Alternative Treatment Schedules Research Articles

Travel-associated carbon emissions of patients receiving cancer treatment from an urban safety net hospital.

e13812 Background: Climate change is one of the grand challenges of the 21st century. The U.S. currently emits 11% of the annual global greenhouse gases, and 8-10% of its emissions result from the healthcare industry. Studies on the contribution of patients' commute for cancer treatment to healthcare-associated CO2 emissions remain limited. This study aims to determine the CO2 emissions of patients’ commute for cancer treatment among patients with malignancies at an urban safety net hospital. Methods: We conducted a retrospective study of patients seen at an oncology clinic from July 1, 2022 - June 30, 2023. Demographic data, data on visit diagnosis and indication (e.g., laboratory, infusion, or follow-up visits), and patients' home addresses were collected from the EMR. Distance between patients’ homes and the hospital was calculated using a Google Map API and a macro for distance. Total CO2 emissions from patients’ travel in miles were estimated at 400 grams of CO2 per mile based on the Environmental Protection Agency’s estimate of the average CO2 emissions for a passenger vehicle. The primary outcome was CO2 emissions from patients’ round-trip travel. The total estimated CO2 emissions were converted to equivalents of coal burned, smartphones charged, and gallons of gasoline used based on the EPA equivalencies calculator. Results: Of the 8,235 visits, 5,095 (61.8%) were follow-up/laboratory visits, and 3,137 (38.1%) were chemotherapy infusion visits. Of the 1,080 patients who attended the clinic, the mean age was 63.8 years, 700 (64.8%) were males, 379 (35.1%) were females, 525 (48.6%) were black or African American, 139 (12.9%) were whites. Breast cancer was the most common diagnosis, with 423 (39.2%) of patients. Each patient traveled an average of 9.6 miles round trip (Range = 0.7-298.6 miles) to receive cancer care. An estimated 1,520 grams of CO2 was emitted for each patient’s visit. A total of 79,582 round trip miles was made in 8,235 visits, which corresponds to 31,832 kg of CO2 emissions, equivalent to 35,658 pounds of coal burned, 1,462 propane cylinders used for a home, or 3,872,250 smartphones charged. Conclusions: Cancer care is associated with significant CO2 emissions. Efforts to decrease the overall carbon footprint of cancer treatment through adoption of telemedicine and alternative treatment schedules, are needed to reduce the effect of cancer treatment on the climate. [Table: see text]

Real-World Results of Cabozantinib Given as Alternative Schedule in Metastatic Renal Cell Carcinoma

BackgroundThe multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently. ObjectiveWe aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing. PatientsThis is a single center retrospective study from the Medical University of Vienna. Outcome Measurements and Statistical AnalysisOverall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule. ResultsBetween January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC criteria, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's. ConclusionsSafety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety.

Abstract 6625: Mathematical modeling of single-cell data reveals the key role of stochasticity - not fitness - in determining the clonal origins of relapse in childhood leukemia

Abstract Acute lymphoblastic leukemia (cALL) is the most common pediatric cancer, and since up to 20% of children relapse after initially responding to chemotherapy treatment, the largest cause of cancer-related childhood deaths in the western world. With the idea that dissecting the evolutionary population dynamics leading to relapse would help explain treatment failure from a mechanistic standpoint, several studies have performed comparisons of genetic heterogeneity at diagnosis and relapse. These showed that as many as 70% of relapses are dominated by a single diagnostic subclone or one of its evolutionary progeny; leading to the prevailing view that treatment selection in cALL primarily operates at the genotype level. However, a crucial caveat of these studies is their reliance, due primarily to technical and economic constraints, on very limited data timepoints. While the dynamics linking said timepoints are often interpreted based on simple intuition. To overcome this sparse data challenge and reconstruct the entire spatial and temporal evolutionary trajectories of individual cALL cells from diagnosis to relapse, we have integrated experimental data with an in silico model. Single-cell WGS and RNAseq data were obtained from primary and xenografted leukemic cells before and after chemotherapy. These were then used to parameterize an agent-based mathematical model allowing tracking of the genotype and evolving phenotype of individual cells over time. When short treatment courses akin to those we delivered in vivo were used, the in silico model closely recapitulated the experimental results. Since cALL treatment lasts several years, it cannot be entirely modelled in vivo. Due to the rarity of post-treatment residual cells and the lack of universal cell surface markers to isolate them, direct analysis of clinical samples is also challenging. However, based on the initial treatment data, our calibrated model provided a unique opportunity to simulate longer remission-relapse dynamics of several leukemias. Mechanistic analysis of the collected data showed that, strikingly, in most cases, clonal dominance at relapse results from stochastic sweeps rather than deterministic differences in clonal fitness. Indeed, independent treatment of the same leukemia with an identical drug regimen more frequently ended with a considerably different clonal landscape (either polyclonal disease or a different dominant clone) than with the same outcome initially observed. Rather than genotype differences, the size of residual disease and a founder effect linked to the stochastic exit, post-treatment, of individual cells from quiescence were the key determinants of the relapse genetic landscape. Altogether, our data highlight the misinterpretation risk associated with snapshot analysis and might inform promising alternative treatment schedules. Citation Format: Virginia Turati, Javier Herrero, Mark Robertson-Tessi, Tariq Enver, Andriy Marusyk, Alexander RA Anderson. Mathematical modeling of single-cell data reveals the key role of stochasticity - not fitness - in determining the clonal origins of relapse in childhood leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6625.

