Response Rates In Clinical Trials Research Articles

Epic: A Second Interim Analysis of the Non-Interventional, Observational Multi-Centre Cohort Study of Patients with Chronic Lymphocytic Leukaemia Treated with First-Line Acalabrutinib through the UK Early Access Programme

Background: Acalabrutinib, a second-generation Bruton Tyrosine Kinase inhibitor (BTKi), has shown an acceptable safety profile and high response rates in clinical trials of treatment naïve patients with chronic lymphocytic leukaemia (CLL). However, real-world data detailing the safety and effectiveness of first-line acalabrutinib treatment for CLL is limited. Here we present a second interim analysis (IA) of patients with CLL who were initiated on first-line acalabrutinib within the UK Early Access Programme (EAP). Methods: This is an ongoing observational multi-centre cohort study involving retrospective data collection from medical records (ClinicalTrials.gov: NCT05557695). Treatment-naïve patients with CLL from 9 UK clinical centres who initiated acalabrutinib as part of the UK EAP between 1 st April 2020 - 1 st April 2021 were eligible to participate. Patients will be followed for up to 60 months from the date of acalabrutinib initiation (index). Collected data for this IA (data cut-off 31 st May 2023) includes baseline demographics, clinical characteristics, and treatment patterns. Results: 101 patients were included in this IA. Median (interquartile range (IQR)) age at index was 73.8 (66.1-78.4) years; 56% (n=57/101) of patients were male; 89% (n=83/93) of patients were White British, 6% (n=6/93) were White other, 3% (n=3/93) were Asian and 1% (n=1/93) were of Mixed ethnicity (missing data n=8). Median (IQR) duration of follow-up was 32.4 (29.2-35.4) months; 89% (n=90/101) of patients had a follow-up duration of ≥1 year and 84% (n=85/101) ≥2 years. 88% (n=52/59) of patients had an Eastern Cooperative Oncology Group performance status (PS) of 0-1, 10% (n=6/59) had a PS of 2 and 2% (n=1/59) had a PS of 3 (missing n=42). 50% (n=40/80) of patients had a creatinine clearance <60 mL/min at index. 5% (n=5/101) of patients had a confirmed ATM mutation and no patients had a confirmed 17p13.1 deletion. 5% (n=5/101) had a confirmed TP53 mutation and of 10 patients with confirmed IgHV mutational status, 20% (2/10) had mutated IgHV (91 unknown). Median (IQR) time between CLL diagnosis and index was 2.8 (1.2-5.4) years. At index, 100 patients received 100 mg of acalabrutinib twice a day, 1 patient received 100 mg daily. The continuation rate (n=100) at 12 and 24 months was 81.0% (95% confidence interval [CI], 73.7%-89.1%) and 74.0% (95% CI, 65.9%-83.1%), respectively (1 patient not recorded). 68% (n=69/101) of patients remained on treatment at the time of data cut. Of those patients reporting reasons for treatment discontinuation, 48% (n=15/31) were due to adverse events (AEs; of the 14/15 patients reporting type of AEs resulting in discontinuation, 14% (2/14) was reported for each of the following AEs; cardiovascular, haematoma, headache and urinary tract infection), 6% (n=2/31) due to disease progression, 3% (n=1/31) due to patients' decision and 42% (n=13/31) other reasons (1 unknown). Of 39 patients with treatment interruptions, 72% (n=28/39) patients had interruptions due to AEs, 15% (n=6/39) due to a minor operation and/or procedure and 21% (n=8/39) other reasons. Of the 22/28 patients reporting type of AE resulting in treatment interruption, the most common AEs were upper respiratory tract infection (23%, n=5/22) and thrombocytopenia (18%, n=4/22). Of those with relevant medical records, 62% (n=40/65) had a recorded COVID-19 diagnosis; of these, 93% (n=37/40) diagnoses were confirmed via test. Sotrovimab was the most common treatment received for COVID-19 (20% of patients, n=8/40). COVID-19 vaccination and biannual boosters is offered to all patients with CLL as per UK guidelines, available data from 58 patients showed that 72% (n=42/58) of patients had received ≥4 COVID-19 vaccination doses and 28% (n=16/58) had received <4 doses at the time of datacut (missing n=43). Conclusion: This IA reports 12 and 24-month real-world acalabrutinib continuation rates of 81.0% (95% CI, 73.7%-89.1%, n=100) and 74.0% (95% CI, 65.9%-83.1%, n=100), respectively, in treatment naïve patients with CLL in UK. These findings provide clinical decision makers with valuable insights into acalabrutinib use in the real-world as well as highlighting the importance of BTKi AE management in a real-world clinical setting. Further IAs are planned.

