The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors.

BACKGROUND: Pharmacokinetic (PK) studies suggest that talazoparib is primarily eliminated unchanged via renal excretion. The current study investigated how varying degrees of renal impairment may affect the PK of talazoparib, and evaluated the safety and tolerability of talazoparib, in patients with advanced solid tumors with/without renal impairment. METHODS: Patients with advanced solid tumors and normal renal function or different degrees of renal impairment measured by estimated glomerular filtration rate (eGFR: mild = 60-89, moderate = 30-59, severe = 15-29 mL/min/1.73 m2) were enrolled in this open-label, non-randomized, phase I study. Talazoparib was administered orally at 0.5 mg/day for 22 days. Primary PK parameters included the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) and maximum observed plasma concentration (Cmax) at steady state (Day 22). Safety and tolerability were also investigated. RESULTS: Thirty-four patients were enrolled. At Day 22, compared with patients with normal renal function (n = 9), patients with mild (n = 9), moderate (n = 8), or severe (n = 8) renal impairment had a 12.2%, 43.0%, and 163.3% increase in talazoparib AUC0-24, and a 11.1%, 31.6%, and 89.3% increase in talazoparib Cmax, respectively. Talazoparib was generally well tolerated, and overall there were no notable differences in the treatment-emergent adverse event profile across renal function groups. CONCLUSIONS: Exposure to talazoparib increased with worsening renal impairment. Overall, this study confirms current dosing recommendations in patients with mild and moderate renal impairment (1 mg/day and 0.75 mg/day, respectively) and indicates that a lower starting dose of 0.5 mg/day should be considered for patients with severe renal impairment. CLINICAL TRIALS REGISTRATION: NCT02997163.

Dose-Ranging and Cohort-Expansion Study of Monalizumab (IPH2201) in Patients with Advanced Gynecologic Malignancies: A Trial of the Canadian Cancer Trials Group (CCTG): IND221.

PURPOSE: Monalizumab binds CD94/NKG2A, preventing HLA-E inhibition of tumor lymphocytes. A dose-ranging/cohort expansion trial of monalizumab for recurrent gynecologic malignancies was conducted to determine the recommended phase II dose (RP2D) and to explore clinical activity, pharmacokinetics, pharmacodynamics, safety, and immunogenicity. PATIENTS AND METHODS: Participants (and part 2 expansion cohorts) included (i) platinum-sensitive ovarian, (ii) platinum-resistant ovarian, (iii) squamous cervical (CX), and (iv) epithelial endometrial (END) carcinomas. Part 1 assessed monalizumab at 1, 4, or 10 mg/kg every 2 weeks. In part 2, ≥4 patients/cohort underwent pre- and on-treatment tumor biopsies. Preset criteria determined cohort expansion. RESULTS: A total of 58 participants were evaluable. The RP2D was 10 mg/kg i.v. every 2 weeks. Dose proportionality and 100% NKG2A saturation were observed. Related adverse events were mild: headache, abdominal pain, fatigue, nausea, and vomiting. Grade 3 related adverse events were nausea (1), vomiting (1), dehydration (1), fatigue (2), anorexia (1), dyspnea (1), and proctitis (1). Dose-limiting toxicities were not observed. Hematologic and biochemical changes were mild and not dose related. Best response was SD: part 1, 7 of 18 (39%) [3.4 months (1.4-5.5)], and part 2, 7 of 39 (18%) [1.7 months (CX) to 14.8 months (END)]. Neither a predictive biomarker for SD nor evidence of pharmacodynamic effects was identified. There was a trend to significance between a reduction in lymphocyte HLA-E total score and pharmacodynamics. CONCLUSIONS: Monalizumab 10 mg/kg i.v. every 2 week is well tolerated in patients with pretreated gynecologic cancers. Short-term disease stabilization was observed. Future studies should assess combinations with other agents, including immunotherapeutics.

Cytokines and cell adhesion molecules exhibit distinct profiles in health, ovarian cancer, and breast cancer.

