A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors.
ABSTRACT: Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ?3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ?3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions.
Project description:Ipilimumab and radiotherapy are commonly used to treat unresectable and metastatic melanoma. Results from preclinical studies and case reports suggest a biologic interaction between these two treatments. To understand the clinical implications of the interaction, we carried out a retrospective study reviewing records of patients treated with ipilimumab and radiotherapy for melanoma at our institution between 2005 and 2011. The review included details of treatment, response, adverse events (AE), and overall survival (OS). Twenty-nine patients underwent 33 courses of non-brain radiotherapy between their first and last dose of ipilimumab. Immune-related AEs (ir-AEs) were observed in 43% of patients receiving ipilimumab at 10 mg/kg and in 22% of patients receiving 3 mg/kg; the frequency of ir-AEs was not significantly different compared with previous studies of ipilimumab alone. Radiotherapy-related AEs were significantly more common in patients receiving higher doses of radiation. Palliation of symptoms was reported by 77% of patients after radiotherapy. Median OS was 9 and 39 months in patients receiving radiotherapy during induction and maintenance with ipilimumab, respectively. In this retrospective study, concurrent ipilimumab and radiotherapy was neither associated with higher than expected rates of AEs nor did it abrogate palliative effects of radiotherapy or survival benefits of ipilimumab. Further studies to prospectively explore the efficacy of this therapeutic combination are warranted.
Project description:Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Results Fifty-one patients with RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ? 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase II dose was established as abexinostat 45 mg/m2 twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanib-refractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment. Conclusion Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance.
Project description:This phase II single-arm trial evaluated afatinib, an irreversible inhibitor of the ErbB receptor family as third-line treatment of Korean patients with advanced non-small cell lung cancer (NSCLC) and tumors with wild-type EGFR. Currently, no standard therapy exists for these patients.Eligible patients had stage IIIB/IV wild-type EGFR lung adenocarcinoma and had failed to benefit from two previous lines of chemotherapy but had not received anti-EGFR treatment. Patients received oral afatinib at 40 mg per day until disease progression or occurrence of intolerable adverse events (AEs). The primary endpoint was confirmed objective tumor response (OR) rate (confirmed complete response [CR] or partial response [PR]). Secondary endpoints included disease control rate (DCR; OR or stable disease for ?6 weeks), progression-free survival (PFS), and safety.Forty-two patients received afatinib treatment, and 38 of those were included in efficacy analyses. No confirmed CRs or PRs were reported. DCR was 24% (9 of 38 patients), with a median disease control duration of 19.3 weeks. Median PFS was 4.1 weeks (95% confidence interval: 3.9-8.0). Frequently reported AEs (mainly grades 1 and 2) were rash/acne (88%), diarrhea (62%), and stomatitis (57%).Heavily pretreated patients with wild-type EGFR NSCLC treated with afatinib monotherapy did not experience an objective response and only 24% had disease stabilization lasting more than 6 weeks. AEs were manageable and consistent with the expected safety profile.
Project description:In India, a considerable proportion of patients with head and neck cancer present with locoregionally advanced disease. Symptom palliation becomes a major objective in these cases when they could not be considered for a curative approach.The aim of this study is to assess the role of palliative radiotherapy for symptom control in patients with locally advanced head and neck cancer.This was a retrospective study.Between July 2015 and June 2016, 98 patients with stage IV head and neck cancer were treated with palliative radiotherapy 25 Gray (Gy)/4 fractions (fr)/1 fraction (6.25 Gy)/week. Presenting symptoms were noted. The primary end point was relief of symptoms in the 4th week after radiotherapy. Percentage symptom relief was quantified by the patient using a rupee scale. Treatment response was noted using the WHO criteria. Acute toxicity was graded as per the Radiation Therapy Oncology Group (RTOG) criteria.The most common presenting symptom was pain. At 4 weeks after radiotherapy completion, all patients had >50% pain relief. Dysphagia was improved in 82% of patients. Respiratory distress was improved in all the symptomatic patients. Tumor complete response (CR) was seen in 2 patients, partial response in 89, stable disease in 3, and progressive disease in 4. RTOG Grade 2 and 3 acute skin and mucosal toxicities were seen in 29% and 27% cases, respectively. No patient had Grade 4 adverse effect.Hypofractionated radiation could provide effective symptom palliation in advanced head and neck cancers. The weekly schedule was well tolerated and found convenient by the patients.
