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Background: Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor., Methods: In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity., Results: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03)., Conclusions: Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

Purpose: Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the antiangiogenesis antibody bevacizumab may augment antitumor activity as well as resensitize cells to anthracyclines., Experimental Design: We initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (N = 136) were enrolled according to a modified 3 + 3 design plus dose expansion in responsive tumor types., Results: The most common cancers were breast (n = 29), epithelial ovarian (n = 23), and colorectal cancer (n = 17). The median number of prior chemotherapy regimens was four (range: 0-16). Grade 3 or higher adverse events (> 5%) included pancytopenia, mucositis, hand-foot syndrome, hypertension, and fistula. This regimen led to a 21% (n = 28) stable disease (SD) ≥ 6 months and 21% (n = 29) rate of partial or complete remission [PR/CR; (total SD ≥ 6 months/PR/CR = 42% (n = 57)]. PR/CR was most common in parotid gland adenocarcinoma (4/6, 67%), metaplastic breast cancer (5/12, 42%), endometrial endometrioid carcinoma (6/15, 40%), and in patients with a PIK3CA mutation and/or a PTEN mutation/loss (11/28, 39%). The maximum tolerated dose was liposomal doxorubicin 30 mg/m(2) and bevacizumab 15 mg/kg every three weeks with temsirolimus 25 mg weekly., Conclusions: Patients tolerated bevacizumab and temsirolimus together with liposomal doxorubicin. Further evaluation, especially in patients with parotid, metaplastic breast, and endometrial endometrioid cancer, and in patients with PIK3CA and/or PTEN aberrations is warranted., (©2012 AACR)

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: To determine whether the Royal Marsden Hospital (RMH; London, UK) prognostic score for phase I patients can be validated in a large group of individuals seen in a different center and whether other prognostic variables are also relevant, we present an analysis of 1,181 patients treated in the MD Anderson Cancer Center (MDACC; Houston, TX) phase I clinic., Experimental Design: Medical records of 1,181 consecutive patients who were treated on at least one trial in the phase I clinic were reviewed., Results: The median age was 58 years and 50% were women. The median number of prior therapies was four and median survival 10 months [95% confidence interval (CI), 9.1-10.9 months]. Independent factors that predicted shorter survival in a multivariate Cox model and could be internally validated included RMH score of >1 (P < 0.0001; albumin <3.5 g/dL; lactate dehydrogenase >upper limit of normal, and >two sites of metastases), gastrointestinal tumor type (P < 0.0001), and Eastern Cooperative Oncology Group performance status ≥ 1 (P = 0.0004). The median survival was 24.0, 15.2, 8.4, 6.2, and 4.1 months for patients with 0, 1, 2, 3, and 4 or 5 of the above risk factors, respectively., Conclusion: The RMH score was validated in a large group of patients at MDACC. Internal validation of the independent prognostic factors for survival led to the development of the MDACC prognostic score, a modification of the RMH score that strengthens it., (©2012 AACR.)

Purpose: An intact immune system likely contributes to the outcome of treatment and may be important for clearance of drug-resistant tumor cells and for prevention of recurrence. Although pharmacologic inhibition of BRAF(V600E) in melanoma patients, which is linked to immune suppression, results in an initial response rate, these responses are typically of limited duration. Combining immunotherapeutic drugs with kinase-targeted agents is an attractive strategy to increase clinical efficacy. Evidence suggesting that mitogen-activated protein kinase pathway activation in tumor cells contributes to immune suppression suggests that the two approaches may be synergistic, provided that BRAF(V600E) inhibitors are nontoxic to immune cells., Methods: To assess effects of mutant BRAF inhibition on systemic immunity, we studied 13 patients with tumors carrying a BRAF mutation who underwent treatment with GSK2118436, a V600 mutant BRAF-specific inhibitor. We carried out peripheral blood immunomonitoring before and following one or two 28-day cycles of treatment., Results: GSK2118436 treatment had no detectable impact on most immune parameters tested, including serum cytokine levels, peripheral blood cell counts, leukocyte subset frequencies, and memory CD4(+) and CD8(+) T-cell recall responses. A slight increase in serum TNF-α over the course of treatment was observed. In addition, three of the four human leukocyte antigen-A2-positive patients experienced a modest increase in circulating tumor antigen-specific CD8(+) T cells following BRAF(V600) inhibitor therapy., Conclusions: GSK2118436 treatment results in no detectable negative impact on existing systemic immunity or the de novo generation of tumor-specific T cells. These findings suggest that future trials combining specific BRAF(V600E) inhibition with immunotherapy should not impair immune response., (©2012 AACR.)