OBJECTIVE: We examined a panel of cytokines and cell adhesion molecules in an attempt to identify cancer specific profiles. DESIGN AND METHODS: Cytokines and cell adhesion arrays (Randox Ltd.) were measured in samples from women with a histological diagnosis of ovarian cancer ([Formula: see text]) or breast cancer ([Formula: see text]) or cancer free ([Formula: see text]). Random forest analysis was used for classification. RESULTS: Ovarian cancer subjects were classified with a sensitivity of 85.7% (95% CI 50-100) and a specificity of 84.2% (95% CI 69.4-93.4). Breast cancer subjects were classified with a sensitivity of 70.8% (95% CI 47.1-86.4) and a specificity of 96.4% (95% CI 82.1-100). DISCUSSION: Cytokine and cell adhesion molecule profiles provide additional information that may be useful for cancer characterization of female cancers.

Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial.

BACKGROUND: The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. METHODS: In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1-10 of each 21-day cycle) plus paclitaxel (175 mg/m(2), administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m(2) on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, number NCT01081951, and has been completed. FINDINGS: Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12.2 months [95% CI 9.7-15.0]) than in the chemotherapy alone group (median 9.6 months [95% CI 9.1-9.7) (HR 0.51 [95% CI 0.34-0.77]; p=0.0012), especially in patients with BRCA mutations (HR 0.21 [0.08-0.55]; p=0.0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group. INTERPRETATION: Olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile. FUNDING: AstraZeneca.

Fractionated stereotactic radiosurgery with concurrent temozolomide chemotherapy for locally recurrent glioblastoma multiforme: a prospective cohort study.

Local recurrence represents a significant challenge in the management of patients with glioblastoma multiforme. Salvage treatment options are limited by lack of clinical efficacy. Recent studies have demonstrated a significant response rate and acceptable toxicity with the use of fractionated stereotactic radiosurgery in this patient population. Our primary objective was to determine the efficacy and toxicity of fractionated stereotactic radiosurgery combined with concurrent temozolomide chemotherapy as a salvage treatment for recurrent glioblastoma multiforme. We prospectively collected treatment and outcome data for patients having fractionated stereotactic radiosurgery for locally recurrent glioblastoma multiforme after radical radiotherapy. Eligible patients had a maximum recurrence diameter of 60 mm without causing significant mass effect. The gross tumor volume was defined as the enhancing lesion on an enhanced fine-slice T1 (spin-lattice) magnetic resonance imaging, and a circumferential setup margin of 1 mm was used to define the planning target volume. All patients were treated using robotic radiosurgery with three dose/fractionation schedules ranging from 25 to 35 Gy in five fractions, depending on the maximum tumor diameter. Concurrent temozolomide 75 mg/m(2) was prescribed to all patients. Tumor response was judged using the Macdonald criteria, and toxicity was assessed using the CTCAE (Common Terminology Criteria for Adverse Events). A total of 31 patients were enrolled in this study. The median overall survival was 9 months, and progression-free survival was 7 months. The 6-month progression-free survival was 60% with a 95% confidence interval of 43%-77%. The a priori stratification factor of small tumor diameter was shown to predict overall survival, while time to recurrence was not predictive of progression-free or overall survival. Three patients experienced grade 3 acute toxicity that responded to increased steroid dosing. One patient experienced a grade 4 acute toxicity that did not respond to increased steroids but did respond to anti-angiogenic therapy. Fractionated stereotactic radiosurgery with concurrent temozolomide has shown good short-term clinical and radiologic control with manageable acute toxicity. This regimen appears to provide superior efficacy to either temozolomide or fractionated radiosurgery alone. The results of this study support the continued evaluation of this regimen.

Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas.

PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients. CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.

Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas.

PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination of decitabine with vorinostat. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg three times a day on days 6-12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1-5 with vorinostat 200 mg twice a day on days 3-9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg twice a day on days 6-12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12/42 (29%) patients evaluable for toxicity. The most common ≥ grade 3 adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for ≥ 4 cycles was observed in 11/38 (29%) evaluable patients. CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.

Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors.

PURPOSE: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. EXPERIMENTAL DESIGN: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. RESULTS: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. CONCLUSIONS: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.

Intraperitoneal chemotherapy in the first-line treatment of women with stage III epithelial ovarian cancer: a systematic review with metaanalyses.

Because women with advanced ovarian cancer have poor outcomes, it is imperative to continue exploring for novel therapies. The opportunity for intraperitoneal treatment, especially in the subgroup of patients with minimal residual disease, in which the intraperitoneal approach may have a biologic rationale for benefit over and above the standard intravenous route, needs to be explored to the fullest extent. The MEDLINE, EMBASE, and Cochrane Library databases were searched up to January 2006 for randomized trials that compared first-line intraperitoneal-containing chemotherapy with first-line intravenous chemotherapy in the treatment of women with stage III epithelial ovarian cancer. Seven randomized, controlled trials were identified, including 3 large Phase III trials and 4 smaller randomized trials. The 3 large Phase III trials detected statistically significant overall survival benefits with intraperitoneal cisplatin-containing chemotherapy compared with intravenous chemotherapy alone. The improvements in survival were 8 months, 11 months, and 16 months, respectively. Pooled analysis from 6 of the 7 randomized trials confirmed the survival effect with intraperitoneal chemotherapy compared with intravenous chemotherapy alone (relative risk, 0.88; 95% confidence interval, 0.81-0.95). Severe adverse events and catheter-related complications with intraperitoneal chemotherapy were significantly more common and often were dose-limiting. The results from this review indicated that cisplatin-containing intraperitoneal chemotherapy should be offered to patients on the basis of significant improvements in overall survival. The appropriate clinical and institutional multidisciplinary facilities are needed for the safe delivery of this treatment in optimally debulked patients. Further research is needed concerning specific aspects of the treatment, such as optimal agent, dose, and scheduling.

A phase II trial of ZD1839 (Iressa) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) appears relevant in the pathogenesis and progression of colorectal cancer. After completing a phase I pharmacodynamic trial of ZD1839, we undertook a dose expansion trial to examine the antitumour efficacy and adverse effect profile of this agent in a homogeneous group of patients with metastatic colorectal cancer (CRC). EXPERIMENTAL DESIGN: Eligible patients with metastatic or recurrent CRC received ZD1839 750 mg daily by mouth. This dose was selected based on a phase I trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). Treatment was continued until unacceptable toxicity or disease progression. RESULTS: Twenty-eight patients were enrolled at three NCIC CTG centers. Twenty-three patients had received prior chemotherapy; 12 patients had received three or more regimens. No objective responses were observed in 24 evaluable patients, although 8 patients had stable disease (median duration of 2.2 months). The most frequent drug related adverse events were diarrhea, rash and nausea. Eleven patients required dosing modification (hold or reduction), while 3 patients discontinued therapy because of toxicity. There were no treatment related deaths. CONCLUSIONS: ZD1839, when given at 750 mg/day to patients with pre-treated metastatic colorectal cancer, does not result in significant tumor regression.

A pharmacodynamic study of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in metastatic colorectal cancer patients.

PURPOSE: Epidermal growth factor receptor (EGFR) appears to play an important role in the pathogenesis of colorectal cancer. We have performed a Phase I/II study of the EGFR tyrosine kinase inhibitor ZD1839 in metastatic colorectal cancer patients in which serial biopsies were taken pre- and posttreatment to assess biological activity. EXPERIMENTAL DESIGN: Paired biopsies were obtained from colorectal cancer patients before and after treatment. Proliferation and apoptosis were assessed using Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated nick end labeling assays, respectively. Immunohistochemistry for EGFR, activated EGFR, phosphorylated Akt, phosphorylated ERK, p27(Kip1), and beta-catenin was also performed. RESULTS: Posttreatment samples showed a statistically significant reduction in the cancer cell proliferation index (mean proliferation index pretreatment 31%; posttreatment 21%; P = 0.047). The mean cancer cell apoptosis index also increased from 6 to 12% in posttreatment samples, although this difference did not achieve statistical significance. All pretreatment samples showed strong staining for EGFR. Loss of immunohistochemical staining for activated EGFR, phosphorylated Akt, and phosphorylated ERK in cancer cells was observed in some patients after treatment. p27(Kip1) was absent in the cancer cells of most pretreatment biopsies; two patients showed a marked increase in staining for nuclear p27(Kip1) after treatment with ZD1839. These two patients also showed large increases in apoptotic index. CONCLUSIONS: ZD1839 inhibits EGFR signaling and proliferation in the cancer cells of patients with metastatic colorectal cancer. ZD1839 may also induce cancer cell apoptosis in a subset of colorectal cancer patients via up-regulation of p27(Kip1).