Project description:BACKGROUND:Hypofractionated palliative radiotherapy for metastatic lung cancer patients is frequently used in order to ease pain, to increase bone stability, to treat local mass effects, or to prolong progression-free survival at critical sites. Recently introduced, immunotherapy for patients with non-squamous non-small cell lung carcinoma (NSCLC) has significantly improved outcome in this cohort. Preclinical and early clinical data suggest that the combination of photon radiation with programmed death-1 (PD-1) targeting immunotherapies may promote a strong and durable immune response against tumor manifestations both within and beyond radiation targets. METHODS/DESIGN:In the present prospective, two-group, non-randomized, open-label phase II trial, 130 patients with stage IV non-squamous NSCLC in 2nd-line or 3rd-line treatment will be included. 65 patients with a clinical indication for palliative radiotherapy to non-cerebral/non-pulmonary metastatic sites will receive 240?mg nivolumab followed by palliative radiotherapy with 5?×?4 Gray (Gy)?=?20?Gy photon radiation, which will be initiated within 72?h after first nivolumab administration (Group A). 65 patients without an indication for radiotherapy will only receive nivolumab (Group B). Nivolumab will be further administered every two weeks in both groups and will be continued until progression and loss of clinical benefit or until occurrence of limiting toxicities. The primary endpoint will be the objective response rate (ORR) according to response evaluation criteria in solid tumors (RECIST) 1.1. Secondary endpoints will be progression-free survival (PFS) according to RECIST 1.1, overall survival, descriptive subgroup analyses according to PD-L1 expression, toxicity and quality of life. Since response patterns following immunotherapies differ from those after conventional cytostatic agents, both objective response rate and progression-free survival will additionally be assessed according to immune-related RECIST (irRECIST) criteria. DISCUSSION:The FORCE study will prospectively investigate response rates, progression-free and overall survival (OS), and toxicity of nivolumab with and without hypofractionated palliative radiotherapy in a group of 130 patients with metastatic non-small cell lung cancer (non-squamous histology) in 2nd-line or 3rd-line treatment. This trial will contribute prospective data to the repeatedly published observation that the combination of hypofractionated photon radiotherapy and medical immunotherapy is not only safe but will also promote antitumoral immune responses. TRIAL REGISTRATION:Clinicaltrials.gov identifier: NCT03044626 (Date of initial registration: 05 January 2017). Eudra-CT Number: 2015-005741-31 (Date of initial registration: 18 December 2015).
Project description:Despite prominent role of radiotherapy in lung cancer management, there is an urgent need for strategies increasing therapeutic efficacy. Reversible epigenetic changes are promising targets for combination strategies using HDAC inhibitors (HDACi). Here we evaluated on two NSCLC cell lines, the antitumor effect of abexinostat, a novel pan HDACi combined with irradiation in vitro in normoxia and hypoxia, by clonogenic assays, demonstrating that abexinostat enhances radiosensitivity in a time dependent way with mean SER10 between 1.6 and 2.5 for A549 and H460. We found, by immunofluorescence staining, flow cytometry assays and western blotting, in abexinostat treated cells, increasing radio-induced caspase dependent apoptosis and persistent DNA double-strand breaks associated with decreased DNA damage signalling and repair. Interestingly, we demonstrated on nude mice xenografts that abexinostat potentiates tumor growth delay in combined modality treatments associating not only abexinostat and irradiation but also when adding cisplatin. Altogether, our data demonstrate in vitro and in vivo anti-tumor effect potentiation by abexinostat combined with irradiation in NSCLC. Moreover, our work suggests for the first time to our knowledge promising triple combination opportunities with HDACi, irradiation and cisplatin which deserves further investigations and could be of major interest in the treatment of NSCLC.
Project description:The purpose of this study was to investigate the prognostic implications of carcinoembryonic antigen (CEA) levels that are inconsistent with Response Evaluation Criteria in Solid Tumor (RECIST) responses in metastatic colorectal cancer patients.We retrospectively evaluated 360 patients with at least one measurable lesion who received first-line palliative chemotherapy. CEA-response was defined as CEA-complete response (CR; CEA normalization), CEA-partial response (PR; ? 50% decrease in CEA levels), CEA-progressive disease (PD; ? 50% increase in CEA levels), and CEA-stable disease (SD; non-CR/PR/PD). Overall survival (OS) and progression-free survival (PFS) were evaluated according to CEA-response.In RECIST-PR patients, poorer CEA-response was associated with disease progression at the subsequent evaluation. In RECIST-SD patients, CEA-CR and -PR were associated with lower disease progression rates than CEA-PD at the subsequent evaluation. Correlations between survival outcome and CEA-response in same-category RECIST patients were assessed. In RECIST-PR patients, discordant CEA-response (CEA-PD/SD) was associated with poorer survival than CEA-CR/PR (median OS and PFS, 44.0 and 15.4 [CEA-CR], 28.9 and 12.5 [CEA-PR], 21.0 and 9.8 [CEA-SD], and 13.0 and 7.0 [CEA-PD] months, respectively; all p < 0.001). In RECIST-SD patients, favorable CEA-response produced better survival (median OS and PFS, 26.8 and 21.0 [CEA-CR], 21.0 and 11.0 [CEA-PR], 16.1 and 8.2 [CEA-SD], and 12.2 and 6.0 [CEA-PD] months, respectively; all p < 0.001). RECIST-PD patients with CEA-CR showed longer OS than those with CEA-PD. Multivariate analysis demonstrated that discordant CEA-response is a powerful prognostic factor for RECIST-PR and RECIST-SD patients.Among patients of the same RECIST-response categories, CEA-response patterns are significantly prognostic and strongly predictive of subsequent evaluation outcomes.