Probabilistic multi-objective optimization of wood torrefaction conditions using a validated mechanistic model

This paper uses a comprehensive computational model to propose optimal wood torrefaction conditions by probabilistic optimization. Its main outcome is to propose tailor-made heat treatment conditions (temperature levels-duration of mild pyrolysis at temperature levels ranging from 200 to 300 °C) to meet users’ expectations in terms of overall mass loss, duration and homogeneity of treatment. To this purpose, beech wood boards were torrefied with a usual 3-steps treatment schedule (drying, heating and cooling) under contrasting configurations in a well-instrumented device. The heterogeneity of the treatment within the wood sample was assessed through X-ray attenuation profile and water vapour sorption isotherm. These results allowed the model to be validated. In particular, it predicts the evolution of the mass loss and internal temperatures with good accuracy, including the temperature overshot. The results highlight the need to adjust the heat treatment schedule to each input parameter such as the wood piece dimensions and its initial moisture content or density, in order to limit the effect of exothermic reactions. The torrefaction model was then embedded in a probabilistic optimization process. A case study demonstrates the ability of the model to propose an alternative 3-steps treatment schedule able to reach the target mass loss while controlling the temperature overshot within the wood piece.

A biomathematical model of atherosclerosis in mice.

Atherosclerosis is one of the leading causes of death worldwide. Biomathematical modelling of the underlying disease and therapy processes might be a useful aid to develop and improve preventive and treatment concepts of atherosclerosis. We here propose a biomathematical model of murine atherosclerosis under different diet and treatment conditions including lipid modulating compound and antibiotics. The model is derived by translating known biological mechanisms into ordinary differential equations and by assuming appropriate response kinetics to the applied interventions. We explicitly describe the dynamics of relevant immune cells and lipid species in atherosclerotic lesions including the degree of blood vessel occlusion due to growing plaques. Unknown model parameters were determined by fitting the predictions of model simulations to time series data derived from mice experiments. Parameter fittings resulted in a good agreement of model and data for all 13 experimental scenarios considered. The model can be used to predict the outcome of alternative treatment schedules of combined antibiotic, immune modulating, and lipid lowering agents under high fat or normal diet. We conclude that we established a comprehensive biomathematical model of atherosclerosis in mice. We aim to validate the model on the basis of further experimental data.

The Impact of Modifying Sunitinib Treatment Scheduling on Renal Cancer Tumor Biology and Resistance.

With sunitinib treatment of metastatic renal cell carcinoma, most patients end up developing resistance over time. Recent clinical trials have shown that individualizing treatment protocols could delay resistance and result in better outcomes. We developed an in vivo xenograft tumor model and compared tumor growth rate, morphological, and transcriptomic differences between alternative and traditional treatment schedules. Our results show that the alternative treatment regime could delay/postpone cancer progression. Additionally, we identified distinct morphological changes in the tumor with alternative and traditional treatments, likely due to the significantly dysregulated signaling pathways between the protocols. Further investigation of the signaling pathways underlying these morphological changes may lead potential therapeutic targets to be used in a combined treatment with sunitinib, which offers promise in postponing/reversing the resistance of sunitinib.

The effectiveness of Tai Chi for postpartum depression: A protocol for systematic review and meta-analysis.

Background:As a specific type of depression, postpartum depression (PPD) causes an adverse hazard to the mother's physical and mental health. Considering the safety requirements for lactation and the expectation of the rapid response to treatment, the search for safe and effective alternative therapies has attracted wide attention. Tai Chi, a traditional Chinese exercise therapy, has been widely used to relieve the symptoms and complications of patients with PPD, which the clinical efficacy is questioned. We conduct a comprehensive systematic review and meta-analysis to find clinical medical evidence of Tai Chi in the treatment of PPD.Methods:PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, China Science, and Technology Journal Database and Chinese Biomedical Literature Database will be searched from their inception of databases to September 30, 2021. Two reviewers will select articles, extract data, and assess the risk of bias independently. Any disagreement will be resolved by discussion with the third reviewer. Review Manager 5.3 software will be used for data synthesis. The Cochrane risk of bias assessment tool will be used to assess the risk of bias.Results:This study will conduct a comprehensive literature search and provide a systematic synthesis of current published data to explore the effectiveness of Tai Chi for PPD.Conclusions:The findings of our study will provide updated evidence to determine whether Tai Chi is an effective intervention for patients with PPD, which will help clinicians make a better alternative treatment schedule of PPD patients and provide a reliable basis for health-related policymakers.Study registration number:CRD42021276676.

