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There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine–tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1–21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine–tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3–6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7–8·2) in the fruquintinib group versus 4·8 months (4·0–5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55–0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. HUTCHMED.

Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8–46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19–64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. Merck Sharp and Dohme.

Fruquintinib, a highly selective, oral inhibitor of all three vascular endothelial growth factor receptors (−1, −2, and −3), is approved for previously treated metastatic colorectal cancer. This phase 1, two‐part, two‐period, fixed‐sequence study (NCT05368805) evaluated the potential inhibitory effect of fruquintinib (5 mg) on the pharmacokinetics (PK) of P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) substrates. In Part A, 20 healthy subjects received a single oral dose of dabigatran etexilate (P‐gp substrate) 150 mg on Day 1 and Day 5, with fruquintinib co‐administered on Day 5. In Part B, 12 healthy subjects received a single oral dose of rosuvastatin (BCRP substrate) 10 mg on Day 1 and Day 5, with fruquintinib co‐administered on Day 5. Plasma samples were collected to evaluate the PK of dabigatran and rosuvastatin over 96 h, and to measure fruquintinib and its major metabolite M11 concentrations over 192 h. Co‐administration of dabigatran etexilate with fruquintinib resulted in a ~10% decrease in the systemic exposure of dabigatran; geometric mean ratios (GMRs) and 90% CIs were 0.90 (0.66–1.23) for Cmax and 0.91 (0.68–1.23) for AUC0–inf. Co‐administration of rosuvastatin with fruquintinib resulted in a decrease in the systemic exposure of rosuvastatin by approximately 16% for Cmax and 19% for AUC0–inf; GMRs and 90% CIs were 0.84 (0.65–1.10) for Cmax and 0.81 (0.65–1.02) for AUC0–inf. Fruquintinib had no clinically significant effect on the PK of P‐gp or BCRP substrates, supporting that dose adjustments for substrates of P‐gp or BCRP are unnecessary when co‐administered with fruquintinib.

This two‐sequence, three‐period study (NCT04645940) was designed to evaluate the effect of food and concomitant rabeprazole, a proton pump inhibitor, on the pharmacokinetics (PK) and safety of fruquintinib and its metabolite M11 after a single oral dose of fruquintinib 5 mg in healthy subjects. In the food effect treatment periods, 14 subjects were randomized in a 1:1 ratio utilizing a two‐sequence (fed/fasted vs. fasted/fed), two‐period, cross‐over design. Fruquintinib was administered on Day 1 (Period 1) and Day 15 (Period 2). In the drug‐interaction period (Period 3), all subjects received rabeprazole 40 mg 1 h prior to fruquintinib under fasted conditions, following a 6‐day lead‐in of rabeprazole 40 mg once daily. PK samples to measure fruquintinib and M11 were collected pre‐dose and over 168 h after fruquintinib dosing. Administration of fruquintinib with a high‐fat meal resulted in similar systemic exposure compared with fasted conditions. In addition, coadministration of fruquintinib with rabeprazole resulted in similar exposure compared with fruquintinib alone. For both evaluations, 90% confidence intervals for the ratio of geometric least square mean of the area under the curve and peak concentration for fruquintinib and M11 were entirely within 80%–125% bounds. The study results showed no effects of food or rabeprazole on fruquintinib PK, and support that fruquintinib can be taken without regard to food or concurrent gastric acid‐reducing agents.

BackgroundPatients with metastatic gastric cancer have a poor prognosis (5-year survival of less than 10%). This study was designed to describe the treatment patterns of patients with gastric cancer and to understand the factors associated with treatment choices to inform evidence-based care.MethodsA retrospective observational study was conducted using two real-world databases to describe treatment trends and to quantify variability in treatment patterns of patients diagnosed with advanced/metastatic gastric cancer between 1/1/2007 and 9/30/2014 in the U.S. Heterogeneity was measured by the Herfindahl–Hirschman Index (HHI). Predictors (baseline clinical, treatment, and demographic variables) of treatment regimen choice were evaluated using logistic regression.ResultsA total of 5772 patients with advanced/metastatic gastric cancer were included in this study [5044 from claims data and 728 from electronic medical records (EMR)]. Of the 5044 from claims data, 2457 had evidence of metastatic disease at diagnosis. Only the fluorouracil + oxaliplatin regimen exceeded 10% utilization in the first-line setting [claims metastatic (12.1%), claims advanced (8.2%), and EMR metastatic (16.6%) cohorts]. The HHI demonstrated extreme heterogeneity (0.14 for first-line therapy and 0.13 for second-line therapy). Patient age and geographic region of residence were significantly associated with treatment choice across all three cohorts in the first-line setting (p < 0.05).ConclusionTreatment of patients with gastric cancer was highly variable. Despite the availability of treatment guidelines, there is a lack of consistent treatment patterns. There is a need to improve evidence-based care for patients with gastric cancer.

