Efficacy and safety of abemaciclib alone and with PI3K/mTOR inhibitor LY3023414 or galunisertib versus chemotherapy in previously treated metastatic pancreatic adenocarcinoma: A randomized controlled trial.

BACKGROUND: Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFß inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. METHODS: This Phase 2 open-label study enrolled patients with metastatic PDAC who progressed after 1-2 prior therapies. Patients were enrolled in a safety lead-in (abemaciclib plus galunisertib) followed by a 2-stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib-containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression-free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. RESULTS: One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4-1.8), 1.8 months (95% CI: 1.3-1.9), and 3.3 months (95% CI: 1.1-5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. CONCLUSION: In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.

nextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer.

BACKGROUND: Abemaciclib is a selective cyclin-dependent kinase 4 and 6 inhibitor administered continuously for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Abemaciclib is associated with dose-dependent early-onset diarrhea. nextMONARCH evaluated abemaciclib monotherapy (with or without prophylactic loperamide) and combined with tamoxifen for endocrine refractory metastatic breast cancer (MBC) after chemotherapy. PATIENTS AND METHODS: nextMONARCH is an open-label, controlled, randomized, phase II study of women with endocrine-refractory HR+, HER2- MBC previously treated with chemotherapy. Patients received abemaciclib 150 mg plus tamoxifen 20 mg (A+T), abemaciclib 150 mg every 12 hours (A-150), or abemaciclib 200 mg plus prophylactic loperamide (A-200). The primary objective was progression-free survival (PFS). PFS analyses tested superiority of A+T to A-200 and informal noninferiority of A-150 to A-200. The secondary objectives included the objective response rate (ORR), safety, and pharmacokinetics. RESULTS: The median PFS was 9.1 months for A+T versus 7.4 months for A-200 (hazard ratio, 0.815; 95% confidence interval, 0.556-1.193; P = .293). The A-200 PFS was comparable to that with A-150 at 6.5 months (hazard ratio, 1.045; 95% confidence interval, 0.711-1.535; P = .811). The ORR was 34.6%, 24.1%, and 32.5% for A+T, A-150, and A-200, respectively. No new safety signals were identified. The incidence and severity of diarrhea (62.3%; grade 3, 7.8%) with A-200 was similar to that with A-150 (67.1%; grade 3, 3.8%). The pharmacokinetics were comparable to previous observations. CONCLUSIONS: The addition of tamoxifen to abemaciclib did not significantly improve PFS or ORR compared with abemaciclib monotherapy but confirmed the single-agent activity of abemaciclib in heavily pretreated HR+, HER2- MBC. Dose reductions and antidiarrheal medication generally managed diarrhea while maintaining efficacy.

Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non-Small Cell Lung Cancer: A Phase Ib Study.

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non-small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC.Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules.Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib-pemetrexed, 25% for abemaciclib-gemcitabine, and 54% for abemaciclib-ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively.Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. Clin Cancer Res; 24(22); 5543-51. ©2018 AACR.

Phase 1 pharmacogenetic and pharmacodynamic study of sorafenib with concurrent radiation therapy and gemcitabine in locally advanced unresectable pancreatic cancer.

PURPOSE: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients received gemcitabine 1000 mg/m(2) intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m(2) intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). RESULTS: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K(trans) in responding patients. CONCLUSIONS: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival.

Contribution of environment and genetics to pancreatic cancer susceptibility.

Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00 ± 0.05) versus both healthy unrelated and related controls (0.70 ± 0.06, p<0.001 and 0.82 ± 0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA -308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.

Phase II trial of erlotinib and docetaxel in advanced and refractory hepatocellular and biliary cancers: Hoosier Oncology Group GI06-101.

