Incurable Solid Tumors Research Articles

Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms (NCT03207347).

e22061 Background: BRCA-associated protein-1 (BAP1) is a ubiquitin ligase associated with regulating cell cycle, cell proliferation, DNA damage pathway, and cell death. It also acts as a tumor suppressor gene as seen in hereditary cancer syndrome associated with germline mutations in BAP1. Preclinical studies have shown that PARP-inhibitor treatment of BAP1 mutant cell lines demonstrated significant synthetic lethality, independent of underlying BRCA status suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of several solid tumors including cholangiocarcinoma, mesothelioma, uveal melanoma, and clear cell renal cell carcinoma. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in two biologically distinct cohorts. Eligible patients (pts) with measurable metastatic and incurable solid tumors are assigned to one of the two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via Next Generation Sequencing (NGS); or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Key inclusion criteria also include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG PS of 0 to 1. Key exclusion criteria include known BRCA1 or BRCA2 mutations or prior PARPi exposure. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate (ORR), and secondary endpoints are progression free survival (PFS), overall survival (OS), toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort B enrollment is closed. Enrollment in Cohort A continues. A maximum of 47 evaluable subjects is planned with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]

Profiling and prognostic implications of variants of unknown significance (VUS) in solid tumors.

e19012 Background: While precision oncology is becoming increasingly integrated into standard of care for most incurable solid tumor malignancies, there is paucity of data regarding the clinical significance of VUS. In this study, we aim to evaluate whether the number of VUS is associated with overall survival (OS). We also analyze racial disparities pertaining to the number of VUS present and identify which, if any, genes possess prognostic implications. Methods: This is a retrospective review of 389 consecutive patients seen at Cleveland Clinic from 2014 to 2016 with incurable solid tumor malignancies, for whom next-generation sequencing (NGS) was ordered using Foundation One™ (Cambridge, MA). Demographics, number of VUS, genes involved, and race were summarized. OS was estimated by Kaplan-Meier and compared by log rank test. Results: Median age was 60 years, 202 (52%) patients were female, 338 (86.7%) were Caucasian, and 31 (8.0%) were African American. On NGS, 376 (97%) patients had VUS reported. The median number of VUS was 9 (range 1-116). When dichotomized at the median, the number of VUS did not affect OS. Genes most commonly implicated in reported VUS were LRP1B (88, 22.6%), MLL3 (83, 21.3%), MLL2 (73, 18.8%), ARID1B (70, 18.0%), PRKDC (60, 15.4%), PREX2 (58, 18.7%), and SPTA1 (56, 14.4%). Patients found to have a variant of unknown significance in MLL2 had worse median OS as compared to those who did not (2.61 vs 3.76 years respectively; p = 0.033). When profiled by race, Caucasians had lower numbers of VUS (p = 0.002; Table). Conclusions: We did not find a clear association between the number of VUS and OS. MLL2, a gene known to predict poor prognosis as a pathogenic variant, was seen in our study to have similarly poor prognostic implications as a variant of unknown significance. Racial disparities in genomics exist as African Americans are under-represented and have greater numbers of VUS as compared to Caucasians. Further research is warranted to elucidate these disparities. [Table: see text]

Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.

TPS591 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks on treatment. Enrollment continues to a maximum of 47 evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]

Quality of Life of Caregivers of Older Patients with Advanced Cancer.

To evaluate the relationships between aging-related domains captured by geriatric assessment (GA) for older patients with advanced cancer and caregivers' emotional health and quality of life (QOL). In this cross sectional study of baseline data from a nationwide investigation of older patients and their caregivers, patients completed a GA that included validated tests to evaluate eight domains of health (eg, function, cognition). Thirty-one community oncology practices throughout the United States. Enrolled patients were aged 70 and older, had one or more GA domain impaired, and had an incurable solid tumor malignancy or lymphoma. Each could choose one caregiver to enroll. Caregivers completed the Generalized Anxiety Disorder-7, Distress Thermometer, Patient Health Questionnaire-2 (depression), and Short Form Health Survey-12 (SF-12 for QOL). Separate multivariate linear or logistic regression models were used to examine the association of the number and type of patient GA impairments with caregiver outcomes, controlling for patient and caregiver covariates. A total of 541 patients were enrolled, 414 with a caregiver. Almost half (43.5%) of the caregivers screened positive for distress, 24.4% for anxiety, and 18.9% for depression. Higher numbers of patient GA domain impairments were associated with caregiver depression (adjusted odds ratio [aOR] = 1.29; P < .001], caregiver physical health on SF-12 (regression coefficient [β] = -1.24; P < .001), and overall caregiver QOL (β = -1.14; P < .01). Impaired patient function was associated with lower caregiver QOL (β = -4.11; P < .001). Impaired patient nutrition was associated with caregiver depression (aOR = 2.08; P < .01). Lower caregiver age, caregiver comorbidity, and patient distress were also associated with worse caregiver outcomes. Patient GA impairments were associated with poorer emotional health and lower QOL of caregivers. J Am Geriatr Soc 67:969-977, 2019.

Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis

Gliomas are incurable solid tumors with extremely high relapse rate and definite mortality. As gliomas readily acquire resistance to only approved drug, temozolomide (TMZ), there is increasing need to overcome drug resistance by novel therapeutics or by repurposing the existing therapy. In the current study, we investigated antitumor efficacy of roscovitine, a Cdk inhibitor, in combination with TMZ in vitro (U87, U373, LN 18 and C6 cell lines) and in vivo (orthotopic glioma model in Wistar rats) glioma models. We observed that TMZ treatment following a pre-treatment with RSV significantly enhanced chemo-sensitivity and suppressed the growth of glioma cells by reducing Cdk-5 activity and simultaneous induction of autophagy and Caspase-3 mediated apoptosis. Additionally, reduced expression of Ki67, GFAP and markers of angiogenesis (CD31, VEGF) was observed in case of TMZ + RSV treatments. Also, presence of reactive astrocytes in peri-tumoral areas and in areas around blood vessels was completely diminished in TMZ + RSV treated brain sections. Taken together, results in the current study provide evidence that RSV in conjunction with TMZ restricts glioma growth, reduces angiogenesis and also eliminates reactive astrocytes thereby preventing the spread of glioma to adjacent healthy brain tissues and thus might be more potent therapeutic option for glioma.

Delivering Precision Oncology in a Community Cancer Program: Results From a Prospective Observational Study.

Precision oncology (PO) is a growing treatment approach in the era of next-generation sequencing (NGS) and matched therapies. Effective delivery of PO in the community has not been extensively studied. Our program developed a virtual molecular tumor board (MTB) strategy to help guide PO care. Over 18 months, eligible adult patients with advanced, incurable solid tumor malignancies were enrolled in a molecular profiling (MP) study using the Foundation Medicine NGS panel. Results were reviewed through a weekly, videoconferenced MTB conducted across our largely rural integrated health system. Recommendations from the MTB were used to identify actionable alterations (AAs). Feasibility of PO care delivery was assessed as the primary outcome. Secondary outcomes included the frequency of AAs, genomic matched treatments, genomic matched clinical trial enrollment, and clinical outcomes. A total of 120 participants with a variety of advanced tumor types were enrolled. Of these, 109 (90.8%) had successful MP. Treatment on the basis of an AA was recommended by the MTB in 58% of patients (63 of 109) who had a successful MP result. For those completing MP, treatments included enrollment in a genomic matched clinical trial (n = 16; 14.6%) and genomic matched treatment with a Food and Drug Administration-approved agent (n = 23; 21.1%). Response and survival data were similar regardless of the matched treatment option chosen. A video-conferenced MTB-facilitated NGS testing and treatment delivery system was implemented in our integrated community oncology program. Continued use of this model aims to increase understanding of the impact of PO in this setting.

Precision Oncology in Solid Tumors: A Longitudinal Tertiary Care Center Experience.