Tre-P-02 - Maintenance therapy with chlormethine gel among patients with mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL): a real-world evidence study

<h3>Background:</h3> Chlormethine gel is a skin-directed therapy approved in US for daily treatment of stage IA/IB mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL). Based on a previous study it has been observed that the alternative treatment schedules and the schedule changes may benefit patients by improving tolerability and response to treatment [1]. This study was carried out to better understand schedule changes before and after achieving partial response (PR) and effect of maintenance therapy i.e., continuing treatment with chlormethine gel after achieving PR, in a real-world setting among MF-CTCL patients. <h3>Methods:</h3> Data is derived from the observational PROVe study using US-based registry of MF-CTCL patients treated with chlormethine gel in combination with other treatments between March 2015 and October 2018. Patients were enrolled across 46 centers and were followed for up to 2 years. Information on patient demographics, clinical characteristics, treatments received for MF-CTCL (including chlormethine gel, topical steroids, phototherapy, radiation therapy, chemotherapy, retinoids and other topical). Responses were collected at enrollment and ongoing visits with no specific visit schedules or clinical assessments due to expected variability in practice patterns. Episodes of treatments with chlormethine gel with start date, stop date and schedule changes were recorded and analyzed. Partial response (PR) was defined as either ≥50% improvement in body surface area (BSA) at least once from gel initiation to the end of study participation or based on the clinical assessment of the physician. For those who achieved PR and following the date of PR, deepening response was defined as achieving either ≥10% additional improvement in BSA (i.e., 60% or more improvement in BSA after achieving 50% improvement at the time of PR) or achieving complete response based on the clinical assessment by physician. Descriptive statistics were reported for schedule changes and maintenance therapy with chlormethine gel. <h3>Results:</h3> Of 298 eligible patients with mean age 61±13 years, 60% were males, and 69% had clinical stage IA/IB. A total of 222 (75%) patients achieved PR following chlormethine gel initiation and during study period. Of these 222, 81% patients did not change their schedule prior to achieving PR and 61% were on a daily schedule immediately prior to PR. Of 203 patients receiving maintenance chlormethine gel post PR, 153 (75%) maintained, 29 (14%) reduced and 24 (12%) increased their dosing schedule in the post-PR period as compared to their schedule prior to PR. Of these 203, 53 (26%) later achieved deepening response. <h3>Conclusions:</h3> 75% of the patients received maintenance therapy with chlormethine gel in combination with other therapies and continued with the same schedule after PR. The study results suggest that continuing maintenance therapy and adjusting chlormethine gel dosing schedule may contribute to deepen treatment responses.

25971 Schedule frequency of chlormethine gel for patients with mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL): A real-world evidence study

Chlormethine gel (also known as mechlorethamine) is a skin-directed therapy approved for daily treatment of MF-CTCL. Previous reports (including Gilmore 2020) explored alternative treatment schedules and suggested schedule changes may benefit patients. Patterns of initial treatment schedule and subsequent changes for chlormethine gel in a real-world setting among patients with MF-CTCL were investigated in an observational US registry between March 2015 and October 2018. Clinical characteristics and treatment information were collected, with patients followed for up to 2 years after baseline, defined here as chlormethine gel initiation.

Venous Thromboembolism in Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease Receiving Synthetic Retinoid Am80

Chronic graft-versus-host disease (GVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of chronic GVHD remains challenging. All-trans retinoic acid (ATRA), a potent vitamin A derivative, can regulate immune responses. Synthetic retinoid Am80, which shows biological activity approximately 10 times more potent than that of ATRA, directly inhibits Th1 cytokine production. We previously reported in an experimental mouse model that Am80 down-regulated both Th1 and Th17 differentiation in donor T cells, resulting in attenuation of chronic GVHD (Nishimori H. et al. Blood 2012). Based on this background, we conducted an open-labeled, multicenter phase II study of Am80 in patients with steroid-refractory chronic GVHD (Maeda Y. et al. Acta Med. Okayama. 2016). Six facilities are participating in this study. Patients take Am80 orally (4 mg/day) for 24 weeks. If any unexpected adverse events with Grade 2 or expected adverse events with Grade 3 develop, the daily dose will be decreased to 2 mg/day, 2 mg every other day, or discontinued.Eighteen patients were enrolled and 5 out of 18 (27.8%) patients experienced venous thromboembolism (VTE). Table 1 shows the patient characteristics of those developed VTEs.It is controversial whether retinoid would enhance the incidence of VTE. Only one patient reported thrombosis when Am80 orally (6 mg/m2) for 2-8 weeks was administrated to approximately 800 patients with acute promyelocytic leukemia. In this study, 5 out of 18 (27.8%) patients experienced thrombosis and the safety committee in this study has stopped the trial due to safety concerns. Recently, a meta-analysis reported the incidence of VTE in chronic GVHD was 35 % (20-54 %). Further studies are needed to confirm the causal relationship between Am80 orally (4 mg/day) for 24 weeks and VTE. And also, alternative treatment schedule in addition to anticoagulants for the prevention of VTE will be investigated in subsequent studies. [Display omitted] DisclosuresNishimori:Toko Pharmaceutical Industries: Other: Investigational drug is provided free of charge.. Maeda:Toko Pharmaceutical Industries: Other: Investigational drug is provided free of charge.