Validation of the Composite Complete Response (cCR) Definitions in the International Working Group (IWG) 2023 Criteria in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Treated with Hypomethylating Agents (HMA) - a Large, Multicenter, Retrospective Analysis from the Validate Database

JPB and TK are co-first authors; RK and AMZ are co-senior authors Introduction: Efficacy of therapies used in HR-MDS pts has long been assessed using IWG 2006 MDS criteria, but important limitations in clinical utility and practical application of these criteria have become apparent. The revised IWG response criteria for HR-MDS were proposed in 2023 (Zeidan et al., Blood 2023) were proposed to address these gaps. IWG 2023 re-defined CR by lowering hemoglobin (Hb) threshold from 11 to 10 g/dL and bone marrow [BM] blasts from ≤5% to <5%. Further, CR with partial hematologic recovery (CRh; <5% BM blasts, no Hb threshold, platelets ≥50 × 10 9/L; neutrophils ≥0.5 × 10 9/L; peripheral blood [PB] blasts 0%), CR with limited count recovery (CR-L; <5% BM and 0% PB blasts + PB parameters for CR met in 1 [CRuni] or 2 lineages [CRbi]), and CR equivalent (CRequ; defined for pts with baseline BM of <5%.) were all proposed as provisional endpoints. Per IWG 2023 hierarchical response assessment, if a pt met criteria for both CR-L and CRh, they would be recorded as CR-L. We sought to validate the IWG 2023 definitions of cCR (CR+CR-L+CRh+CRequ) in a large, multi-center dataset of HR-MDS pts who received HMAs. Methods: The VALIDATE database includes HR-MDS pts treated with HMA-based therapies in frontline setting from 14 specialized centers. HR-MDS was defined as IPSS ≥1.5 or IPSS-R >3.5 (n=213 pts excluded). Pts were excluded (N=90) if age at diagnosis was <18 years, BM blasts ≥20% or unknown at HMA initiation, or if survival status, follow-up time, HMA type or initiation date were unknown. To preserve validity of response assessments, pts also were excluded (N=290) if no BM evaluation was performed or if first BM assessment was >180 days after HMA initiation, except in cases of overt disease progression. Best responses were assessed based on IWG 2006 and 2023 criteria. Kaplan-Meier analysis estimated OS from HMA initiation, and the log-rank test was used to compare subgroups. Cox multivariable regression models identified predictors of OS. This study was supported by an independent research grant from AbbVie. Results: Of 1,223 pts in VALIDATE database, 629 were met eligibility. Median age was 68 years, 27.7% and 27.4% were red blood cell and platelet transfusion-dependent, respectively, 38.1% had TP53 mutations, and 45.3% underwent allogeneic transplantation (allo-HCT). Most pts (71.6%) received HMA monotherapy (51.7% azacitidine, 19.9% decitabine), while 28.4% received HMA-based combinations. Median duration of therapy was 4 cycles (Range: 1-94). Median OS of different subgroups pts are shown in Figure 1. Median OS for pts with IWG 2023-defined cCR (CR+CR-L+CRh+CRequ; N = 230) was 26.5 months (mo; 95% CI: 20.7 - 32.2 mo) vs 14.3 mo (95% CI: 12.5 - 16.9 mo) for pts who did not achieve cCR (p=0.002). Median OS for pts who achieved IWG 2023-defined CR (N = 90) was 29.8 (95% CI: 23.1 - 41.8) vs. 26.4 mo (95% CI: 22.0 - 41.3) for IWG 2006-defined CR (p=0.71). The 124 pts (19.7%) who achieved CR-L had a median OS of 26.4 mo (95% CI: 17.6 - 36.2 mo); of those 67 pts achieved CRbi and had a median OS of 29.1 mo (95% CI: 20.7 - not reached), while 57 pts achieved CRuni and had a median OS of 18.7 mo (95% CI: 15.5 - 54.4 mo), with no significant difference in OS between CRbi and CRuni (Hazard ratio: 1.24; 95% CI: 0.78-1.98, p=0.71). Given the hierarchical prioritization of CR-L designation over CRh in IWG 2023 if a pt meets both response definitions, only 6 pts achieved CRh which precluded a reliable estimate of their OS. Similarly, CRequ was achieved only in 10 pts limiting a reliable assessment of OS in these pts. In a multivariable Cox model that adjusted for sex, HMA type, age, allo-HCT, complex karyotype, TP53 mutation, and IPSS-M risk group, achieving a cCR per IWG 2023 criteria was statistically significantly associated with improved OS was associated with improved OS compared to those who did not achieve cCR (HR: 1.64; 95% CI: 1.30 - 2.08; p<0.001, Figure 2). Discussion: In this real-world analysis of HR-MDS pts treated with HMA-based therapy, cCR according to IWG 2023 were associated improved OS. In particular, CR and CRL (including CRbi and CR uni) were associated with improved OS, supporting their inclusion in the overall response rate in clinical trials. The number of pts who achieved CRh and CRequ was too small to reliably assess their specific association with OS. Additional pts are being added to the database and detailed analyses will be presented in the meeting.

