Trial Of Combination Therapy Research Articles

Oligopelvis-GETUG P07: A multicenter phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer.

93 Background: Oligorecurrent pelvic nodal relapse of prostatic cancer is a challenge for regional salvage treatments. We conducted OLIGOPELVIS – GETUG P07, a phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer (NCT02274779). Methods: OLIGOPELVIS–GETUG P07 was a prospective multi-center phase II trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron-emission-tomography (FCH- PET)-positive pelvic lymph nodes (PLN), combined with six-month androgen blockade (LH-RH agonist or antagonist injections). The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathological PLN. Toxicity (CTCAE v4) and complete response rates (PSA < 0.20 ng/ml) were analyzed. The main objective was to assess biochemical-clinical failure defined by a cluster of events including PSA progression (≥25 % and ≥ 2 ng/ml above the nadir) or clinical evidence of local or metastatic progression or post- treatment initiation of hormonal therapy or prostate cancer-related death. We hypothesized that salvage treatment would achieve a 2-year relapse-free survival of 70 %. Results: Seventy-four patients were recruited in fifteen French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included sixty-seven patients. Half of them had received prior prostatic/prostate bed irradiation. Median age was 67.7. Grade 2+ two-year urinary and intestinal toxicity were 10% and 2% respectively. At 2 and 3 years, 73.1 and 45.9% of patients achieved a persisting complete response respectively. After a median follow-up of 34 months, the 2-year progression-free survival rate was 77.6%. Median progression-free survival was 40.1 months. Conclusions: Combined pelvic salvage radiotherapy and hormone therapy allowed for prolonged tumor control in oligorecurrent pelvic node relapses of prostate cancer with limited toxicity. Clinical trial information: NCT02274779.

Abstract P3-10-16: Identification of molecules that enhance the efficacy of eribulin in TNBC and IBC cell lines

Abstract BACKGROUND: Eribulin mesylate, a non-taxane microtubule-dynamics inhibitor, is an effective chemotherapy drug for patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens. We are seeking to enhance the anti-tumor activity of eribulin in metastatic breast cancer cell lines. The purpose of this study was to identify kinase targets that markedly enhance the efficacy of eribulin using high-throughput nonbiased synthetic lethal RNA interference (RNAi) screening and to validate these targets in combination with eribulin using triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) cell lines which are heterogeneous diseases and characterized by their high metastatic potential and poor prognosis. METHODS: High-throughput RNAi screening (709-human-kinome library) was performed to identify target kinases. The Bliss scoring method was used to identify potential targets from the screening (using a Bliss score cut-off of 0.15), and protein-protein interactome analysis (STRING V.11) and Ingenuity Pathway Analysis (IPA) were used to identify therapeutic target pathways. To validate the in vitro efficacy of selected targets, we performed CellTiter-Blue or sulforhodamine B cell proliferation and anchorage-independent colony-formation assays in 18 TNBC and 6 IBC cell lines treated with eribulin with or without inhibitors of the discovered targets. RESULTS: In vitro proliferation data demonstrated that single-agent eribulin had a nanomolar range of half-maximal inhibitory concentrations (0.2 - 4.0 nM) in most of the tested cell lines. RNAi screening identified 130 relevant kinase targets. IPA and STRING analysis revealed PI3K/AKT/mTOR, MAPK, JNK, and PAK1 as major canonical pathways that could be targeted to enhance the cytotoxic effect of eribulin. In in vitro cell line validation, PAK1 inhibitor NVS-PAK1-1 and mTOR inhibitor everolimus showed strong combinational anti-tumor effect (combination index values = 0.1 - 0.9), and JNK inhibitor JNK-In-8 showed moderate combinational anti-tumor effect (combination index values = 0.5 - 0.9) in combination with eribulin. Inhibitors of PI3K (copanlisib) and MEK (trametinib) showed combinational anti-tumor effect in some cell lines. CONCLUSION: We identified that PAK1, mTOR, and JNK inhibitors enhanced the anti-proliferation effects of eribulin in TNBC and IBC cell lines. Our data inform new treatment strategies with eribulin for TNBC and IBC that could lead to clinical trials of innovative combination therapy based on eribulin. Citation Format: Jangsoon Lee, Jon A Fuson, Huey Liu, Troy Pearson, Debu Tripathy, Bora Lim, Naoto T Ueno. Identification of molecules that enhance the efficacy of eribulin in TNBC and IBC cell lines [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-16.