Single arm, phase two study of low-dose metronomic eribulin in metastatic breast cancer

BackgroundTreatment options for metastatic breast cancer (MBC) refractory to anthracyclines and taxanes are limited. In a phase III trial, eribulin demonstrated a significant improvement in overall survival compared to treatment of physician’s choice, but had limited tolerability because of neutropenia and peripheral neuropathy. Based on prior studies of alternative treatment schedules with other therapies, we hypothesized that a low-dose metronomic schedule of eribulin would permit patients to remain on treatment more consistently without treatment delays, resulting in longer time to progression, and improved toxicity profile.MethodsWe conducted a multi-site single arm, phase II trial patients with MBC. All patients were treated with metronomic eribulin (0.9 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle.) Treatment was continued until the patient developed disease progression, unacceptable toxicity, or chose to stop the study. Patients must have had prior taxane exposure. The primary endpoint was progression-free survival. Secondary end points were overall survival, response rate, and clinical benefit rate. Exploratory biomarkers were performed to analyze change in levels of circulating endothelial cells (CECs), circulating endothelial precursors, and carbonic anhydrase IX (CAIX) with response to therapy.FindingsWe consented 86 patients and 59 were evaluable for final analysis. Median age was 59 years; 78% had HER2 negative tumors. The median progression-free survival (PFS) was 3.5 months with overall survival (OS) of 14.3 months. Objective response rate was 15% with clinical benefit rate of 48%. Reported grade 3 neutropenia and peripheral neuropathy were 18% and 5%, respectively. Treatment discontinuation due to toxicity was seen in 3% of patients.InterpretationMetronomic weekly low-dose eribulin is an active and tolerable regimen with significantly less myelosuppression, alopecia, and peripheral neuropathy than is seen with the approved dose and schedule, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen.

Activity of tumor-associated macrophage depletion by CSF1R blockade is highly dependent on the tumor model and timing of treatment

Tumor-associated macrophages (TAMs) are abundant in solid tumors where they exhibit immunosuppressive and pro-tumorigenic functions. Inhibition of TAM proliferation and survival through CSF1R blockade has been widely explored as a cancer immunotherapy. To further define mechanisms regulating CSF1R-targeted therapies, we systematically evaluated the effect of anti-CSF1R treatment on tumor growth and tumor microenvironment (TME) inflammation across multiple murine models. Despite substantial macrophage depletion, anti-CSF1R had minimal effects on the anti-tumor immune response in mice bearing established tumors. In contrast, anti-CSF1R treatment concurrent with tumor implantation resulted in more robust tumor growth inhibition and evidence of enhanced anti-tumor immunity. Our findings suggest only minor contributions of CSF1R-dependent TAMs to the inflammatory state of the TME in established tumors, that immune landscape heterogeneity across different tumor models can influence anti-CSF1R activity, and that alternative treatment schedules and/or TAM depletion strategies may be needed to maximize the clinical benefit of this approach.

Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER+ Breast Cancer.

Recent preclinical data suggest that cyclin-dependent kinase 4/6 (CDK4/6) inhibition may be harnessed to sensitize estrogen receptor-positive (ER+) breast cancer to radiotherapy. However, these findings were obtained in human ER+ breast cancer cell lines exposed to subclinical doses of CDK4/6 inhibitors with limited attention to treatment schedule. We investigated the activity of radiotherapy combined with the prototypic CDK4/6 inhibitor palbociclib placing emphasis on therapeutic schedule. We combined radiotherapy and palbociclib in various doses and therapeutic schedules in human and mouse models of ER+ and ER-negative (ER-) breast cancer, including an immunocompetent mouse model that recapitulates key features of human luminal B breast cancer in women. We assessed proliferation, cell death, cell-cycle control, and clonogenic survival in vitro, as well as tumor growth, overall survival, and metastatic dissemination in vivo. Radiotherapy and palbociclib employed as standalone agents had partial cytostatic effects in vitro, correlating with suboptimal tumor control in vivo. However, while palbociclib delivered before focal radiotherapy provided minimal benefits as compared with either treatment alone, delivering focal radiotherapy before palbociclib mediated superior therapeutic effects, even in the absence of p53. Such superiority manifested in vitro with enhanced cytostasis and loss of clonogenic potential, as well as in vivo with improved local and systemic tumor control. Our preclinical findings demonstrate that radiotherapy delivered before CDK4/6 inhibitors mediates superior antineoplastic effects compared with alternative treatment schedules, calling into question the design of clinical trials administering CDK4/6 inhibitors before radiotherapy in women with ER+ breast cancer.

