Clinical Trials In Cancer Patients Research Articles

Pre-Clinical Murine Models: Syngeneic Models for Immuno-Oncology

Experimental animal models are crucial in the study of the pathological development of cancer and evaluation of the efficacy of novel therapeutic or preventive agents. To date, several newer targeted therapeutics have been unsuccessful. Novel therapeutics that have often appeared to perform well in preclinical models have failed in the clinic. Many factors contribute to these failures, but the one most often highlighted relates to the short-comings of the preclinical models. Several animal models are available, including a wide variety of genetic mouse models, cell line xenografts, patient derived xenografts, and syngeneic xenografts. These models have generated an enormous amount of information useful for the understanding of cancer. The complexities and strategies of these models is beyond the scope of this mini-review, the aim here is to briefly discuss the strengths and weaknesses of some of the popular models. Given the progress in the rapidly developing field of immuno-oncology, particular emphasis will be placed on the potential for syngeneic murine models as a means of testing novel immune-modulatory compounds. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly lead to the success of future human clinical trials for cancer patients.

Targeting IL4/IL4R for the treatment of epithelial cancer metastasis.

While progress has been made in treating primary epithelial tumors, metastatic tumors remain largely incurable and still account for 85-90% of all cancer-related deaths. Interleukin-4 (IL4), a Th2 cytokine, and the IL4/IL4 receptor (IL4R) interaction have well defined roles in the immune system. Yet, IL4 receptors are over-expressed by many epithelial cancers and could be a promising target for metastatic tumor therapy. The IL4/IL4R signaling axis is a strong promoter of pro-metastatic phenotypes in epithelial cancer cells including enhanced migration, invasion, survival, and proliferation. The promotion of breast cancer growth specifically is also supported in part by IL4-induced glutamine metabolism, and we have shown that IL4 is also capable of inducing glucose metabolism in breast cancer cells. Importantly, there are several types of FDA approved medications for use in asthma patients that inhibit the IL4/IL4R signaling axis. However, these approved medications inhibit both the type I IL4 receptor found on immune cells, and the type II IL4 receptor that is predominantly expressed by some non-hematopoietic cells including epithelial cancer cells. This article reviews existing therapies targeting IL4, IL4R, or IL4/IL4R signaling, and recent findings guiding the creation of novel therapies that specifically inhibit the type II IL4R, while taking into consideration effects on immune cells within the tumor microenvironment. Some of these therapies are currently in clinical trials for cancer patients, and may be exploitable for the treatment of metastatic disease.

Abstract LB-166: PARP inhibition effects on endocrine therapy and resistance in estrogen receptor positive (ER+) breast cancer models

Abstract Background: Poly [ADP-ribose] polymerase (PARP) is an important mediator of DNA damage repair. Preclinical and clinical studies have indicated PARP inhibitors (i) as promising agents in DNA-repair-defective cancers, especially in the presence of BRCA1/2 alterations. Recent evidence also suggests a role for additional DNA damage-independent functions of PARP, involving transcriptional and epigenetic regulation. Particularly, PARP-1 can interact with the estrogen receptor (ER) and modulate its transcriptional activity in vascular smooth muscle cells, and PARPi can circumvent endocrine resistance in prostate cancer cells. However, the effect of PARPi on the efficacy of endocrine therapy (EndoTx) in ER+ breast cancer is unknown. Here we aimed to establish these effects using the PARPi olaparib (AZD2281, Olap) in our preclinical models. Methods: The effects of Olap (0.01-1μM) alone or in combination with EndoTx [estrogen deprivation (ED) or tamoxifen (Tam)] were tested in vitro in three ER+ parental cell lines (MCF7, ZR75-1, and T47D; BRCAwt) and their endocrine resistant (R) derivatives. Clonogenic assays were used to assess Olap-induced changes in cell growth. In vivo, ovariectomized nude mice bearing 200 mm3 tumors growing in the presence of estrogen supplementation (E2 pellets), were randomized to either continued E2 (control), ED, or ED+Tam; all ± oral Olap (100mg/kg daily). Results: In MCF7 parental cells in vitro, Olap, in a dose dependent manner, inhibited E2-stimulated growth and increased the growth inhibitory effect of EndoTx. In addition, at a clinically relevant dose (1μM), Olap significantly inhibited the growth of MCF7 EndoR cell derivatives. Similar results were also observed in the other 2 ER+ cell models. In vivo, long-term Olap-treatment in the presence of EndoTx (Tam ∼200days, and ED ∼300days) was well tolerated and no apparent drug-related toxicity was observed. Olap did not affect the growth of E2-stimulated MCF7 xenografts. In contrast, Olap enhanced sensitivity to Tam by delaying time to tumor progression (TTP; size doubling) from a median of 95 days to 155 days (p = 0.03), and numerically but not significantly reduced time to tumor regression (TTR; size halving) from 138 to 51 days (p = 0.2). Olap also numerically accelerated median time to tumor regression in the presence of ED (34 ED vs. 25 days ED+Olap; p = 0.23), but had no effect on TTP (P = 0.36). Conclusion: Our results suggest a potential role for Olap in enhancing EndoTx efficacy and circumventing resistance in the absence of BRCA mutations. The absence of any toxicity and negative interaction by adding Olap to EndoTx in the in vivo experiment supports the inclusion of ER+ breast cancer patients in clinical trials using PARPi. Further studies are warranted to better understand the biology of PARP and the efficacy of PARPi in ER+ breast cancer, especially in the presence of EndoTx and resistance. Citation Format: Agostina Nardone, Amit Goldstein, Martin J. Shea, Tamika Mithchell, Xiaoyong Fu, Carmine De Angelis, Huizhong Hu, Xiaowei Xu, Mahitha Rajendran, Mark O'Connor, Gershon Locker, Susan Hilsenbeck, Kent Osborne, Rachel Schiff. PARP inhibition effects on endocrine therapy and resistance in estrogen receptor positive (ER+) breast cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-166. doi:10.1158/1538-7445.AM2015-LB-166