Purpose GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295. Patients and methods Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m 2 . GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks. Results A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m 2 . Observed dose-limiting toxicities (all grade 3) were as follows: fatigue ( n  = 2, 5%), increased AST ( n  = 1, 2.5%), hypokalemia ( n  = 1, 2.5%), and hypoxia ( n  = 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event ( n  = 13; 33%). Gastrointestinal toxicities of diarrhea ( n  = 12, 31%), nausea ( n  = 8, 21%), and vomiting ( n  = 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m 2 and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9–11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m 2 dose level. Conclusions The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.

BackgroundLimited real-world research has investigated ramucirumab for the treatment of patients with gastric or gastroesophageal junction (GEJ) cancer. This study was designed to describe ramucirumab monotherapy or combination therapy use in a community oncology practice setting.MethodsThis was a retrospective observational cohort study to describe the treatment of adult patients with gastric or GEJ cancer who initiated ramucirumab treatment between 4/21/14 and 6/30/16 within the US Oncology Network. Kaplan–Meier method and Cox proportional hazards regression analyses were used to assess clinical outcomes. Multivariable logistic regression models were used to assess patient-level predictors of ramucirumab monotherapy or combination therapy.ResultsA total of 505 patients (mean age 64.4 years; 75.1% male) were included in the analysis; subgroups included: monotherapy (22.8%; n = 115), combination therapy (77.2%; n = 390). Monotherapy patients were significantly older (67.7 vs. 63.4 years; P = 0.0006), received ramucirumab approximately 3 months later after diagnosis (16.9 vs. 14.1 months; P = 0.0318) and more frequently initiated ramucirumab in the third or later lines of treatment (38.3 vs. 8.2%; P<0.0001) than patients receiving combination therapy. Median overall survival (OS) for monotherapy and combination therapy from the start of second-line therapy was 5.5 months (confidence interval [CI] 4.3, 7.8) and 7.4 months (CI 6.6, 8.8), respectively.ConclusionsThe results showed that patients who received ramucirumab monotherapy started ramucirumab therapy later after diagnosis and were older than those who received ramucirumab in combination. Additionally, survival data suggest that outcomes observed in community oncology practices are similar to data from phase 3 clinical trials.

Summary Background . A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. Methods . In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1–3 along with cisplatin on day 1 and etoposide on days 1–3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. Results . Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1–3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. Conclusions . AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.

Summary Background RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors. Methods Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m 2 twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle. Results Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration. Conclusions The recommended phase 2 dose is capecitabine 1,000 mg/m 2 orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1–3, 8–10 and 15–17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.

Summary Purpose To assess the maximum well-tolerated dose (MWTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and pharmacodynamics of zibotentan, a novel specific endothelin-A receptor antagonist, in patients with metastatic prostate cancer. Methods Patients with metastatic, castrate-resistant prostate cancer (CRPC) were treated with escalating doses of oral zibotentan (ZD4054) 10–200 mg once daily. The initial cohort received 28 daily doses (Period 1). Patients who had evidence of clinical benefit and who had not met any of the criteria for withdrawal were allowed to receive zibotentan at their current dose level until they no longer derived clinical benefit (Period 2). PK of zibotentan and changes in prostate-specific antigen and bone markers were also assessed. Results Sixteen patients were evaluable for the safety and single-dose PK analyses. Eleven patients completed Period 1, and nine patients proceeded to Period 2. DLTs were encountered at 22.5 mg; one patient had grade 3 dyspnea and peripheral edema and a second patient had grade 3 headache and intraventricular hemorrhage. Enrollment was expanded at the 15 mg dose level to further determine the safety and tolerability of zibotentan. No DLTs were seen at 15 mg, and the most frequent adverse events were headache, peripheral edema, fatigue, nasal congestion and nausea. Conclusions The MWTD for zibotentan was 15 mg orally daily. The predominant adverse events observed were consistent with those reported for this class of drugs, and prolonged stable disease was noted in some patients. Phase III studies with zibotentan in men with metastatic CRPC are ongoing.