Precision oncology is widely discussed, but cohort studies are limited. We previously reported our prospective experience of precision oncology in solid tumors, and here we report our longitudinal experience, focusing on therapeutic impact. We conducted a retrospective review of 600 consecutive patients seen at Cleveland Clinic from 2013 to 2016 for treatment of incurable solid tumor malignancies for whom tumor genomic profiling was ordered using FoundationOne (Cambridge, MA). Results were discussed at our multidisciplinary genomics tumor board. Data analyzed included subsequent therapy and overall survival (OS). Median age was 59 years (range, 18 to 94 years), 308 (51.3%) were female, and 533 (88.8%) were white. Targeted therapy was recommended in 310 patients (51.7%). After results, 313 patients (52.2%) started any subsequent therapy; of these, 95 (30%; 15.8% overall) received genomics-driven therapy (G), and 218 (70%) received non-genomics-driven treatment (NG). For the G versus NG group, the on-label, off-label, and clinical trial therapy breakdowns were 23% versus 88%, 47% versus 3%, and 30% versus 9%, respectively. Median OS for patients receiving no therapy after tumor genomic profiling was 5.5 months; for the G and NG groups, it was 18 (P < .001) and 14.4 (P < .001) months, respectively (P = NS for G v NG). The use of G increased from 10% in the first 250-patient cohort (reported earlier) to 20% in the subsequent 350-patient cohort. Tumor genomic profiling influenced treatment in 15.8% of patients. More patients received treatment via clinical trials in the G cohort, and although not statistically significant, there was a trend toward increased OS in the G (v NG) group. These data can further guide real-world applications of precision oncology.

The institution of a white cell growth factor appropriate non-use policy for incurable metastatic solid tumors within a community oncology practice.

33 Background: Texas Oncology (TO) is a community-based practice. with over 250 physicians (MD) who order chemotherapy. In 2015, pegfilgrastim (pgcsf) was the highest individual drug in billed claims. Concurrently, TO was participating in the United Healthcare (UHC) Episode of Care (EOC) program and anticipating the Oncology Care Model. Patient and program expense dictated understanding pgcsf utilization. Methods: Data were obtained in 9/2015 from EOC claims to identify overall and individual pgcsf use in solid tumor metastatic disease (MDx). Chart review was done for the top prescribers. In 3/16, ASCO pgcsf guidelines and TO education materials were emailed to all physicians. In 3/17 appropriate non-use recommendations were communicated and a real-time internal approval process begun. On 10/1/2017, UHC instituted a pgcsf prior authorization (PA) program. Retrospective data from the iKnowMed EHR system was collected in 3-month intervals from April 2016 through March 2018 and evaluated for number of pgcsf administrations at TO for MDx, as well as, administrations/provider/quarter for TO and The US Oncology Network. MDx was defined by any of the following criteria: stage IV at diagnosis (with certain disease exceptions); TNM M value of “1” or “+”; a metastatic line of therapy; evidence of metastatic disease documented within the EHR. Results: Initial survey of EOC claims indicated 16% of patients received pgcsf for MDx. Rates per MD ranged from 0 to 57%. Review of the top users indicated 90% of uses could have been addressed with dose reduction. In the first measured quarter of April to June 2016 to the last, October to December 2017, pgcsf use dropped by 50%. Changes for some diseases were dramatic: Use in colon cancer fell from 132 uses/quarter to a low of 46, and for non-small lung cancer – 80 to 23 respectively. Conclusions: The deadopting of low value care can be challenging. In the case of pgcsf substantial reductions in use were achieved using data and guidelines for education in the setting of value based contracts. Ultimately, the most change was achieved by an internal real time approval process. This was reinforced by a payer PA requirement.

Nutrient scavenging in cancer.

While cancer cell proliferation depends on access to extracellular nutrients, inadequate tumour perfusion means that glucose, amino acids and lipids are often in short supply. To overcome this obstacle to growth, cancer cells utilize multiple scavenging strategies, obtaining macromolecules from the microenvironment and breaking them down in the lysosome to produce substrates for ATP generation and anabolism. Recent studies have revealed four scavenging pathways that support cancer cell proliferation in low-nutrient environments: scavenging of extracellular matrix proteins via integrins, receptor-mediated albumin uptake and catabolism, macropinocytic consumption of multiple components of the tumour microenvironment and the engulfment and degradation of entire live cells via entosis. New evidence suggests that blocking these pathways alone or in combination could provide substantial benefits to patients with incurable solid tumours. Both US Food and Drug Administration (FDA)-approved drugs and severalagents in preclinical or clinical development shut down individual or multiple scavenging pathways. These therapies may increase the extent and durability of tumour growth inhibition and/or prevent the development of resistance when used in combination with existing treatments. This Review summarizes the evidence suggesting that scavenging pathways drive tumour growth, highlights recent advances that define the oncogenic signal transduction pathways that regulate scavenging and considers the benefits and detriments of therapeutic strategies targeting scavenging that are currently under development.

