Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2 + /HR + metastatic breast cancer.

PURPOSE: Dual anti-HER2 targeted therapy and chemotherapy is the current first-line standard of care for HER2 + metastatic breast cancer (MBC), with endocrine therapy (ET) the backbone of treatment in hormone receptor positive (HR +) disease. The potential ET benefit in HER2 + /HR + patients is unknown as pivotal dual anti-HER2 clinical trials precluded ET use. METHODS: Real-world data from a multi-site registry of consecutive HER2 + MBC patients treated at clinician discretion were examined. Patients that were HR + (ER + and/or PR +) and had received first-line chemotherapy alongside trastuzumab and pertuzumab were explored. Of 362 patients in the registry, 215 were excluded due to being HR- (n = 210) or not receiving chemotherapy (n = 5). RESULTS: Of the 147 patients included, 91 (62%) received concurrent ET and 56 (38%) had not. Comparing the groups, there were no significant differences in age, performance status, metastatic sites, use of previous therapy and de novo metastatic disease. More patients with ER + PR + disease versus those with ER + PR- or ER-PR + received ET (73 vs 45%). The addition of ET was associated with significantly improved 5-year PFS (HR 0.58, CI 0.37-0.89, p = 0.014) and OS (HR 0.52, CI 0.31-0.90, p = 0.018), with no increase in adverse events noted. CONCLUSION: The addition of ET to first-line dual anti-HER2 therapy post chemotherapy in patients with HER2 + /HR + MBC was associated with major gains in PFS and OS with no safety concerns evident. Further studies of this combination are justified, along with studies of how best to integrate other agents that are active in this patient subset, including CDK4/6 inhibitors.

Real-World Outcomes in Patients With Brain Metastases Secondary to HER2-Positive Breast Cancer: An Australian Multi-centre Registry-based Study.

BACKGROUND: The development of brain metastases occurs commonly in HER2-positive metastatic breast cancer and is associated with a poorer prognosis. The advent of HER2-targeted therapy has improved overall survival, but the benefit in patients with brain metastases is unclear, as these patients are often excluded from clinical trials. This study aimed to explore real-world outcomes in patients with brain metastases in HER2-positive MBC. MATERIALS & METHODS: Data was extracted from the TABITHA registry, which consists of patient data collected prospectively from 16 Australian sites from 24th February 2015 to 31st October 2021. Data analysed included characteristics of brain metastases, treatment received and survival outcomes. RESULTS: A total of 135 (37%) of 361 patients with HER2-positive MBC were diagnosed with brain metastases during their clinical course, including 45 (12%) with brain metastases at time of MBC diagnosis. 61 (45%) had ≥4 brain lesions. The most common local therapy given was whole brain radiation therapy (WBRT) (36%) followed by multi-modality treatment with both surgery and radiation therapy (27%). The majority of patients received first-line HER2-targeted treatment with trastuzumab and pertuzumab followed by second-line trastuzumab emtansine (T-DM1) but third-line therapy was heterogenous. The median overall survival in patients who developed brain metastases was significantly shorter than those who did not develop brain metastases (58.9 vs. 96.1 months, P = .02). CONCLUSION: Real-world patients diagnosed with brain metastases in HER2-positive MBC have a relatively poor prognosis, despite advances in HER2-targeted treatment. As the range of HER2-targeted treatment expands, it is important to pursue clinical trials that focus on patients with brain metastases.

A Phase 1 Proof of Concept Study Evaluating the Addition of an LSD1 Inhibitor to Nab-Paclitaxel in Advanced or Metastatic Breast Cancer (EPI-PRIMED).