Abstract 2505: Therapeutic efficacy of the ZVex™ and GLAAS™ platforms in a B16-F10/hCAIX melanoma mouse model

Abstract ZVex™ and GLAAS™ are two dendritic-cell (DC) targeting platform technologies designed to enhance immune responses through the in vivo induction of antigen specific CD8 and CD4 T-cells, respectively. ZVex™ is a lentiviral vector pseudotyped with a modified Sindbis virus envelope engineered to deliver tumor antigen-encoding nucleic acids to dendritic cells in vivo. GLAAS™(Glucopyranosyl Lipid A Adjuvant System) activates DC by binding to the TLR-4 receptor and inducing strong Th1 type CD4 responses against co-delivered recombinant proteins. Currently both platform technologies are being investigated in phase I clinical trials in cancer patients. Human carbonic anhydrase 9 (hCAIX) is a tumor-associated transmembrane antigen that is over-expressed on various cancer cell types. We mapped hCAIX specific, multi-functional CD8 and CD4 T-cell epitopes within the extracellular and transmembrane regions of the protein for the mouse haplotype H-2b by intracellular cytokine staining. Mice lethally challenged s.c. on the flank with a B16-F10 tumor cell line expressing the hCAIX protein (designated BC.12) fully controlled large tumors (>100 mm2) when therapeutically immunized (subcutaneously at the base of tail) with ZVex™ encoding hCAIX or the recombinant hCAIX protein with GLAAS™ (either s.c. or i.m.). In both models, tumor control was dose-dependent. Additionally, the presence of a strong transmembrane H-2b restricted CD8 T-cell epitope was required for tumor control and regression. hCAIX-specific CD8 T-cell responses were detectable as far out as day 67 post challenge in mice displaying full regression of tumor. These results demonstrate proof of concept for ZVex™ and GLAAS™ platform technologies in an aggressive murine melanoma model. Citation Format: David J. Campbell, Rebecca S. Reeves, Patrick A. Flynn, Scott H. Robbins, Peter Berglund, Jan H. ter Meulen. Therapeutic efficacy of the ZVex™ and GLAAS™ platforms in a B16-F10/hCAIX melanoma mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2505. doi:10.1158/1538-7445.AM2015-2505

Abstract 2506: Preclinical characterization of LV305, a lentiviral vector targeting tumors expressing NY-ESO-1

