Clinical Trials In Cancer Patients Research Articles

Factors associated with clinical trial screening failures in gynecologic oncology

ObjectiveLow enrollment of adult cancer patients in clinical trials is an ongoing challenge in cancer research. We sought to determine factors associated with clinical trial screening failures in women with gynecologic malignancies at a large urban university health system. MethodsA retrospective review was conducted of women with gynecologic malignancies who presented to an urban university system between 12/2009 and 12/2012. Data collected included demographic, clinico-pathologic and trial-related factors, as well as reasons for non-participation. ResultsTwo hundred twenty-one patients were eligible for a clinical trial. Of these, 44% participated while 56% did not. There were more screening failures when trials were offered at the time of primary treatment than at recurrence (62% vs. 38%, p=0.001). There was no significant difference in participation based on age, ethnicity, hospital setting, payor status, family history, comorbidities, prior treatment, substance abuse, recent surgery or trial type. Of the non-participants, 62% declined the study due to perceived harm and 10% due to socio-economic barriers while 20% were excluded due to co-morbidities and 8% due to noncompliance. ConclusionsSignificantly more screening failures for clinical trials occurred when trials were offered at the time of primary treatment. The majority of patients declined based on perceived harm from enrolling in a clinical trial, although 20% of eligible patients were not offered enrollment despite not meeting any exclusion criteria. Our findings underscore the importance of appropriate counseling when offering clinical trials, as well as overcoming physician biases in deciding who is an appropriate candidate.

Hemorrhagic events in cancer patients treated with aflibercept: a meta-analysis.

Aflibercept (Ziv-aflibercept, VEGF Trap, AVE005) is an engineered protein that functions as a decoy receptor to bind vascular endothelial growth factor A (VEGF-A). Hemorrhagic events, including epistaxis, gastrointestinal bleeding, and pulmonary bleeding, is one of its major adverse effects, but the incidence rate and overall risk has not been systematically studied. Therefore, we conducted a meta-analysis of published clinical trials to investigate the incidence and relative risk of hemorrhagic events in cancer patients treated with aflibercept. Electronic databases including PubMed, Embase, Cochrane databases, and American Society of Clinical Oncology abstracts were searched. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with aflibercept with toxicity profile on hemorrhagic events. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated using fixed or random effects models depending on the heterogeneity of the included studies. A total of 4,538 patients with a variety of solid tumors from 13 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade hemorrhagic events in cancer patients were 22.1 % (95 % CI, 16.5-29.7 %) and 4.2 % (95 % CI, 3.9-4.6 %), respectively. The relative risks of hemorrhagic events of aflibercept compared to control were increased for all-grade (RR = 2.63; 95 % CI, 2.07-3.34) and high-grade (RR = 2.45, 95 % CI, 1.62-3.72) hemorrhagic events. The risk of developing high-grade hemorrhagic events with aflibercept was comparable to that of bevacizumab (RR = 1.26; 95 % CI, 0.89-1.79). Aflibercept is associated with an increased risk of developing hemorrhagic events in patients with solid tumors. Close monitoring and management of hemorrhagic events are recommended.

Organizational and physician factors associated with patient enrollment in cancer clinical trials.