Project description:Integration of hypofractionated body radiotherapy (H-RT) into immune checkpoint inhibitor (ICI) therapy may be a promising strategy to improve the outcomes of ICIs, although sufficient data is lacking regarding the safety and efficacy of this regimen. We, hereby, reviewed the safety and efficacy of this combination in 59 patients treated with H-RT during or within 8 weeks of ICI infusion and compared results with historical reports of ICI treatment alone. Most patients had RCC or melanoma. Median follow-up was 11 months. Most patients received either Nivolumab alone or with Ipilimumab; 83% received stereotactic RT and 17% received conformal H-RT. Any grade adverse events (AEs) were reported in 46 patients, and grade 3-4 in 12 patients without any treatment-related grade 5 toxicity. The most common grade 3 AEs were fatigue and pneumonitis. Grade 3-4 toxicities were higher with ICI combination and with simultaneous ICIs. Overall, most any-grade or grade ≥3 AE rates did not differ significantly from historically reported rates with single-agent or multi-agent ICIs. Toxicity did not correlate with H-RT site, dose, fraction number, tumor type, or ICI and H-RT sequencing. Median progression-free survival was 6.5 months. Objective response rate (ORR) was 26%; 10% had complete response (CR). Median duration of response was 9.4 ± 4.6 months. H-RT of lung lesions was more likely to achieve CR than other sites. H-RT of bone lesions had a lower ORR than non-bone H-RT. In conclusion, combining body H-RT with ICIs is safe and promising. Prospective validation is warranted.
Project description:PURPOSE:Pembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC. PATIENTS AND METHODS:Eligible patients included those with oral cavity (excluding lip), oropharyngeal, hypopharyngeal, or laryngeal stage III to IVB HNSCC (according to American Joint Committee on Cancer, 7th edition, staging system) eligible for cisplatin-based, standard-dose (70 Gy) chemoradiotherapy. Pembrolizumab was administered concurrently with and after chemoradiotherapy with weekly cisplatin. Safety was the primary end point and was determined by incidence of chemoradiotherapy adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on end-of-treatment (EOT) imaging or with pathologic confirmation at 100 days postradiotherapy completion. Key secondary end points included overall (OS) and progression-free survival (PFS). RESULTS:The study accrued 59 patients (human papillomavirus [HPV] positive, n = 34; HPV negative, n = 25) from November 2015 to October 2018. Five patients (8.8%) required discontinuation of pembrolizumab because of irAEs, all of which occurred during concurrent chemoradiotherapy; 98.3% of patients completed the full planned treatment dose (70 Gy) of radiotherapy without any delays ? 5 days; 88.1% of patients completed the goal cisplatin dose of ? 200 mg/m2. EOT CR rates were 85.3% and 78.3% for those with HPV-positive and -negative HNSCC, respectively. CONCLUSION:Pembrolizumab in combination with weekly cisplatin-based chemoradiotherapy is safe and does not impair delivery of curative radiotherapy or chemotherapy in HNSCC. Early efficacy data support further investigation of this approach.
Project description:Purpose:A phase I/II study of intrathecal pemetrexed (IP) combined with involved-field radiotherapy (IFRT) was performed to determine feasibility, safety, and antitumor activity for leptomeningeal metastases (LM) from solid tumors. Methods:Participants first received induction IP administration, followed by concomitant radiotherapy within 3?days. The concomitant regimen consisted of IP (pemetrexed 10?mg, dexamethasone 5?mg, once per week, 4 times in 4?weeks) and IFRT (40?Gy in 20 fractions). Six participants were recruited to assess feasibility in phase I, and then 28 patients were recruited further. All patients were assessed to investigate safety, efficacy, and outcomes. Results:Between April 2018 and December 2018, 34 patients (male: 15; female: 19; median age: 56?years) were enrolled, including non-small-cell lung cancer (21), small-cell lung cancer (5), breast cancer (4), and others (4). Thirty-two patients received concurrent therapy and 25 (74%) patients completed the treatment. Major adverse events (AEs) consisted of myelosuppression, the elevation of hepatic aminotransferases, and radiculitis. Total AEs rate was 53% (18/34), including 6 (18%) patients with grade 3 and 1 (3%) with grade 4 AEs. The response rate was 68% (23/34). The median overall survival was 5.5 (0.3-16.6) months. Median neurological progression-free survival (NPFS) was 3.5 (0.3-15.2) months. Six-month NPFS rate was 47%. One-year survival rate was 21.6%. Conclusion:IP at a 10?mg dose on a schedule of 1-2 times per week presented good efficacy and safety in CSF. The concomitant regimen is an efficacious therapeutic option for LM patients with solid tumors. Trial Registration:This study (IPLM) was registered at https://register.clinicaltrials.gov [ClinicalTrials.gov identifier: NCT03507244].