Abstract The cancer-testis antigen, NY-ESO-1, is an attractive tumor antigen target for cancer immunotherapy, because it is expressed in numerous cancer types (e.g., melanoma, breast cancer, sarcoma, lung cancer) but not in normal adult tissues except the testis or placenta. Although recent studies using various NY-ESO-1 formulations show promising results, an optimal immunotherapeutic strategy to generate T cell responses for controlling tumor growth is still lacking. Lentiviral vectors (LVs) are proven tools for delivering nucleic acid payloads into cells due to their ability to transduce not only dividing cells but also quiescent cells, such as dendritic cells (DCs). Because DCs are essential for the initiation of T cell responses, we have engineered LV305 (a product candidate from ZVex™, our LV-based discovery platform) to selectively deliver the antigen-encoding NY-ESO-1 gene to human DCs in vivo. To develop tools to evaluate LV305 in a preclinical setting, we 1) generated a cell line, CIN.23, which is a CT26 murine colon cancer cell line that stably expresses human NY-ESO-1 protein; and 2) mapped and confirmed NY-ESO-1 CD8 and CD4 T cell epitopes recognized by H2d. Mice immunized with LV305 developed strong, dose-dependent, poly-functional, and cytotoxic NY-ESO-1-specific CD8 T cells within 14 days post-immunization and could be boosted with LV305 at least three times to recall peak-level CD8 T cell responses. Immunization with LV305 protected mice against CIN.23 tumor challenge, which was abrogated upon depletion of CD8 T cells. Adoptive transfer of CD8 T cells, together with CD4 T cells or NK cells, from LV305-immunized donor mice to tumor-bearing mice conferred significant protection against metastatic tumor growth. This protection was not observed when CD8 T cells alone were adoptively transferred. Taken together, these findings suggest that CD8 T cells are required but not sufficient for mediating LV305-induced anti-tumor efficacy. We have demonstrated the anti-tumor therapeutic potential of LV305-mediated in vivo DC immunization in murine models and are currently investigating LV305 in a phase I clinical trial in cancer patients with tumors expressing NY-ESO-1. Citation Format: Tina C. Albershardt, David J. Campbell, Andrea J. Parsons, Jan H. ter Meulen, Peter Berglund. Preclinical characterization of LV305, a lentiviral vector targeting tumors expressing NY-ESO-1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2506. doi:10.1158/1538-7445.AM2015-2506

Electron Transfer-Based Compounds: A Novel Weapon in the Cancer Battlespace?

In 1971, US President Nixon announced the “war on cancer”. This declaration not only sparked global interest in this devastating disease but also fuelled large investments. Interdisciplinary and international consortia in academic and commercial cancer research and drug development were fostered around the world. Some 40years later, our understanding of the cellular and molecular pathophysiology of many cancer entities has tremendously increased (Hanahan and Weinberg, 2011). This impressive knowledge has led to the establishment of cancer prevention programs, early diagnostics and more effective treatment strategies.

Collection of grade 3/4 adverse event (AE) data in a subgroup of patients in cancer clinical trials supporting supplemental indications: A comprehensive analysis.

e17640 Background: Comprehensive collection of safety data in clinical trials provides a complete AE profile of therapies at a significant cost. Kaiser et al (JCO 2010; 28:5046-5053) proposed a sam...

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics.

Procaspase-activating compound 1 (PAC-1) is an o-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues were designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater area under the curve values for each of the four compounds, suggesting them as promising candidates for further development.

New dimension in therapeutic targeting of BCL-2 family proteins.

Proteins of the BCL-2 family control the mitochondrial pathway of apoptosis. Targeting these proteins proves to be an attractive strategy for anticancer therapy. The biological context is based on the fact that BH3-only members of the family are specific antagonists of prosurvival members. This prompted the identification of "BH3 mimetic" compounds. These small peptides or organic molecules indeed mimic the BH3 domain of BH3-only proteins: by selectively binding and antagonizing prosurvival proteins, they can induce apoptosis in malignant cells. Some small-molecule inhibitors of prosurvival proteins have already entered clinical trials in cancer patients and two of them have shown significant therapeutic effects. The latest developments in the field of targeting BCL-2 family proteins highlight several new antagonists of prosurvival proteins as well as direct activators of proapoptotic proteins. These compounds open up novel prospects for the development of BH3 mimetic anticancer drugs.