BACKGROUND: Patients with advanced hepatocellular (HCC) and biliary tract carcinomas (BTC) have poor prognosis. While the EGFR pathway is overactive in HCC and BTC, single agent anti-EGFR therapies confer modest activity. Preclinical data showed synergistic antiproliferative and proapoptotic effects between anti-EGFR therapies and taxanes. We conducted a phase I study of erlotinib and docetaxel in solid tumors, and noted good tolerability and sustained complete (5 years +) and partial responses in patients with HCC and BTC. This trial evaluated the efficacy of erlotinib with docetaxel in refractory hepatobiliary cancers. METHODS: Eligible patients were allowed to have two prior systemic therapies. Docetaxel 30 mg/m2 i.v. was administered on days 1, 8, 15, and erlotinib 150 mg was dosed orally on days 2-7, 9-14, 16-28 of each 28-day cycle. The primary endpoint was 16 weeks progression-free survival (PFS), and secondary endpoints included response, stable disease, and overall survival. Tumor samples were analyzed for KRAS gene mutations and E-cadherin expression by immunohistochemistry (IHC). Patients with BTC and HCC were accrued and assessed in separate strata for the efficacy endpoints, but for the two-stage initial design of the study, combined PFS was considered. A Simon optimal two-stage design tested the hypothesis that the 16-week PFS is ≤ 15% (clinically inactive) versus the alternative of ≥ 30% (warranting further study). RESULTS: Twenty-five patients, 14 with HCC and 11 with BTC, were enrolled. Common toxicities were rash (76%), diarrhea (56%), and fatigue (52%), mostly grade 1 or 2. No objective responses were seen. Seven BTC (64%) and 6 HCC patients (46%) had stable disease as best response, with a median duration of 16.1 weeks (95% CI 3.7-56.3) for BTC, and 17.6 weeks (95% CI 8.1-49.8) for HCC. The 16-week PFS was 64% for BTC (95% CI 29.7-84.5), and 38% for HCC (95% CI 14.1-62.8). Median overall survival was 5.7 and 6.7 months for BTC and HCC patients, respectively. BTC patients with grade ≥ 2 rash had higher median PFS (6.2 vs 2.2 months) and OS (14.2 vs. 4.2 months). HCC patients with negative/low E-cadherin expression had higher median PFS (6.7 vs. 2.1 months) and OS (14.5 vs. 4 months). CONCLUSION: Erlotinib with docetaxel met the 16-week PFS ≥ 30% endpoint, but overall survival was comparable to that seen with single-agent erlotinib. With the limitation of small numbers of patients, grade ≥ 2 rash (in BTC), and negative/low E-cadherin expression (HCC) were associated with higher PFS and OS. Discussion Refractory biliary tract and hepatocellular cancers are difficult to treat, and no chemotherapy or biologically targeted therapies have impacted survival. Based on preclinical synergism and prior phase I data, we conducted a multi-institutional study sequentially combining the EGFR-targeted agent erlotinib with docetaxel. Results from this study show that the primary endpoint, 16-week PFS of ≥ 30%, was met for the combined group of BTC and HCC patients (as originally planned in the study design), as well as in each disease category: 63.6% for BTC and 38.5% for HCC patients. Nevertheless, no patients attained an objective response and the median survival of 5.7 months for BTC, and 6.7 months for HCC patients (while heavily pretreated), is comparable to that seen with single-agent EGFR-targeted therapies. Safety analysis shows that this regimen was generally well tolerated, and most adverse events were grade 1 or 2. Few patients had reversible grade 3 transaminase elevation (8%), and severe anorexia, fatigue, and rash were uncommon. As expected, patients with grade ≥ 2 rash experienced higher PFS and OS, but this was noted only among the BTC group, likely because too few HCC patients had grade ≥ 2 rash. KRAS is an important predictive marker for anti-EGFR therapies for lung and colorectal cancers, but for HCC or the heterogeneous group of BTC (with 10-50% KRAS mutations) no significant correlations have been established. We were not able to identify a correlation between KRAS and benefit from erlotinib-based therapy, as all but one HCC patient had KRAS wild type gene status. Preclinical data in multiple tumor types showed that E-cadherin, a signature marker for an "epithelial" tumor phenotype when overexpressed, predicts EGFR pathway activation and determines sensitivity to EGFR-targeted agents. E-cadherin is often seen as a poor prognostic marker when downregulated, as noted during cancer progression. Not all studies demonstrate beneficial effects from E-cadherin overexpression, possibly due to histological expression variability or tumor type specificity for this biomarker. Six BTC and 8 HCC patients had evaluable tumor samples for E-cadherin analysis. While the numbers were small and conclusions should be viewed with caution, negative/low E-cadherin expression was associated with improved PFS and OS for hepatobiliary cancers (most significant in HCC) in this refractory patient population where we expected lower expression levels. In conclusion, the combination of erlotinib with docetaxel provided a 16-week PFS of ≥ 30% but showed no appreciable differences in overall survival from historical data with single-agent erlotinib. While EGFR represents an important target in this group of malignancies, it is clear that hepatobiliary cancers are heterogeneous, thus a meaningful improvement in survival most likely will require careful treatment selection based on patient tumor's molecular and genetic profiling.

Social support mediates the relations between role strains and marital satisfaction in husbands of patients with fibromyalgia syndrome.

Husbands of patients with fibromyalgia syndrome (HFMS) report poorer physical and mental health than husbands of women without illness, as well as role strains because of their wives' condition. There are no published reports regarding the impact of fibromyalgia on their marital relationship. In the present study, we used Lazarus and Folkman's (1984) model of stress and coping as a framework to examine marital satisfaction among HFMS. We hypothesized that role strains would be related to marital satisfaction, mediated or moderated by social support and problem and emotion focused coping. HFMS (n=135) and husbands of healthy women (n=153) completed the Locke Wallace Marital Adjustment Test, the Interpersonal Support Evaluation List, and the Ways of Coping Questionnaire. Only HFMS completed the Psychological Adjustment to Illness Scale-Spouse Version. HFMS reported lower marital satisfaction than comparison husbands. Among HFMS, sexual and domestic roles strains and social support were related to marital satisfaction. Social support alone mediated the relationship between role strain and marital satisfaction, and no variable moderated the relationship. These findings support prior research that shows that these husbands are significantly impacted by their wives' condition, and suggest the need to focus more attention on this population, possibly targeting social support for interventions.