Objective: Lysine-Specific Demethylase-1 (LSD1) is overexpressed in breast cancer cells and facilitate mesenchymal properties which may contribute to therapeutic resistance and cancer progression. The purpose of this study was to investigate the safety of combination, nab-paclitaxel and phenelzine, an irreversible LSD1 inhibitor in patients with metastatic breast cancer (mBC). Methods: Eligible patients with mBC were treated with nab-paclitaxel (100mg/m2) weekly for 3 weeks with one week break in a 28-day cycle. Dose escalation of phenelzine followed the Cumulative Cohort Design and phenelzine treatment commenced from day 2 of first cycle. Eleven patients were screened, and eligible patients were enrolled in cohorts with the dose of phenelzine ranging from 45mg to 90mg. Results: The Optimum Biological Dose was established at 60mg of phenelzine daily in combination with nab-paclitaxel and considered as the recommended phase 2 dose. Most (95%) of adverse events were grade 1 or 2 with two grade 3 events being diarrhea and neutropenia at 45mg and 60mg phenelzine respectively, with no unexpected toxicity/deaths. Commonly reported toxicities were fatigue (n=4,50%), dizziness (n=6,75%), neutropenia (n=3,37.5%), peripheral neuropathy (n=3,37.5%), diarrhea (n=2,25%), and hallucination (n=2,25%). After a median follow up of 113 weeks, all patients showed disease progression on trial with 4 patients being alive at the time of data cut off, including one patient with triple negative breast cancer. Median progression-free survival was 34 weeks. Significant inhibition of LSD1 and suppression of mesenchymal markers in circulating tumor cells were noted. Conclusion: Phenelzine in combination with nab-paclitaxel was well tolerated, without any unexpected toxicities in patients with mBC and demonstrated evidence of antitumor activity. For the first time, this proof-of-concept study showed in-vivo inhibition of LSD1 suppressed mesenchymal markers, which are known to facilitate generation of cancer stem cells with metastatic potential. Clinical Trial Registration: ClinicalTrials.Gov NCT03505528, UTN of U1111-1197-5518.

Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8+ T Cells in Immunotherapy-Resistant and Metastatic Cancers.

Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8+ T cells isolated from stage IV immunotherapy-resistant metastatic cancer patients. We show for the first time that nPKC-θ complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1+/CD8+ T cells. nPKC-θi2 inhibited the ZEB1/PKC-θ repressive complex to induce cytokine production in CD8+ T cells isolated from patients with immunotherapy-resistant disease. These data establish for the first time that nPKC-θ mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8+ T cells. Disrupting nPKC-θ but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy.

Uptake of bone-modifying agents in patients with HER2+ metastatic breast cancer with bone metastases - prospective data from a multi-site Australian registry.

BACKGROUND: International practice guidelines recommend administration of bone-modifying agents (BMA) in metastatic breast cancer (MBC) patients with bone metastases to reduce skeletal-related events (SRE). Optimal delivery of BMA in routine clinical practice, including agent selection and prescribing intervals, remains unclear. AIM: To describe real-world practice of Australian breast oncologists. METHODS: Prospective data from February 2015 to July 2020 on BMA delivery to MBC patients with bone metastases was analysed from Treatment of Advanced Breast Cancer in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Australian Patient (TABITHA), a multi-site Australian HER2+ MBC registry. RESULTS: Of 333 HER2+ MBC patients, 171 (51%) had bone metastases at diagnosis, with a mean age of 58.1 years (range, 32-87). One hundred and thirty (76%) patients received a BMA, with 90 (69%) receiving denosumab and 40 (31%) receiving a bisphosphonate. Patients who received a BMA were more likely to have received concurrent first-line systemic anti-HER2 therapy (95% vs 83%; P = 0.04), to present with bone-only metastases at diagnosis (24% vs 7%; P = 0.02) and less likely to have visceral metastases (51% vs 71%; P = 0.03). Ten of 40 (25%) bisphosphonate patients and 45 of 90 (50%) denosumab patients received their BMA at the recommended 4-weekly interval. Prescribing intervals varied over time. Adverse events reported were consistent with clinical trial data. CONCLUSION: Three-quarters of Australian HER2+ MBC patients with bone metastases receive a BMA, often at different schedules than guidelines recommend. Further studies, including all MBC subtypes, are warranted to better understand clinicians' prescribing rationale and potential consequences of current prescribing practice on SRE incidence.

Simple and effective bacterial-based intratumoral cancer immunotherapy.

BACKGROUND: We describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund's adjuvant (CFA)) in three preclinical species and in human cancer patients. METHODS: Efficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient. RESULTS: Significantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided. CONCLUSION: Our data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.

Impact of prior (neo)adjuvant trastuzumab (NAT) exposure on the efficacy of HER2-targeted therapy for metastatic breast cancer.

