Clinicopathological characteristics and treatment outcomes of oesophageal cancer patients in Uganda.

Background: Oesophageal cancer is the seventh most common cancer and the sixth leading cause of cancer death worldwide, and its incidence varies globally. In Uganda, the incidence and trend are on the increase. However, there is a paucity of published data regarding this population's oesophageal cancer clinicopathologic characterisation and treatment outcomes. Objectives: To study the patients' clinicopathologic characteristics and treatment outcomes of oesophageal cancer over 10 years at the Uganda Cancer Institute. Methods: Patients' charts with histologically confirmed diagnoses of oesophageal cancer for 2009-2019 were identified. Case information, which included patient demographics, history of alcohol use or smoking, tumour location, histological type, tumour grade, clinical TNM (Tumour, Node, Metastasis) staging treatment exposure and treatment outcomes, was evaluated retrospectively. The median survival time was estimated with the Kaplan-Meier method and the median follow-up period was estimated using the reverse Kaplan-Meier. Results: 1,965 oesophageal cancer patients were identified; 1,380(70.23%) were males and 585(29.77 %) females, their mean age was 60.20 years (±12.66). Most males had a history of both alcohol consumption and smoking 640(46.38%). The lower third of the oesophagus was the most common anatomical location 771(39.24%). The majority had squamous cell carcinoma histological type 1,783(90.74%) followed by adenocarcinomas 182(9.26%) in the distal oesophagus. Poorly differentiated tumour grade 743(37.81%) was predominant. The majority of the patients were in stage IVB, 733(37.30%), and most patients were planned for the best supportive care, 731(37.20%). Radiation alone was offered to 621(31.60%) and feeding gastrostomy to 249(12.70%). Treatment outcomes: at the time of the current analysis, 58.68% had died, 1.48% were alive and 39.84% were lost to follow-up. The median follow-up period was 65 months (IQR:35.83-83.30) with a median survival time of 4.47 months (95% CI: 4.17-4.80). Conclusion: Treatment outcomes of Ugandan oesophageal cancer patients seeking care are poor as most patients present with advanced disease. There is a significant loss of follow-up after treatment initiation. Therefore, reduction in exposure to known modifiable risk factors, early detection and timely referral for treatment strategies are needed to improve outcomes of these patients in our population. Designing interventions to improve treatment adherence is necessary.

Operational Metrics for the ELAINE 2 Study Combining a Traditional Approach With a Just-in-TIME Model.

PURPOSE: There are numerous barriers to enrollment in oncology biomarker-driven studies. METHODS: The ELAINE 2 study (ClinicalTrials.gov identifier: NCT04432454) is an open-label phase 2 study of lasofoxifene combined with abemaciclib in patients with advanced or metastatic estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer with an ESR1 mutation. ELAINE 2 opened clinical sites by using a Traditional approach, which activated a site before patient identification, and the Tempus TIME Trial network, which opened a site only after identifying an eligible patient. This manuscript presents the operational metrics comparing the Traditional and TIME Trial site data. RESULTS: The study enrolled patients over 34 weeks and 16 sites (six Traditional and 10 TIME Trial) participated. Duration for full clinical trial agreement execution for Traditional sites and TIME Trial sites averaged 200.5 (range, 142-257) and 7.6 days (range, 2-14), respectively. Institutional review board approval time for Traditional sites and TIME Trial sites was 27.5 (range, 12-71) and 3.0 days (range, 1-12), respectively. Duration from study activation to first consent was 33.3 (range, 18-58) and 8.8 days (range, 1-35) for Traditional and TIME Trial sites, respectively. The first patient on study was at a TIME Trial site 115 days before a Traditional site and the first seven patients enrolled were at TIME Trial sites. Traditional sites consented 23 and enrolled 16 patients, while TIME Trial sites consented 16 and enrolled 13. The trial enrolled 29 patients in 8.5 months with the anticipated enrollment duration being 12-18 months. CONCLUSION: The TIME Trial network opened earlier and enrolled the first study patients. These results demonstrate that the Just-in-TIME model, along with a Traditional model, can improve enrollment in biomarker-driven studies.

Characteristics and outcomes of patients with multiple myeloma at the Uganda Cancer Institute.

