Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal,Non-Small Cell Lung,and Pancreatic Cancer

Lessons Learned

• Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy.
• Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d.
• Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined.

BackgroundAntitumor effects of MEK inhibitors are limited in KRAS‐mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3‐kinase–AKT pathway. Therefore, this phase I trial was initiated with the pan‐HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild‐type tumors.MethodsAfatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy.ResultsTwenty‐six patients were enrolled with colorectal cancer (n = 19), non‐small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose‐limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response.ConclusionAfatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.     

Phase I study of lapatinib plus trametinib in patients with KRAS -mutant colorectal,non-small cell lung,and pancreatic cancer

KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.     

Gray and white matter density changes in monozygotic and same-sex dizygotic twins discordant for schizophrenia using voxel-based morphometry

Global gray matter brain tissue volume decreases in schizophrenia have been associated to disease-related (possibly nongenetic) factors. Global white matter brain tissue volume decreases were related to genetic risk factors for the disease. However, which focal gray and white matter brain regions best reflect the genetic and environmental risk factors in the brains of patients with schizophrenia remains unresolved. 1.5-T MRI brain scans of 11 monozygotic and 11 same-sex dizygotic twin-pairs discordant for schizophrenia were compared to 11 monozygotic and 11 same-sex dizygotic healthy control twin-pairs using voxel-based morphometry. Linear regression analysis was done in each voxel for the average and difference in gray and white matter density separately, in each twin-pair, with group (discordant, healthy) and zygosity (monozygotic, dizygotic) as between subject variables, and age, sex and handedness as covariates. The t-maps (critical threshold value mid R:tmid R: > 6.0, P < 0.05) revealed a focal decrease in gray matter density accompanied by a focal increase in white matter density in the left medial orbitofrontal gyrus and a focal decrease in white matter density in the left sensory motor gyrus in twin-pairs discordant for schizophrenia as compared to healthy twin-pairs. Focal changes in left medial (orbito)frontal and left sensory motor gyri may reflect the increased genetic risk to develop schizophrenia. Focal changes in the left anterior hemisphere may therefore be particularly relevant as endophenotype in genetic studies of schizophrenia.     

Brain network analysis reveals affected connectome structure in bipolar I disorder

The notion that healthy brain function emerges from coordinated neural activity constrained by the brain's network of anatomical connections—i.e., the connectome—suggests that alterations in the connectome's wiring pattern may underlie brain disorders. Corroborating this hypothesis, studies in schizophrenia are indicative of altered connectome architecture including reduced communication efficiency, disruptions of central brain hubs, and affected “rich club” organization. Whether similar deficits are present in bipolar disorder is currently unknown. This study examines structural connectome topology in 216 bipolar I disorder patients as compared to 144 healthy controls, focusing in particular on central regions (i.e., brain hubs) and connections (i.e., rich club connections, interhemispheric connections) of the brain's network. We find that bipolar I disorder patients exhibit reduced global efficiency (?4.4%, P =0.002) and that this deficit relates (r = 0.56, P < 0.001) to reduced connectivity strength of interhemispheric connections (?13.0%, P = 0.001). Bipolar disorder patients were found not to show predominant alterations in the strength of brain hub connections in general, or of connections spanning brain hubs (i.e., “rich club” connections) in particular (all P > 0.1). These findings highlight a role for aberrant brain network architecture in bipolar I disorder with reduced global efficiency in association with disruptions in interhemispheric connectivity, while the central “rich club” system appears not to be particularly affected. Hum Brain Mapp 37:122–134, 2016. © 2015 Wiley Periodicals, Inc.     

Regulation of CXCR4 conformation by the small GTPase Rac1: implications for HIV infection

The chemokine receptor CXCR4 is a critical regulator of cell migration and serves as a coreceptor for HIV-1. The chemokine stromal cell derived factor-1, also known as CXCL12, binds to CXCR4 and exerts its biologic functions partly through the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). We show in different cell types, including CD34(+) hematopoietic stem and progenitor cells, that inhibition of Rac1 causes a reversible conformational change in CXCR4, but not in the related receptors CXCR7 or CCR5. Biochemical experiments showed that Rac1 associates with CXCR4. The conformational change of CXCR4 on Rac1 inhibition blocked receptor internalization and impaired CXCL12-induced Gα(i) protein activation. Importantly, we found that the conformation adopted by CXCR4 after Rac1 inhibition prevents HIV-1 infection of both the U87-CD4-CXCR4 cell line and of primary peripheral blood mononuclear cells. In conclusion, our data show that Rac1 activity is required to maintain CXCR4 in the responsive conformation that allows receptor signaling and facilitates HIV-1 infection; this implies that Rac1 positively regulates CXCR4 function and identifies the Rac1-CXCR4 axis as a new target for preventing HIV-1 infection.     

Development of a telemedical monitoring concept for the care of malnourished geriatric home-dwelling patients: a pilot study

Elderly patients are at high risk of malnutrition and sarcopenia, promoting further morbidity which in turn decreases quality of life and increases the claiming of medical services and associated costs. Early and sustained administration of oral nutritional supplements has been shown to improve the nutritional status with robust clinical benefit. Many patients however, poorly adhere to prescribed supplements, so consistent monitoring is needed. Clinical monitoring usually ends with the discharge rendering the continuation of nutritional supplement therapy in the patient's home problematic. We developed a telemedicine based health care concept for intensive home monitoring. In a first randomized controlled prospective study we analyzed the feasibility of this innovative approach. The intervention group received oral nutritional supplements and telemedical monitoring with daily assessment of body weight, number of taken oral energy supplements and state of health. The control group received usual care. 13 patients were included in each group, eight patients of the intervention group left the study prematurely, five patients were closely monitored and used the devices for a mean 67 ± 63.5 days. Follow up data of body weight and BMI showed no relevant differences between both groups. The results and experiences gained in this pilot study demonstrate that telemedical systems provide encouraging new options to enable an intensive monitoring of malnourished patients. A continuous intensive therapy monitoring of this patient group however, is a particular challenge. Albeit possibilities, limitations and useful parameters were identified, which will be used to improve the conception in an ongoing prospective randomized trial.     

Mixed anxiety depression should not be included in DSM-5

Subthreshold anxiety and subthreshold depressive symptoms often co-occur in the general population and in primary care. Based on their associated significant distress and impairment, a psychiatric classification seems justified. To enable classification, mixed anxiety depression (MAD) has been proposed as a new diagnostic category in DSM-5. In this report, we discuss arguments against the classification of MAD. More research is needed before reifying a new category we know so little about. Moreover, we argue that in patients with MAD symptoms and a history of an anxiety or depressive disorder, symptoms should be labeled as part of the course trajectories of these disorders, rather than calling it a different diagnostic entity. In patients with incident co-occurring subthreshold anxiety and subthreshold depression, subthreshold categories of both anxiety and depression could be classified to maintain a consistent classification system at both threshold and subthreshold levels.