PURPOSE: Trastuzumab, pertuzumab, and docetaxel are the standard first-line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC). However, only 10% of patients received neoadjuvant and/or adjuvant trastuzumab (NAT) in the registration trial (NCT00567190). In contemporary practice, the majority of recurrent HER2+ MBC patients had prior NAT. We explore any impact of prior therapy on the efficacy of dual HER2-targeted antibody with taxane therapy for metastatic disease. METHODS: Utilising a prospective national registry, clinico-pathological, treatment, and outcome data for HER2+ MBC patients diagnosed between October 2006 and January 2019 were collected. Survival was estimated by the Kaplan-Meier method and compared among groups by log-rank test. RESULTS: Of 287 HER2+ MBC patients, 222 (77%) received first-line trastuzumab, pertuzumab, and taxane therapy. There were 130 (45%) with de novo MBC. Of the recurrent MBC patients 107/157 (68%) had received NAT. The median progression-free survival (PFS) among patients who received NAT was 15.8 months compared with 24.3 months without prior NAT (hazard ratio [HR] 1.45, 95% CI 1.05-2.03, p = 0.03). The median overall survival (OS) was 42.7 months in patients who had NAT, and was not reached in those who did not (HR 1.80, 95% CI 1.12-2.90, p = 0.02). However, when excluding de novo MBC patients, prior NAT exposure was no longer significantly associated with survival (p = 0.11). De novo MBC patients had the longest median PFS (25.2 months) and OS (91.2 months). CONCLUSIONS: Prior receipt of NAT was associated with inferior median PFS following first-line HER2-based therapy in the metastatic setting. However, prior NAT exposure did not significantly impact OS, supporting the efficacy of taxane, trastuzumab, pertuzumab combination for first-line HER2+ MBC regardless of prior NAT exposure. Patients with de novo MBC had the longest survival, suggesting stratification for synchronous versus metachronous disease in prospective clinical trials of MBC should be considered.

Association between tyrosine-kinase inhibitor induced hypertension and treatment outcomes in metastatic renal cancer.

BACKGROUND: Tyrosine-kinase inhibitor (TKI) drugs have been considered first line treatment for metastatic renal cell cancer (RCC) for over a decade. TKI-induced hypertension is a common adverse-event in patients treated for metastatic RCC. AIM: This study was aimed at investigating an association between TKI-induced hypertension and treatment outcomes for metastatic RCC patients. METHODS AND RESULTS: Retrospective data pertaining to patients with histologically or radiologically confirmed metastatic RCC treated with sunitinib, pazopanib, sorafenib, axitinib or cabozantinib between June 2012 and May 2019 were evaluated. Clinical information and serial blood pressure measurements were extracted from medical records for each patient. We compared objective response rate, progression-free survival (PFS), and 12-month survival between TKI-induced hypertension (TIH) and non-TIH groups using χ2 and Mann-Whitney tests. Out of 72 patients screened, 52 met study eligibility criteria. The median age at diagnosis was 61 years (range: 42-85 years) with a clear male predominance. The majority of patients had a history of nephrectomy with clear cell pathology. Almost all patients were on first-line TKI therapy with sunitinib or pazopanib. Median follow-up was 11 months. About half of patients developed TKI-induced hypertension (grade 2-3). In the TIH group 82% were commenced on an antihypertensive agent. Median PFS measured 30.5 weeks for TIH group compared to 22.2 weeks for non-TIH (P = .05). The 6 month and 12 month survival rates for TIH were 82% and 56%, respectively, as compared to 76% and 44% for non-TIH. CONCLUSION: The occurrence of TKI-induced hypertension was found to be a positive prognostic factor for progression in patients with metastatic RCC.

Targeting Nuclear LSD1 to Reprogram Cancer Cells and Reinvigorate Exhausted T Cells via a Novel LSD1-EOMES Switch.

Lysine specific demethylase 1 (LSD1) is a key epigenetic eraser enzyme implicated in cancer metastases and recurrence. Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) has been shown to be critical for the development of breast cancer stem cells. Here we show that circulating tumor cells isolated from immunotherapy-resistant metastatic melanoma patients express higher levels of nLSD1p compared to responders, which is associated with co-expression of stem-like, mesenchymal genes. Targeting nLSD1p with selective nLSD1 inhibitors better inhibits the stem-like mesenchymal signature than traditional FAD-specific LSD1 catalytic inhibitors such as GSK2879552. We also demonstrate that nLSD1p is enriched in PD-1+CD8+ T cells from resistant melanoma patients and 4T1 immunotherapy-resistant mice. Targeting the LSD1p nuclear axis induces IFN-γ/TNF-α-expressing CD8+ T cell infiltration into the tumors of 4T1 immunotherapy-resistant mice, which is further augmented by combined immunotherapy. Underpinning these observations, nLSD1p is regulated by the key T cell exhaustion transcription factor EOMES in dysfunctional CD8+ T cells. EOMES co-exists with nLSD1p in PD-1+CD8+ T cells in resistant patients, and nLSD1p regulates EOMES nuclear dynamics via demethylation/acetylation switching of critical EOMES residues. Using novel antibodies to target these post-translational modifications, we show that EOMES demethylation/acetylation is reciprocally expressed in resistant and responder patients. Overall, we show for the first time that dual inhibition of metastatic cancer cells and re-invigoration of the immune system requires LSD1 inhibitors that target the nLSD1p axis.

Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer.

DUSP6 is a dual-specificity phosphatase (DUSP) involved in breast cancer progression, recurrence, and metastasis. DUSP6 is predominantly cytoplasmic in HER2+ primary breast cancer cells, but the expression and subcellular localization of DUSPs, especially DUSP6, in HER2-positive circulating tumor cells (CTCs) is unknown. Here we used the DEPArray system to identify and isolate CTCs from metastatic triple negative breast cancer (TNBC) patients and performed single-cell NanoString analysis to quantify cancer pathway gene expression in HER2-positive and HER2-negative CTC populations. All TNBC patients contained HER2-positive CTCs. HER2-positive CTCs were associated with increased ERK1/ERK2 expression, which are direct DUSP6 targets. DUSP6 protein expression was predominantly nuclear in breast CTCs and the brain metastases but not pleura or lung metastases of TNBC patients. Therefore, nuclear DUSP6 may play a role in the association with cancer spreading in TNBC patients, including brain metastasis.

Eligibility criteria for phase I clinical trials: tight vs loose?

PURPOSE: The purpose of the current study is to analyze a series of phase I cancer clinical trials, examine and compare trial protocols based on patients' eligibility criteria. METHODS: We evaluated all dose escalation phase I trial protocols with accessible or published results performed at Institute for Drug Development, Cancer Therapy and Research Center (San Antonio) between 1991 and 2016. Study protocols were categorized as non-restrictive (NRP) or restrictive (RP) based on several eligibility parameters. Fisher's Exact and Chi-square tests were used to compare characteristics of NRP and RP. RESULTS: Of 284 protocols screened, 231 dose escalation phase I trial protocols (with accessible results) of solid tumors were included in this review. There were 145 NRP (involving 3190 patients) and 86 RP (involving 1892 patients). The median number of exclusion criteria for NRP and RP were 14 and 23, respectively. The most common reasons that made trial protocol to be restrictive were ECOG ≤ 1, strict requirements for renal or hepatic function (≤ 2.5 times upper limit of normal) and exclusion of subjects with brain metastases. The median accrual time for NRP was significantly shorter as compared to RP (17 vs 26 months). The median number of dose levels explored in NRP and RP were 9 and 6, respectively. RP had a higher screen failure as well as premature closure rate. The rates of DLTs, SAEs, toxicity-related death and response were not different between the two groups. CONCLUSIONS: Our study findings are in support of devising well thought and justified phase I study eligibility criteria.

Increasing complexity in oncology phase I clinical trials.

Clinical trials in oncology have become increasingly complex because of incorporation of predictive biomarkers and patient selection based on molecular profiling of tumors. We have examined the change in procedures and work intensity in phase 1 oncology trials over the years with several parameters used as surrogates of complexity. Categories that were included as events were clinical evaluations, pharmacokinetic (PK) laboratory tests, non-PK laboratory tests, specific molecular or histological characteristics, questionnaires and subjective assessments, routine clinical and physical examinations, imaging, invasive procedures and others. The information was extracted using a standardized form including study type, tumor type, information on agent, participant characteristics and study mandated events during the first 3 cycles of each protocol. A total of 102 phase I oncology and hematology study protocols that were active at a single institution in 1996, 2006 and 2016 were evaluated. In 2016, there were significantly more (P < 0.05) median number of procedures, outpatient tests, subjective assessments, PK's, molecular profiling, biopsies and medication dispensing times. There were higher median numbers of procedures in studies in hematologic malignancies, testing immunotherapies and those with over 15 inclusion or exclusion criteria. These values also differed significantly (P < .005) when the median values were compared in nonparametric tests. Our results suggest that study related procedures in cancer phase I trials have substantially increased over the last two decades. The successful conduct of early-phase oncology clinical trials in future will require additional research resources.