Sustained, cell-intrinsic versus intermittent, cell-extrinsic checkpoint blockade in solid tumor CAR T-cell therapy.

16 Background: We and others have published that antigen-stress induced functional exhaustion of chimeric antigen receptor (CAR) T cells can be rescued by addition of anti-PD1 agents. To avoid the need for multiple administrations of anti-PD1 agent, we developed CAR T-cell intrinsic PD1 dominant negative receptor (PD1 DNR). Herein, we investigated the anti-tumor efficacy of cell-extrinsic versus intrinsic anti-PD1 strategies. Methods: Human T cells transduced with CD28 costimulated mesothelin-targeted CAR T cells (M28z) with or without anti-PD1 agent, and M28zPD1DNR CAR T cells were investigated against mesothelin-expressing cancer cells with inducible or constitutive PDL1 over expression. In vitro, cytotoxicity upon single and multiple antigen stimulation and proliferation, inhibitory receptor expression (PD1, TIM3 LAG3) were tested. In vivo, tumor burden regression kinetics and median survival were determined in an orthotopic model of pleural mesothelioma. Results: Following single antigen stimulation, both CAR T cells exhibited equivalent cytotoxicity. Following multiple antigen stimulations (antigen stress test), M28z PD1DNR CARs showed sustained and relatively higher cytotoxicity and proliferation compared to M28z CAR T cells, even when combined with anti-PD1 agent. PD1, TIM3 and LAG3 expression upregulation was noticed in both CAR T cells. CAR T cell therapy combined with extrinsic PD1 blockade or intrinsic PD1 DNR demonstrated enhanced and sustained tumor regression and prolonged survival (median survival 66 and 60 days) compared to CAR T cell therapy alone (27.5 days). In mouse model with constitutive PDL1 overexpressing cancer, similar trend is observed (74, 69 versus 28 days). Conclusions: A single dose of M28z CAR T cells with cell-intrinsic PD1DNR demonstrated equal anti-tumor efficacy compared to multiple doses of extrinsic anti-PD1 agent administration in models with inducible and constitutive high-PDL1 expressing cancer with no on-target, off-tumor toxicity with either strategy. This data provides the rationale for our ongoing phase II trial of combination therapy with M28z CAR T cells and anti-PD1 agent, and upcoming M28zPD1DNR CAR T cell trial in 2020.

Pharmacological, psychological, and non-invasive brain stimulation interventions for treating depression after stroke.

Pharmacological, psychological, and non-invasive brain stimulation interventions for treating depression after stroke.

Immune checkpoint inhibitor – antiangiogenic drugs combination in treatment-naïve metastatic clear cell renal cell carcinoma: Why should immunotherapy have all the fun!

Clear cell histology is the most common subtype of renal cell carcinoma (RCC). Immune dysregulation and angiogenic pathways are the main drivers of the pathophysiology of RCC. The prognosis of metastatic RCC has very steadily improved from the era of interferon-alpha to tyrosine kinase inhibitors (TKIs) and then with immune checkpoint inhibitors (IOs). The safety and efficacy of both TKIs and IOs as well as the dire unmet need of further improvement in survival has unfolded the feasibility of successful conduction of IO based combination therapy trials. This has led to the approval of IO-IO and IO-TKI combinations, altering the treatment algorithm altogether once again. In this review, we are trying to look at the robustness of IO–antiangiogenic drugs combination data in upfront setting and its real-life application.

A trial of combination therapy with mirror therapy in a stroke patient with severe upper-extremity paresis:

A trial of combination therapy with mirror therapy in a stroke patient with severe upper-extremity paresis:

Co-expression of EGFR and MET has a synergistic effect on the prognosis of patients with oral squamous cell carcinoma.

