Phase 1/1b open-label, dose-escalation study of fruquintinib in patients with advanced solid tumors in the United States.

This open-label, phase 1/1b study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of fruquintinib in United States (U.S.) patients to confirm the recommended phase 2 dose (RP2D) established in China. Patients with advanced solid tumors who had progressed on approved systemic therapy, were enrolled into 2 successive dose escalation cohorts, fruquintinib 3 mg (n = 7) or 5 mg (n = 7), orally, once daily (QD), 3 weeks on and 1 week off (3/1) with a 3 + 3 design followed by a dose expansion cohort at the RP2D 5 mg dose (n = 6). PK samples were collected on Days 1, 14, and 21 (Cycle 1). One of 6 dose-limiting toxicity (DLT)-evaluable patients in the 3 mg cohort had a DLT of grade 4 hypertension; there were no DLTs in the 5 mg cohort. The RP2D was confirmed to be 5 mg QD 3/1. All 20 patients experienced a treatment-emergent adverse event; grade ≥ 3 in 5 (71.4%; 3 mg dose) and 12 (92.3%; 5 mg dose) patients. Two patients had a confirmed partial response. After single and multiple doses, median peak plasma concentrations occurred at 2 h post-dose. Steady-state was achieved after 14 days of QD dosing with systemic exposure four-fold higher than that after a single dose. Fruquintinib was well tolerated, and the safety and PK profile at the 5 mg RP2D in U.S. patients with advanced solid tumors was consistent with dose-finding studies in China. Preliminary anticancer activity was observed. This study is registered at Clinicaltrials.gov NCT03251378.

Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: HUTCHMED.

FRESCO-2: a global Phase III study investigating the efficacy and safety of fruquintinib in metastatic colorectal cancer.

Fruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy. Approximately 687 patients will be randomized 2:1 to fruquintinib plus best supportive care or placebo plus best supportive care. Primary and key secondary end points are overall survival and progression-free survival, respectively. FRESCO-2 is enrolling in the USA, Europe, Australia and Japan.

Lay abstract Fruquintinib is a drug that slows down, reduces or prevents the growth of vessels that supply blood to certain tumors. Fruquintinib is approved in China for the treatment of cancer of the colon and rectum that has spread to these parts of the body from the primary site of cancer: metastatic colorectal cancer. The FRESCO-2 study is being conducted globally to determine how safe and effective fruquintinib is at treating patients with metastatic colorectal cancer that has grown or spread following other forms of treatment, such as chemotherapy. About 687 patients will be enrolled globally to receive either fruquintinib or a matching placebo in a 2:1 ratio, respectively. The FRESCO-2 study is enrolling patients in the USA, Europe, Australia and Japan. Clinical trial registration: NCT04322539 (ClinicalTrials.gov).

Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab.

BACKGROUND & AIMS: Radiological progression patterns to first-line sorafenib have been associated with post-progression and overall survival in advanced hepatocellular carcinoma, but these associations remain unknown for therapies in second- and later-line settings. This post hoc analysis of REACH and REACH-2 examined outcomes by radiological progression patterns in the second-line setting of patients with advanced hepatocellular carcinoma treated with ramucirumab or placebo. METHODS: Patients with advanced hepatocellular carcinoma, Child-Pugh A and Eastern Cooperative Oncology Group Performance Status 0 or 1 with prior sorafenib were randomized to receive ramucirumab 8mg/kg or placebo every 2 weeks. Among 625 patients with ≥1 progression pattern (new extrahepatic lesion [including new macrovascular invasion], new intrahepatic lesion, extrahepatic growth or intrahepatic growth), data were analysed by trial and for pooled individual patient data for REACH-2 and REACH (alpha-fetoprotein ≥400 ng/mL). Cox models evaluated prognostic implications of progression patterns on overall and post-progression survival. RESULTS: Post-progression survival was worse among those with new extrahepatic lesions in REACH (HR 2.33, 95% CI 1.51-3.60), REACH-2 (HR 1.49, 95% CI 0.72-3.08) and the pooled population (HR 1.75, 95% CI 1.12-2.74) compared to other progression patterns. Overall survival was also significantly reduced in those with new extrahepatic lesions across studies. Ramucirumab provided an overall survival benefit across progression patterns, including patients with new extrahepatic lesions (HR 0.56, 95% CI 0.39-0.80) in the pooled population. CONCLUSIONS: The emergence of new extrahepatic lesions in the second-line setting is a poor prognostic factor for post-progression survival. The benefit of ramucirumab for overall survival was consistent across progression patterns.

