Shifting the paradigm in personalized cancer care through next-generation therapeutics and computational pathology.

The incorporation of novel therapeutic agents such as antibody-drug conjugates, radio-conjugates, T-cell engagers, and chimeric antigen receptor cell therapies represents a paradigm shift in oncology. Cell-surface target quantification, quantitative assessment of receptor internalization, and changes in the tumor microenvironment (TME) are essential variables in the development of biomarkers for patient selection and therapeutic response. Assessing these parameters requires capabilities that transcend those of traditional biomarker approaches based on immunohistochemistry, in situ hybridization and/or sequencing assays. Computational pathology is emerging as a transformative solution in this new therapeutic landscape, enabling detailed assessment of not only target presence, expression levels, and intra-tumor distribution but also of additional phenotypic features of tumor cells and their surrounding TME. Here, we delineate the pivotal role of computational pathology in enhancing the efficacy and specificity of these advanced therapeutics, underscoring the integration of novel artificial intelligence models that promise to revolutionize biomarker discovery and drug development.

Diversity of US participants in AstraZeneca-sponsored clinical trials.

BACKGROUND: To develop medicines that are safe and efficacious to all patients, clinical trials must enroll appropriate target populations, but imbalances related to race, ethnicity and sex have been reported. A comprehensive analysis and improvement in understanding representativeness of patient enrollment in industry-sponsored trials are key public health needs. METHODS: We assessed race/ethnicity and sex representation in AstraZeneca (AZ)-sponsored clinical trials in the United States (US) from 2010 to 2022, compared with the 2019 US Census. RESULTS: In total, 246 trials representing 95,372 patients with complete race/ethnicity and sex records were analyzed. The proportions of different race/ethnicity subgroups in AZ-sponsored clinical trials and the US Census were similar (White: 69.5% vs 60.1%, Black or African American: 13.3% vs 12.5%, Asian: 1.8% vs 5.8%, Hispanic: 14.4% vs 18.5%). We also observed parity in the proportions of males and females between AZ clinical trials and US Census (males: 52.4% vs 49.2%, females: 47.6% vs 50.8%). Comparisons of four distinct therapy areas within AZ (Respiratory and Immunology [R&I]; Cardiovascular, Renal, and Metabolism [CVRM]; Solid Tumors; and Hematological Malignancies), including by trial phases, revealed greater variability, with proportions observed above and below US Census levels. CONCLUSION: This analysis provides the first detailed insights into the representativeness of AZ trials. Overall, the proportions of different race/ethnicity and sex subgroups in AZ-sponsored clinical trials were broadly aligned with the US Census. We outline some of AZ's planned health equity initiatives that are intended to continue to improve equitable patient enrollment.

A View on Drug Development for Cancer Prevention.

Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention. SIGNIFICANCE: The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.

Comorbidity between lung cancer and COVID-19 pneumonia: role of immunoregulatory gene transcripts in high ACE2-expressing normal lung.

Background: SARS-CoV-2 (COVID-19) elicits a T-cell antigen-mediated immune response of variable efficacy. To understand this variability, we explored transcriptomic expression of angiotensin-converting enzyme 2 (ACE2, the SARS-CoV-2 receptor) and of immunoregulatory genes in normal lung tissues from patients with non-small cell lung cancer (NSCLC). Methods: This study used the transcriptomic and the clinical data for NSCLC patients generated during the CHEMORES study [n = 123 primary resected (early-stage) NSCLC] and the WINTHER clinical trial (n = 32 metastatic NSCLC). Results: We identified patient subgroups with high and low ACE2 expression (p = 1.55 × 10-19) in normal lung tissue, presumed to be at higher and lower risk, respectively, of developing severe COVID-19 should they become infected. ACE2 transcript expression in normal lung tissues (but not in tumor tissue) of patients with NSCLC was higher in individuals with more advanced disease. High-ACE2 expressors had significantly higher levels of CD8+ cytotoxic T lymphocytes and natural killer cells but with presumably impaired function by high Thymocyte Selection-Associated High Mobility Group Box Protein TOX (TOX) expression. In addition, immune checkpoint-related molecules - PD-L1, CTLA-4, PD-1, and TIGIT - are more highly expressed in normal (but not tumor) lung tissues; these molecules might dampen immune response to either viruses or cancer. Importantly, however, high inducible T-cell co-stimulator (ICOS), which can amplify immune and cytokine reactivity, significantly correlated with high ACE2 expression in univariable analysis of normal lung (but not lung tumor tissue). Conclusions: We report a normal lung immune-tolerant state that may explain a potential comorbidity risk between two diseases - NSCLC and susceptibility to COVID-19 pneumonia. Further, a NSCLC patient subgroup has normal lung tissue expressing high ACE2 and high ICOS transcripts, the latter potentially promoting a hyperimmune response, and possibly leading to severe COVID-19 pulmonary compromise.