Establishing Real-World Data-Driven Response Criteria in Pediatric Acute Myeloid Leukemia

Introduction: Disease response criteria in pediatric acute myeloid leukemia (pAML) include complete remission (CR), complete remission without platelet count recovery (CRp), and complete remission with incomplete count recovery (CRi). Although clinicians use CR, CRp, and CRi as valid endpoints, the FDA only accepts CR as a valid response endpoint with the Cheson/European Leukemia Network (ELN) response criteria of absolute neutrophil count (ANC) >1,000 and platelets >100,000. Recent adult data show improved survival in patients achieving CR relative to CRp or CRi. Pediatric data from the Children's Oncology Group (COG) demonstrate similar survival regardless of achieving an ANC >500 or platelets >50,000. However, actual ANC and platelet data were not known, and COG data may not reflect outcomes of patients treated off study. Exclusion of CRp and CRi as valid efficacy endpoints limits clinical trials by potentially excluding patients who achieve remission but proceed to subsequent chemotherapy prior to meeting ELN recovery criteria. To address this data gap, we defined the ANC and platelet count trajectories in a 13-day window at end of course bone marrow (BM) after Induction I/II and Reinduction I/II of relapse therapy. We compared disease-free (DFS) and overall survival (OS) among CR categories and hypothesized that CR, CRp, and CRi after Induction I and Reinduction I would be associated with similar DFS and OS. Methods: Newly diagnosed pAML patients from 2011-2022 with at least one frontline chemotherapy course at one of six pediatric centers (Children's Hospital of Philadelphia, Children's Healthcare of Atlanta, Children's Hospital of Michigan, C.S. Mott Children's Hospital, Lurie Children's Hospital, and Texas Children's Hospital) underwent manual chart abstraction to capture demographic, therapy, toxicity, and BM response data: morphologic and minimal residual disease (MRD). The highest daily ANC and platelet counts were abstracted ±13 days around the last BM aspirate after Induction I/II and reinduction I/II post relapse. ELN and COG recovery criteria for ANC (>1,000 and >500, respectively) and platelet (>100,000 and >50,000, respectively) defined CR, CRp and CRi; CRi was further divided into CRnoANC and CRnoANCnoPlatelet. Standard descriptive statistics and Kaplan-Meier (KM) methods were used for analyses. Course-specific evaluations were restricted to subjects with an end of course BM documenting morphological response and ANC/platelet values on the day of course ending BM or 1 day prior. Results: The source population contained 486 patients with the analysis cohort restricted as described above to include 313 patients in Induction I, 290 patients in Induction II, 70 patients in Reinduction I, and 34 patients in Reinduction II. This represents 707 total courses and 8933 ANC/platelet observation days, restricted from 1166 courses (371 without morphologic response and 88 lacked ANC/platelet at course end BM). Demographic covariates included age, sex, race, ethnicity, risk group, MRD, extramedullary disease, weight category, and insurance. At Induction I, MRD differed significantly by CR category for ELN and COG criteria; risk group approached but did not reach significance; and Hispanic ethnicity differed by CR category only in COG criteria. No covariates differed significantly at Reinduction I in either ELN or COG criteria. At Induction I, CR proportion differed between ELN and COG criteria: 40.9% (95% CI 35.5-46.6%) vs 69.6% (95% CI 64.2%-74.7%). At Reinduction I, CR proportion differed between ELN and COG criteria: 18.6% (95% CI 10.3-29.7%) vs 47.1% (95% CI 35.1-59.4%). Panel 1a shows median ANC at Induction I BM is <1000 (ELN) but >500 (COG) in >75% of individuals. KM analyses showed no significant differences in CR strata in ELN or COG criteria in DFS or OS at Induction I. At Reinduction I, ELN CR strata did not differ, but COG CR strata were significantly different in DFS (p = 0.0007) and OS (p = 0.0019) with CRp and CRnoANC with higher DFS than CR or CRnoANCnoPlatelet (Panel 1b). Conclusion: These real-world data suggest that ELN/COG response criteria may lead to markedly different CR rates that may impact reported response rates in clinical trials. These analyses also support COG CR response criteria in de novo pAML and CR, CRp, and CRnoANC in relapsed pAML, recognizing that the modest relapsed pAML sample size requires additional data to determine optimal response criteria.

Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction

Despite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma.

Abstract 6799: A porous silicon particle based particulate anti-cancer vaccine for immunotherapy

Abstract Background: Anti-cancer vaccine is a widely-studied strategy that activates innate and adaptive host immunity via its adjuvant components and tumor antigens against cancer. Unfortunately, its response rate in clinical trials was not promising. On the vaccine part, sufficient stimulation of strong and long-lasting local and systemic immunity and efficient promotion of intratumoral infiltration of cytotoxic T lymphocytes are among the critical issues determining the therapeutic efficacy of cancer vaccines in addition to the innate features of tumor. Our project aims to develop a porous silicon particle based particulate vaccine against cancer, and investigate the therapeutic mechanism and combinational effects with current first-line strategies. Method: We first screened the combinations of ligands of Toll-like receptors (TLRs) expressing on antigen presenting cells (APCs) and selected the most powerful combo for immune stimulation. We then loaded the identified adjuvants in addition to antigen peptides to produce vaccine particles. Stimulation and licensing of APCs were tested in vitro, and its therapeutic efficacies were evaluated on multiple orthotopic and systemic metastasis cancer murine models of breast and colon cancers. Furthermore, we investigated the vaccine’s synergistic effects and impacts on tumor microenviroment (TME) with an immunogenic chemotherapeutic oxaliplatin on a CT26 colon cancer model. Result: According to the adjuvant screening assays, we identified a capable combination of CpG1826 (CpG) and 2’3’-cGAMP (cGAMP), which extensively stimulated the activation, maturation and type-I interferon secretion of APCs. A µGCVax formulation composed by these two adjuvants and antigen peptides was then applied on primary and metastatic HER2+ breast cancer TUBO bearing mice. µGCVax potently promoted the activation and lymph node migration of CD8+ and CD103+ dendritic cells in vivo. Distal metastatic tumor nodules in all different tissues vanished after two vaccinations. Functional cure of cancer and extension of animal survival were achieved. Moreover, oxaliplatin treatment on colon cancer caused immunogenic cell death and generated an immune favorable TME in a subcutaneous CT26 colon cancer model. The combination of µGCVax with the oxaliplatin effectively blocked the progression of large tumor mass. We finally revealed that the reprogramming of TME and the promotion of efficacy were mostly achieved from diminishing myeloid-derived suppressor cells (MDSCs) in tumor. Conclusion: µGCVax is an effective and board-spectrum formulation for cancer immunotherapy. It effectively induces APC activation and licensing, and stimulates the innate and adaptive immunity against multiple cancers. The combination with oxaliplatin further promotes the therapeutic efficacy of µGCVax by decreasing tumor MDSCs. Citation Format: Junhua Mai, Yongbin Liu, Dongfang Yu, Haifa Shen. A porous silicon particle based particulate anti-cancer vaccine for immunotherapy. [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 6799.

Predictors of Placebo Induction Response and Remission in Ulcerative Colitis

High placebo response rates in clinical trials of ulcerative colitis (UC) have been reported previously. However, data from patient-level analyses are lacking. We assessed factors associated with clinical and endoscopic placebo response among placebo-treated patients in clinical trials of UC. We performed a post hoc analysis of pooled clinical trial data from GEMINI-1, ACT-1, ACT-2, PURSUIT, ULTRA-2, OCTAVE-1, and OCTAVE-2. Predictors were assessed in placebo-treated patients for their association with end of induction (week 6 of 8) clinical response (reduction in total Mayo score of ≥3 and ≥30% from baseline with ≥1 point decrease in rectal bleeding subscore [RBS] or absolute RBS ≤1); clinical remission (total Mayo score ≤2 and no subscore >1); endoscopic healing (Mayo endoscopic subscore ≤1); partial Mayo score of 0; patient-reported outcome 2-item remission (RBS of 0 and stool frequency ≤1), resolution of rectal bleeding, and stool frequency normalization. Predictors on univariate analyses with P < .05 were included in multivariate logistic regression models. Placebo-treated patients with normal serum C-reactive protein and albumin levels were more likely to attain clinical response (71 of 437 [16.3%] vs 49 of 660 [7.4%]; adjusted odds ratio, 2.76; 95% confidence interval, 1.19-5.41; P= .018). Compared with patients with a Mayo endoscopic score of 2, patients with a Mayo endoscopic score of 3 were less likely to attain clinical response (105 of 556 [18.8%] vs 179 of 675 [25.9%]; adjusted odds ratio, 0.33; 95% confidence interval, 0.16-0.68; P= .003). Similar findings were observed for clinical remission and resolution of rectal bleeding. Biomarkers such as normal serum C-reactive protein and albumin and baseline endoscopic severity were found to affect placebo response rates in clinical trials of UC. These findings have implications for clinical trial design in UC.