Doxycycline decreases tumor burden in a bone metastasis model of human breast cancer.

Bone is one of the most frequent sites for metastasis in breast cancer patients,often resulting in significant clinical morbidity and mortality. Increased matrix metalloproteinase (MMP) activity of tumor cells correlates with a higher invasive and metastatic potential. Members of the tetracycline family of antibiotics, including doxycycline, have potential treatment value for bone metastasis; they inhibit cancer cell proliferation, and they are also potent MMP inhibitors and are highly osteotropic. Doxycycline treatment in an experimental bone metastasis mouse model of human breast cancer MDA-MB-231 cells resulted in a 70% reduction in total tumor burden when compared with placebo control animals. In tumor-bearing animals, the amount of doxycycline incorporated into the radius/ulna as assessed by ELISA was lower than in non-tumor-bearing animals. In doxycycline-treated mice, bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface, and volume, whereas a decrease in bone resorption was also observed. Doxycycline treatment may be beneficial for breast cancer patients with or at risk for osteolytic bone metastasis; it greatly reduces tumor burden and could also compensate for the increased bone resorption associated with the disease.

A comparison of two prophylactic regimens for hypersensitivity reactions to paclitaxel.

OBJECTIVE: The aim of this study was to compare the rates of hypersensitivity reactions to paclitaxel with the conventional prophylactic regimen of two doses of oral corticosteroids and a modified regimen of a single dose of intravenous corticosteroid. METHODS: This was a retrospective historical cohort study assessing the rates of hypersensitivity reactions in patients receiving paclitaxel for ovarian or primary peritoneal carcinoma at the Hamilton Regional Cancer Centre from 1996 to 2000. Until 1998, all patients received the conventional prophylactic regimen consisting of two doses of oral dexamethasone (20 mg), 12 and 6 h prior to paclitaxel. From 1998 to the present, patients received a single dose of intravenous dexamethasone (20 mg), 30 min prior to paclitaxel. All patients also received an H(1) and H(2) blocker intravenously prior to paclitaxel administration. The analysis was corrected for potential covariates such as dose of paclitaxel and rate of infusion. The primary outcome measure was the rate of hypersensitivity reactions as defined by the National Cancer Institute of Canada-Clinical Trials Group. The Yates-corrected chi(2) test was used to compare the rates of these reactions, and a logistic regression analysis was used to determine whether any of the covariates were significant factors in these reactions. RESULTS: One hundred seven patients received the conventional corticosteroid prophylaxis prior to paclitaxel, and 110 received the single-dose intravenous corticosteroid prophylaxis. Of the 107 patients in the conventional prophylaxis group, 8 had a hypersensitivity reaction (7.5%), and only 1 of these was severe (0.9%). In contrast, of the 110 patients in the single-dose IV corticosteroid group, 19 had a hypersensitivity reaction (17.3%), and 8 of these were severe (7.3%). The difference in hypersensitivity reaction rates was significant (chi(2), P = 0.047). In the logistic regression analysis, the only significant factor related to hypersensitivity reactions was the type of prophylactic steroid regimen. CONCLUSIONS: In this series, the single-dose intravenous corticosteroid prophylactic regimen appeared to be associated with a higher rate of hypersensitivity reactions to paclitaxel than the conventional two-dose oral corticosteroid regimen.