PURPOSE: Data on multiple myeloma (MM) in sub-Sahara Africa is scarce. In Uganda, there is a progressively increasing incidence of MM over the years. METHODS: We performed a retrospective study on 217 patients with MM at the UCI using purposive sampling method. The objectives of the study were to determine the clinical characteristics, treatment outcomes, 5 year overall survival and predictors of survival of patients with MM at the UCI from 01 January 2008 to 31 December 2012. RESULTS: There were 119 (54.8%) males; the mean(SD) age of the study population at presentation was 59(12.8) years; 183(84.3%) patients presented with bone pain, and 135 (61.9%) had skeletal pathology; 186(85.3%) were HIV negative, and 152(70%) had Durie-Salmon stage III. The median overall survival was 2.5 years, (95% CI, 0.393-0.595); factors significantly associated with worse survival were Durie-Salmon stage III disease, HR=5.9, 95% CI (1.61 - 21.74; P=0.007) and LDH >225 U/L HR=3.3, 95% CI (0.57 - 5.92; P=0.029). CONCLUSION: Most patients with multiple myeloma at the UCI were diagnosed at a relatively young age, presented with late stage disease and bone pain, and had a shorter survival time. Factors associated with worse survival were Durie-Salmon stage III and LDH >225 U/L.

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial.

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.

BACKGROUND: Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. METHODS: We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964. FINDINGS: 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 µg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 µg/mL (CV% 33.0) and from 123 µg/mL (CV% 31.2) to 156 µg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). INTERPRETATION: This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. FUNDING: Eli Lilly and Company.

Prostate Cancer Burden at the Uganda Cancer Institute.

PURPOSE: In Uganda, the incidence of prostate cancer is increasing at a rate of 5.2% annually. Data describing presentation and outcomes for patients with prostate cancer are lacking. METHODS: A retrospective review of medical records for men with histologically confirmed prostate cancer at the Uganda Cancer Institute (UCI) from January 1 to December 17, 2012, was performed. RESULTS: Our sample included 182 men whose mean age was 69.5 years (standard deviation, 9.0 years). Patients who presented to the UCI had lower urinary tract symptoms (73%; n = 131), bone pain (18%; n = 32), increased prostate-specific antigen (PSA; 3%; n = 5), and other symptoms (6%; n = 11). Median baseline PSA was 91.3 ng/mL (interquartile range, 19.5-311.3 ng/mL), and 51.1% of the patients (n = 92) had a PSA value above 100 ng/mL. Gleason score was 9 or 10 in 66.7% of the patients (n = 120). Ninety percent (n = 136) had stage IV disease, and metastatic sites included bone (73%; n = 102), viscera (21%; n = 29), and lymph nodes (4%; n = 5). Spinal cord compression occurred in 30.9% (n = 55), and 5.6% (n = 10) experienced a fracture. A total of 14.9% (n = 27) underwent prostatectomy, and 17.7% (n = 32) received radiotherapy. Gonadotropin-releasing hormone agonist was given to 45.3% (n = 82), 29.2% (n = 53) received diethylstilbestrol, and 26% (n = 47) underwent orchiectomy. Chemotherapy was administered to 21.6% (n = 39), and 52.5% (n = 95) received bisphosphonates. During the 12 months of study, 23.8% of the men (n = 43) died, and 54.4% (n = 98) were lost to follow-up. CONCLUSION: UCI patients commonly present with high PSA, aggressive Gleason scores, and stage IV disease. The primary treatments are hormonal manipulation and chemotherapy. Almost 25% of patients succumb within a year of presentation, and a large number of patients are lost to follow-up.

National Trends of Local Ablative Therapy Among Young Patients With Small Renal Masses in the United States.

OBJECTIVE: To assess national trends in the usage of local ablative therapy for small renal masses (SRMs) in a cohort of young patients. Ablation of SRMs has been shown to offer cancer control with limited follow-up. Although ablation is considered effective for patients with limited life expectancy, its use among younger patients may be considered controversial. METHODS: We used the National Cancer Data Base to identify patients between the ages of 40 and 65 years who were diagnosed with SRMs from 2004 to 2011. The primary outcome was the use of local ablative therapy. Multivariable logistic regression analysis was used to identify patient and hospital factors associated with ablation therapies in this cohort. RESULTS: During the study period, we identified 49,441 patients with SRMs, of which 2789 (5.6%) were treated with ablative therapies. The proportion of patients undergoing ablation gradually rose from 2.2% in 2004 to 6.2% in 2011 (P < .001). On multivariable analysis, patients were more likely to receive local ablation at academic hospitals (odds ratio [OR]: 1.5; P < .001) compared with community hospitals, or primarily insured by Medicaid (OR: 1.4; P < .001) or Medicare (OR: 1.3; P < .001) compared with private insurance. CONCLUSION: The use of local ablative therapies is gradually rising but has so far been limited to a small fraction of young patients with SRMs. Patients treated at high-volume, academic hospitals or insured with Medicaid or Medicare were treated to a greater degree with ablation. These results have important implications for the adoption of ablation and the need for long-term surveillance.