Engineered NK Cells Against Cancer and Their Potential Applications Beyond.

Cell therapy is an innovative therapeutic concept where viable cells are implanted, infused, or grafted into a patient to treat impaired or malignant tissues. The term was first introduced circa the 19th century and has since resulted in multiple breakthroughs in different fields of medicine, such as neurology, cardiology, and oncology. Lately, cell and gene therapy are merging to provide cell products with additional or enhanced properties. In this context, adoptive transfer of genetically modified cytotoxic lymphocytes has emerged as a novel treatment option for cancer patients. To this day, five cell therapy products have been FDA approved, four of which for CD19-positive malignancies and one for B-cell maturation antigen (BCMA)-positive malignancies. These are personalized immunotherapies where patient T cells are engineered to express chimeric antigen receptors (CARs) with the aim to redirect the cells against tumor-specific antigens. CAR-T cell therapies show impressive objective response rates in clinical trials that, in certain instances, may reach up to 80%. However, the life-threatening side effects associated with T cell toxicity and the manufacturing difficulties of developing personalized therapies hamper their widespread use. Recent literature suggests that Natural Killer (NK) cells, may provide a safer alternative and an ‘off-the-shelf’ treatment option thanks to their potent antitumor properties and relatively short lifespan. Here, we will discuss the potential of NK cells in CAR-based therapies focusing on the applications of CAR-NK cells in cancer therapy and beyond.

Immune Checkpoint Blockade for the Treatment of Hodgkin Lymphoma.

Classical Hodgkin lymphoma is biologically different than other lymphomas. The cancer cells only occupy a small amount of the lymph node and evade the immune system by amplification of PD-L1 and PD-L2. Therefore, checkpoint inhibitors are a logical treatment option for Hodgkin lymphoma patients to unlock the immune system. Checkpoint inhibitors have shown high response rates in clinical trials in advanced-stage Hodgkin lymphoma. The two most commonly used checkpoint inhibitors are pembrolizumab and nivolumab, both FDA approved as third-line therapy. There is increasing interest in the use of checkpoint inhibitors with combination chemotherapy or with other targeted agents in the second-line or even frontline setting. In this review, we will highlight the clinical trials that led to approvals of checkpoint inhibitors for Hodgkin lymphoma.

Cholesterol modified DP7 and pantothenic acid induce dendritic cell homing to enhance the efficacy of dendritic cell vaccines

Dendritic cell (DC)-based cancer vaccines have so far achieved good therapeutic effects in animal experiments and early clinical trials for certain malignant tumors. However, the overall objective response rate in clinical trials rarely exceeds 15%. The poor efficiency of DC migration to lymph nodes (LNs) (< 5%) is one of the main factors limiting the effectiveness of DC vaccines. Therefore, increasing the efficiency of DC migration is expected to further enhance the efficacy of DC vaccines. Here, we used DP7-C (cholesterol modified VQWRIRVAVIRK), which can promote DC migration, as a medium. Through multiomics sequencing and biological experiments, we found that it is the metabolite pantothenic acid (PA) that improves the migration and effectiveness of DC vaccines. We clarified that both DP7-C and PA regulate DC migration by regulating the chemokine receptor CXCR2 and inhibiting miR-142a-3p to affect the NF-κB signaling pathway. This study will lay the foundation for the subsequent use of DP7-C as a universal substance to promote DC migration, further enhance the antitumor effect of DC vaccines, and solve the bottleneck problem of the low migration efficiency and unsatisfactory clinical response rate of DC vaccines.