This study aimed to elucidate the correlation between gene amplification, protein expression of receptor tyrosine kinase, and prognosis of patients with oral squamous cell carcinoma (OSCC) using immunohistochemistry (IHC) and next-generation sequencing data. We evaluated data pertaining to 208 patients with OSCC using IHC for epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET). High expressions of EGFR and MET were detected in 60 and 41 patients, respectively. We evaluated the association of clinicopathological variables with high expressions of EGFR and/or MET. Distant metastasis was found in 9 of 41 patients (22.0%) and 6 of 15 patients (40.0%) with high expression of MET and high co-expressions of EGFR and MET, respectively; statistically significant differences were detected in both high expression of MET (P=.003) and high co-expressions of EGFR and MET (P=3.41×10-5 ). The cumulative 5-year survival rate of patients with high and low expressions of EGFR or MET was approximately 65% and 85%, respectively. Conversely, among cases with high expressions of EGFR or MET, there was no additional decrease in the survival rate of patients harboring TP53 mutations. Moreover, the survival rate of patients with high co-expression of both EGFR and MET was very poor (22.0%) (P<1.0×10-9 ). Our findings suggest that evaluation of protein expressions of EGFR and MET may facilitate prognostic assessment of patients with OSCC; in addition, patients with OSCC should be screened for enrollment in clinical trials of combination therapy with EGFR and MET inhibitors.

Predicting Optimal Combination LT4 + LT3 Therapy for Hypothyroidism Based on Residual Thyroid Function.

Objective: To gain insight into the mixed results of reported combination therapy studies conducted with levothyroxine (LT4) and liothyronine (LT3) between 1999 and 2016.Methods: We defined trial success as improved clinical outcome measures and/or patient preference for added LT3. We hypothesized that success depends strongly on residual thyroid function (RTF) as well as the LT3 added to sufficient LT4 dosing to normalize serum T4 and TSH, all rendering T3 levels to at least middle-normal range. The THYROSIM app was used to simulate “what-if” experiments in patients and study designs corresponding to the study trials. The app graphically provided serum total (T4) and free (FT4) thyroxine, total (T3) and free (FT3) triiodothyronine, and TSH responses over time, to different simulated LT4 and combination LT4 + LT3 dosage inputs in patients with primary hypothyroidism. We compared simulation results with available study response data, computed RTF values that matched the data, classified and compared them with trial success measures, and also generated nomograms for optimizing dosages based on RTF estimates.Results: Simulation results generated three categories of patients with different RTFs and T3 and T4 levels at trial endpoints. Four trial groups had >20%, four <10%, and five 10–20% RTF. Four trials were predicted to achieve high, seven medium, and two low T3 levels. From these attributes, we were able to correctly predict 12 of 13 trials deemed successful or not. We generated an algorithm for optimizing dosage combinations suitable for different RTF categories, with the goal of achieving mid-range normal T4, T3 and TSH levels. RTF is estimated from TSH, T4 or T3 measurements prior to any hormone therapy treatment, using three new nonlinear nomograms for computing RTFs from these measurements. Recommended once-daily starting doses are: 100 μg LT4 + 10–12.5 μg LT3; 100 μg LT4 + 7.5–10 μg LT3; and 87.5 μg LT4 + 7.5 μg LT3; for <10%, 10–20%, and >20% RTF, respectively.Conclusion: Unmeasured and variable RTF is a complicating factor in assessing effectiveness of combination LT4 + T3 therapy. We have estimated and partially validated RTFs for most existing trial data, using THYROSIM, and provided an algorithm for estimating RTF from accessible data, and optimizing patient dosing of LT4 + LT3 combinations for future combination therapy trials.