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND: Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. METHODS: We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. RESULTS: A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. CONCLUSIONS: Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.).

Upper gastrointestinal diseases in patients for endoscopy in South-Western Uganda.

BACKGROUND: There is a paucity of published data regarding upper gastrointestinal diseases in Ugandans with upper gastrointestinal symptoms referred for endoscopy. OBJECTIVES: To study the presenting complaints, pathology and Helicobacter pylori prevalence among patients with upper gastrointestinal symptoms in South-Western Uganda. METHODS: Patients presenting with upper gastrointestinal symptoms underwent upper endoscopy and a urease test for Helicobacter Pylori, all suspicious lesions were biopsied for histopathology review as appropriate. RESULTS: The most common presenting complaints were epigastric pain (51.6%), dysphagia (13.6%) and odynophagia (7.1%). The most common endoscopy finding was gastritis (40.2%), followed by normal examination (15.2%), oesophageal cancer (13.6%), gastric ulcer (7.6%) and gastric cancer (7.1%). Patients older than 40 years (n=110) had significant findings including gastritis (50.9%), oesophageal cancer (22.7%) and gastric cancer (11.8%). However in younger patients, with the age range of 18-40 years (n=74), most examinations were normal (92.9%). Of the 176 patients able to undergo Helicobacter pylori testing 75.6% were positive. Helicobacter pylori infection was associated with statistically significant increase in gastritis, oesophageal cancer, gastric ulcer, gastric cancer, and duodenal ulcers (p-values< 0.05). CONCLUSION: Gastritis, ulcerative disease, and upper gastrointestinal malignancies are common in South-Western Ugandans and are associated with a high prevalence of Helicobacter pylori.

Incidence of hypercoagulable events after image-guided percutaneous cryoablation of renal tumors: a single-center experience.

PURPOSE: To identify retrospectively hypercoagulable events that occurred over time in patients who underwent image-guided percutaneous renal cryoablation and compare the incidence with a cohort of patients who underwent surgical partial nephrectomy (PN) during the same time period. MATERIALS AND METHODS: An electronic medical record database was queried for patients who underwent percutaneous image-guided renal mass cryoablation or PN between September 2006 and June 2012. Records were examined for thrombotic events during the year following the procedure in each group. Incidence rates, Kaplan-Meier estimates, and patient demographic variables were compared using the stratified log-rank test and t test for independent samples. RESULTS: The study comprised 114 cryoablation cases. The cumulative incidence of thrombotic events after 1 year was 4.39%. The incidence per 100 person-years was 4.84. There were 105 PN cases. The cumulative incidence of thrombotic events after 1 year was 1.0%. The incidence per 100 person-years was 1.14. The person-time incidence rate difference for these two groups did not reach statistical significance (P = .0894). CONCLUSIONS: The incidence of thrombotic events in patients who underwent percutaneous renal cryoablation in this study was not significantly different than a comparable cohort who underwent surgical PN during the same time period.

Phase I trial of pomalidomide given for patients with advanced solid tumors.