In silico Prediction Followed By I n Vitro validation Identifies a Survivin Inhibitor and an MCL-1 Inhibitor As a Potent Secondary Drug Against Refractory or Relapsed Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm that develops from malignant B-lymphocytes in the outer edge or mantle zone of a lymph node. This is a sub-type of B-cell non-Hodgkin lymphoma characterized by rapid clinical progression and poor response rate to conventional chemotherapeutic drugs with recurrent relapse resulting in a short estimated 5-year overall survival (OS) of 2-5 years depending on the clinical risk. Combination therapies such as R-CHOP, R-DHAP, Hyper-CVAD, VcR-CAP constitute the front-line chemotherapeutic treatment landscape for MCL. Despite good initial response to the combination regimens, all patients develop resistance over time. The Bruton's tyrosine kinase inhibitor (BTKi) Ibrutinib and the proteasome inhibitor (PI) Bortezomib are FDA-approved therapies for refractory or relapsed (R/R) MCL with demonstrated high initial response rate in clinical trials. However, highly variable treatment response along with dose-limiting toxicities has limited the efficacy in real-world settings with the median progression-free survival (PFS) of <15 months and Over-al of 1-2 years.Thus, the identification of novel drugs that function either alone or as combination to curb the oncogenic progression as well as to reduce drug-associated toxicities is of high clinical significance.We have designed a novel optimization-regularization-based computational prediction algorithm called “secDrug” that uses large-scale pharmacogenomics databases like the GDSC1000 to identify novel secondary drugs for the management of treatment-resistant B-cell malignancies. We hypothesize that combination of our predicted secDrugs with BTKi/ PI will be useful in curbing oncogenic progressions of R/R MCL and abrogate drug resistance through simultaneous inhibition of multiple oncogenic factors/pathways. When applied to BTKi/PI-resistant R/R MCL, the top predicted secondary drugs (secDrugs) were YM155 (Survivin inhibitor) and S63845 (selective MCL-1 inhibitor). Interestingly, both Survivin and MCL-1 are reported to be over-expressed in MCL, and their expression is strongly correlated with the oncogenic progression and survivability of the patients.To validate our in-silico predictions, we performed in vitro cytotoxicity assays with the top predicted secDrugs (YM155 and S63845) as single agents (IC50 for YM155 4.87±0.66 nM, for S63845 0.9±1.1 uM) as well as in combination with BTKi/PI against a panel of MCL cell lines representing PI/BTKi sensitive, innate resistant (representing refractory MCL) and clonally-derived acquired resistant (representing relapsed MCL). Our results showed that the YM155 and S63845 exhibited significant synergistic cell killing activities (Combination index/ CI value of 0.31±0.49 as calculated using Chou-Talalay's CI theorem, C.I>1 depicts synergism) alone and in combination with Bortezomib (PI) and Ibrutinib (BTKi), especially in R/R MCL cell lines. Further, our results also showed that both YM155 and S63845 in combination with BTKi/PI were able to significantly lower the effective dose of both BTKi/PI required to achieve desired therapeutic response by >12 times (Dose Reduction Index or DRI for YM155 in combination is 15.87±4.93; DRI for S63845 in combination is 12.34±2.67), thereby making the cell lines relatively more BTKi/PI sensitive. Next, we performed next-generation RNA sequencing analysis to identify mechanisms of secDrug action and synergy. Our Gene expression profiling and Ingenuity pathway analysis of the RNAseq data among YM155-treated MCL cell lines revealed eIF4-p70S6K signaling and mTOR signaling as the top canonical pathways.Our study thus identified YM155 and S63845 as potential novel candidates for repurposing as secondary drugs in combination with BTKi/PI for the treatment of R/R MCL. Currently, we are exploring the probable subclonal molecular mechanisms governing the synergistic drug action by using single-cell transcriptomics analysis. As both YM155 and S63845 have reported activity against cancer stem-ness, we will further investigate the effect of our novel drugs on the cancer stem-like cells in MCL, which have a potential role in treatment resistance.The secDrug algorithm promises to serve as a universal prototype for the discovery of novel drug combination regimens for treatment outcomes in any cancer type by enhancing sensitivity or overcoming resistance to standard of care drugs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

What can be done to control the placebo response in clinical trials? A narrative review

The desire to reduce high placebo response rates in clinical trials is a popular concept. However, few studies have rigorously examined the effectiveness of methods to control for placebo responses that are relevant to randomized controlled trials. The primary objective of this review was to evaluate the effect of experimental placebo manipulations in randomized controlled trials (RCTs). We critically reviewed studies designed to manipulate placebo responses including positive expectations regarding the effectiveness of the placebo treatment, manipulating the time spent with subjects, and training study staff and subjects to accurately report symptom severity. These efforts have generally resulted in reduced placebo response and improved discrimination between drug and placebo. Interventions that neutralize staff and subject expectations and improve the ability of subjects to accurately report symptom severity have shown the most promise. Reduction of the placebo response has the potential to accelerate the development of new therapeutics.