Daratumumab in Patients with Multiple Myeloma and Renal Impairment - Real-World Data from a Single-Center Institution

Background: Renal impairment is a frequent complication of multiple myeloma (MM) associated with poor prognosis and decreased overall survival; and can complicate drug dosing, limit treatment options and lead to a higher incidence of adverse events. Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of patients with MM which does not require dose modification in the setting of renal impairment. Real-world data regarding its efficacy in patients with renal impairment and the rate of renal response are lacking. Methods: We performed a retrospective, single-center analysis of patients with relapsed/refractory MM treated with daratumumab as monotherapy or in combination with novel agents. Patients were grouped by renal function as calculated by their eGFR using the MDRD equation: &lt;30, 30-59, &gt;=60 mL/min/1.73m2. Renal response was defined as an eGFR &gt;= 60 in two consecutive visits for patients with baseline renal impairment. Results: We identified 91 patients who started treatment with daratumumab between 2015-06-11 and 2018-08-16. The median age was 69 years old (range 40-93) and 25% were over the age of 75; 49 patients (54%) were female. Six patients (9%) were Hispanic, 16 (20%) were African American and 57 (71%) were Caucasian. High-risk cytogenetics were present in 58% of patients; defined as the presence of a complex karyotype, 1q gain, t(4;14), t(14;16), t(14;20) or del17p. Patients underwent a median of 5 prior lines of therapy (range 1-13), 45% had received an autologous stem cell transplant, 91% had been exposed to an immunomodulatory agent, 96% to a proteasome inhibitor, and 89% to both. Upon initial treatment, 53 patients (58%) had an eGFR &gt;=60 mL/min/1.73m2, while 27 (30%) and 11 (12%) patients had an eGFR of 30-59 and &lt;30 mL/min/1.73m2, respectively. The overall response rate (ORR) was 81% with a very good partial response (VGPR) or better of 47% and an unconfirmed complete response rate (uCR) of 23%. The median progression-free survival (mPFS) was 17.5 months while median overall survival (mOS) was not reached. There was no difference in mPFS or mOS between renal function groups. Of the 38 patients with baseline renal impairment (eGFR &lt;60 mL/min/1.73m2), 11 patients (29%) achieved a renal response, however, none of these patients had severe renal impairment. When compared to patients with chronic renal impairment, those with acute renal impairment were more likely to achieve a renal response (80% vs 21%, p=0.02). No significant difference in mPFS or mOS was observed by renal response (mPFS: 25.7m vs 17.5m, p=0.2; mOS: NR vs NR, p=0.8). Each renal function group was well balanced for the above parameters, including adverse events of interest and concurrent myeloma therapy as shown in the table, except where indicated (*). Discussion: The results of this analysis provide comparable efficacy - independent of the degree of baseline renal impairment - to the results seen in clinical trials of combination therapy with daratumumab. Furthermore, the high renal response rate (29%) seen, as compared to the one in the subgroup analysis of ENDEAVOR (15%), highlights the utility of daratumumab in reversing renal end-organ damage in patients with relapsed/refractory MM without an increase in adverse events compared to patients with preserved renal function. These results suggest that daratumumab may be able to abrogate the adverse prognostic factor that impaired baseline renal function portends. A limitation of this study is its retrospective nature, the confounding effect of concurrent myeloma therapy and the small number of patients included with renal impairment. Table Disclosures Coleman: Merck: Research Funding; Pharmacyclics: Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Rossi:Janssen, Celgene, Amgen: Consultancy; BMS: Research Funding.

Venetoclax Is Synergistic with Idelalisib or MK2206 Against Primary CLL Cells in an in Vitro Model of the Microenvironment