COVD-03. ASSESSING THE IMPACT OF CORONAVIRUS 19 PANDEMIC ON NEURO-ONCOLOGY AT GUY’S CANCER CENTRE LONDON

BACKGROUNDImmunosuppressive treatment increases COVID-19 risk. Neuro-oncology patients may not qualify for ITU if they deteriorate, but without oncological treatment, prognosis is poor. The pandemic has seen the introduction of new guidelines; including alternative treatment schedules which balance risks of contracting COVID-19, against safely delivering effective cancer treatment. We assess COVID-19 impact on neuro-oncology treatment at Guy’s Cancer Centre, London.METHODSNotes of patients seen March-April 2020 were reviewed. Demographic data, tumour grade, treatment and changes due to COVID-19 recorded.RESULTS111 patients were identified (69 male: 42 female, median age 51years). 65 were WHO Grade 4, 24 Grade 3, 17 Grade 2, 2 Grade 1, 1 metastatic-neuroblastoma, 1 anaplastic-medulloblastoma and 1 radiological diagnosis of high-grade-glioma. 14% (32) of consultations were in person (16 new, 7 consents, 9 attending for treatment); 86% (198) were telephone. 8 had concurrent chemo-radiotherapy, 22 radiotherapy alone, 64 chemotherapy alone, 15 had active-surveillance and 2 best-supportive-care. To minimise COVID-19 risk, 22.5% (25) had treatment altered: - A 76-year-old had a radiological diagnosis; - 4 had hypofractionated radiotherapy (30Gy in 6#) to minimise hospital visits; - 7 had no chemotherapy (5 were unmethylated /age, 2 patient choice); - 4 switched from PCV to Lomustine; - 11 stopped chemotherapy early; - 50% (36) were given prophylactic GCS-F; - No patients were recruited for trials. 19 reported possible COVID-19 symptoms – 7 had delays and 3 stopped treatment. 4 tested COVID-19 positive (although not all tested). 1 died of COVID-19 (off treatment). Review of March-April 2020 service showed similar new patient referrals compared to the same time in 2019 (16 and 19 respectively).CONCLUSIONDespite concern about decreasing new referrals during the pandemic, this wasn’t the case for our service. 77.5% of patients had no treatment changes due to COVID-19 and all 22 patients on trial were able to continue treatment throughout this period.

Phase I study of rucaparib and irinotecan in advanced solid tumors with homologous recombination deficiency (HRD) mutations.

3513 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for multiple tumor types with HRD mutations. In efforts to prolong durations of response, combination treatments of PARPi and chemotherapy are being explored. However, expected overlapping toxicities have previously limited the tolerability of PARPi-chemotherapy combinations. Preclinical studies suggest that the inhibition of PARP will prevent the repair of topoisomerase induced DNA strand breaks. In this Phase I trial, we test whether pulse dosing and alternate treatment schedules of rucaparib and irinotecan are safe and tolerable. Methods: Rucaparib and irinotecan were dose escalated in a 3+3 design. Patients with advanced solid tumors and somatic or germline known or suspected pathogenic mutations in HRD were accepted on trial. 15 patients have been enrolled in 3 cohorts and treated with rucaparib 400 mg BID (days 1-7) and irinotecan 65 mg/m2 (cohort 1) or 100 mg/m2 (cohort 2) every 2 weeks or 100 mg/m2 every 3 weeks (cohort 2i). Results: Tumor types on trial are heterogeneous and include pancreatic ductal adenocarcinoma (PDAC: 3), cholangiocarcinoma, neuroendocrine carcinoma of the pancreas, ovarian cancer/primary peritoneal carcinoma (3), prostate cancer, small bowel carcinoma, squamous cell carcinoma of the tonsil, testicular cancer, triple negative breast cancer, and urothelial carcinoma. 14/15 patients had 3+ prior lines of therapy. Mutation types include: 7 ATM, 3 BRCA1, 3 BRCA2, 1 CHEK2, and 1 PALB2. All patients were previously exposed to platinum chemotherapies; 8/15 had progressive disease while on platinum. 5/15 patients had prior PARPi with progression. There were 3 DLT events, all of which were related to grade 3 or 4 neutropenia. Of the 13 patients evaluable for response, there was one confirmed partial response (PR). 5 patients have remained on study for longer than 6 months and 3 patients with ATM mutations have remained on study for longer than one year (primary peritoneal cancer, small bowel carcinoma, PNET). 4/5 patients with clinical benefit had prior platinum progression and 1/5 had previously progressed on a PARPi. Our current recommended phase 2 dose is rucaparib 400 mg BID days 1-7 and irinotecan 100 mg/m2 every 3 weeks. Conclusions: The pulse dosing schedule of rucaparib and irinotecan has allowed for long term tolerability and exposure to both agents with encouraging efficacy in patients with ATM mutations. Further testing of PARPi and topoisomerase inhibitors at this schedule in patients with ATM mutations is planned. Clinical trial information: NCT03318445 .

Treatment of keratinocyte carcinoma in elderly patients - a review of the current literature.