Optimizing poly (ADP-ribose) polymerase inhibition through combined epigenetic and immunotherapy.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune-directed therapies for other solid organ malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination DNA repair-deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in homologous recombination that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed cell death-ligand 1 (PD-L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death-1 (PD-1)/PD-L1 inhibitors to PARPi might improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine-specific histone demethylase-1A and histone deacetylase inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as lysine-specific histone demethylase-1A inhibitors or histone deacetylase inhibitors with PARPi/anti-PD-1/PD-L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach could pave the way for the identification of new upstream epigenetic and genetic signatures.

A comparison of the quality of informed consent for phase I oncology trials over a 30-year period.

PURPOSE: Efforts are underway in improving the informed consent process. The success of these efforts to improve quality of informed consent forms (ICFs) for phase I oncology trials has not been previously measured. METHODS: We reviewed and compared ICFs of all phase I trials for metastatic cancer conducted between 1986 and 1999 and 2000-2015 periods at our institution. Information pertaining to ICF length, study purpose description, research regimen/methods, potential risks and benefits was extracted. The reading level was assessed by Flesch-Kincaid readability tests. RESULTS: Of 364 ICFs screened, 310 ICFs were included in this analysis. The median length of ICFs from 1986 to 1999 and 2000-2015 was 12 and 23 pages, respectively. Only 42% (1986-1999) and 57% (2000-2015) of ICFs stated that individual participants might not benefit from treatment. Only 21% (1986-1999) and 12% (2000-2015) of all ICFs were written at ≤ 8th grade reading level. The median FRE, FKGL and GFI readability scores of ICFs from 1986 to 1999 were 53.6, 8.8, and 9.5, respectively. The median FRE, FKGL, and GFI scores of studies from 2000 to 2015 were 48.5, 10.7, and 12.4, respectively. These scores indicate that the ICF text was too hard for most people to read. The mechanism of action of the treatment, study schema/calendar, possibility of experiencing unexpected risks or death, and risks to pregnant/lactating women were not reported in a substantial number of forms. CONCLUSIONS: Our results show that ICFs for phase I oncology trials over last 30 years have become longer, more difficult to read but are still lacking some important information.

A phase I pharmacokinetic and pharmacodynamic study of GTI-2040 in combination with gemcitabine in patients with solid tumors.

PURPOSE: GTI-2040 is a novel antisense oligonucleotide inhibitor of the R2 subunit of ribonucleotide reductase. This phase I study assessed safety and maximum tolerated dose (MTD) of GTI-2040 in combination with weekly gemcitabine in patients with advanced solid tumors. METHODS: GTI-2040 was given as a 14-day continuous intravenous infusion, while gemcitabine was administered on days 1, 8, and 15. This combination was repeated every 4 weeks and study followed a modified 3 + 3 Fibonacci schema. Incidence, severity of adverse events, pharmacokinetics (PK), and pharmacodynamics (PD) was assessed. Responses were assessed using RECIST criteria version 1.0 with CT scans performed after every other cycle. RESULTS: A total of 16 patients received at least one dose of GTI-2040/gemcitabine and were included in the safety analysis. The MTD of this regimen is 100 mg/m2/day of GTI-2040 over 14 days combined with 400 mg/m2/day of gemcitabine administered weekly on days 1, 8, and 15. The dose-limiting toxicities (DLTs) included grade 3 fatigue and thrombocytopenia with hematemesis (both at 100/600 mg/m2/day). The most common adverse events were grade 1/2 fatigue, nausea, vomiting, diarrhea, and anorexia. There was no evidence of alteration in gemcitabine PKs. PD modulation of R2mRNA expression in peripheral blood mononuclear cells was observed. No objective tumor response was observed although stable disease was seen in 25% patients. CONCLUSIONS: The combination of GTI-2040 and gemcitabine has an acceptable safety profile in a heavily pre-treated patient population with advanced solid tumors. No clear signal of anti-tumor activity was observed; however, several patients had prolonged stable disease.

Role of immunotherapy in bladder cancer: past, present and future.

As research focus in oncology has recently shifted from oral targeted therapy to immunomodulation, the era of successful drug development in bladder cancer has just begun. This has led to unprecedented approval of five immunotherapeutic agents by regulatory agencies for metastatic bladder cancer within a span of 12 months. With an initial triumph of anti-programmed cell death-1 (anti-PD-1) and anti-programmed cell death ligand-1 (anti-PDL-1) drugs, ongoing efforts are aimed at identification and validation of new druggable immune targets to consolidate the initial gains. In this paper, we review the role of immunotherapy in the treatment of bladder cancer as well as the various emerging immunotherapeutic agents and their possible use in bladder cancer.