Background The PI3-kinase signaling pathway and the Bcl-2-family of proteins play crucial roles in regulating the survival and proliferation of chronic lymphocytic leukemia (CLL) cells in the bone marrow and lymph nodes. Trials of ibrutinib, idelalisib and venetoclax illustrate the potential of targeting the B-cell receptor (BCR) signaling pathway and Bcl-2, however disease relapse is still common. Several pre-clinical studies and on-going clinical trials [Rogers et al., 2018, Jain et al., 2019] suggest that combinations of BCR inhibitors with venetoclax may be an effective treatment strategy for CLL patients with high risk disease. We sought to investigate the effects of combining idelalisib or the AKT inhibitor MK2206 with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Methods Primary CLL cells were co-cultured with CD40L-expressing mouse L-fibroblasts. Cell viability was assessed using the mitochondrial membrane potential dye DilC1(5), propidium iodide and flow cytometry (n = 6). Synergy between idelalisib or MK2206 and venetoclax was evaluated by calculating combination indices (CI) using the Compusyn software. The mechanisms of action of the drugs and synergies between the drugs were investigated by immunoblotting (n = 6). Results Venetoclax was highly synergistic in combination with idelalisib or MK2206 against CLL cells co-cultured with CD40L-fibroblasts, with CI values of 0.2 and 0.5 at a fractional effect of 0.9, respectively (Figure 1). This synergy was consistent with a significant (P &lt; 0.05) reduction in the IC50 for venetoclax, idelalisib and MK2206. Immunoblotting suggests that MK2206, as a single agent or in combination with venetoclax, was more effective than idelalisib in inhibiting the phosphorylation of AKT and NF-κB. Both MK2206 and idelalisib as single agents and in combination with venetoclax significantly reduced expression of Mcl-1 and Bfl-1, two pro-survival members of the Bcl-2 family of proteins in primary CLL cells co-cultured with CD40L-fibroblasts. Conclusions The synergy observed, which was associated with a significant decrease in the IC50s for idelalisib and MK2206, may mitigate some of the toxicities associated with PI3-kinase pathway inhibitors. Comparison of the two PI3-kinase-pathway inhibitors suggests that MK2206 may be more effective than idelalisib at blocking BCR-mediated signaling as a single agent and in combination with venetoclax. The mechanisms underlying the synergy include down-regulation of expression of Bcl-2 family proteins that are not targeted by venetoclax as a single agent. The data presented support the rationale for on-going and future clinical trials of combination therapies incorporating a PI3-kinase inhibitor with venetoclax for the treatment of high risk CLL. Figure 1 Disclosures No relevant conflicts of interest to declare.

Combination Therapy for Bladder Dysfunction in Patients with Neurogenic Detrusor Overactivity

Neurogenic bladder is a common condition and top health priority present in 20–70% of patients with neurologic diseases including multiple sclerosis (MS), Parkinson’s disease (PD), spinal cord injury (SCI), and cerebrovascular accidents (CVA). Current gold-standard medications for overactive bladder (OAB), such as anti-muscarinics, have undesirable side effects, or have limited data in neurogenic patients. Combining therapy for urinary urge incontinence (UUI) has shown the potential to increase efficacy while maintaining or improving tolerability of treatment. Our objective was to review and synthesize recent combination therapy studies for UUI in patients with neurogenic detrusor overactivity (NDO). Non-pharmacologic and pharmacologic combination therapies have been investigated for UUI in patients with NDO. Adding intravaginal neuromuscular electrical stimulation (IVES) or transcutaneous tibial stimulation (TTNS) may not be superior to pelvic floor muscle training (PFMT) on its own. Recent studies on dual therapies have focused on combining drugs with different mechanisms. In adults, a combination of desmopressin with mirabegron showed superior efficacy compared to either drug alone or solifenacin. In children, combination studies have focused on adding gabapentin to drug regimens with promising safety and efficacy. Overall, there are few combination therapy trials for OAB in neurogenic patients compared to those in patients with idiopathic OAB. There is an unmet medical need for combination therapies in patients with UUI due to neurogenic bladder. It is important to gather practice patterns and encourage providers to share their experiences. In addition, more rigorous clinical studies are needed to explore new combinations.

COMBINATION THERAPY FOR MYELOFIBROSIS

Introduction.Ruxolitinib presents itself as a drug for the pathogenetic treatment of myelofibrosis (MF). New drugs have recently been developed for the treatment of MF. A search for optimal combinations of these drugs with ruxolitinib appears to be a logical approach to the development of MF therapy.Aim.To summarize data on the use of ruxolitinib in combination with various drugs approved or currently being studied in terms of their applicability for MF treatment.General findings.The review analyses data in publications retrieved from the PubMed and Elibrary.ru databases, including clinical cases, original research papers and reviews. We discuss preliminary results of clinical trials of various rational combination therapies, which have demonstrated a high efficacy for the forms of the disease untreatable with ruxolithinib monotherapy, e.g. bone marrow fibrosis and anemia. Combinations of ruxolithinib with azacytidine, panobinostat and α-interferon have shown the most promising results.