Experimental studies of a vaccine formulation of recombinant human VEGF antigen with aluminum phosphate

CIGB-247 is a cancer vaccine that is a formulation of a recombinant protein antigen representative of the human vascular endothelial growth factor (VEGF) with a bacterially-derived adjuvant (VSSP). The vaccine has shown an excellent safety profile in mice, rats, rabbits, not-human primates and in recent clinical trials in cancer patients. Response to the vaccine is characterized by specific antibody titers that neutralize VEGF/VEGFR2 binding and a cytotoxic tumor-specific response. To expand our present anti-VEGF active immunotherapy strategies, we have now studied in mice and non-human primates the effects of vaccination with a formulation of our recombinant VEGF antigen and aluminum phosphate adjuvant (hereafter denominated CIGB-247-A). Administered bi-weekly, CIGB-247-A produces high titers of anti-VEGF IgG blocking antibodies in 2 mice strains. Particularly in BALB/c, the treatment impaired subcutaneous F3II mammary tumor growth and reduced the number of spontaneous lung macro metastases, increasing animals' survival. Spleen cells from specifically immunized mice directly killed F3II tumor cells in vitro. CIGB-247-A also showed to be immunogenic in non-human primates, which developed anti-VEGF blocking antibodies and the ability for specific direct cell cytotoxic responses, all without impairing the healing of deep skin wounds or other side effect. Our results support consideration of aluminum phosphate as a suitable adjuvant for the development of new vaccine formulations using VEGF as antigen.

Cachexia: clinical features when inflammation drives malnutrition.

Cachexia is a clinically relevant syndrome which impacts on quality of life, morbidity and mortality of patients suffering from acute and chronic diseases. The hallmark of cachexia is muscle loss, which is triggered by disease-associated inflammatory response. Cachexia is a continuum and therefore a staging system is needed. Initially, a three-stage system (i.e. pre-cachexia, cachexia and refractory cachexia) was proposed. More recent evidence supports the use of a five-stage classification system, based on patient's BMI and severity of weight loss, to better predict clinical outcome. Also, large clinical trials in cancer patients demonstrated that cachexia emerging during chemotherapy has greater influence on survival than weight loss at baseline. Therefore, becoming widely accepted is the importance of routinely monitoring patients' nutritional status to detect early changes and diagnose cachexia in its early phases. Although cachexia is associated with the presence of anabolic resistance, it has been shown that sustained yet physiological hyperaminoacidaemia, as well as the use of specific nutrients, is able to overcome impaired protein synthesis and revert catabolism. More importantly, clinical evidence demonstrates that preservation of nutritional status during chemotherapy or improvement of body weight after weight loss is associated with longer survival in cancer patients.

Development of Drugs Targeting the PI3K Signalling Pathway in Leukaemias and Lymphomas

The phosphoinositide 3-kinase (PI3K) family of signalling enzymes play a key role in the transduction of signals from activated cell surface receptors controlling cell growth and proliferation, survival, metabolism, and migration. The intracellular signalling pathway from activated receptors to PI3K and its downstream targets v-akt murine thymoma viral oncogene homolog (Akt) and mechanistic target of rapamycin (mTOR) is very frequently deregulated by genetic and epigenetic mechanisms in human cancer, including leukaemia and lymphoma. In the past decade, an arsenal of small molecule inhibitors of key enzymes in this pathway has been developed and evaluated in pre-clinical studies and clinical trials in cancer patients. These include pharmacological inhibitors of Akt, mTOR, and PI3K, some of which are approved for the treatment of leukaemia and lymphoma. The PI3K family comprises eight different catalytic isoforms in humans, which have been subdivided into three classes. Class I PI3K isoforms have been extensively studied in the context of human cancer, and the isoforms p110α and p110δ are validated drug targets. The recent approval of a p110δ-specific PI3K inhibitor (idelalisib/Zydelig®) for the treatment of selected B cell malignancies represents the first success in developing these molecules into anti-cancer drugs. In addition to PI3K inhibitors, mTOR inhibitors are intensively studied in leukaemia and lymphoma, and temsirolimus (Torisel®) is approved for the treatment of a type of lymphoma. Based on these promising results it is hoped that additional novel PI3K pathway inhibitors will in the near future be further developed into new drugs for leukaemia and lymphoma.

Awareness and Perceptions of Clinical Trials in Cancer Patients and Their Families in Saudi Arabia.

