pretreated cohort. As shown in preclinical models, testing of PS-341 in combination with an apoptotic trigger such as chemotherapy, is a rational clinical approach. A trial of topotecan plus PS-341 has been initiated to test this concept.