Reliability of Conclusions from Early Analyses of Real-World Data for Newly Approved Drugs in Advanced Gastric Cancer in the United States.

BACKGROUND: As real-world data resources expand and improve, there will increasingly be opportunities to study the effectiveness of interventions. There is a need to ensure that study designs explore potential sources of bias and either acknowledge or mitigate them, in order to improve the accuracy of findings. The objective of this study was to understand newly approved drug utilization patterns in real-world clinical settings over time. METHODS: This retrospective study included three sources of real-world data (claims, electronic health records, and recoded data from a quality care program) collected from patients diagnosed with gastric cancer who initiated therapy with either trastuzumab or ramucirumab. Linear regression was used to investigate trends in the use of these drugs for the care of patients with gastric cancer over time from Food and Drug Administration (FDA) approval. RESULTS: Eligible patients (n=1700) had consistent demographic and clinical characteristics over time. After regulatory approval, trastuzumab was used in later lines of therapy and then shifted to earlier lines (p=0.002), while ramucirumab utilization remained consistent over time after FDA approval (p=0.49). Ramucirumab augmentation, defined as the addition of the drug after initiation of a line of therapy, decreased over time (p=0.03), and trastuzumab augmentation remained consistent over time (p=0.58). CONCLUSION: Since treatment effectiveness may change across lines of treatment, bias may arise if there are changes in the use of the drug (such as line migration) during the time period of analysis using real-world data.

The relationship between Eastern Cooperative Oncology Group performance status and healthcare resource utilization among patients with advanced or metastatic colorectal, lung or gastric cancer.

AIMS: The ability of a patient to receive anti-cancer treatment depends on a variety of factors, including performance status (PS), which is typically measured using the Eastern Cooperative Oncology Group (ECOG) scale. This study hypothesized that there would be a strong and positive correlation between ECOG PS values and healthcare resource utilization (HCRU) and a strong and negative correlation with the use of anti-cancer therapy. MATERIALS AND METHODS: Patients with colorectal, lung or gastric cancer were included in this retrospective analysis of administrative claims data linked to electronic medical records (EMR). All-cause HCRU (hospitalization/inpatient care, emergency room visits, systemic anti-cancer therapy, radiation therapy, outpatient physician visits, hospice, home health care and key supportive care treatments such as anti-emetics, hematopoietic treatments, transfusions, and durable medical equipment) was evaluated by baseline ECOG PS value and PS over time. Adjusted multivariable regression analysis was used to assess the relationship between baseline ECOG PS and HCRU. Regression analyses were conducted to explore the relationship between other baseline variables and HCRU. RESULTS: There were 1311 patients included in this study. There was low correlation between PS and any HCRU variable or receipt of anti-cancer therapy (correlation coefficients all <0.10). In regression analyses, the proportion of patients with poor PS (PS = 2+) who were hospitalized was not significantly different from those with good PS (PS = 0/1) (28.9% versus 19.3%, p = .07). LIMITATIONS: The low rate of reporting of PS and the small sample size of patient groups in this study. CONCLUSIONS: There is very little evidence of a relationship between ECOG PS and HCRU, ECOG PS, or anti-cancer therapy in this study, in part due to low rates of and lack of variability in reported PS. There is some evidence that baseline comorbidities were significantly associated with HCRU and should be accounted for in future research evaluating HCRU.

Biology and significance of alpha-fetoprotein in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths globally due, in part, to the majority of patients being diagnosed with intermediate or advanced stage disease. Our increased understanding of the heterogeneous molecular pathogenesis of HCC has led to significant developments in novel targeted therapies. Despite these advances, there remains a high unmet need for new treatment options. HCC is a complex disease with multiple pathogenic mechanisms caused by a variety of risk factors, making it difficult to characterize with a single biomarker. In fact, numerous biomarkers have been studied in HCC, but alpha-fetoprotein (AFP) remains the most widely used and accepted serum marker since its discovery over 60 years ago. This review summarizes the most relevant studies associated with the regulation of AFP at the gene and protein levels; the pathophysiology of AFP as a pro-proliferative protein; and the correlation of AFP with molecular HCC subclasses, the vascular endothelial growth factor pathway and angiogenesis. Also described are the historical and current uses of AFP for screening and surveillance, diagnosis, its utility as a prognostic and predictive biomarker and its role as a tumour antigen in HCC. Taken together, these data demonstrate the relevance of AFP for patients with HCC and identify several remaining questions that will benefit from future research.