Background: A key end point of early cancer clinical trials is the assessment of toxicities and their possible association with new experimental drugs. Therefore, the concurrent use of complementary and alternative medicine (CAM) in patients with advanced malignancies seen in a dedicated phase 1 clinic was evaluated., Methods: An investigator-designed survey was anonymously completed by patients seen in the phase 1 clinic. Pharmacologic CAM included any oral, topical, or intravenous agent, including vitamins, dietary supplements, and herbal products. Nonpharmacologic CAM included prayer, meditation, hypnosis, massage, and acupuncture., Results: Of the 404 patients approached about completing the CAM survey, 394 (98%) agreed to respond, and 309 (78%) surveys were returned. Of those 309 patients, 162 (52%) used 1 or more CAM. Of the 162 CAM users, 77% utilized pharmacologic CAM, 71% used nonpharmacologic CAM, and 48% used both modalities. The most frequent CAM used were vitamins (70%), prayer (57%), and herbal products (26%). CAM utilization was not significantly associated with race, age, level of education, employment, or income level but was used more by women than men (P < .01). There was no statistically significant association between the use of CAM and quality of life as perceived by patients. Of the CAM users, 43% of patients had been using CAM for >5 years. Only 5% reported having side effects from using CAM, whereas 23% did not fully disclose their CAM use to their physicians., Conclusions: CAM usage is common in patients with advanced malignancies seen in a phase 1 clinic., (Copyright © 2011 American Cancer Society.)

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.

Background: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic., Methods: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome., Results: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients., Conclusions: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation.

Background: Research biopsies are crucial for exploring the impact of novel agents on putative targets. The current study assesses the safety and success rate associated with performing such biopsies., Methods: We reviewed the medical records of 155 consecutive patients who had one or more research biopsies as part of a phase I trial from September 2004 to October 2009., Results: Of 281 research biopsies performed, 118 were paired before and after treatment biopsies (total = 236 biopsies). The most common sites of biopsy were superficial lymph node (19.9%), followed by liver (16.4%), and then soft tissue (15.7%). Ultrasound-guided biopsies were the most frequent type (53.7%). Among 142 patients who consented for mandatory biopsy, 86.6% had the biopsy performed, compared with 4.4% of 911 patients offered a biopsy on an optional basis (p < .0001). Biopsy was obtained most frequently on industry-sponsored trials; lack of funding on nonindustry trials was the most common reason that biopsies were not obtained. Of 281 single biopsies, only 4 (1.4%) had complications: pneumothorax requiring chest tube placement (n = 2), infection requiring admission (n = 1), and arrhythmia with hypotension (n = 1). All but one biopsy was successful in obtaining tissue. No deaths were attributable to biopsy., Conclusions: Our experience demonstrates that research biopsies in early phase clinical trials are safe (1.4% risk of serious complications), and a higher percentage of patients underwent mandatory biopsies (86.6%) compared with that of the patients with optional biopsies (4.4%).

Objective: Disseminated gynecologic cancers are usually fatal due to chemoresistance. Recently, rationally developed, targeted agents are entering the early clinical trials setting. We assessed patients with metastatic gynecologic cancers in a dedicated phase I clinical trials clinic in order to determine their outcome., Methods: We reviewed records for 89 consecutive patients with gynecologic cancers referred to the Phase I Clinical Trials Program, 85 (96%) of whom were treated on > or = 1 trial., Results: Cancer diagnoses were ovarian (N=43), uterine (N=19), cervix (N=17), and other. Median age was 58 years; median number of prior cytotoxic regimens, five. Two patients (2.4%) achieved a CR; four (4.7%), a PR; and eight (9.4%), SD > or = 6 months (total CR/PR/SD > or = 6 months=16.5%) for the first phase I trial. Twenty-five patients enrolled on a second trial and three, on a third (N=113 trials total). Combining response data for all trials, of the 85 patients, two achieved CR (2.4%), nine achieved PR (10.6%), and 12 (14%) had SD for > or = 6 months. One-year survival was 30% (95% CI, 21% to 44%). There was no difference in time-to-treatment failure (TTF) on phase I versus the patient's last standard treatment., Conclusion: Twenty-three of 85 patients (27%) with advanced, heavily pretreated, gynecologic cancers achieved CR/PR/SD > or = 6 months on a phase I trial, and overall TTF on phase I was comparable to that of last conventional therapy, suggesting that participation in a phase I trial is a reasonable option for these patients., (Copyright 2010 Elsevier Inc. All rights reserved.)