Despite the increasing number of medical articles being published from the Middle East, clinical research is still lagging behind compared to other regions. Enrolling participants into clinical trials presents an important challenge. We wanted to explore the perception, knowledge, and willingness of cancer patients to participate in oncology clinical trials and to recommend strategies to overcome these challenges. A 31-item questionnaire was administered to cancer patients and their family members in an outpatient clinic. Two hundred four patients and family members were enrolled between December 2011 and February 2013. Fifty-eight percent of the participants were aware of clinical trials. Some misconceptions included the following: 22% believed that no clinical trials were conducted in the Arab world, 19% believed that clinical trials in the Arab world were not under any regulatory authority supervision, and 15% believed that local clinical trials are conducted on subjects without their consent. One third of patients assumed that clinical trials are executed on animals instead of humans, and greater than 40% believed that clinical trials are performed for new medications only. Finally, 61% of the survey participants who were aware of clinical trials expressed their willingness to participate in trials. This large cohort survey demonstrated that a relatively significant number of Saudi cancer patients and their families are aware of clinical trials and a similarly high number of participants are willing to participate in clinical trials. This leads us to believe that patients' awareness and perception of clinical trials are not a significant limiting factor in clinical trial recruitment in our region.

Metformin: a modulator of bevacizumab activity in cancer? A case report

Recurrent type I endometrial cancer (EC) has poor prognosis and demands novel therapeutic approaches. Bevacizumab, a VEGF-A neutralizing monoclonal antibody, has shown clinical activity in this setting. To our knowledge, however, although some diabetic cancer patients treated with bevacizumab may also take metformin, whether metformin modulates response to anti-VEGF therapy has not yet been investigated. Here, we report the case of a patient with advanced EC treated, among other drugs, with bevacizumab in combination with metformin. The patient affected by relapsed EC G3 type 1, presented in march 2010 with liver, lungs and mediastinic metastases. After six cycles of paclitaxel and cisplatin she underwent partial response. Later on, she had disease progression notwithstanding administration of multiple lines of chemotherapy. In march 2013, due to brain metastases with coma, she began steroid therapy with development of secondary diabetes. At this time, administration of Bevacizumab plus Metformin improved her performance status. CT scans performed in this time window showed reduced radiologic density of the lung and mediastinic lesions and of liver disease, suggestive of increased tumor necrosis. Strong 18F-FDG uptake by PET imaging along with high levels of monocarboxylate transporter 4 and lack of liver kinase B1 expression in liver metastasis, highlighted metabolic features previously associated with response to anti-VEGF therapy and phenformin in preclinical models. However, clinical benefit was transitory and was followed by rapid and fatal disease progression. These findings—albeit limited to a single case—suggest that tumors lacking LKB1 expression and/or endowed with an highly glycolytic phenotype might develop large necrotic areas following combined treatment with metformin plus bevacizumab. As metformin is widely used among diabetes patients as well as in ongoing clinical trials in cancer patients, these results deserve further clinical investigation.

Incidence and risk of proteinuria with aflibercept in cancer patients: a meta-analysis.

BackgroundAflibercept is a human recombinant fusion protein with antiangiogenic effects that functions as a decoy receptor to bind vascular endothelial growth factor A. Proteinuria is one of its major adverse effects with a substantial variation in the incidence rate, and the overall risk of proteinuria has not been systematically studied. We performed a meta-analysis of published clinical trials to quantify the incidence and relative risk of proteinuria in cancer patients treated with aflibercept.MethodsThe electronic databases were searched, including PubMed, Embase, Cochrane databases, and ASCO (American Society of Clinical Oncology) abstracts. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with aflibercept with toxicity data on proteinuria. 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.ResultsA total of 4,596 patients with a variety of solid tumors from 16 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade proteinuria in cancer patients were 33.9% (95% CI: 27.3–42.1%) and 7.9% (95% CI: 6.1–10.2%). The relative risks of proteinuria of aflibercept compared to control were increased for all-grade (RR = 1.41, 95% CI: 1.13–1.77) and high-grade (RR = 6.18, 95% CI: 3.78–10.12) proteinuria. The risk of developing all-grade and high-grade proteinuria with aflibercept was substantially higher than that of bevacizumab (all-grade: RR 1.85, 95% CI: 1.63–2.11; high-grade: RR 2.37, 95% CI: 1.84–3.05).ConclusionsAflibercept is associated with an increased risk of developing proteinuria. Appropriate monitoring and treatment is strongly recommended to prevent potential renal damage. Future studies are still needed to investigate the risk reduction and possible use of aflibercept in cancer patients.

Alleviating financial burden for cancer patients in clinical trials.