Transcriptomics in Tumor and Normal Lung Tissues Identify Patients With Early-Stage Non-Small-Cell Lung Cancer With High Risk of Postsurgery Recurrence Who May Benefit From Adjuvant Therapies.

PURPOSE: The prognosis of patients with non-small-cell lung cancer (NSCLC), traditionally determined by anatomic histology and TNM staging, neglects the biological features of the tumor that may be important in determining patient outcome and guiding therapeutic interventions. Identifying patients with NSCLC at increased risk of recurrence after curative-intent surgery remains an important unmet need so that known effective adjuvant treatments can be offered to those at highest risk of recurrence. METHODS: Relative gene expression level in the primary tumor and normal bronchial tissues was used to retrospectively assess their association with disease-free survival (DFS) in a cohort of 120 patients with NSCLC who underwent curative-intent surgery. RESULTS: Low versus high Digital Display Precision Predictor (DDPP) score (a measure of relative gene expression) was significantly associated with shorter DFS (highest recurrence risk; P = .006) in all patients and in patients with TNM stages 1-2 (P = .00051; n = 83). For patients with stages 1-2 and low DDPP score (n = 29), adjuvant chemotherapy was associated with improved DFS (P = .0041). High co-overexpression of CTLA-4, PD-L1, and ICOS in normal lung (28 of 120 patients) was also significantly associated with decreased DFS (P = .0013), suggesting an immune tolerance to tumor neoantigens in some patients. Patients with DDPP low and immunotolerant normal tissue had the shortest DFS (P = 2.12E-11). CONCLUSION: TNM stage, DDPP score, and immune competence status of normal lung are independent prognostic factors in multivariate analysis. Our findings open new avenues for prospective prognostic assessment and treatment assignment on the basis of transcriptomic profiling of tumor and normal lung tissue in patients with NSCLC.

Rethinking Cancer Clinical Trial Conduct Induced by COVID-19: An Academic Center, Industry, Government, and Regulatory Agency Perspective.

The COVID-19 pandemic brought about major changes in cancer clinical trials. In its aftermath, the community has an opportunity to incorporate some of these changes as part of the future of trial conduct to make it more patient centered.

Antibiotic use towards the end of life: development of good practice recommendations.

OBJECTIVES: Development of evidence-based good practice recommendations for clinicians considering the use of antibiotics in patients towards the end of life. DESIGN: A multiprofessional group of experts in end-of-life care and antimicrobial stewardship was convened. Findings from a scoping review of the literature and a consultation of clinicians were triangulated. Expert discussion was used to generate consensus on how to approach decision-making. SETTING: Representatives from hospital and a range of community health and care settings. PARTICIPANTS: Medical, pharmacy and nursing professionals. MAIN OUTCOME MEASURES: Good practice recommendations based on published evidence and the experience of prescribers in Scotland. RESULTS: The findings of 88 uncontrolled, observational studies of variable quality were considered alongside a survey of over 200 prescribers. No national or international guidelines were identified. Antibiotic use towards the end of life was common but practice was highly variable. The potential harms associated with giving antibiotics tended to be less well considered than the potential benefits. Antibiotics often extended the length of time to death but this was sometimes at the cost of higher symptom burden. There was strong consensus around the importance of effective communication with patients and their families and making treatment decisions aligned to a patient's goals and priorities. CONCLUSIONS: Good practice recommendations were agreed with focus on three areas: making shared decisions about future care; agreeing clear goals and limits of therapy; reviewing all antibiotic prescribing decisions regularly. These will be disseminated widely to support optimal care for patients towards the end of life. A patient version of the recommendations has also been produced to support implementation.

Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development.