A large percentage of the patients with keratinocyte carcinoma (KC, formerly known as non‐melanoma skin cancer) is of advanced age and often too frail for standard therapies. However, no specific treatment recommendations are given for this population. This review aimed to give an overview of the current literature on the best practice for the treatment of elderly patients with KC. A literature search was performed in MEDLINE, using ‘keratinocyte carcinoma’, ‘elderly’, ‘treatment’ and various synonyms. Case reports, reviews, comments, non‐English literature and studies with a sample size <15 were excluded. After selection, a total of 47 studies were reviewed. Two types of studies were identified, focusing on (I) the effect of age on treatment outcomes and (II) alternative treatment schedules for elderly patients. Studies on surgery, the gold standard, describe larger lesions and defect size in the elderly population. Recurrence rate, complication rate and disease‐specific survival were not affected by age. Depending on the expected morbidity of a suggested (re‐)excision and patient preferences, a conservative watchful waiting policy can be agreed upon as a shared decision. Other common treatment modalities, such as adjuvant radiotherapy, photodynamic therapy and systemic therapy for basal cell carcinoma (BCC), show comparable results in the elderly and younger population. Alternative treatment schedules for elderly patients include primary hypofractionated radiotherapy, which seems effective and well‐tolerated, although research is limited to case series. Additionally, localized and topical treatments seem safe and effective especially for low‐risk tumours. Data are lacking on the efficacy of systemic therapies of metastatic KC in elderly patients. Efficacy of most treatments (with the exception of photodynamic therapy) is not dependent on age. There is need for more research on the efficacy of adjusted treatment modalities, such as hypofractionated radiotherapy and palliative or curative systemic treatment.

Abstract 32: Development of a three-dimensional spheroid model system to more accurately evaluate schedule dependent mechanistic differences between metronomic and conventional dosing of topotecan

Abstract Alternative treatment schedules, such as low-dose, high-frequency (metronomic; METRO) of some chemotherapeutics enhance efficacy and reduce toxicity in some cancers when compared to chemotherapy given conventionally (CONV). Previously, we demonstrated that low-dose, prolonged exposure to topotecan (30-day infusion 0.1 mg/kg/day via Alzet pump) improved survival and reduced tumor volume ~120%, compared to topotecan given CONV (4 mg/kg, every 4 days) in xenograft model of aggressive prostate cancer in athymic mice. Yet, detailed examination of the mechanisms underlying this enhanced activity and optimization of treatment schedules is limited with existing 2-dimension (2D) cell culture models that do not adequately reflect in vivo reality. Therefore, we developed and applied a 3D spheroid model that allows for the evaluation of longer drug exposures. We used PC-3-Luc-GFP, an aggressive, metastatic castration-resistant prostate cancer that expresses luciferase (Luc) and green fluorescent (GFP) that support bioluminescent and fluorescence imaging. Cell growth and cytotoxicity studies were performed using 2D or 3D models. Briefly, 3D spheroids were formed by seeding cells in a poly-HEMA coated 96-well plate with 2.5% recombinant basement membrane followed by centrifugation (5 min at 1000 g) to encourage spheroid generation. The 2D cell cultures reached confluency in 72-96 hr. While we previously demonstrated enhanced activity in vivo, the 2D model showed no benefit (improved potency) over this time frame, ie, METRO vs CONV dosing (logIC50 2.278 (177nM), 95% CI [1.781-2.776] vs logIC50 2.248 (189 nM) 95% CI [1.723-2.773]. Attempts to reduce seeding density to increase study duration resulted in poor and inconsistent cell growth and greater variability. 3D spheroids yielded reproducible round spheroids of similar size (~800 μm) that grew for up to 28 days, thus permitting evaluation of long treatment exposures. Tumor stromal cells are also known to alter tumor pathology, drug delivery and responsiveness to therapy. Therefore, 3D spheroids with PC-3-Luc-GFP and macrophages and endothelial cells in different cell proportions (1:1:1, 1:2:1, etc.,) were examined. Growth of 3D spheroids was altered based on cell type and cell proportion. Further, differences in rates of growth and cellular morphology were observed for tumor activated vs wild macrophages. Overall, we developed a high-throughput, liquid overlay, scaffold-based 3D co-culture spheroid that can be kept for 28 days. This model will permit evaluation of single agent and concomitant therapy over prolonged periods better mimicking clinical practice. Further, this model will allow for more detailed molecular analysis and ability to discern the effect of tumor microenvironment on alternate treatment schedules. Citation Format: Joshua Davis, Taraswi Mitra Ghosh, Lani Jasper, Matthew Eggert, Jeff Warner, Brian Cummings, Robert Arnold. Development of a three-dimensional spheroid model system to more accurately evaluate schedule dependent mechanistic differences between metronomic and conventional dosing of topotecan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 32.

Systematic Review of Non-Conventional Dosing of Oral Anticancer Therapies in Malignant Haematology