PURPOSE: To determine the safety, the maximal tolerated dose, and to assess for any clinical activity of pomalidomide given to patients with advanced solid tumors. PATIENTS AND METHODS: Patients with incurable solid tumors were enrolled. Two different dosing schedules were explored. In Cohort A patients were given pomalidomide once daily for 21 days followed by a 7 day rest. For Cohort B additional patients were recruited to receive pomalidomide given once daily for 28 consecutive days. Dose-limiting toxicity was defined as ≥grade 3 non-hematological toxicity that occurs during cycle 1 and that does not resolve to ≤grade 1 by day 35. Subjects must have received optimal symptomatic treatment for ≥grade 3 nausea, vomiting, or diarrhea to be considered a DLT. Grade 4 transaminitis was considered to be a DLT while grade 3 transaminitis must be present >7 days to be a DLT. Grade 3 febrile neutropenia was considered a DLT. Grade 4 neutropenia, without a fever, was a DLT if the neutropenia did not improve to ≤grade 1 by day 35 of cycle one. Platelet count ≤25,000/mm(3) must improve to ≥75,000/mm(3) by day 35 of cycle one in order not to be considered a DLT. If a patient did not complete one cycle of therapy, for reasons other than a DLT, a replacement subject was added to the same cohort level. RESULTS: A total of 40 patients were enrolled. In Cohort A, three patients received pomalidomide at 5 mg daily without any significant toxicity. Two patients in the 10 mg cohort experienced dose-limiting toxicities of two episodes of grade 3 dyspnea and one grade 4 neutropenia. Six patients were then enrolled at the 7 mg daily of pomalidomide, and no dose-limiting events were observed. In Cohort B, 29 patients were enrolled and the maximal tolerated dose was 4 mg once daily. Stable disease in a variety of tumors was observed. CONCLUSIONS: Pomalidomide was well tolerated and the recommended phase II dosing schedules are 7 mg daily given for 21 days followed by a 7-day rest or pomalidomide 4 mg given on an uninterrupted daily schedule.

Phase I trial of sunitinib and gemcitabine in patients with advanced solid tumors.

PURPOSE: Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy. METHODS: We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale. RESULTS: Two different MTDs were determined. The schedule of gemcitabine 800 mg/m(2) on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m(2) on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m(2) on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily. CONCLUSIONS: This combination is well-tolerated and has significant clinical activity.

A phase II study of tandutinib (MLN518), a selective inhibitor of type III tyrosine receptor kinases, in patients with metastatic renal cell carcinoma.

Therapies which target VEGF and mTOR are now available for patients with metastatic renal cell carcinoma, but there is a continued need to develop agents for patients who become refractory to these initial agents. Tandutinib is a relatively selective inhibitor of type III tyrosine kinase receptor kinases with promising activity in some tumors. In this trial, 10 patients with metastatic renal cell carcinoma refractory to previous therapy with sunitinib or sorafenib (median age 61 years, 80% performance status 0, 60% intermediate MSKCC risk classification) received tandutinib 500 mg bid daily with RECIST-defined response as the primary endpoint and progression-free survival (PFS) and overall survival (OS) as secondary endpoints. No patient had more than 2 cycles of therapy and 50% of patients only received 1 cycle with 70% of patients discontinuing for progressive disease and 30% for toxicity. Tandutinib was not well tolerated with dose reduction in 60% of patients due to adverse events. The most common grade 3 toxicity was fatigue (30%). Tandutinib had no clinical activity and due to the excessive toxicity should not be developed further in patients with sunitinib or sorafenib-refractory metastatic renal cell carcinoma.

A phase I study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors.

PURPOSE: MN-029 (denibulin HCl) is a novel vascular-disrupting agent that reversibly inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor vascular endothelial cells. This study determined the safety, pharmacokinetics, and acute anti-vascular effects of MN-029. METHODS: Patients were treated with escalating doses of MN-029 (4.0-225 mg/m(2)) administered IV at 3-week intervals. This first-in-human study followed an accelerated titration design, with intra-patient dose escalation. Plasma samples were assayed to determine PK parameters. DCE-MRI scans were acquired at baseline and at 6-8 h post-dose. RESULTS: Thirty-four patients received 151 infusions of MN-029. The most common toxicities of MN-029 included nausea and vomiting (which appeared to be dose related), diarrhea, fatigue, headache, and anorexia. No clinically significant myelotoxicity, stomatitis or alopecia was observed. There was no evidence of cumulative toxicity in patients receiving multiple courses of therapy. The cohort at 180 mg/m(2) was expanded to six patients due to a reversible episode of acute coronary ischemia, without sequelae and with preservation of myocardial function. Two dose-limiting toxicities occurred at 225 mg/m(2), a transient ischemic attack and grade 3 transaminitis, thus ending dose escalation. Pharmacokinetic data indicated dose-related increases in C (max) and AUC values, although substantial inter-subject variability was observed. No objective responses were noted; however, five patients had stable disease ≥6 months. A significant linear correlation was found between reduction in K (trans) and exposure to MN-029. CONCLUSIONS: MN-029 was generally well tolerated and showed decrease in tumor vascular parameters. The maximum tolerated dose was 180 mg/m(2).

A phase I study of rebeccamycin analog in combination with oxaliplatin in patients with refractory solid tumors.

Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1-5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m(2)/d for five days along with oxaliplatin 130 mg/m(2) on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development.

A phase I study of sunitinib plus bevacizumab in advanced solid tumors.

PURPOSE: Bevacizumab is an antibody against vascular endothelial growth factor; sunitinib is an inhibitor of vascular endothelial growth factor and related receptors. The safety and maximum tolerated dose of sunitinib plus bevacizumab was assessed in this phase I trial. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level, 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level, 5 mg/kg) on days 1, 15, and 29 of a 42-day cycle. Dose-limiting toxicities during the first 6-week cycle were used to determine the maximum tolerated dose. RESULTS: Thirty-eight patients were enrolled. Patients received a median of 3 cycles of treatment (range, 1-17(+)). There was one dose-limiting toxicity (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed Response Evaluation Criteria in Solid Tumors-defined partial response (18%; 95% confidence interval, 8-34%). Nineteen of the 32 patients with a postbaseline scan (59%) had at least some reduction in overall tumor burden (median, 32%; range, 3-73%). CONCLUSIONS: The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Antitumor activity was observed across multiple solid tumors.

Phase II study of sorafenib in patients with metastatic or recurrent sarcomas.

PURPOSE Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma. PATIENTS AND METHODS We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued. Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies. CONCLUSION As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.

A phase II trial of fosbretabulin in advanced anaplastic thyroid carcinoma and correlation of baseline serum-soluble intracellular adhesion molecule-1 with outcome.

BACKGROUND: Fosbretabulin is a novel vascular-disrupting agent that has antitumor activity against anaplastic thyroid cancer (ATC) cell lines, xenografts, and demonstrable efficacy in a phase I trial. This phase II study determined the efficacy and safety of fosbretabulin in patients with advanced ATC and whether fosbretabulin altered the natural history of ATC by virtue of doubling the median survival. A secondary aim evaluated the prognostic value of serum soluble intracellular adhesion molecule-1 (sICAM). METHODS: Twenty-six patients received fosbretabulin 45 mg/m(2) as a 10-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. sICAM levels were obtained at baseline, over the first two cycles, and end of therapy. Treatment was continued until disease progression. RESULTS: Fosbretabulin was well tolerated; grade 3 toxicity was observed in nine patients (35%), and grade 4 toxicity in one (4%). QTc prolongation delayed treatment in four causing one to stop treatment. Median survival was 4.7 months with 34% and 23% alive at 6 and 12 months, respectively. Median duration of stable disease in seven patients was 12.3 months (range, 4.4-37.9 months). Baseline serum sICAM levels were measured in 24 patients with a median 253.5 ng/mL. There was a significant difference in event-free survival among tertiles of baseline sICAM levels (p < 0.009). CONCLUSIONS: There were no objective responses seen with single-agent fosbretabulin as administered in this trial, and we did not observe a doubling of survival as our primary endpoint. This is among the largest prospective trials ever conducted for ATC. Fosbretabulin has an acceptable safety profile in patients with advanced ATC, and one-third survived more than 6 months. Despite a small sample size, low baseline sICAM levels were predictive of event-free survival. Further prospective validation of sICAM as a therapeutic biomarker and exploring combination regimens with fosbretabulin are warranted.

Phase I trial of docetaxel given every 3 weeks and daily lenalidomide in patients with advanced solid tumors.

PURPOSE: Cytotoxic and anti-angiogenic drugs are efficacious in malignancies. This trial was undertaken to evaluate the toxicity of a novel regimen combining docetaxel and lenalidomide. PATIENTS AND METHODS: Patients with advanced solid tumors were eligible. Docetaxel was administered on day 1, and lenalidomide was given on days 1-14 of each 21-day cycle. Since significant myelosuppression occurred, pegfilgrastim was added on day 2. Dose limiting toxicity (DLT) was defined as >or=grade 3 non-hematologic toxicity, grade 4 neutropenia with fever, or grade 4 anemia or thrombocytopenia. RESULTS: Thirty-three patients were enrolled. DLTs included neutropenia, nausea/vomiting, and dyspnea. Of the evaluable patients, 69% had stable disease, and 3% had partial response. CONCLUSIONS: This regimen was well tolerated and provided stable disease in the majority of advanced cancer patients. The recommended phase II dosing is docetaxel 75 mg/m(2) on day 1, lenalidomide 25 mg on days 1-14, and pegfilgrastim 6 mg on day 2, given every 3 weeks.