Our purpose was to identify physicians' individual characteristics, attitudes, and organizational contextual factors associated with higher enrollment of patients in cancer clinical trials among physician participants in the National Cancer Institute's Community Clinical Oncology Program (CCOP). We hypothesized that physicians' individual characteristics, such as age, medical specialty, tenure, CCOP organizational factors (i.e. policies and procedures to encourage enrollment), and attitudes toward participating in CCOP would directly determine enrollment. We also hypothesized that physicians' characteristics and CCOP organizational factors would influence physicians' attitudes toward participating in CCOP, which in turn would predict enrollment. We evaluated enrollment in National Cancer Institute-sponsored cancer clinical trials in 2011 among 481 physician participants using Structural Equation Modeling. The data sources include CCOP Annual Progress Reports, two surveys of CCOP administrators and physician participants, and the American Medical Association Masterfile. Physicians with more positive attitudes toward participating in CCOP enrolled more patients than physicians with less positive attitudes. In addition, physicians who practiced in CCOPs that had more supportive policies and practices in place to encourage enrollment (i.e. offered trainings, provided support to screen and enroll patients, gave incentives to enroll patients, instituted minimum accrual expectations) also significantly enrolled more patients. Physician status as CCOP Principal Investigator had a positive direct effect on enrollment, while physician age and non-oncology medical specialty had negative direct effects on enrollment. Neither physicians' characteristics nor CCOP organizational factors indirectly influenced enrollment through an effect on physician attitudes. We examined whether individual physicians' characteristics and attitudes, as well as CCOP organizational factors, influenced patient enrollment in cancer clinical trials among CCOP physicians. Physician attitudes and CCOP organizational factors had positive direct effects, but not indirect effects, on physician enrollment of patients. Our results could be used to develop physician-directed strategies aimed at increasing involvement in clinical research. For example, administrators may want to ensure physicians have access to support staff to help screen and enroll patients or institute minimum accrual expectations. Our results also highlight the importance of recruiting physicians for volunteer clinical research programs whose attitudes and values align with programmatic goals. Given that physician involvement is a key determinant of patient enrollment in clinical trials, these interventions could expand the overall number of patients involved in cancer research. These strategies will be increasingly important as the CCOP network continues to evolve.

Rash to the mTOR Inhibitor Everolimus

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for treatment of renal cell carcinoma, subependymal giant cell astrocytoma, breast cancer, and progressive neuroendocrine tumors of pancreatic origin. Its use may be hindered because of adverse events, including rash. The reported incidence and risk of a rash to everolimus varies widely and has not been closely investigated. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing a rash. We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology from 1998 to December 2011 using the keyword "everolimus" to identify relevant clinical trials. Eligible studies included prospective phase II and III clinical trials of cancer patients on 10 mg of everolimus daily with available data on incidence of rash. The summary incidence and relative risk (RR) of rash were calculated using either the random-effects or fixed-effects model, depending on the heterogeneity of the constituent studies. A total of 2242 patients with various malignancies from 13 clinical trials were included in the analysis. The summary incidences of all-grade and high-grade rash in patients on everolimus were 28.6% [95% confidence interval (CI), 20.8-38.0] and 1.0% (95% CI, 0.6-1.8), respectively. Everolimus was associated with a statistically significant increased risk of all-grade rash (RR=3.853, 95% CI, 2.470-6.013, P=0.000), but the RR for high-grade rash (RR=2.997, 95% CI, 0.633-14.185) was not statistically significant, with a P value of 0.166. Everolimus is associated with a significant risk of developing a rash. Management of rash to everolimus is critical to prevent dose modifications and decreased quality of life, both of which can negatively affect overall clinical outcomes.

Comparison of Survival Outcomes Among Cancer Patients Treated In and Out of Clinical Trials

Clinical trials test the efficacy of a treatment in a select patient population. We examined whether cancer clinical trial patients were similar to nontrial, "real-world" patients with respect to presenting characteristics and survival. We reviewed the SWOG national clinical trials consortium database to identify candidate trials. Demographic factors, stage, and overall survival for patients in the standard arms were compared with nontrial control subjects selected from the Surveillance, Epidemiology, and End Results program. Multivariable survival analyses using Cox regression were conducted. The survival functions from aggregate data across all studies were compared separately by prognosis (≥50% vs <50% average 2-year survival). All statistical tests were two-sided. We analyzed 21 SWOG studies (11 good prognosis and 10 poor prognosis) comprising 5190 patients enrolled from 1987 to 2007. Trial patients were younger than nontrial patients (P < .001). In multivariable analysis, trial participation was not associated with improved overall survival for all 11 good-prognosis studies but was associated with better survival for nine of 10 poor-prognosis studies (P < .001). The impact of trial participation on overall survival endured for only 1 year. Trial participation was associated with better survival in the first year after diagnosis, likely because of eligibility criteria that excluded higher comorbidity patients from trials. Similar survival patterns between trial and nontrial patients after the first year suggest that trial standard arm outcomes are generalizable over the long term and may improve confidence that trial treatment effects will translate to the real-world setting. Reducing eligibility criteria would improve access to clinical trials.