IntroductionSurvival outcomes for patients with lymphoid, myeloid and plasma cell malignancies, have improved with the use of oral small molecule inhibitory agents. Oral anti-cancer therapies are often administered continuously and can have significant side-effects, which can adversely impact adherence, quality of life (QoL) and survival outcomes. In order to improve tolerability, non-standard dosing strategies are increasingly adopted in clinical practice; although, with limited guidance. A systematic review was conducted to identify evidence of, and outcomes from, non-conventional dosing of oral anti-cancer therapy in malignant haematology.MethodsA comprehensive search of all oral anti-cancer therapy listed in the British National Formulary for use to treat haematological malignancies was undertaken using the following databases: MEDLINE®, EMBASE®, and Cochrane Library©, and Cumulative Index to Nursing and Allied Health Literature (CINAHL©). The search was expanded using prospective citation chaining in the Web of Science and retrospective snowballing of reference lists of included studies to ensure a sensitive, comprehensive search. Studies were selected based on predefined inclusion/exclusion criteria, and were critically appraised. Extracted data were tabulated to summarise key findings, which were analysed by type of non-dosing strategy: dose interruption; dose reduction; and other dosing strategies.ResultsEleven studies were included and reviewed: two late phase clinical trials, four cohort studies, and five case reports. Findings from each included study (aim, design, treatment schdeule, reported efficacy/toxicty/QoL outcomes) are presented in the accompanying Table 1. These studies evaluated non-standard dosing of dasatinib, imatinib, lenalidomide and thalidomide. Four studies were conducted in Italy, four in the US, and one in Brazil, South Korea and UK. Dose reductions were the most commonly reported strategy (five studies). Two studies reported dose interruptions and four reported other dosing strategies. The quality of the studies ranged from moderate to high (e.g. clinical trials) to moderate to low (e.g. case reports).Russo et al (2015) conducted a single arm, open-label trial, in which the use of one month on/one month off schedule of imatinib was investigated in 96 CML patients aged ≥65 years. Although this trial did not report toxicity or QoL outcomes, there were no transformations (progressions) of CML to an accelerated or blast phase of disease using this alternative schedule. Therefore, results do not draw definitive conclusions that intermittent treatment can be offered to optimal and stable responders. However, they indicate a role for alternative treatment schedules tailored to individual patients, particularly those experiencing significant toxicities.Mangiacavalli et al (2012) investigated efficacy and adverse effects of a one-week interruption of thalidomide following daily administration for three weeks, compared to continuous therapy. Limited patient numbers (13 vs. 10) prevented this trial from obtaining definitive data regarding efficacy, but there was a trend for worse overall survival (OS, p< 0.001) and progression free survival (PFS, p=0.02) in the intermittent arm compared to the continuous one, with no difference in peripheral neuropathy.Dose reduction was reported in two imatinib retrospective cohort studies and three case reports (2 dasatinib, 1 imatinib). Results were inconclusive, primarily due to limitations in the design of the studies, small sample sizes and lack of detail in reporting toxicities and QoL outcomes. Lenalidomide was investigated in two small prospective cohort studies using alternate-day dosing in myelodysplastic syndrome and multiple myeloma. Toxicity outcomes were only reported in the myeloma study and QoL outcomes were reported in neither study.ConclusionsThis review identified limited evidence to support non-standard dosing strategies in malignant haematology. Imatinib dose interruption in optimally responsive CML patients warrants further investigation in large-scale, prospective, ideally blinded trials. DisclosuresDjebbari:Pfizer: Other: conference registration; Takeda: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding.

Abstract CT084: A Phase I dose-escalation study of ATR inhibitor monotherapy with AZD6738 in advanced solid tumors (PATRIOT Part A)

Abstract Many cancers have high levels of replication stress and a poorly functional G1/S DNA damage checkpoint. This may render them more susceptible than normal tissues to inhibition of ATR, an apical kinase in the DNA damage response and critical part of the response to DNA replication stress. We report the early results of the monotherapy dose-escalation phase of the PATRIOT study of AZD6738, an orally active ATR inhibitor in patients (pts) with advanced solid tumors (NCT02223923), whose endpoints were MTD, safety, tolerability, pharmacokinetics (PK) and preliminary efficacy. 26 pts were enrolled between July 2014 and July 2016 in a 3+3 design. Pts received continuous BD dosing. PK analyses were performed. Dose limiting toxicities (table 1) were thrombocytopenia (G3 with epistaxis, 1 participant; G4, 2 participants), pancytopenia (G4, 1 participant), increased amylase (G3, 1 participant). Other treatment-related AEs (probably or definitely caused by AZD6738) affecting ≥2 participants were fatigue (9; 35% G1-4, 0% G3-4), anemia (7; 23% G1-4, 12% G3-4), nausea (4; 15% G1-4, 0% G3-4), thrombocytopenia (5; 19% G1-4, 15% G3-4), anorexia (3; 12% G1-4, 0% G3-4), dysgeusia (3; 12% G1-4, 0% G3-4), vomiting (2; 8% G1-4, 0% G3-4). The MTD was 160 mg BD, given continuously. Two RECIST partial responses were observed in pts with SCCHN and nasopharyngeal carcinoma, one confirmed. Median duration taking AZD6738 was 97 days, range 30-279 days (evaluable patients only). Two pts remain on treatment, three pts discontinued due to treatment-related toxicity. Expansion cohorts have been initiated at 160mg BD, exploring a number of alternative treatment schedules designed to offset cumulative toxicity and test efficacy of AZD6738 monotherapy and the presence of high replication stress, DNA damage response deficiencies or ATM loss. Schedules include: AZD6738 given at 160mg BD for 21 of a 28 day cycle and 5 days on, 2 days off. A parallel study is investigating AZD6738 in combination with palliative radiotherapy.[Funded by CRUK CRUKD/14/007] Dose Level (mg)Evaluable (total treated)Number DLTsG3-4 AEs203 (3)0elevation GGT (1, G3)403 (3)0nil806 (7)1Thrombocytopenia with epistaxis (1, G3)1606 (6)0Anaemia (1, G3)2406 (7)4Thrombocytopenia (2, G4), pancytopenia (1, G4), elevated amylase (1, G3), photosensitivity (1, G3), mucositis (1, G3), anemia (1, G3)Baseline DemographicsTumor TypesMedian (range) age59 (40-79)SCCHN6 (23%)Median (range) prior systemic therapy2 (1-4)Colorectal6 (23%)% Female31Nasopharyngeal2 (8%)Other12 (46%) Citation Format: Magnus T. Dillon, Aude Espinasse, Sally Ellis, Kabir Mohammed, Lorna G. Grove, Lyndall McLellan, Simon A. Smith, Graham Ross, Sola Adeleke, Kin Woo, Eleni Josephides, James F. Spicer, Martin D. Forster, Kevin J. Harrington. A Phase I dose-escalation study of ATR inhibitor monotherapy with AZD6738 in advanced solid tumors (PATRIOT Part A) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT084. doi:10.1158/1538-7445.AM2017-CT084