A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction.

AIMS: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. METHODS: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. RESULTS: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. CONCLUSION: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.

Treatment patterns and survival outcomes for patients receiving second-line treatment for metastatic colorectal cancer in the USA.

BACKGROUND: Colorectal cancer is the third most common cause of cancer death in the USA. It is important to identify patients who may experience poor outcomes from available treatments. METHODS: In this retrospective observational study, treatment patterns and survival outcomes were described among adult patients from the Flatiron Health electronic medical records database who were treated with at least two lines of therapy for metastatic colorectal cancer in the USA between January 2013 and May 2018. Patients with rapid progression were defined as those whose time from start of first- to second-line therapy was ≤ 183 days. RESULTS: A total of 14,315 patients formed the study cohort. The most common first-line treatments were FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) plus bevacizumab, received by 34.7% (n = 4962) of patients, followed by FOLFOX alone (17.1%, n = 2445). Of all patients, 6991 (48.9%) also received second-line anti-cancer therapy and of those, 3338 (47.7%) had rapid progression and 3653 (52.3%) did not. Median overall survival from the start of first- and second-line therapy was 20.8 months (95% CI 20.2-21.3) and 14.5 months (95% CI 13.9-15.0) for the entire study population, respectively. Median overall survival from the start of second-line therapy was 14.1 (95% CI 13.2-14.8) for patients with rapid progression and 14.6 months (95% CI 13.8-15.4) for patients without rapid progression. CONCLUSIONS: Patients diagnosed with metastatic colorectal cancer lived less than 2 years in this real-world database. While the time to initiation of second-line therapy was by definition longer among patients without rapidly progressing disease, survival outcomes were comparable from initiation of second-line therapy.

Ramucirumab for the treatment of patients with gastric or gastroesophageal junction cancer in community oncology practices.

BACKGROUND: Limited 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. METHODS: This 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. RESULTS: A 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. CONCLUSIONS: The 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.

Predictors of heterogeneity in the first-line treatment of patients with advanced/metastatic gastric cancer in the U.S.

BACKGROUND: Patients 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. METHODS: A 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. RESULTS: A 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). CONCLUSION: Treatment 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.

Patient Experience After Receiving a Diagnosis of Gastric Cancer in the USA.

PURPOSE: This study investigated the patient perspective during cancer treatment and throughout the survivorship period and to understand how the patient experience may be related to choices for the treatment of gastric cancer. METHODS: Eligible patients in the Vector Oncology electronic medical records database were ≥18 years of age, diagnosed with gastric cancer, and received active treatment. Quality of life (QOL) was collected using the Patient Care Monitor (PCM). Time to deterioration in QOL and overall survival were measured, adjusting for demographic and baseline clinical characteristics. Logistic regression model and classification and regression trees (CART) were used to identify factors associated with treatment choice. RESULTS: There were 776 patients in this study, of whom 301 (38.8%) reported QOL data. Most patients reported problems on all PCM subscales; problems were more common during the treatment period. Median time to deterioration of PCM subscales ranged from 42 days for treatment side effects to 331 days for impaired performance. Median survival was low: 6.9 and 5.5 months from the start of first- and second-line therapy, respectively. The choices made between therapeutic options were primarily associated with the site at which the oncologist practiced. CONCLUSIONS: Patients with gastric cancer report a considerable number of concerns on all subscales of the PCM, particularly during active treatment periods. The treatment heterogeneity and relative lack of clinical and symptom- or QOL-related factors associated with treatment choice suggest a gap in evidence that must be filled.

Heterochromatin Protein 1 Binding Protein 3 Expression as a Candidate Marker of Intrinsic 5-Fluorouracil Resistance.