Myeloid-Derived Suppressor Cells in Cancer: Therapeutic, Predictive, and Prognostic Implications

Immune evasion is a hallmark of cancer. While there are multiple different mechanisms that cancer cells employ, myeloid-derived suppressor cells (MDSCs) are one of the key drivers of tumor-mediated immune evasion. MDSCs begin as myeloid cells recruited to the tumor microenvironment, where they are transformed into potent immunosuppressive cells. However, our understanding of the clinical relevance of MDSCs in cancer patients has significantly lagged behind the preclinical literature in part due to the absence of a cognate molecule present in mice, as well as to the considerable heterogeneity of MDSCs. However, if one evaluates the clinical literature through the filter of clinically robust endpoints, such as overall survival, three important phenotypes emerge: promyelocytic, monocytic, and granulocytic. Based on these studies, MDSCs have clear prognostic importance in multiple solid tumors, and emerging data support the utility of circulating MDSCs as a predictive marker for cancer immunotherapy, and even as an early leading marker for predicting clinical response to systemic chemotherapy in patients with advanced solid tumors. More recent preclinical data in immunosuppressed murine models suggest that MDSCs play an important role in tumor progression and the metastatic process that is independent of their immunosuppressive properties. Consequently, targeting MDSCs either in combination with cancer immunotherapy or independently as part of an approach to inhibit the metastatic process appears to be a very clinically promising strategy. We review different approaches to target MDSCs that could potentially be tested in future clinical trials in cancer patients.

Translational Therapeutics in Genetically Engineered Mouse Models of Cancer

Advances in knowledge of the molecular alterations of human cancers, refinements in technologies for the generation of genetically engineered mouse models (GEMMs), and the development of cancer therapies have accelerated in recent years. Progress in these fields provides the foundation for clinically relevant studies to be performed in GEMMs, through which it is possible to glean information on drug efficacy and to identify determinants of sensitivity and resistance to drugs and drug combinations. GEMMs used in pre-, co-, and postclinical studies must closely recapitulate the genetics, histopathology, and response to therapy of the human disease. Prevention and intervention trials can be designed in GEMMs to test the effects of drugs on tumor initiation, regression, and progression. Given their complexity, careful consideration of the infrastructure requirements and practical aspects of each individual experiment, including enrollment, tumor monitoring, and dose and schedule, must be considered in the design of therapeutic studies in GEMMs. Advantages of GEMMs include the ability to rapidly perform drug efficacy studies in a defined genetic background, the ease of pharmacodynamic and pharmacokinetic assessments, and the possibility of experimentally manipulating model systems to address questions that cannot be addressed in patients. In light of these features, GEMMs are useful tools for translational studies to inform clinical trials in cancer patients.

Smac mimetics and innate immune stimuli synergize to promote tumor death

Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in Phase I clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may only be efficacious in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. As such, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe “cytokine storm”. Here we show that oncolytic viruses and adjuvants such as poly(I:C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFNβ), tumor necrosis factor alpha (TNFα) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.

PARP inhibitors for anticancer therapy

PARP-1 [poly(ADP-ribose) polymerase-1], which plays a key role in DNA repair, was discovered 50years ago. PARPi (PARP inhibitors), originally made to probe the function of the enzyme, inhibit DNA repair and increase the potency of anticancer cytotoxic agents. PARPi of increasing potency were developed as chemo- and radio-sensitizers and first entered clinical trial in cancer patients in 2003. However, it was the revelation in 2005 that they were synthetically lethal in cells with DNA repair defects, found almost exclusively in some tumours, that led to a major interest in this class of drug. Several PARPi have entered clinical trials and show promising activity in breast, ovarian and other cancers associated with BRCA (breast cancer early-onset) mutations or other defects in homologous recombination DNA repair. It is likely that at least one of these will be licensed soon. The present review describes key events from the discovery to clinical application of PARPi.

Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis

The tumor suppressor p53 is thought to play a role in megakaryocyte (MK) development. To assess the influence of the p53 regulatory pathway further, we studied the effect of RG7112, a small molecule MDM2 antagonist that activates p53 by preventing its interaction with MDM2, on normal megakaryocytopoiesis and platelet production. This drug has been previously been evaluated in clinical trials of cancer patients where thrombocytopenia was one of the major dose-limiting toxicities. In this study, we demonstrated that administration of RG7112 in vivo in rats and monkeys results in thrombocytopenia. In addition, we identified two distinct mechanisms by which RG7112-mediated activation of p53 affected human megakaryocytopoiesis and platelet production in vitro. RG7112 promoted apoptosis of MK progenitor cells, resulting in a reduction of their numbers and RG7112 affected mature MK by blocking DNA synthesis during endomitosis and impairing platelet production. Together, the disruption of these events provides an explanation for RG7112-induced thrombocytopenia and insight into the role of the p53-MDM2 auto-regulatory loop in normal megakaryocytopoiesis.

Helper cell-independent antitumor activity of potent CD8+ T cell epitope peptide vaccines is dependent upon CD40L

Peptide vaccines derived from CD8+ T-cell epitopes have shown variable efficacy in cancer patients. Thus, some peptide vaccines are capable of activating CD8+ T-cell responses, even in the absence of CD4+ T-cell epitopes or dendritic cell (DC)-activating adjuvants. However, the mechanisms underlying the clinical activity of these potent peptides are poorly understood. Using CT26 and ovalbumin-expressing B16 murine allograft tumor models, we found that the antitumor effect of helper cell-independent CD8 T-cell peptide vaccines is inhibited by the blockade of CD40 ligand (CD40L) in vivo. Furthermore, in vitro stimulation with antigenic peptides of cells derived from immunized mice induced the expression of CD40L on the surface of CD8+ T cells and fostered DC maturation, an effect that was partially inhibited by CD40L-blocking antibodies. Interestingly, CD40L blockade also inhibited CD8+ T-cell responses, even in the presence of fully mature DCs, suggesting a role for CD40L not only in promoting DC maturation but also in mediating CD8+ T-cell co-stimulation. Importantly, these potent peptides share features with bona fide CD4 epitopes, since they foster responses against less immunogenic CD8+ T-cell epitopes in a CD40L-dependent manner. The analysis of peptides used for the vaccination of cancer patients in clinical trials showed that these peptides also induce the expression of CD40L on the surface of CD8+ T cells. Taken together, these results suggest that CD40L expression induced by potent CD8+ T-cell epitopes can activate antitumor CD8+ T-cell responses, potentially amplifying the immunological responses to less immunogenic CD8+ T-cell epitopes and bypassing the requirement for CD4+ helper T cells in vaccination protocols.

Abstract C42: Development and validation of an IHC-based detection method for studying indoleamine 2,3-dioxygenase 1 (IDO1) expression in human cancers.