Abstract 1644: Progression-free survival (PFS) as a surrogate for overall survival (OS)

Abstract Background: PFS is criticized as being not reliably predictive of OS, and statistically significant gains may be clinically insignificant. However, PFS has the advantage as an endpoint of needing shorter follow up/fewer patients and is not rendered falsely negative by crossover (CO) and long post progression survival (PPS). Absolute PFS gain may be a surrogate for absolute OS gain (Ann Oncol 2016;27:373). Method: We extracted PFS/OS data from randomized drug comparisons with &amp;gt;200 incurable solid tumor patients published 01/2007-06/12/2017 in J Clinical Oncology and New England J Medicine. For comparisons with CO unspecified or in &amp;lt;20% of patients, and p&amp;lt;0.05 for PFS or OS, we used nonlinear regression analysis (NLRA) of PFS/OS curves (omitting curve sections with &amp;lt;~10 residual patients) to determine PFS/OS half-lives (t1/2s: time to progression/death in half the remaining patients). We calculated ΔmPFS and ΔmOS (experimental minus control arm medians) and ΔPFSt1/2 and ΔOSt1/2 (experimental minus control arm t1/2s). Results: 249 trials and 287 across-arm comparisons were evaluable. The table presents ΔPFS/ΔOS associations for studies with PFS p&amp;lt;0.05 and CO&amp;lt;20% or unspecified. PFS changenNo. (%) of comparisons with associated change in OS (ΔmOS for ΔmPFS or ΔOSt1/2 for ΔPFSt1/2)ΔOS &amp;lt;2 monthsΔOS &amp;gt; 2 monthsΔmPFS: &amp;lt;1.5 months3224 (75%)8 (25%)&amp;gt;1.5 months4722 (47%)25 (53%)ΔPFSt1/2: &amp;lt;1.5 months3531 (89%)4 (11%)&amp;gt;1.5 months6210 (16%)52 (84%)&amp;gt;2 months414 (10%)37 (90%)ΔOS &amp;lt;3 monthsΔOS &amp;gt;3 monthsΔPFSt1/2: &amp;gt;3 months263 (12%)23 (88%)ΔOS &amp;lt;4 monthsΔOS &amp;gt;4 monthsΔPFSt1/2: &amp;gt;4 months131 (8%)12 (92%)Concordance of ΔOS with ΔPFS for ΔPFS &amp;lt; vs &amp;gt;1.5 months better for t1/2s than medians, Fisher's exact test p=0.0004, and correlation of ΔOS with ΔPFS was also better for t1/2s (R2=0.60, p&amp;lt;0.0001, slope = 1.51) than for medians (R2=0.37, p&amp;lt;0.0001, slope = 0.88) To assess the risk of ΔPFS under-predicting ΔOS, we then assessed all comparisons, irrespective of CO and PFS significance. Of 287 comparisons, 13 (5%) had ΔOS &amp;gt;2m with p&amp;lt;0.05 but ΔPFS &amp;lt;1.5m or ΔPFS p&amp;gt;0.05. In 7/13, PFS curves fit NLRA 2-phase decay models (suggesting 2 distinct subpopulations), vs 25/100 with PFS 2-phase decay in other comparisons (Fisher's exact test p=0.047). Conclusions: Demonstrating ΔPFSt1/2 &amp;gt;1.5-2.0 months with p&amp;lt;.05 indicates an 84-90% probability of a ΔOSt1/2 gain &amp;gt;2 months, and could be a useful ΔOSt1/2 surrogate. This endpoint could mitigate impact of CO and PPS while making trials faster/cheaper. T1/2s are superior to medians. If PFS curves fit NLRA 2 phase models in phase II trials one should collect full phase III OS data (censored at CO) to reduce risk of a false negative. Citation Format: David J. Stewart, Dominick Bosse, John Hilton, Glenwood Goss, Michael Fung-Kee-Fung, Derek Jonker. Progression-free survival (PFS) as a surrogate for overall survival (OS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1644.