Single institutional series of neuroendocrine tumors managed in the Australian Capital Territory.

AIMS: Retrospective review of neuroendocrine tumors (NETs) treated within the Australian Capital Territory to describe the local epidemiology and assess prognostic clinicopathological factors. METHODS: Patients with histologically proven non-pulmonary low to intermediate grade NETs were identified from our hospital clinical database. Data were analyzed according to epidemiological, clinical and histopathological characteristics. RESULTS: Of the 107 included patients, the most common primary tumor site was jejunum/ileum (32%), followed by rectum (22%) and pancreas (11.2%). In total, 32% had distant metastases at presentation, most commonly in the liver. Most patients were symptomatic at diagnosis, while 22.4% of cases were found incidentally. Second malignancies, in particular of gastrointestinal origin, were diagnosed in 33.6%. Surgical debulking was the most common treatment (59.8%) while 18% had multimodality therapy. With a median follow-up of 25 months from diagnosis, about 78% of patients are still alive. Median time to first relapse was 15 months and the 5-year survival rate was 80% for NETs of jejunum/ileum. Univariate survival analysis revealed tumor location, high Ki67 index, raised plasma chromogranin A, and urine 5-hydroxyindoleacetic acid upon diagnosis to be associated with shorter 5-year survival. CONCLUSION: The epidemiologic characteristics and long-term outcome in our series are comparable to other reported studies. This analysis presents some important prognostic factors which could be used for risk stratification in patients with NETs.

Advanced Cancer Patients' Understanding and Perceptions of Phase I Clinical Trials.

This questionnaire-based study assessed the understanding and perceptions of cancer patients who were participating in a Phase I clinical trial at baseline and determined any changes after enrollment. Thirty-six patients participated. Less than one-third of respondents (28.5%) thought the purpose of Phase I trials was dose escalation for safety and efficacy. Patients anticipated varying degree of therapeutic benefit ranging from stable disease (47.1%) to complete shrinkage of the tumor (32.4%). No change in measured themes was observed. Patients participating in Phase I trials need further education to improve their understanding of the true intent of early Phase trials.

Phase I study of intravenously administered ATI-1123, a liposomal docetaxel formulation in patients with advanced solid tumors.

PURPOSE: ATI-1123 is a liposomal formulation of docetaxel and may be administered without the premedications and hypersensitivity reactions. This Phase I study examines the safety, tolerability, pharmacokinetics (PKs), and antitumor activity of ATI-1123. METHODS: Patients with advanced solid malignancies received escalating doses of ATI-1123 intravenously over 1-h every 3 weeks. The dosing commenced using an accelerated titration design and was followed by a modified 3 + 3 Fibonacci schema to determine maximally tolerated dose (MTD). Plasma was analyzed for encapsulated/non-encapsulated docetaxel; PK analyses were performed using model independent method. Response was assessed using RECIST criteria. RESULTS: In total, 29 patients received doses ranging from 15 to 110 mg/m(2). At 110 mg/m(2), two of six patients experienced dose-limiting toxicities including grade 3 stomatitis and febrile neutropenia. The 90 mg/m(2) cohort was expanded to ten patients and identified as the MTD. The most common adverse events were fatigue, nausea, neutropenia, anemia, anorexia, and diarrhea. ATI-1123 exhibited linear and dose proportional PKs. One patient with lung cancer had confirmed partial response, and stable disease was observed in 75 % patients. CONCLUSIONS: ATI-1123 demonstrated an acceptable tolerability and favorable PK profile in patients with solid tumors. Our results provide support for Phase II trials to determine the antitumor activity of this drug.

Eligibility of patients with renal impairment for Phase I trials: Time for a rethink?

Since the inception of Phase I clinical trials in cancer, patients with renal dysfunction have commonly been excluded from participation because of a poor outlook. Most cancer drugs are approved with limited information on the pharmacokinetics and/or pharmacodynamics of the drugs in patients with renal dysfunction, and no formal renal dysfunction study is ever undertaken. Patients with asymptomatic mild to moderate renal dysfunction pose an increasingly frequent challenge for clinicians. In this paper, we discuss that a subset of patients with asymptomatic mild to moderate renal impairment might be appropriately entered into selected Phase I trials. This will provide physicians timely data of the new agents in this patient population and increase patients' access to experimental treatments.