Benefit, burden, and impact for a cohort of post-approval cancer combination trials.

After approval, drug developers often pursue trials aimed at extending the uses of a new drug by combining it with other drugs. Little is known about the risk and benefits associated with such research. To establish a historic benchmark of risk and benefit, we searched Medline and Embase for clinical trials testing anti-cancer drugs in combination within 5 years of approval by the Food and Drug Administration of 12 anti-cancer "index" drugs first licensed 2005-2007 inclusive. Risk was assessed based on grade 3 or above drug-related adverse events; benefit was assessed based on efficacy outcomes and advancement of combinations into clinical practice guidelines or approval by the Food and Drug Administration. We captured 323 published post-approval trials exploring combinations, including 266 unique combination-indication pairings and enrolling 29,835 patients. The pooled risk ratios for treatment-related grade 3-4 severe adverse events and deaths attributed to the study drugs for trials randomized between a combination arm and a comparator were 1.54 (1.33-1.79) and 1.51 (1.16-1.97), respectively. The pooled hazard ratios for overall survival and progression-free survival were 0.99 (0.92-1.05) and 0.85 (0.79-0.93), respectively. None of the combination-indication pairings launched after initial drug approval received approval by the Food and Drug Administration, and 13 pairings (4.9%) were recommended by the National Comprehensive Cancer Network within 5 years of the first trial within that pairing. The proportion of patients in our sample who participated in trials leading to an approval by the Food and Drug Administration or a National Comprehensive Cancer Network guideline recommendation was 12.7% with 5 years of follow-up, and 22.3% among pairings for which there were 8 years of follow-up. Patients were just as likely to benefit in the treatment arm as the control arm in terms of overall survival, but they were more likely to experience a treatment-related severe adverse event in post-approval trials of combination therapy.

EP1.04-09 A Cross-Sectional Study of Clinical Trials on Radiotherapy Combined with Immunotherapy for Lung Cancer

For patients with lung cancer, remarkable advances have been made in Immune-Oncology (IO) therapy, especially immune checkpoint inhibitors (ICI). However, multi-modality treatment is needed to improve the efficacy or enlarge the beneficial populations of IO treatment. This study is to comprehensively summarize and analyze the clinical trials focusing on radiotherapy (RT) combined with IO therapy, explore the trend of research, as well as provide a view of the latest landscape of combination strategies. Trials registered on the electronic database (https://clinicaltrials.gov) between Jan 2009 and Jan 2019 were searched using “Radiotherapy AND Immunotherapy | Recruiting, Not yet recruiting, Active, not recruiting, Completed, Enrolling by invitation Studies | Interventional Studies | Lung Cancer”. SPSS 20.0 was used to analyze the data. Totally 69 clinical trials of RT and IO combination therapy for lung cancer were recorded, including 54 active and 15 completed. Geographically, most of the trials were carried out in the USA (n=47, 68.1%), followed by the European countries (n=18, 26.1%). From timeline, the past 2 years has seen a soaring number of 40 clinical trials accounting for 58.0% of the total. The combination therapy trials were more often in non-small cell lung cancer (NSCLC) (n=52, 75.4%) than small cell lung cancer (SCLC) (n=10, 14.5%), with the remaining 7 trials unspecified. As for combination strategies, trials of tumor vaccine combined with RT were the most frequent before 2016. But at present, ICI has exceeded tumor vaccine in the combination with RT and makes up the absolute most (n=62, 89.9%). On the whole, most of the combination therapy trials are in phase I/II (n=64, 92.8%). Although most trials are set for advanced or metastatic cancers (n=43, 62.3%), there are a few exploring the safety and effectiveness of combination therapy for early stage cancers or as adjuvant therapy (n=9, 13.0%). One trial was set as neo-adjuvant therapy. As for RT details, 22 trials were SBRT combined with IO therapy. Two trials were exploring the optimal sequence of RT and IO therapy. And one trial is to compare high versus low dose RT in the combination with ICI in NSCLC. From the trials of RT and IO combination therapy for lung cancer, those of ICI combined with RT are increasing rapidly, although most are in phase I/II. Further studies are needed to explore the more detailed rational combination strategies, such as the sequencing, fractionation and dose of RT, and the optimal IO agent.