Precision oncology in pancreatobiliary cancers: A longitudinal study.

399 Background: Precision oncology – the use of next-generation sequencing (NGS) to identify therapeutic options for advanced cancer patients – is being used widely, but its utility in patients with pancreatobiliary (PB) cancers has not been studied systematically. We evaluated the prevalence of actionable alterations and their impact on therapeutic decision-making in patients with PB cancers. Methods: We conducted a retrospective cohort study of consecutive patients seen at the Cleveland Clinic between 2013 and 2016 with incurable solid tumor malignancies, in whom FoundationOne™ (Cambridge, MA) NGS was ordered. All results were reviewed at a multidisciplinary genomics tumor board (GTB), which determined actionability and made therapeutic recommendations. Treatment decisions (on label, off label, or clinical trials) based on said recommendations were reviewed. Results: The study population was 600 patients, of whom 53 had PB cancers. For these 53, median age was 59.6 years; 62.2% (33/53) were female; 86.8% (46/53) were Caucasian. Eight samples (15.1%) had inadequate tissue; of 45 resulted cases, 21 (46.7%) were recommended treatment, including clinical trials (n = 19) and off-label drugs (n = 2). The most common targets for therapy were FGFR (5/21) and CDKN2 (3/21). Of 21 patients with recommendations, only two (9.5%) received genomics-driven therapy, compared with 31.7% (86/271) of patients with other solid tumor malignancies (p = 0.03). One received an IDH1 inhibitor, and one received dabrafenib and trametinib for a BRAF alteration; both on clinical trials. At time of last follow-up, best responses were unknown and partial response, respectively. Unavailability of clinical trials in the vicinity (9.5%), and clinical trial ineligibility, mainly due to poor performance status (9.5%), were common reasons for lack of actionability. Conclusions: Benefit from precision oncology in the PB population is low, with only 4.4% (2/45) of patients with NGS results eventually receiving genomics-driven therapy. Benefit to patients will not improve until access to clinical trials is enhanced and patients are evaluated for these trials earlier in the course of their disease, when their performance status is likely to be higher.

Clinical course and end-of-life care in patients who have died after allogeneic stem cell transplantation.

PurposeAllogeneic stem cell transplantation may cure approximately 50% of patients, however, a significant part of the other half might benefit from a high-quality palliative care medicine at the end of life. Somatic, psychic and spiritual needs of these patients may differ from those of patients suffering from incurable solid tumours and are not comprehensively evaluated so far.MethodsTo address this question, data from charts of 123 patients who have died after allogeneic stem cell transplantation were extracted. In detail, the time line of the clinical course, the symptoms, the administered drugs and other applied procedures were analysed.ResultsApproximately one half of the patients, who have died after stem cell transplantation, did not live more than 5 months. Two-thirds of patients died within 14 months after SCT. 28.5% of the patients could not be discharged after transplantation. However, a significant proportion had a low ECOG-score (0–1) prior to death, indicating a high degree of mobility. Major symptoms were weakness, fatigue and need for aid at daily activities. Severe pain, dyspnoea and obstipation, as known from patients suffering from advanced solid tumours, were rare. In consequence, use of opioids seemed to be less frequent than in patients with solid tumours. Measures of intensive care and i.v.-drug administration were applied to a significant proportion of patients.ConclusionThe present investigation indicates that the somatic, psychic and spiritual end-of-life-care after allogeneic stem cell transplantation could be optimised. A significant problem for the transplantation team seems to be the realisation of necessity to switch the curative concept into a palliative ambition. Requirements are a subsequent prospectively conducted investigation and an intensification of cooperation between transplant and palliative care teams.

Palliative care utilization in patients with newly diagnosed, incurable solid tumor malignancies: The experiences of an institution new to palliative care.