Abstract Indoleamine 2,3-dioxygenase-1 (IDO1) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. The depletion of tryptophan and the generation of tryptophan metabolites have been demonstrated to be an important regulator of immune function. IDO1 is induced by interferons and TLR agonists and is expressed in a wide variety of human cancers as well as in the tumor-draining lymph nodes. High IDO1 expression is significantly associated with more rapid disease progression and poor prognosis in multiple cancer types. Numerous studies have shown that IDO1 negatively regulates immune functions via several potential cellular mechanisms, which in turn allows tumor escape from host immune surveillance. Therefore, inhibition of IDO1 may have therapeutic potential in cancer and IDO1 expression may serve as a selective marker of a responsive population. INCB024360, a novel IDO1-selective inhibitor, is currently being evaluated in clinical trials of cancer patients. To support the clinical development of INCB024360, we have developed and validated an immunohistochemistry (IHC)-based method using rabbit polyclonal antisera that specifically detects IDO1 protein expression. The method has been used to determine IDO1 expression in primary biopsies from patients studied in INCB024360 clinical trials. The method can be used to determine the prevalence of IDO1 expression in a variety of human cancers, identify histologic subtypes that might be associated with IDO1 expression and examine IDO1 coexpression with other immune modifying pathways. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C42. Citation Format: Xiangdong Liu, Gengjie Yang, Alexander Margulis, Rich Wynn, Peggy Scherle, Robert Newton. Development and validation of an IHC-based detection method for studying indoleamine 2,3-dioxygenase 1 (IDO1) expression in human cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C42.

Drug-conjugated antibodies for the treatment of cancer.

Despite considerable effort, application of monoclonal antibody technology has had only modest success in improving treatment outcomes in patients with solid tumours. Enhancing the cancer cell-killing activity of antibodies through conjugation to highly potent cytotoxic 'payloads' to create antibody-drug conjuates (ADCs) offers a strategy for developing anti-cancer drugs of great promise. Early ADCs exhibited side-effect profiles similar to those of 'classical' chemotherapeutic agents and their performance in clinical trials in cancer patients was generally poor. However, the recent clinical development of ADCs that have highly potent tubulin-acting agents as their payloads have profoundly changed the outlook for ADC technology. Twenty-five such ADCs are in clinical development and one, brentuximab vedotin, was approved by the FDA in August, 2011, for the treatment of patients with Hodgkin's lymphoma and patients with anaplastic large cell lymphoma, based on a high rate of durable responses in single arm phase II clinical trials. More recently, a second ADC, trastuzumab emtansine, has shown excellent anti-tumour activity with the presentation of results of a 991-patient randomized phase III trial in patients with HER2-positive metastatic breast cancer. Treatment with this ADC (single agent) resulted in a significantly improved progression-free survival of 9.6 months compared with 6.4 months for lapatinib plus capecitabine in the comparator arm and significantly prolonged overall survival. Besides demonstrating excellent efficacy, these ADCs were remarkably well tolerated. Thus these, and other ADCs in development, promise to achieve the long sought goal of ADC technology, that is, of having compounds with high anti-tumour activity at doses where adverse effects are generally mild.

Nelfinavir and bortezomib inhibit mTOR activity via ATF4-mediated sestrin-2 regulation

Endoplasmic reticulum (ER) stress and autophagy are two basic cell survival mechanisms often occurring in concert. Extensive ER stress in cancer cells deliberately induced by chemotherapeutic drugs may lead to growth arrest and cell death. However, the link between ER stress and autophagy is not well understood. In this study, the treatment of cancer cells with ER stress-inducing drug nelfinavir resulted in the expression of endogenous mTOR inhibitor sestrin-2 (SESN2). Upregulation of SESN2 expression was associated with expression of ER stress markers ATF4, ATF3, and CHOP. SESN2 upregulation also occurred in cells treated with the proteasome inhibitor bortezomib. Ectopic expression of ATF4, but not of ATF3 or CHOP, caused transcriptional upregulation of SESN2 expression, indicating expressional regulation of SESN2 by ATF4. Transient overexpression of ectopic SESN2 resulted in mTOR inhibition and autophagy, confirming a link between ER stress, SESN2 upregulation, and mTOR inhibition. Accordingly, cancer cells treated with the ER stress-inducing agent nelfinavir showed reduced mTOR activity and associated increases in the expression levels of ATF4 and SESN2. These results show that ATF4-regulated SESN2 expression presents a new link between ER stress and mTOR inhibition and autophagy. mTOR inhibition by nelfinavir, which is currently in clinical trials for cancer patients, may also explain its observed ability to induce autophagy, growth arrest, and radiosensitization in cancer cells.