1365P - Final results from phase II of combination with canerpaturev (formerly HF10), an oncolytic viral immunotherapy, and ipilimumab in unresectable or metastatic melanoma in second-or later line treatment

1365P - Final results from phase II of combination with canerpaturev (formerly HF10), an oncolytic viral immunotherapy, and ipilimumab in unresectable or metastatic melanoma in second-or later line treatment

Single-Arm Phase II Trials of Combination Therapies: A Review of the CTEP Experience 2008-2017.

Designing and interpreting single-arm phase II trials of combinations of agents is challenging because it can be difficult, based on historical data, to identify levels of activity for which the combination would be worth pursuing. We identified Cancer Therapy Evaluation Program single-arm combination trials that were activated in 2008-2017 and tabulated their design characteristics and results. Positive trials were evaluated as to whether they provided credible evidence that the combination was better than its constituents. A total of 125 trials were identified, and 120 trials had results available. Twelve had designs where eligible patients were required to be resistant or refractory to all but one element of the combination. Only 17.8% of the 45 positive trials were deemed to provide credible evidence that the combination was better than its constituents. Of the 10 positive trials with observed rates 10 percentage points higher than their upper (alternative hypothesis) targets, only five were deemed to provide such credible evidence. Many trials were definitively negative, with observed clinical activity at or below their lower (null hypothesis) targets. Ideally, use of single-arm combination trials should be restricted to settings where each agent is known to have minimal monotherapy activity (and a randomized trial is infeasible). In these settings, an observed signal is attributable to synergy and thus could be used to decide whether the combination is worth pursuing. In other settings, credible evidence can still be obtained if the observed activity is much higher than expected, but experience suggests that this is a rare occurrence.

A Cross-Sectional Study of Clinical Trials on Radiotherapy Combined with Immunotherapy for Lung Cancer

For patients with lung cancer, remarkable advances have been made in Immune-Oncology (IO) therapy, especially immune checkpoint inhibitors (ICI). However, multi-modality treatment is needed to improve the efficacy or enlarge the beneficial populations of IO treatment. This study is to comprehensively summarize and analyze the clinical trials focusing on radiotherapy (RT) combined with IO therapy, explore the trend of research, as well as provide a view of the latest landscape of combination strategies. Trials registered on the electronic database (https://clinicaltrials.gov) between Jan.2009 and Jan.2019 were searched using “Radiotherapy AND Immunotherapy | Recruiting, Not yet recruiting, Active, not recruiting, Completed, Enrolling by invitation Studies | Interventional Studies | Lung Cancer”. Statistical analysis software was used to analyze the data. Totally 69 clinical trials of RT and IO combination therapy for lung cancer were recorded, including 54 active and 15 completed. Geographically, most of the trials were carried out in the USA (n=47, 68.1%), followed by the European countries (n=18, 26.1%). From timeline, the past 2 years has seen a soaring number of 40 clinical trials accounting for 58.0% of the total. The combination therapy trials were more often in non-small cell lung cancer (NSCLC) (n=52, 75.4%) than small cell lung cancer (SCLC) (n=10, 14.5%), with the remaining 7 trials unspecified. As for combination strategies, trials of tumor vaccine combined with RT were the most frequent before 2016. However, at present, ICI has exceeded tumor vaccine in the combination with RT and makes up the absolute most (n=62, 89.9%). On the whole, most of the combination therapy trials are in phase I/II (n=64, 92.8%). Although most trials are set for advanced or metastatic cancers (n=43, 62.3%), there are a few exploring the safety and effectiveness of combination therapy for early stage cancers or as adjuvant therapy (n=9, 13.0%). One trial was set as neo-adjuvant therapy. As for RT details, 22 trials were SBRT combined with IO therapy. Two trials were exploring the optimal sequence of RT and IO therapy. In addition, one trial is to compare high versus low dose RT in the combination with ICI in NSCLC. From the trials of RT and IO combination therapy for lung cancer, those of ICI combined with RT are increasing rapidly, although most are in phase I/II. Further studies are needed to explore the more detailed rational combination strategies, such as the sequencing, fractionation, and dose of RT, and the optimal IO agent.