Radiotherapy is an effective anticancer treatment, but combinations with targeted agents that maximize efficacy while sparing normal tissue are needed. Here, we assess the radiopotentiation profiles of DNA damage response inhibitors (DDRi) olaparib (PARP1/2), ceralasertib (ATR), adavosertib (WEE1), AZD0156 (ATM), and KU-60648 (DNA-PK). We performed a radiotherapy combination screen and assessed how drug concentration and cellular DDR deficiencies influence the radiopotentiation ability of DDRi. We pre-selected six lung cancer cell lines with different genetic/signaling aberrations (including mutations in TP53 and ATM) and assessed multiple concentrations of DDRi in combination with a fixed radiotherapy dose by clonogenic assay. The effective concentration of DDRi in radiotherapy combinations is lower than that required for single-agent efficacy. This has the potential to be exploited further in the context of DDR deficiencies to increase therapeutic index and we demonstrate that low concentrations of AZD0156 preferentially sensitized p53-deficient cells. Moreover, testing multiple concentrations of DDRi in radiotherapy combinations indicated that olaparib, ceralasertib, and adavosertib have a desirable safety profile showing moderate increases in radiotherapy dose enhancement with increasing inhibitor concentration. Small increases in concentration of AZD0156 and particularly KU-60648, however, result in steep increases in dose enhancement. Radiopotentiation profiling can inform on effective drug doses required for radiosensitization in relation to biomarkers, providing an opportunity to increase therapeutic index. Moreover, multiple concentration testing demonstrates a relationship between drug concentration and radiotherapy effect that provides valuable insights that, with future in vivo validation, can guide dose-escalation strategies in clinical trials.

The Porto European Cancer Research Summit 2021.

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures - namely translational research, clinical/prevention trials and outcomes research - were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.

Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma.

Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) by ipilimumab leads to immune-mediated tumor regression and immune-related adverse events (irAEs), including diarrhea and colitis. The current analyses were undertaken to promote an understanding of the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of ipilimumab-induced gastrointestinal irAEs. Treatment-naïve or previously treated patients with unresectable stage III/IV melanoma (n = 115) received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) and were randomized to receive concomitant blinded prophylactic oral budesonide (9 mg/d with gradual taper through week 16) or placebo. Outcome measures included histologic assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease (IBD), fecal calprotectin levels, and polymorphisms in immune-related genes. Ipilimumab resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by altered antibody levels to enteric flora, inflammatory cell infiltration into gastrointestinal mucosa, and increased fecal calprotectin associated with diarrhea and clinical evidence of colitis. The pattern of ipilimumab-induced antibody titers to microbial flora and the histologic features and location of the inflammation were distinct from classic IBD. Prophylactic budesonide did not prevent ipilimumab-induced bowel inflammation. Despite an observed association between colonic inflammation and grade 2 or higher diarrhea, no baseline biomarkers could reliably predict development of gastrointestinal toxicity. Although classic IBD and ipilimumab-related gastrointestinal toxicity are both immune mediated, the observed pattern of biomarkers suggests ipilimumab-related gastrointestinal toxicity may be a distinct clinicopathologic entity.

Optimization of donor management goals yields increased organ use.

Multiple strategies have been used in an effort to increase the pool of organs for transplantation. Standardizing donor management has produced promising results. Donor management goals (DMGs) are now being used as end points of intensive care unit care during the prerecovery phase but no prospective results have been reported. Data from the United Network for Organ Sharing Region 11 were collected for successful achievement of eight common donor management goals (mean airway pressure [MAP], central venous pressure [CVP], pH, PaO2, sodium, glucose, single pressor use, and urine output) before organ recovery. Two time periods were studied with different panels of DMGs. The analysis identified the success rate of transplantation. Goals were stratified by their statistical correlation with the number of organs transplanted per donor (OTPD) in an effort to identify the most important parameter(s). Eight hundred five organ donors were studied with 2685 organs transplanted. DMGs were assessed through two phases of the study. Achieving DMGs rose from 18 to 66 per cent associated with significant improvement in OTPD (range, 2.96 to 3.45). The success of transplantation was primarily associated with limitations in vasopressor use and PaO2. Tight glucose control did affect the rate of pancreatic transplants. Thoracic organs were the most sensitive to DMGs with a 10- to 15-fold increase in lung transplantation when PaO2 rose above 100 mmHg. MAP, CVP, pH, sodium, and urine output had little effect on transplantation. Standardization of end points of donor management was associated with increased rates of transplantation. Surprisingly, not all standard goals are necessary for optimal organ use. The most significant parameters were the low use of vasopressor agents and oxygenation. Donor management strategies should strive to optimize these goals.

Metabolism and disposition of dasatinib after oral administration to humans.

SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [(14)C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of <4 h. Dasatinib was the major drug-related component in human plasma. At 2 h, dasatinib accounted for 25% of the TRA in plasma, suggesting that metabolites contributed significantly to the total drug-related component. There were many circulating metabolites detected that included hydroxylated metabolites (M20 and M24), an N-dealkylated metabolite (M4), an N-oxide (M5), an acid metabolite (M6), glucuronide conjugates (M8a,b), and products of further metabolism of these primary metabolites. Most of the administered radioactivity was eliminated in the feces (85%). Urine recovery accounted for <4% of the dose. Dasatinib accounted for <1 and 19% of the dose in urine and feces, respectively, suggesting that dasatinib was well absorbed after p.o. administration and extensively metabolized before being eliminated from the body. The exposures of pharmacologically active metabolites M4, M5, M6, M20, and M24 in patients, along with their cell-based IC(50) for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.

Report from the SWOG Radiation Oncology Committee: Research Objectives Workshop 2017.

The Radiation Therapy Committee of SWOG periodically evaluates its strategic plan in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2017 Strategic Planning Workshop included leaders in cancer basic sciences, molecular theragnostics, pharmaceutical and technology industries, clinical trial design, oncology practice, and statistical analysis. The committee discussed high-priority research areas, such as optimization of combined modality therapy, radiation oncology-specific drug design, identification of molecular profiles predictive of radiation-induced local or distant tumor responses, and methods for normal tissue-specific mitigation of radiation toxicity. The following concepts emerged as dominant questions ready for national testing: (i) what is the role of radiotherapy in the treatment of oligometastatic, oligorecurrent, and oligoprogressive disease? (ii) How can combined modality therapy be used to enhance systemic and local response? (iii) Can we validate and optimize liquid biopsy and other biomarkers (such as novel imaging) to supplement current response criteria to guide therapy and clinical trial design endpoints? (iv) How can we overcome deficiencies of randomized survival endpoint trials in an era of increasing molecular stratification factors? And (v) how can we mitigate treatment-related side effects and maximize quality of life in cancer survivors? The committee concluded that many aspects of these questions are ready for clinical evaluation and example protocol concepts are provided that could improve rates of cancer cure and quality of survival. Clin Cancer Res; 24(15); 3500-9. ©2018 AACR.

Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18.

PURPOSE: To determine whether BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor (MMPI), added to systemic chemotherapy improved survival in advanced non-small-cell lung cancer (NSCLC). In early phase studies, BMS- 275291 was not associated with dose-limiting joint toxicity seen with other MMPIs. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB/IV NSCLC, performance status (PS) 0 to 2, and adequate organ function were eligible. All patients received paclitaxel 200 mg/m2 plus carboplatin (area under the curve, 6 mg/mL-min) intravenously every 21 days for up to 8 cycles, and were randomly assigned to receive BMS-275291, 1,200 mg orally daily, or placebo until disease progression. The primary study end point was survival (OS); secondary end points included progression-free survival (PFS), response rates (RR), toxicity, and quality of life. RESULTS: From 2000 to 2002, 774 patients were randomly assigned. Pretreatment characteristics were well balanced between arms: median age, 61 years; male sex, 73%; stage IV, 79%; PS 0 to 1, 88%. Interim safety analysis revealed no survival advantage and increased toxicity in the experimental arm, and study treatment was stopped. Median OS, PFS and RR in the final analysis in the BMS-275291 arm were 8.6 months, 4.9 months, and 25.8% respectively, and in the control arm 9.2 months, 5.3 months, 33.7%. Toxicity was significantly higher in the BMS-275291 arm, including flu-like symptoms, rash, hypersensitivity reactions (8.6% v 2.4%), and febrile neutropenia (9.7% v 5.5%). CONCLUSION: BMS-275291 added to chemotherapy increases toxicity and does not improve survival in advanced NSCLC.

ZD6126: a novel vascular-targeting agent that causes selective destruction of tumor vasculature.