T Cell Costimulation with Anti-CD137 Monoclonal Antibodies Is Mediated by K63–Polyubiquitin-Dependent Signals from Endosomes

Agonist anti-CD137 (4-1BB) mAbs enhance CD8-mediated antitumor immunity. Agonist anti-human CD137 mAbs binding to four distinct epitopes on the CD137 glycoprotein costimulated T cell activation irrespective of the engaged epitope or its interference with CD137L binding. CD137 perturbation with all these agonist mAbs resulted in Ag and Ab internalization toward an endosomal vesicular compartment. Internalization was observed in activated T lymphocytes from humans and mice, not only in culture but also in Ab-injected living animals. These in vivo experiments were carried out upon systemic i.v. injections with anti-CD137 mAbs and showed CD137 internalization in tumor-infiltrating lymphocytes and in activated human T cells transferred to immunodeficient mice. Efficient CD137 internalization required K63 polyubiquitination and endocytosed CD137-containing vesicles recruited TNFR-associated factor (TRAF) 2 and were decorated with K63 polyubiquitins. CD137 stimulation activates NF-κB through a K63-linked polyubiquitination-dependent route, and CD137-associated TRAF2 becomes K63 polyubiquitinated. Consistent with a role for TRAF2 in CD137 signaling, transgenic mice functionally deficient in TRAF2 showed delayed immunotherapeutic activity of anti-CD137 mAbs. As a whole, these findings advance our knowledge of the mechanisms of action of anti-CD137 immunostimulatory mAbs such as those currently undergoing clinical trials in cancer patients.

Risk of proteinuria with the new angiogenesis inhibitor axitinib in patients with cancer.

e20602 Background: The use of axitinib, a potent inhibitor of vascular endothelial growth factor receptor (VEGFR), is associated with proteinuria, which may cause morbidity and treatment interruptions in cancer patients. We performed a systematic review and meta-analysis of published clinical trials to assess the overall risk of proteinuria with axitinib. Methods: Potentially relevant studies were identified by searching databases including Pubmed and abstracts presented at the American Society of Clinical Oncology annual meetings until June, 2012. Eligible studies included prospective clinical trials in cancer patients treated with axitinib containing data on proteinuria. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated using the fixed- or random-effects models. Results: A total of 1,671 patients with advanced renal cell carcinoma (RCC) and other solid tumors from 9 studies were included for analysis. The overall incidences of all-grade and high-grade (grade 3 or 4) proteinuria with axitinib were 22.7% (95% CI: 10.4-42.6%) and 3.8% (95% CI: 2.6-5.7%) respectively. The risk did not vary significantly with tumor types (P=0.13). There was no significant difference between RCC and non-RCC patients (P=0.45), although the incidence in RCC patients was higher (30.0%, 95% CI: 8.4-66.7 versus 17.5%, 95% CI: 7.4-36.3%). In comparison with a control (gemcitabine), axitinib significantly increased the incidence of high-grade proteinuria (3.3%, 95% CI: 1.6-6.5% versus 0.1%, 95% CI: 0-2.3%; P=0.031). When compared to another angiogenesis inhibitor sorafenib, axitinib did not have a significantly higher risk of all-grade (RR=1.48, 95% CI: 0.92-2.38, P=0.10) and high-grade proteinuria (RR=1.81, 95% CI: 0.68-4.85, P=0.24). Conclusions: There was a significant risk of proteinuria associated with the use of axitinib in cancer patients.

Abstract 1244: Phosphatidylserine-targeting antibody reactivates tumor immunity and destroys tumor vasculature in mice.