92 Background: Early palliative care (PC) referral can enhance quality of life (QOL) in patients with metastatic cancer and even improve overall survival in non-small cell lung cancer. Despite compelling data showing benefits of early integration of PC, barriers to care exist. Our institution recently established an outpatient PC service. To improve utilization of this new service we identified clinicians’ attitudes and barriers to PC, and provided education on the PC referral process. The effects of this intervention on PC utilization were assessed. Methods: We conducted a retrospective chart review of outpatient Hematology/Oncology (HO) referrals to identify patients referred for newly diagnosed, solid tumor malignancies with no curative options. Hospice referrals were excluded. We then formally surveyed clinicians participating in multi-disciplinary tumor boards to identify PC referral practices and attitudes/barriers to PC referrals. Education on PC and instruction on PC referral process were provided during this period. Post-intervention review of PC referrals over 4 months was conducted. Results: Prior to our intervention, of the 53 new consultations reviewed meeting study criteria only three (5.7%) patients were referred to PC. Our survey revealed that 66% (31/47) of oncology providers did not know the institution had onsite PC available and only eight (17%) knew how to place a referral. After education was provided, a second cohort revealed 24.1% (7/29) of patients were appropriately referred for early outpatient PC representing an 18.4% absolute increase. Conclusions: We significantly increased early PC referrals for HO patients with advanced or metastatic disease. However, other efforts to improve institutional awareness and change the culture of care to ensure that majority of these patients are appropriately referred. Longitudinal evaluation will further ensure that timely adjustments are made and that effects are permanent.

Fatigue in Patients With Advanced Terminal Cancer Correlates With Inflammation, Poor Quality of Life and Sleep, and Anxiety/Depression.

To assess which laboratory and clinical factors are associated with fatigue in patients with terminal cancer. We evaluated 51 patients with advanced incurable solid tumors using the Chalder Fatigue Questionnaire (CFQ) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale for fatigue; the Pittsburgh Sleep Quality Index (PSQI-BR) for sleep quality; the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression; the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire, Version 3.0 (QLQ C-30); and Functional Assessment of Cancer Therapy (FACT) for quality of life. We also analyzed several inflammatory markers and the modified Glasgow prognostic score (mGPS). We observed severe fatigue in 19 (38%) patients (FACIT-F score >36). There was a significant correlation between fatigue as evaluated by the CFQ and quality of sleep and between the CFQ mental fatigue subscale scores and TNF-α level. When fatigue was evaluated using the FACIT-F scale, we observed a significant association between fatigue and anxiety/depression, quality of sleep, mGPS, and hemoglobin levels. Fatigue measured both with the CFQ and FACIT-F scale correlated with poor quality of life according to the EORTC QLQ C-30. In patients with advanced cancer, fatigue is a common symptom associated with the presence of inflammation, poor quality of sleep, depression/anxiety, and poor quality of life.

Phase I study of sapacitabine and seliciclib in patients with advanced solid tumors.

2503Background: Sapacitabine is an oral nucleoside analogue; the active metabolite CNDAC generates ssDNA breaks that are converted to dsDNA breaks (DSB) during subsequent replication, resulting in cell death. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is an oral CDK2, 7 and 9 inhibitor, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation. This phase I study evaluates sequential and concomitant sapacitabine and seliciclib treatment. Methods: Dose escalation was conducted in patients with incurable solid tumors with sapacitabine b.i.d. x 7 consecutive days (d 1-7) followed by seliciclib b.i.d. x 3 consecutive days (d 8-10) or sapacitabine q.d. concomitantly with seliciclib q.d. x 5 days per week x 2 weeks (d 1-5, 8-12). MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine and seliciclib treatment. Res...

Fatigue and its associated psychosocial factors in cancer patients on active palliative treatment measured over time.

PurposeFatigue is a frequently reported symptom by patients with advanced cancer, but hardly any prospective information is available about fatigue while on treatment in the palliative setting. In a previous cross-sectional study, we found several factors contributing to fatigue in these patients. In this study, we investigated the course of fatigue over time and if psychosocial factors were associated with fatigue over time.MethodsPatients on cancer treatment for incurable solid tumors were observed over 6 months. Patients filled in the Checklist Individual Strength monthly to measure the course of fatigue. Baseline questionnaires were used to measure disease acceptance, anxiety, depressive mood, fatigue catastrophizing, sleeping problems, discrepancies in social support, and self-reported physical activity for their relation with fatigue over time.ResultsAt baseline 137 patients and after 6 months 89 patients participated. The mean duration of participation was 4.9 months. At most time points, fatigue scores were significantly higher in the group dropouts in comparison with the group participating 6 months (completers). Overall fatigue levels remained stable over time for the majority of participants. In the completers, 42 % never experienced severe fatigue, 29 % persisted being severely fatigued, and others had either an increasing or decreasing level. Of the investigated factors, low reported physical activity and non-acceptance of cancer were associated significantly to fatigue.ConclusionA substantial number of participants never experienced severe fatigue and fatigue levels remained stable over time. For those who do experience severe fatigue, non-acceptance of having incurable cancer and low self-reported physical activity may be fatigue-perpetuating factors.

Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study

Epigenetic alterations have been strongly associated with tumour formation and resistance to chemotherapeutic drugs, and epigenetic modifications are an attractive target in cancer research. RRx-001 is activated by hypoxia and induces the generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation. The aim of this phase 1 study was to assess the safety, tolerability, and pharmacokinetics of RRx-001. In this open-label, dose-escalation, phase 1 study, we recruited adult patients (aged >18 years) with histologically or cytologically confirmed diagnosis of advanced, malignant, incurable solid tumours from University of California at San Diego, CA, USA, and Sarah Cannon Research Institute, Nashville, TN, USA. Key eligibility criteria included evaluable disease, Eastern Cooperative Group performance status of 2 or less, an estimated life expectancy of at least 12 weeks, adequate laboratory parameters, discontinuation of all previous antineoplastic therapies at least 6 weeks before intervention, and no residual side-effects from previous therapies. Patients were assigned to receive intravenous infusions of RRx-001 at increasing doses (10 mg/m(2), 16·7 mg/m(2), 24·6 mg/m(2), 33 mg/m(2), 55 mg/m(2), and 83 mg/m(2)) either once or twice-weekly for at least 4 weeks, with at least three patients per dose cohort and allowing a 2-week observation period before dose escalation. Samples for safety and pharmacokinetics analysis, including standard chemistry and haematological panels, were taken on each treatment day. The primary objective was to assess safety, tolerability, and dose-limiting toxic effects of RRx-001, to determine single-dose pharmacokinetics, and to identify a recommended dose for phase 2 trials. All analyses were done per protocol. Accrual is complete and follow-up is still on-going. This trial is registered with ClinicalTrials.gov, number NCT01359982. Between Oct 10, 2011, and March 18, 2013, we enrolled 25 patients and treated six patients in the 10 mg/m(2) cohort, three patients in the 16·7 mg/m(2) cohort, three patients in the 24·6 mg/m(2) cohort, four patients in the 33 mg/m(2) cohort, three patients in the 55 mg/m(2), and six patients in the 83 mg/m(2) cohort. Pain at the injection site, mostly grade 1 and grade 2, was the most common adverse event related to treatment, experienced by 21 (84%) patients. Other common drug-related adverse events included arm swelling or oedema (eight [32%] patients), and vein hardening (seven [28%] patients). No dose-limiting toxicities were observed. Time constraints related to management of infusion pain from RRx-001 resulted in a maximally feasible dose of 83 mg/m(2). Of the 21 evaluable patients, one (5%) patient had a partial response, 14 (67%) patients had stable disease, and six (29%) patients had progressive disease; all responses were across a variety of tumour types. Four patients who had received RRx-001 were subsequently rechallenged with a treatment that they had become refractory to; all four responded to the rechallenge. RRx-001 is a well-tolerated novel compound without clinically significant toxic effects at the tested doses. Preliminary evidence of activity is promising and, on the basis of all findings, a dose of 16·7 mg/m(2) was recommended as the targeted dose for phase 2 trials. EpicentRx (formerly RadioRx).

NCIC CTG IND.181: Phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies

AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.

Abstract LB-202: Responses to sequential sapacitabine and seliciclib in patients with BRCA-deficient solid tumors.