Monotherapy for toenail onychomycosis: a systematic review and network meta-analysis.

Onychomycosis is a fungal infection of the nail caused by dermatophytes, yeasts and nondermatophyte moulds that accounts for approximately 50% of all nail-related disease. This study aims to assess the effectiveness and safety of monotherapy and combination treatments for toenail onychomycosis using a network meta-analysis (NMA). Quality of evidence was assessed using Cochrane-compliant rules and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Efficacy and safety outcomes were compared using a random-effects NMA to estimate pooled odds ratios (ORs) of direct and indirect comparisons among oral and topical treatments (PROSPERO 2015: CRD42018086912). There were not enough eligible combination and device-based therapy trials to include in the NMA. Of 77 randomized controlled trials, 26 were included in the ORs (8136 patients). There were no significant inconsistencies between the direct and indirect evidence. Relative effects show that the odds of mycological cure with continuous terbinafine 250 mg or continuous itraconazole 200 mg are significantly greater than topical treatments. Fluconazole, pulse regimens of terbinafine and itraconazole, and topical treatments did not differ significantly in the odds of achieving mycological cure. The ORs of adverse events occurring with oral or topical treatments were not significantly different from each other. For mycological cure, evidence was of moderate or high quality while evidence ranged from very low to high quality for adverse events. Our review suggests that oral and topical treatments for toenail onychomycosis are safe and effective in producing mycological cure. What's already known about this topic? Topical treatments traditionally have lower success rates than oral treatments. Oral treatments have the advantage of shorter treatment durations, but also present challenges in cases of drug-drug interactions or immunosuppression. A network meta-analysis (NMA) gathers data from indirect evidence to gain confidence about all treatment comparisons and allows for estimation of comparative effects that have not been investigated in head-to-head randomized clinical trials (RCTs). What does this study add? This NMA of efficacy and safety includes all RCTs of oral, topical, combination and device-based treatments for toenail onychomycosis, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for NMA. The odds of achieving mycological cure with continuous terbinafine 250 mg or continuous itraconazole 200 mg were significantly greater than topical treatments. Fluconazole, pulse regimens of terbinafine and itraconazole, and topical treatments did not differ significantly in the odds of achieving mycological cure.

A 6-day combined wake and light therapy trial for unipolar depression

BackgroundThere are a dozen studies on double or triple chronotherapy in depression (sleep deprivation [wake therapy] + light therapy + sleep advance/stabilization). We investigated efficacy and feasibility of a modified triple chronotherapy protocol. MethodsThirty-five hospitalized patients with moderately severe non-seasonal depressive disorder, mostly free from antidepressants, underwent a 6-day protocol consisting of partial sleep deprivation late in the second half of the night (from 4:00 to 8:00) in a light therapy room (blue-enhanced white light increased hourly from 600→1300→2200→2800 lx) alternating with recovery nights with morning light treatment from 7:00 to 8:00. Patients were randomized to wear glasses with no filter (clear, N = 19) or filtering blue wavelength (orange-appearance, light intensity diminution by ∼70%, N = 16) during the treatments. Sleep was targeted to be shifted at least 1 h earlier. Depression was scored using HDRS-17 (Hamilton Depression Rating Scale) and BDI-II (Beck Depression Inventory-II) – before and after the 6-days treatment, HDRS-6-SR – daily, and visual analogue scales (VAS) for mood and energy – several times every day. ResultsDepression levels significantly declined following the first night and after 6-days treatment, with no difference between white and orange lights. Nevertheless, some superiority of white light emerged with respect to response rate (mood VAS), immediate effect during the 4-h treatment sessions (energy VAS), and expected treatment outcomes. All patients successfully advanced bedtime/wake-up (by 30–40 minutes) and resisted naps during daytime. LimitationsRelatively small sample size. ConclusionsThe modified triple chronotherapy was well tolerated and improved depression. Light spectrum/intensity plays some role in the response.

Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma

BackgroundPatients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors.MethodsWe analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.ResultsA total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years.ConclusionsFirst-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.)