Physiological differences between tumor and normal vasculature provide a target for drug discovery. In particular, the immature nature of tumor vasculature may render it intrinsically sensitive to disruption by agents affecting the endothelial cell cytoskeleton, including tubulin-binding agents. In this article, we report the synthesis of a water-soluble phosphate prodrug, ZD6126, of the tubulin-binding agent N-acetylcolchinol. In vitro studies demonstrate the comparative tubulin-binding properties of the prodrug and active drug, and show the induction of pronounced, reversible changes in endothelial cell morphology at subcytotoxic doses. Neither ZD6126 nor N-acetylcolchinol showed effects on the growth of human umbilical vein endothelial cells at concentrations below 100 micro M. In contrast, changes in endothelial cell morphology were seen at much lower, noncytotoxic concentrations (0.1 micro M) of ZD6126 and more pronounced effects were seen in proliferating versus confluent endothelial cell cultures. In vivo studies were carried out using a murine tumor model (CaNT) with single administration of a dose well below the maximum tolerated dose. These studies showed a large reduction in vascular volume, induction of extensive necrosis in tumors, and a reduced tumor cell yield in a clonal excision assay, consistent with vascular rather than cytotoxic effects. A viable rim of tumor remained after single-dose administration and minimal growth delay was observed. However, well-tolerated, multiple administration regimens led to pronounced tumor-growth delay. In the human xenograft FaDu, the growth delay given by a single dose of paclitaxel was enhanced by combination with a single dose of ZD6126, and the growth delay given by the combination was greater than the sum of the growth delays from the individual treatments. These findings show that ZD6126 is a promising antivascular agent for the treatment of solid tumors.

Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. PATIENTS AND METHODS: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m(2) had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity-time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study. RESULTS: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. CONCLUSION: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.

Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results.

PURPOSE: A phase I trial was performed with combretastatin A4 phosphate (CA4P), a novel tubulin-binding agent that has been shown to rapidly reduce blood flow in animal tumors. PATIENTS AND METHODS: The drug was delivered by a 10-minute weekly infusion for 3 weeks followed by a week gap, with intrapatient dose escalation. Dose escalation was accomplished by doubling until grade 2 toxicity was seen. The starting dose was 5 mg/m2. RESULTS: Thirty-four patients received 167 infusions. CA4P was rapidly converted to the active combretastatin A4 (CA4), which was further metabolized to the glucuronide. CA4 area under the curve (AUC) increased from 0.169 at 5 mg/m2 to 3.29 micromol * h/L at 114 mg/m2. The mean CA4 AUC in eight patients at 68 mg/m2 was 2.33 micromol * h/L compared with 5.8 micromol * h/L at 25 mg/kg (the lowest effective dose) in the mouse. The only toxicity that possibly was related to the drug dose up to 40 mg/m2 was tumor pain. Dose-limiting toxicity was reversible ataxia at 114 mg/m2, vasovagal syncope and motor neuropathy at 88 mg/m2, and fatal ischemia in previously irradiated bowel at 52 mg/m2. Other drug-related grade 2 or higher toxicities seen in more than one patient were pain, lymphopenia, fatigue, anemia, diarrhea, hypertension, hypotension, vomiting, visual disturbance, and dyspnea. One patient at 68 mg/m2 had improvement in liver metastases of adrenocortical carcinoma. CONCLUSION: CA4P was well tolerated in 14 of 16 patients at 52 or 68 mg/m2; these are doses at which tumor blood flow reduction has been recorded.

Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging.

PURPOSE: Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment. MATERIALS AND METHODS: Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2. RESULTS: A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor Ktrans in six of 16 patients treated at >or= 52 mg/m2, with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium-diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle Ktrans or in kidney AUC in group analysis of the clinical data. CONCLUSION: CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

A randomized phase II feasibility trial of BMS-275291 in patients with early stage breast cancer.

PURPOSE: This pilot trial was performed to evaluate the safety, pharmacokinetics and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor (MMPI), into adjuvant breast cancer therapy. EXPERIMENTAL DESIGN: Patients with stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles (AC>T). Patients were stratified by planned adjuvant therapy and randomized (2:1 ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year. RESULTS: Seventy-two patients were recruited from March 2001 to July 2002. Grade >or=2 musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2% of patients receiving BMS-275291 compared with 16.7% of patients receiving placebo; difference = 19.5% (95% confidence interval: -0.06, 0.44; P = NS). Two patients receiving BMS-275291 developed palpable nodules along tendons. Grade >or=3 rash was reported by 8.5% of patients receiving BMS-275291 compared with 4.2% of patients receiving placebo; difference = 4.3% (95% confidence interval: -0.18, 0.3; P = NS). Overall, 33% of BMS-275291 patients and 21% of placebo patients discontinued treatment due to adverse events. BMS-275291 trough levels tended to decrease over time; 9 of 47 (19%) had >or=50% of trough concentrations > 124 ng/ml (IC(90) for matrix metalloproteinase-9). CONCLUSIONS: The pattern of arthralgia in BMS-275291-treated patients was consistent with matrix metalloproteinase inhibitor toxicity. Although the differential incidence of arthralgia did not reach statistical significance, the trial was terminated. An adjuvant trial in this patient population is not feasible.