Summary 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/m2 , 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/m2 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.
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 m
2
) 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 (AUC
0–24
) and maximum observed plasma concentration (
C
max
) 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 AUC
0–24
, and a 11.1%, 31.6%, and 89.3% increase in talazoparib
C
max
, 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.
This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat.
Patients with advanced solid tumors or ...non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed ...high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib.
This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6–12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients.
Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months 95% CI 16·3–25·7) than with placebo (5·5 months 5·2–5·8; hazard ratio HR 0·30 95% CI 0·22–0·41, p<0·0001). The most common adverse events of grade 3 or worse severity were anaemia (38 19% of 195 patients in the olaparib group vs two 2% of 99 patients in the placebo group), fatigue or asthenia (eight 4% vs two 2%), and neutropenia (ten 5% vs four 4%). Serious adverse events were experienced by 35 (18%) patients in the olaparib group and eight (8%) patients in the placebo group. The most common in the olaparib group were anaemia (seven 4% patients), abdominal pain (three 2% patients), and intestinal obstruction (three 2% patients). The most common in the placebo group were constipation (two 2% patients) and intestinal obstruction (two 2% patients). One (1%) patient in the olaparib group had a treatment-related adverse event (acute myeloid leukaemia) with an outcome of death.
Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Apart from anaemia, toxicities with olaparib were low grade and manageable.
AstraZeneca.
Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or ...endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival.
This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0–1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients.
Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 66%) or placebo (n=99 34%). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6–69·3) with olaparib and 64·5 months (63·4–68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5–59·1) with olaparib and 38·8 months (31·4–48·6) with placebo (hazard ratio 0·74 95% CI 0·54–1·00; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 21% of 195 patients in the olaparib group and two 2% of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome n=3 and acute myeloid leukaemia n=3).
Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients.
AstraZeneca and Merck.
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