Abstract The immunosuppressive lipid, phosphatidylserine (PS), becomes exposed on tumor blood vessels and tumor cells responding to therapy. The exposed PS contributes to the immunosuppressed tumor microenvironment. Bavituximab is a phosphatidylserine (PS)-targeting antibody that is being combined with chemotherapy in clinical trials in cancer patients. Here, we tested the hypothesis that innate immunity against cancer can be elicited by combining chemotherapy with a monoclonal antibody that indirectly binds exposed phosphatidylserine (PS). We used a murine version of bavituximab, 2aG4, plus docetaxel to treat prostate tumors in mice. Combination treatment markedly retarded tumor growth, prolonged survival times and delayed progression to androgen-independent disease. Antibody treatment reduced the presence of myeloid-derived suppressor cells (MDSCs) in the tumors and caused macrophages to repolarize from the immunosuppressive, proangiogenic M2-like state into a tumoricidal M1-like state. The reactivated macrophages destroyed antibody-coated tumor vasculature and tumor cells. Addition of 2aG4 to MDSCs in vitro caused them to differentiate into M1-like macrophages and DCs. Thus, PS-targeting antibodies appear to reactivate innate immunity in tumors resulting in tumor growth inhibition. Citation Format: Yi Yin, Xianming Huang, Dan Ye, Philip Thorpe. Phosphatidylserine-targeting antibody reactivates tumor immunity and destroys tumor vasculature in mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1244. doi:10.1158/1538-7445.AM2013-1244

The risk of proteinuria with the angiogenesis inhibitor axitinib in patients with cancer.

439 Background: The use of axitinib, a potent inhibitor of the vascular endothelial growth factor receptor (VEGFR), is associated with proteinuria, which may cause morbidity and treatment interruptions in cancer patients. We performed a systematic review and meta-analysis of published clinical trials to assess the overall risk of severe proteinuria when treated with axitinib. Methods: Potentially relevant studies were identified by searching databases from PubMed and abstracts presented at the American Society of Clinical Oncology annual meetings until June 2012. Eligible studies included prospective clinical trials in cancer patients treated with axitinib containing data on all-grade and/or high-grade proteinuria. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated using the fixed- or random-effects models. Results: A total of 1,671 patients with advanced renal cell carcinoma (RCC) and other solid tumors from 9 studies were included for analysis. The overall incidence of all-grade proteinuria with axitinib was 22.7% (95% CI: 10.4-42.6%). There was no significant difference between RCC and non-RCC patients (p = 0.45), although the incidence in RCC patients was higher (30.0%, 95% CI: 8.4-66.7 vs. 17.5%, 95% CI: 7.4-36.3%). The overall incidence of high-grade (grade 3 or 4) proteinuria with axitinib was 3.8% (95% CI: 2.6-5.7%). In comparison with a control (gemcitabine), axitinib significantly increased the incidence of high-grade proteinuria (3.3%, 95% CI: 1.6-6.5% vs. 0.1%, 95% CI: 0-2.3%; p=0.031). When compared to sorafenib, another angiovsgenesis inhibitor, axitinib has elevated risk of proteinuria but without statistical significance (RR=1.48 for all-grade, 95% CI: 0.92-2.38, p = 0.10; RR=1.81 for high-grade, 95% CI: 0.68-4.85, p = 0.24). Conclusions: There was a significant risk of high-grade proteinuria associated with the use of axitinib in cancer patients. Adequate monitoring and appropriate use of axitinib is recommended to reduce renal complications.

APR-246/PRIMA-1 MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

p53 and p63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1(MET) (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities.

Parametric Maximum Likelihood Estimation of Cure Fraction Using Interval-Censored Data

A significant proportion of patients in cancer clinical trials can be cured. That is, the symptoms of the disease disappear completely and the disease never recurs. In this article, the focus is on estimation of the proportion of patients who are cured. The parametric maximum likelihood estimation method was used for estimation of the cure fraction based on application of the bounded cumulative hazard (BCH) model to interval-censored data. We ran the analysis using the EM algorithm considering two cases: i) when no covariates were involved in the estimation, and ii) when some covariates were involved. This paper shows derivation of the estimation equations for the cure rate parameter followed by a simulation study.