A Summary of the Meetings of the Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS) International Multidisciplinary Consensus

A Summary of the Meetings of the Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS) International Multidisciplinary Consensus

Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS): An International Multidisciplinary Consensus

Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS): An International Multidisciplinary Consensus

The PI3K∂-Selective Inhibitor Idelalisib Induces T- and NK-Cell Dysfunction Independently of B-Cell Malignancy-Associated Immunosuppression.

B-cell receptors, multiple receptor tyrosine kinases, and downstream effectors are constitutively active in chronic lymphocytic leukemia (CLL) B cells. Activation of these pathways results in resistance to apoptosis and enhanced survival of the leukemic cells. Idelalisib is a highly selective inhibitor of the PI3K p110∂ isoform and is approved for the treatment of CLL in patients with relapsed/refractory disease or in those harboring 17p deletions or tp53 mutations. Despite the initial excitement centered around high response rates in clinical trials of idelalisib, its therapeutic success has been hindered by the incidence of severe opportunistic infections. To examine the potential contribution of idelalisib to the increased risk of infection, we investigated the effects of idelalisib on the immune cell compartments of healthy donors (HDs) and CLL patients. PI3K∂ blockade by idelalisib reduced the expression levels of inhibitory checkpoint molecules in T cells isolated from both HDs and CLL patients. In addition, the presence of idelalisib in cultures significantly decreased T-cell-mediated cytotoxicity and granzyme B secretion, as well as cytokine secretion levels in both cohorts. Furthermore, idelalisib reduced the proliferation and cytotoxicity of HD NK cells. Collectively, our data demonstrate that both human T and NK cells are highly sensitive to PI3K∂ inhibition. Idelalisib interfered with the functions of T and NK cell cells from both HDs and CLL patients. Therefore, idelalisib might contribute to an increased risk of infections regardless of the underlying B-cell malignancy.

Computational immune infiltration analysis of pediatric high-grade gliomas (pHGGs) reveals differences in immunosuppression and prognosis by tumor location.

Immunotherapy for cancer has moved from pre-clinical hypothesis to successful clinical application in the past 15 years. However, not all cancers have shown response rates in clinical trials for these new agents, high-grade gliomas in particular have proved exceedingly refractory to immunotherapy. In adult patients, there has been much investigation into these failures, and researchers have concluded that an immunosuppressive microenvironment combined with low mutational burden render adult glioblastomas "immune cold". Pediatric cancer patients develop gliomas at a higher rate per malignancy than adults, and their brain tumors bear even fewer mutations. These tumors can also develop in more diverse locations in the brain, beyond the cerebral hemispheres seen in adults, including in the brainstem where critical motor functions are controlled. While adult brain tumor immune infiltration has been extensively profiled from surgical resections, this is not possible for brainstem tumors which can only be sampled at autopsy. Given these limitations, there is a dearth of information on immune cells and their therapeutic and prognostic impact in pediatric high-grade gliomas (pHGGs), including hemispheric tumors in addition to brainstem. In this report we use computational methods to examine immune infiltrate in pHGGs and discover distinct immune patterns between hemispheric and brainstem tumors. In hemispheric tumors, we find positive prognostic associations for regulatory T-cells, memory B-cells, eosinophils, and dendritic cells, but not in brainstem tumors. These differences suggest that immunotherapeutic approaches must be cognizant of pHGG tumor location and tailored for optimum efficacy.

Placebo response mitigation with a participant-focused psychoeducational procedure: a randomized, single-blind, all placebo study in major depressive and psychotic disorders

The remarkably high and growing placebo response rates in clinical trials for CNS indications, such as depression and schizophrenia, constitute a major challenge for the drug development enterprise. Despite extensive literature on participant expectancies and other potent psychosocial factors that perpetuate placebo response, no empirically validated participant-focused strategies to mitigate this phenomenon have been available. This study evaluated the efficacy of the Placebo-Control Reminder Script (PCRS), a brief interactive procedure that educates participants about factors known to cause placebo response, which was administered prior to the primary outcome assessments to subjects with major depressive or psychotic disorders who had at least moderate depression. Participants were informed they would participate in a 2-week randomized clinical trial with a 50% chance of receiving either an experimental antidepressant medication or placebo. In actuality, all participants received placebo. Participants randomly assigned to receive the PCRS (n = 70) reported significantly smaller reductions (i.e., less placebo response) in depression than those who did not receive the PCRS (n = 67). The magnitude of this effect was medium (Cohen’s d = 0.40) and was not significantly impacted by diagnostic status. The number of adverse events (i.e., nocebo effect) was also lower in the PCRS group, particularly in the first week of the study. These findings suggest that briefly educating participants about placebo response factors can help mitigate the large placebo response rates that are increasingly seen in failed CNS drug development programs.