BACKGROUND: Despite receiving post-operative 5-fluorouracil (5-FU)-based chemotherapy, approximately 50% of patients with stage IIIC colon cancer experience recurrence. Currently, no molecular signature can predict response to 5-FU. MATERIALS AND METHODS: Mouse models of colon cancer have been developed and characterized. Individual tumors in these mice can be longitudinally monitored and assessed to identify differences between those that are responsive and those that are resistant to therapy. Gene expression was analyzed in serial biopsies that were collected before and after treatment with 5-FU. Colon tumors had heterogeneous responses to treatment with 5-FU. Microarray analysis of pre-treatment biopsies revealed that Hp1bp3, a gene encoding heterochromatin protein 1 binding protein 3, was differentially expressed between sensitive and resistant tumors. CONCLUSION: Using mouse models of human colorectal cancer, Hp1bp3 was identified as a candidate marker of intrinsic 5-FU resistance and may represent a potential biomarker for patient stratification or a target of clinical importance.

A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors.

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.

Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer.

PURPOSE: TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. RESULTS: Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation. CONCLUSION: PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

Quantitative hepatic perfusion modeling using DCE-MRI with sequential breathholds.

PURPOSE: To develop and demonstrate the feasibility of a new formulation for quantitative perfusion modeling in the liver using interrupted DCE-MRI data acquired during multiple sequential breathholds. MATERIALS AND METHODS: A new mathematical formulation to estimate quantitative perfusion parameters using interrupted data was developed. Using this method, we investigated whether a second degree-of-freedom in the tissue residue function (TRF) improves quality-of-fit criteria when applied to a dual-input single-compartment perfusion model. We subsequently estimated hepatic perfusion parameters using DCE-MRI data from 12 healthy volunteers and 9 cirrhotic patients with a history of hepatocellular carcinoma (HCC); and examined the utility of these estimates in differentiating between healthy liver, cirrhotic liver, and HCC. RESULTS: Quality-of-fit criteria in all groups were improved using a Weibull TRF (2 degrees-of-freedom) versus an exponential TRF (1 degree-of-freedom), indicating nearer concordance of source DCE-MRI data with the Weibull model. Using the Weibull TRF, arterial fraction was greater in cirrhotic versus normal liver (39 ± 23% versus 15 ± 14%, P = 0.07). Mean transit time (20.6 ± 4.1 s versus 9.8 ± 3.5 s, P = 0.01) and arterial fraction (39 ± 23% versus 73 ± 14%, P = 0.04) were both significantly different between cirrhotic liver and HCC, while differences in total perfusion approached significance. CONCLUSION: This work demonstrates the feasibility of estimating hepatic perfusion parameters using interrupted data acquired during sequential breathholds.

A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

BACKGROUND: Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. METHODS: Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. RESULTS: 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. CONCLUSIONS: The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

Dynamic tumor growth patterns in a novel murine model of colorectal cancer.

Colorectal cancer often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which polyps progress and which remain benign is difficult. We developed a novel long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived Apc(Min/+) mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of ß-catenin was higher in adenomas that became intratumoral carcinomas than those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features is needed to determine which features can be used to risk-stratify polyps for progression to colorectal cancer and potentially guide prevention strategies.

High-spatial and high-temporal resolution dynamic contrast-enhanced perfusion imaging of the liver with time-resolved three-dimensional radial MRI.

PURPOSE: Detection, characterization, and monitoring the treatment of hepatocellular carcinomas (HCC) in patients with cirrhosis is challenging because of their variable and rapid arterial enhancement. Multiphase dynamic contrast-enhanced MRI is used clinically for HCC assessment; however, the method suffers from limited temporal resolution and difficulty in coordinating imaging and breath-hold timing within a narrow temporal window of interest. In this article, a volumetric, high-spatial resolution, and high-temporal resolution dynamic contrast-enhanced liver imaging method for improved detection and characterization of HCC is demonstrated. METHODS: A time-resolved three-dimensional radial acquisition with iterative sensitivity-encoding reconstruction images the entire abdomen and thorax with high spatial and temporal resolution, using real-time three-dimensional fluoroscopy to match the breath hold to contrast arrival. The sequence was tested on 17 subjects, including eight patients with HCC or other hypervascular focal lesions. RESULTS: This technique was successful in acquiring volumetric imaging of the entire liver with 2.1-mm isotropic spatial and true 4-s temporal resolution. CONCLUSION: This technique may be suitable for detecting, characterizing, and monitoring the treatment of HCC. It also holds significant potential for perfusion modeling, which may provide a noninvasive means to rapidly determine the efficacy of chemotherapeutic agents in these tumors over the entire liver volume.

A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer.

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.