Previous studies have demonstrated that peripheral denervation of the skin is reflected in the CNS as a reorganization of somatotopic representations. In cases in which peripheral nerve regeneration occurs there is a gradual reactivation of cortex by novel receptive fields that is reversed as regenerated nerves reestablish connections with the original skin surface. Functional recovery appears to depend on the pattern in which somatotopic organization in the cortex is reestablished. The relationship between functional recovery and cortical topography is not precise, however, since the descriptions of postinjury representations in the cortex have been largely descriptive and not quantitative. The purpose of this study was to derive an index to quantify deviations from normal somatotopic organization in the somatosensory cortex. Multiunit recordings of cutaneous representations in the somatosensory cortex (S1) of the rat were defined using Semmes-Weinstein monofilaments to stimulate the skin over the distal hindlimb of the rat 2 and 4 months after a sciatic nerve crush. To derive a sensitive index of topography, the sciatic nerve crush was selected as the injury model since nerve regeneration following crush injuries has been reported to reinstate preinjury cortical topography. Group comparisons were made with an intact control group. The results show that there were subtle, but significant differences in topography between rats with a regenerated sciatic nerve and normal rats. In addition, average thresholds for evoking cortical responses were higher than normal (but within normal range) 2 and 4 months after the crush. These results demonstrate that the index of topography derived for this study can reveal deviations that may not be distinguishable from normal topography when based on qualitative descriptions.

Tuberculosis screening and preventive therapy among the homeless has been a challenge because of the lack of coordinated follow-up. Homeless persons at a homeless shelter in inner city New Orleans were screened for tuberculosis infection and referred for follow-up evaluation and preventive therapy. Fifty-two percent of the 104 persons screened completed the initial evaluation. Twenty-two percent of these patients had latent tuberculosis infection. Forty-two percent of infected patients completed the referral and follow-up process. Patients during the second 3 months of the program were twice as likely to complete the initial evaluation, the referral, and the follow-up process as were patients during the first 3 months due to enhanced awareness and increased educational intervention. A competent referral system for homeless persons may be achieved by implementing a single-clinic, on-site tuberculosis screening and follow-up system with the active participation and coordination of state agencies, the medical community, and organizations which operate homeless facilities.

While a large number of studies have examined receptive field alterations in the cerebral cortex after peripheral nerve injury, descriptions of neuronal sensitivity have been largely qualitative. In the present study, quantitative changes in minimal force thresholds evoking cortical responses were examined in somatosensory cortex (S1) of the rat after peripheral nerve injury. Cutaneous receptive fields were defined by conventional multi-unit recording techniques. Thresholds for evoking cortical responses were defined using Semmes-Weinstein monofilaments to stimulate the skin over the distal and proximal hindlimb, and over the adjacent tail, lower back and abdomen. Then minimal force thresholds and representational areas were compared. Receptive fields were recorded before and within 3 h after a sciatic nerve crush injury. Group comparisons were also made with intact (control) rats in which more detailed maps were derived. The results show that the minimal force thresholds for activation of newly emerged responses were not statistically different from thresholds for evoking pre-crush responses. These quantitative data provide strong support for the notion that functional boundaries in S1 between saphenous and sciatic representations and between distal and proximal hindlimb representations are actively maintained by selective inhibition of subsets of overlapping inputs. Formerly inhibited responses can be activated by low-threshold cutaneous stimulation immediately following peripheral nerve injury.