10 Background: Financial barriers may prevent cancer patients from enrolling into clinical trials. This financial burden has yet to be fully explored. The goal of this study is to establish the feasibility of a financial assistance program for cancer patients enrolled in clinical trials and to analyze patient characteristics associated with financial aid requests. Methods: We performed a cross-sectional analysis of cancer clinical trial patients who registered for a financial assistance program at a tertiary cancer center. This program is designed to fund non-clinical expenses related to clinical trial participation (e.g. travel, lodging). Patients were referred to the program by their provider and enrolled if they expressed interest. After registration, applicants were required to request reimbursement monthly in order to receive funding. Descriptive statistics and univariate analyses compared characteristics of patients who requested funding vs. those who did not. Results: From November 2013 to April 2014, a total of 86 participants enrolled into the financial assistance program; 43 received funds and 43 did not. Most patients were <65 years old (73%), female (70%), white (86%), married (67%), and enrolled in a phase 1 trial (69%). Patients with lower incomes were more likely to request funds than those with incomes > $75,000 (61% vs. 38%, p=0.01). Patients currently employed were more likely to pursue funds than disabled or unemployed patients (58% vs. 21%, p<0.01). Out-of-state patients were more likely to ask for funds than in-state patients (64% vs.19%, p<0.01). Patients who requested funds were less likely to have disease progression after enrollment than those who did not request funds (19% vs. 42%, p=0.03). Conclusions: Enrolling clinical trial participants onto a financial assistance program is both feasible and informative. The patients who requested financial aid in our program were more likely to have lower incomes, remain employed, and reside out of state. Those who requested funding were less likely to have disease progression after program enrollment. Future efforts should continue to explore and improve interventions aimed to alleviate the financial burden experienced by cancer patients enrolled in clinical trials.

Treatment-related fatigue with everolimus and temsirolimus in patients with cancer-a meta-analysis of clinical trials.

Mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are approved for the treatment of a variety of malignancies. Fatigue has been described with these agents as a common side effect, although the overall incidence and risk remain unclear. We performed a meta-analysis to calculate the overall incidence of fatigue in cancer patients treated with everolimus and temsirolimus and to compare the differences in incidence with placebo. The electronic databases PubMed, Embase, Web of Science, and Cochrane databases were searched for studies to include in the meta-analysis. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with single drug everolimus or temsirolimus with toxicity data on fatigue. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included studies. A total of 9,760 patients with a variety of malignancies from 56 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade fatigue in cancer patients treated with mTOR inhibitor (everolimus or temsirolimus) were 45.4% (95% CI 36.9-55.8%) and 8.7% (95% CI 7.2-10.4%), respectively. The relative risks of fatigue of mTOR inhibitor compared to placebo were increased for all-grade (RR = 1.22, 95% CI 1.08-1.38, P = 0.002) and high-grade (RR = 1.82, 95% CI 1.24-2.69, P = 0.002) fatigue. The incidence of all-grade fatigue of patients treated with everolimus was higher than those with temsirolimus (RR = 1.85, 95% CI 1.71-2.01, P < 0.001). No significant difference was detected with between everolimus and temsirolimus in terms of high-grade fatigue (RR = 1.15, 95% CI 0.94-1.41, P = 0.18). Treatment with mTOR inhibitor, everolimus and temsirolimus, is associated with an increased incidence of fatigue in patients with cancer. Early detection and management of fatigue is needed.

Abstract 4658: Use of a defined oleander extract by advanced cancer patients: Case reports on toxicity and tumor-related outcomes

Abstract The present study reports cases of advanced cancer patient taking an extract of Nerium oleander now in Phase 1 clinical trials in cancer patients. A phytochemical constituent of the extract, oleandrin, has multiple anticancer activities including inhibition of NF-kappaB and induction of apoptosis. We present case reports of 9 metastatic cancer patients who received the extract on personal use exemptions. Five of the patients also received full integrative programs at an integrative medicine center. Cases included 4 colon cancer patients, 3 pancreatic cancer patients (1 neuroendocrine and 2 adenocarcinoma), 1 renal cell carcinoma and 1 lung cancer patient. For the patients at the integrative center, all of whom took the extract during periods when they were receiving chemotherapy, toxicity grading of chemotherapy side effects was performed. We analyzed the case records for potential effects of the extract on tumor regression/stability in the absence of chemotherapy, survival time, use concurrent with chemotherapy and toxicity. The renal cell patient experienced tumor regression for 12 months with the extract alone; the 3 pancreatic cancer patients and a colon cancer patient experienced disease stabilization. Survival times were extended for all patients with survival times ranging from 32 months to 11 years for these patients with metastatic disease. Chemotherapy was well tolerated by colon cancer patients with only grade 1-2 toxicity during as many as 70 cycles of chemotherapy. Mild toxicities thought to be related to the extract included lightheadedness and mild tingling and burning of the mouth with use of the sublingual preparation. Severe toxicities including one myocardial infarction and one deep-vein thrombosis were observed but not suspected to be related to the extract. Good clinical outcomes and low toxicity were thus observed for the extract in these patients. Citation Format: Keith I. Block, Charlotte Gyllenhaal, Robert A. Newman. Use of a defined oleander extract by advanced cancer patients: Case reports on toxicity and tumor-related outcomes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4658. doi:10.1158/1538-7445.AM2014-4658

