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Purpose: BT5528 is a Bicycle Toxin Conjugate, a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting EphA2 tumor antigen, linked to a cytotoxin (monomethyl auristatin E [MMAE]). EphA2 is overexpressed in many solid tumors and contributes to oncogenesis, tumor-associated angiogenesis, and metastasis., Materials and Methods: The primary objectives were to investigate the safety and tolerability of BT5528 and to define the maximum-tolerated dose, if observed, and recommended phase II dose (RP2D)/expansion dose. Dose escalation exploring once every week or once every 2 weeks administration of BT5528 employed a 3 + 3 dose-escalation design for the first two dose levels, followed by a Bayesian logistic regression model. Secondary and exploratory end points included preliminary efficacy and the pharmacokinetics of BT5528 and MMAE., Results: Forty-five patients were enrolled and received BT5528 doses between 2.2 mg/m 2 once every week to 10.0 mg/m 2 once every 2 weeks within the dose-escalation stage of the study. The most frequent BT5528-related adverse events (AEs) were nausea (44.4%), diarrhea (35.6%), and fatigue (33.3%), and the most common grade ≥3 BT5528-related AE was neutropenia/neutrophil count decrease (22.2%). Dose level 6.5 mg/m 2 once every 2 weeks was selected as a RP2D. At 6.5 mg/m 2 once every 2 weeks, the overall response rate was 6.7%, and the disease control rate was 20.0%. BT5528 and MMAE pharmacokinetics are generally dose proportional. BT5528 has a short half-life (0.4-0.7 hours), and the half-life of MMAE is longer (35-47 hours)., Conclusion: BT5528 was well tolerated and demonstrated favorable and preliminary antitumor activity. We believe these data provide preliminary validation of a Bicycle Toxin Conjugate approach to EphA2 tumor antigen. The study is ongoing and is evaluating BT5528 as monotherapy at a RP2D of 6.5 mg/m 2 once every 2 weeks.

Purpose: Patients with advanced malignancies referred for early clinical trials have a short life expectancy. We designed this survey to ascertain the status of advance care planning in this population., Patients and Methods: Patients who were seen in a phase I clinic were asked to anonymously complete an investigator-designed survey., Results: Of 435 individuals approached, 215 (49%) returned completed or partially completed surveys, whereas many others stated that they wanted to avoid the topic, because they had come to the phase I clinic for cancer therapy. Most patients (n = 149; 69%) were still hopeful about their future. Approximately 42% of patients (n = 90) reported having a living will, 46% had a medical power of attorney (n = 98), and 19% had a do-not-resuscitate (DNR) order (n = 40). Approximately 20% of participants (n = 43) had not discussed advance care planning. Fifty-nine percent of patients wanted to discuss advance care planning with their physician. Having a DNR order in place was significantly more common in individuals who had a living will and/or a medical power of attorney., Conclusion: Although most patients referred to a phase I clinic remained optimistic, many had discussed a living will, medical power of attorney, and/or DNR order with their physician, family, and/or attorney. However, a significant minority had not addressed this issue with anyone, and many refused to take a survey on the topic. More than half of the patients wanted to discuss these matters with their physician. These observations suggest that extra effort to address advance care planning is needed for these patients.

Purpose: This study assessed outcomes of individuals with advanced cancer who required admission to an intensive care unit (ICU) after referral for an early clinical trial because they did not respond to conventional therapy., Patients and Methods: Outcome analyses were conducted for 212 consecutive patients admitted to The University of Texas MD Anderson Cancer Center ICU after being seen in the phase I clinic starting on May 1, 2007. All data were obtained by a review of electronic medical records of patients., Results: The median survival of 212 patients with advanced cancer referred to phase I care after the initial ICU admission was 3.2 weeks (95% CI, 2.5 to 4.9 weeks). Patients who underwent cardiopulmonary resuscitation (CPR) succumbed within a median survival of 1 day (75% and 25% estimated survival of 1 and 3 days, respectively). Patients admitted for a postsurgical intervention did better than patients admitted for a nonsurgical intervention (median survival, 21.5 versus 2.1 weeks; P < .0001). The multivariate analysis revealed that a nonsurgical intervention, hypoalbuminemia, and higher Acute Physiology and Chronic Health Evaluation II scores were associated with poor overall survival., Conclusion: The outcome of patients in a phase I clinic after initial ICU admission was poor, particularly when admission was for a nonsurgical intervention and/or when CPR was needed.