HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: Preliminary phase 1 results in patients with solid tumors3018 Background: HKI-272 is a potent, low molecular weight, orally active, irreversible pan erbB receptor tyrosine kinase inhibitor. It inhibits the growth of tumor cells that express erbB-1 (epidermal growth factor receptor, EGFR) and erbB-2 (HER-2) in culture and xenografts. HKI-272 also inhibits the growth of cultured cells that contain sensitizing and resistance-associated EGFR mutations (Kwak et al, Proc Natl Acad Sci USA 102:7665–70, 2005). We are conducting a phase 1 study in patients (pts) with advanced-stage tumors that express EGFR or HER-2 to assess HKI-272 for tolerability, safety, pharmacokinetics, and preliminary antitumor activity. Methods: Pts (3–6/cohort) received 40, 80, 120, 180, 240, 320, or 400 mg HKI-272 orally once on day 1 and then once daily beginning on day 8. Timed blood samples were collected on days 1 and 21 for pharmacokinetic analysis. Results: Enrollment of 73 pts is complete. Preliminary data for 51 pts as of 28 Nov 2005 are presented. Patients were a median 60 years and 26% men. The most frequently occurring tumor types at primary diagnosis were breast (23 pts), non-small cell lung (9), and colorectal, ovarian, and renal (3 pts each). Dose escalation ended when 2 pts who received 400 mg HKI-272/day had drug-related dose-limiting toxicity of grade 3 diarrhea. Thus, the maximum tolerated dose (MTD) was 320 mg HKI-272/day. HKI-272-related adverse events (AEs), any grade, that occurred in ≥10% of pts were diarrhea (84%), nausea (55%), asthenia (45%), anorexia (31%), vomiting (29%), chills (12%), and rash (10%). Grade 3 related AEs that occurred in >1 pt were diarrhea (11) and asthenia (4). HKI-272 C max and AUC increased in a dose-dependent manner. At steady state at the MTD, mean values were C max : 112±58 ng/mL, AUC: 1618±930 ng.h/mL, t 1/2 : 15±2.5 h. Day 1 and 21 AUC values were comparable. Tumor assessments (modified RECIST criteria) were made at baseline and at the end of alternate cycles (28 days/cycle). Two breast cancer pts had confirmed partial responses (PRs) and 2 had unconfirmed PRs. Conclusions: When HKI-272 was administered on a continuous, once-daily, oral treatment schedule, the MTD was 320 mg/day, with diarrhea as the most frequently occurring related AE. HKI-272 has antitumor activity in HER-2-positive breast cancer. [Table: see text]
The Correlative Strength of Objective Physical Assessment Against the ECOG Performance Status Assessment in Individuals Diagnosed With CancerBACKGROUND: Individuals with cancer experience loss of function and disability due to disease and cancer-related treatments. Physical fitness and frailty influence treatment plans and may predict cancer outcomes. Outcome measures currently used may not provide sufficiently comprehensive assessment of physical performance. OBJECTIVE: The objectives of this study are to: (1) describe the development of a functional measure, the Bellarmine Norton Assessment Tool (BNAT), for individuals with cancer; and (2) assess the relationship between the BNAT and the Eastern Cooperative Oncology Group (ECOG) Performance Status, a commonly used classification system by oncologists. DESIGN: This was a prospective cohort correlation study. METHODS: The BNAT encompasses 1 self-reported physical activity question and 4 objective tests: 2-Minute Step Test, 30-Second Sit to Stand, Timed Arm Curl, and Timed Up and Go. The BNAT score and its components were compared with ECOG Performance Status scores assigned by oncologists and analyzed for correlation and agreement. RESULTS: A total of 103 male and female individuals (ages 33-87 years) with various cancer diagnoses participated. The mean (SD) ECOG Performance Status score was 0.95 (0.87), range 0 to 3, and the mean BNAT score was 14.9 (4.3), range 5 to 24. Spearman agreement association of BNAT and ECOG Performance Status scores revealed a significant moderate negative relationship (r = -0.568). LIMITATIONS: The BNAT was compared with the ECOG Performance Status, a commonly used but subjective measure. Additionally, a common data set was used for both deriving and evaluating the BNAT performance scale. CONCLUSIONS: There was a moderate negative linear relationship of BNAT to ECOG Performance Status scores across all participants. Utilization of the BNAT may reflect overall physical performance and provide comprehensive and meaningful detail to influence therapeutic decisions.
Development of a stop light tool using the bellarmine norton assessment tool (BNAT) for physical therapy referral.e19067 Background: Individuals with cancer experience fatigue, pain and decline in function. The Bellarmine Norton Assessment Tool (BNAT) was developed to give an objective measure identifying a person’s overall functional ability through a variety of physical assessments focused on mobility and strength. The purpose of this study was to develop a referral tool to provide health care professionals an easy determinant for physical therapy referrals. The referral tool was designed as a Red, Yellow, Green light for easy interpretation and use. Methods: The BNAT is composed of 1 self-reported physical activity question and 4 objective tests: 2-Minute Step Test (2MST); 30-Second Sit-to-Stand; Timed Arm Curl; and Timed Up and Go. A previously collected data set of BNAT scores was utilized to develop the referral tool with the poorest performance corresponding to Red and the best corresponding to Green. Three variations of normative scaling examined optimal distribution for classification. The first model averaged normative data of 70-74 age group of healthy individuals. No participants in our study achieved 50% of population norms. Therefore, the Green light represented 35% of the normative values, the Yellow light ranged from 15-34% and the Red light identified < 15%. A second model used frequency histograms for each BNAT elements. Groupings were made based on the natural break of the data to depict the Red, Yellow or Green light. A third approach combined normative and frequency distribution for each element as compared to the respective BNAT scores. The outcome assigned BNAT score of 1 and 2 to Red light, 3 to Yellow light and 4 and 5 to Green light. Except for the 2MST, these models were similar for the cutoff between color categories. The third model best fit the study population with respect to the individual’s total BNAT score. Results: Of the 161 subjects, 47 subjects (29%) fell into the Red category, 81 (50%) into Yellow and 33 (21%) into Green. Using this scaling system for the total BNAT score, 13 score combinations result in Red light, 6 scores for Yellow light and 6 scores for Green light. Regardless of the model, most individuals were assigned a Yellow light. Conclusions: The literature is void of functional cut off scores and normative distributive data for the oncology population. We defined a referral tool with scaling based off normative scores and functional assessments that reflect the distribution of oncology patients. The third model may be used as a simple referral tool among multiple health care professionals aiding in a referral for physical therapy.