Molecular Prescreening Vs. Unselected Clinical Trials for Cancer Patients in a Tertiary Oncology Department

ABSTRACT Aim: Introduction: In the recent years the use of molecular biomarker–based in patient tumour samples has become more frequent for novel agents entering clinical development. However this strategy does not seem to translate into greater clinical benefit. Our study analyses the current clinical trial development scenario and if there are differences in terms of clinical results for patients participating in clinical trials (CTs) that require molecular prescreening comparing to patients who participate in unselected CTs. Methods: All clinical studies for patients with cancer refractory to standard therapy from Jan to Dec 2013 participating in our Clinical Trials Unit were analysed. Electronic medical records of patients enrolled in clinical trials according to molecular prescreening results, tumor type, previous lines of chemotherapy and number of cycles and best clinical response to the novel agent were recorded retrospectively. We analysed if molecular screening were performed in formalin-fixed, paraffin-embedded (FFPE) or in fresh biopsy samples. Results: A total of 126 patients with metastatic disease were treated in 34 CTs. Of those, 26,5 % were phase I, 38,24% were phase II and 26,5% were phase III. 48,8% CTs were performed in melanoma cancer patients, 17,5% in colon cancer pts, 13,5% in stomach-esophagus pts, 7,9% in breast and ovarian cancer pts each one, and in less percentage CTs were done in head and neck, pancreas and GBM cancer pts. 73% CTs required a mandatory biopsy for molecular screening, 50% were from archival tumour sample and 50% were from fresh biopsy. The median number of cycles were 4. Best complete response was CR 2,38%, PR 22,2%, SD 18,25%, PD 23,8% and 33,3% non evaluable. We did not observe any significant difference with regards median of treatment cycles nor response between CTs with molecular prescreening and those unselected CTs. Furthermore, there were no difference with regards clinical response between CTs using archival tumour samples vs. CTs using fresh biopsy. Conclusions: Molecular prescreening does not seem to add clinical benefit comparing to unselected CTs. More robust preclinical validation is required to better identify reliable molecular markers to predict clinical response. Disclosure: All authors have declared no conflicts of interest.

Choosing relevant endpoints for older breast cancer patients in clinical trials: an overview of all current clinical trials on breast cancer treatment.

With the ongoing ageing of western societies, the proportion of older breast cancer patients will increase. For several years, clinicians and researchers in geriatric oncology have urged for new clinical trials that address patient-related endpoints such as functional decline after treatment of older patients. The aim of this study was to present an overview of trial characteristics and endpoints of all currently running clinical trials in breast cancer, particularly in older patients. The clinical trial register of the United States National Institutes of Health Differences was searched for all current clinical trials on breast cancer treatment. Trial characteristics and endpoints were retrieved from the register and differences in characteristics between studies in older patients specifically (defined as a lower age-limit of 60years or older) and trials in all patients were assessed using χ(2) tests. We included 463 clinical trials. Nine trials (2%) specifically investigated breast cancer treatment in older patients. Ninety-one breast cancer trials included any patient-related endpoint (20%), while five trials specifically addressing older patients included any patient-related endpoint (56%, P=0.02). Five of the trials in older patients incorporated a geriatric assessment (56%). Clinical trials still rarely incorporate patient-related endpoints, even in trials that specifically address older patients. Trials that are specifically designed for older patients do not often incorporate a geriatric assessment in their design. This implicates that current clinical studies are not expected to fill the gap in knowledge concerning treatment of older breast cancer patients in the next decade.