Abstract Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite, CNDAC (2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine), generates single-strand DNA breaks that are converted to double-strand DNA breaks (DSBs) during subsequent replication, resulting in cell death if unrepaired. Repair of CNDAC-induced DSBs is dependent on the homologous recombination (HR) repair pathway. Depletion or inhibition of components of the HR pathway (including ATM, BRCA1/2, Rad 51, and XRCC3) greatly sensitizes tumor cell lines to CNDAC-induced cell death in vitro. Seliciclib is an orally bioavailable inhibitor of cyclin-dependent kinases (CDKs) 2, 7 and 9. CDK2 has been shown to participate in DNA repair and to be a therapeutic target in BRCA-deficient cancers. Seliciclib inhibits DSB repair, and also reduces BRCA1 and BRCA2 mRNA levels in cancer cell lines, sensitizing tumor cells to CNDAC. This phase I study evaluates sequential sapacitabine and seliciclib. Methods: Dose escalation was conducted in patients with incurable solid tumors and adequate organ function with sapacitabine bid x 7 consecutive days (d1-7), seliciclib bid x 3 consecutive days (d8-10) followed by 11 days of rest. At least 3 patients were evaluated per dose level. MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine (d8 vs pre-treatment) and further augmentation of DNA damage after seliciclib (d11 vs d8). Results: 38 patients were treated. The MTD is sapacitabine 50 mg bid/seliciclib 1200 mg bid. DLTs were reversible transaminase elevations and neutropenia. The most frequent adverse events (all cycles, regardless of causality) included, fatigue, abdominal pain, diarrhea, constipation, decreased appetite, nausea, vomiting, anemia, neutropenia, pyrexia, AST elevation, alkaline phosphatase elevation, creatinine elevation, hyperglycemia, hypophosphatemia, cough, and alopecia, the majority mild to moderate in intensity. Skin biopsies showed a 2.3-fold increase in γ-H2AX staining post-sapacitabine (n=16; p=0.007) and a further 0.58-fold increase post-seliciclib (n=12; p=0.069). Four confirmed PRs occurred in patients with pancreatic, breast (2 pts) and ovarian cancer, all BRCA mutation carriers, lasting 21, 78+, 36+ and 42+ weeks, respectively. SD as best response ≥= 12 weeks was observed in 8 additional patients, including two BRCA mutation carriers with ovarian and breast cancer, lasting 64 and 21 weeks, respectively. Conclusions: Sequential sapacitabine and seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier status may be a potential biomarker for response across multiple tumor types. An alternative schedule with concomitant administration of sapacitabine and seliciclib is currently under evaluation. Citation Format: Geoffrey I. Shapiro, John Hilton, James M. Cleary, Sara M. Tolaney, Leena Ghandi, Eunice L. Kwak, Jeffrey W. Clark, Andrew Wolanski, Tracy Bell, John Schulz, Sheelagh Frame, Chiara Saladino, Morag Hogben, Scott J. Rodig, Judy H. Chiao, David Blake. Responses to sequential sapacitabine and seliciclib in patients with BRCA-deficient solid tumors. [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 LB-202. doi:10.1158/1538-7445.AM2013-LB-202

Successful Allogeneic Hematopoietic Cell Engraftment after a Minimal Conditioning Regimen in Children with Relapsed or Refractory Solid Tumors

Children with relapsed or refractory solid tumors face dismal prognoses, and novel therapies are desperately needed. Allogeneic hematopoietic cell transplantation (HCT) offers potential for cell-based therapy, but the toxicity of myeloablation limits this approach in heavily pretreated patients. We sought to determine the feasibility of HCT in a cohort of 24 children with incurable solid tumors using human leukocyte antigen–matched sibling or unrelated donors and a minimal conditioning regimen. Before stem cell infusion, all patients received 3 daily doses of 30 mg/m2 fludarabine followed by 2 Gy of total body irradiation. Hematopoietic cell recovery was rapid and reliable. Median time to neutrophil engraftment was 13.5 days for sibling donors and 12 days for unrelated donors. Donor lymphocyte infusions were used safely in 4 patients, all of whom had either improved chimerism or apparent tumor response. Graft-versus-host disease was comparable across donor sources and did not affect survival. Relapse remains a substantial barrier, although objective graft-versus-tumor effect was observed in several patients. Four patients with detectable disease before HCT achieved a complete response for at least 30 days after HCT, and two remain long-term survivors. Three patients were in complete response before HCT and remained in remission for 3, 6, and 74 months after HCT. Early disease response was associated with improved survival. Allogeneic HCT using this conditioning regimen offers a potential platform for novel immunotherapies.