Abstract P5-15-05: Randomized phase II study evaluating different schedules of nab-paclitaxel in metastatic breast cancer (MBC): Results of the SNAP study

Abstract Background Longer chemotherapy (CT) duration is associated with a significant improvement in progression-free survival (PFS) and a moderate, but significant improvement in overall survival (OS) in MBC patients (pts). Prolonged CT administration, however, must be weighed against the side effects of continuous CT delivery. The SNAP trial was designed to improve the tolerability of prolonged CT by studying alternative treatment schedules. Methods The SNAP trial enrolled 258 women from April 2013 to Aug 2015. Eligibility criteria included HER2- MBC, no prior CT for advanced disease, measurable and/or non-measurable disease. All eligible pts were randomized to one of three arms. Pts received the same induction chemotherapy consisting of 3 cycles of nab-Paclitaxel given days 1,8,15 Q28, followed by one of the three maintenance therapy schedules. Originally, the dose of the induction chemotherapy was 150 mg/m2, but this was reduced to 125 mg/m2 following the first safety review of 48 treated pts. The three schedules of nab-Paclitaxel used as maintenance therapy were (Arm A) nab-Paclitaxel 150 mg/m2 d 1,15 Q28; (Arm B) nab-Paclitaxel 100 mg/m2 d 1,8,15 Q28; (Arm C) nab-Paclitaxel 75 mg/m2 d 1,8,15,22 Q28. The primary objective is to evaluate the efficacy of three nab-Paclitaxel regimens as measured by progression-free survival (PFS), using the historical reference of PFS (based on AVADO study) of docetaxel for first-line treatment of metastatic breast cancer. Each of the three regimens is compared to the historic 7-month median PFS to determine whether any of the three regimens are worthy of further investigation. Secondary endpoints include tolerability, feasibility, response rate, OS and QoL. Results Two-hundred-fifty-eight pts have been randomised and 255 are available for primary endpoint evaluation. At 18.2 months' median follow-up, 182 PFS events and 85 deaths have been observed. Median PFS was 7.9 months (90%CI 6.8-8.4) in Arm A, 9.0 months (90%CI 8.1-10.9) in Arm B and 8.5 (90%CI 6.7-9.5) in Arm C. PFS in Arm B was significantly longer than the historic PFS of first-line docetaxel (one-sided log-rank p=0.03). As expected, neurotoxicity was the most frequent adverse event. In the induction phase, grade≥2 sensory neuropathy was reported in 14.8% of pts at the starting dose of 150 mg/m2 and 7.5% at the starting dose of 125 mg/m2; grade≥3 sensory neuropathy occurred in 2.5% and 0% of the pts, respectively. In the maintenance phase, grade≥2 sensory neuropathy was reported in 37.9% of pts in Arm A, 36.1% in Arm B and 31.2% in Arm C; grade≥3 sensory neuropathy occurred in 9.1%, 5.6% and 6.6% of the pts, respectively. 199 pts started the maintenance phase. The median number of maintenance cycles was 3, 4, and 5, respectively. Stopping maintenance for reasons other than objective progression occurred in 41%, 58%, and 53%, respectively. Conclusion The SNAP trial indicates that alternative maintenance chemotherapy schedules with reduced doses after a short term induction phase at conventional doses are feasible and significantly more active than the historical PFS of docetaxel in the first line treatment of advanced breast cancer. Citation Format: Gennari A, Sun Z, Hasler-Strub U, Colleoni M, Kennedy J, von Moos R, Cortes J, Vidal M, Hennessy B, Walshe J, Amillano Parraga K, Morales Murrillo S, Pagani O, Barbeaux A, Borstnar S, Rabaglio M, Maibach R, Regan MM, Jerusalem G. Randomized phase II study evaluating different schedules of nab-paclitaxel in metastatic breast cancer (MBC): Results of the SNAP study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-05.