Quantifying the natural variation in lesion counts over time in untreated hidradenitis suppurativa: Implications for outcome measures and trial design

BackgroundHidradenitis suppurativa (HS) demonstrates high placebo response rates in clinical trials, possibly due to the natural variability of the disease. No quantification of variability in lesion counts of untreated disease has been undertaken.ObjectiveTo quantify the variability of untreated HS.MethodsDeidentified individual patient data from the placebo arms of PIONEER studies were analyzed, and measurements of within-subject coefficients of variation were examined. Variability was stratified by disease-associated variables (Hurley stage, BMI, sex, smoking, family history) and body site.ResultsAnalysis of within-subject coefficients of variation demonstrated that half of the participants had a middle spread [difference between 75th and 25th percentiles of the subject's abscess and nodule counts] greater than 33% and 40% of their median abscess and nodule counts, and 25% of the subjects had a middle spread greater than 70% and 78% of their median abscess and nodule counts in PIONEER I and II, respectively. Hurley stage 2 participants had significantly greater within-subject variation than Hurley stage 3 patients. Variation was greater in the axillary and groin regions than in other anatomical locations.LimitationsLimitations include the use of precollected clinical trial data.ConclusionThe within-subject variability of the lesion counts in untreated HS was greater than previously appreciated. This has profound effects on outcome measures and the conduct of future clinical trials of HS.

Impact of Clinical Outcome Measures on Placebo Response Rates in Clinical Trials for Chronic Constipation: A Systematic Review and Meta-analysis.

OBJECTIVES:Chronic constipation (CC) is a recurrent functional bowel disorder worldwide. The purpose of this study is to examine its pooled placebo response rate and compare placebo response level in randomized controlled trials (RCTs) with different endpoint assessments.METHODS:PubMed, Cochrane Library, and Embase were electronically searched for therapeutic RCTs of CC with placebo control. Data extraction and assessment of risk of bias were performed independently by 2 reviewers. All the statistical calculation and analysis were performed using R 3.6.0. Our protocol has registered in PROSPERO with registration number: CRD42019121287.RESULTS:There were 46 studies included with 5,992 constipated patients allocated to the placebo arm in total. The pooled placebo response rate was 28.75% (95% confidence interval: 23.83%–33.67%) with significant heterogeneity among trials (= 93.6%). Treatment efficacy assessed using subjective improvement had a significantly higher placebo response rate than that assessed with improvement in complete (spontaneous) bowel movements or composite improvement (41.40% vs 18.31% or 20.35%, P < 0.001). According to the results of meta-regression, active treatment and endpoint assessment were most likely to lead to the huge heterogeneity among studies.DISCUSSION:Patients with CC have significant response level to placebo. Based on findings in this study, we do not recommend subjective improvement as endpoint while designing therapeutic RCTs for chronic constipated patients.

Future Challenges in Cancer Resistance to Immunotherapy.

Cancer immunotherapies, including checkpoint inhibitors, adoptive T cell transfer and therapeutic cancer vaccines, have shown promising response rates in clinical trials. Unfortunately, there is an increasing number of patients in which initially regressing tumors start to regrow due to an immunotherapy-driven acquired resistance. Studies on the underlying mechanisms reveal that these can be similar to well-known tumor intrinsic and extrinsic primary resistance factors that precluded the majority of patients from responding to immunotherapy in the first place. Here, we discuss primary and secondary immune resistance and point at strategies to identify potential new mechanisms of immune evasion. Ultimately, this may lead to improved immunotherapy strategies with improved clinical outcomes.

Rethinking clinical trial endpoints in myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a heterogeneous collection of clonal, hematopoietic disorders primarily affecting an older population, making successful drug development a complicated process. A sole focus on response rate in clinical trials is likely not clinically meaningful if not accompanied by substantive response duration, improvement in quality of life, and ideally prolongation of survival. The process of receiving a new therapy should not be more burdensome than the MDS sequela it is intended to ameliorate. We review challenges in drug development in MDS with respect to aligning trial endpoints for lower and higher risk patients with treatment goals meaningful to patients.