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This article addresses the problem of identifying the maximum tolerated dose (MTD) in Phase I dose-finding clinical trials with late-onset toxicities. The main design challenge is how best to adaptively allocate study participants to tolerable doses when the evaluation window for the toxicity endpoint is long relative to the accrual rate of new participants. We propose a new design framework based on order-restricted statistical inference that addresses this challenge in sequential dose assignments. We illustrate the proposed method on real data from a Phase I trial of bortezomib in lymphoma patients and apply it to a Phase I trial of radiotherapy in prostate cancer patients. We conduct extensive simulation studies to compare our design's operating characteristics to existing published methods. Overall, our proposed design demonstrates good performance relative to existing methods in allocating participants at and around the MTD during the study and accurately recommending the MTD at the study conclusion.

The aim of this investigation is to characterize vaginal apex "dog ears" and their association with patterns of treatment failure in patients with endometrial cancer treated with adjuvant high-dose-rate (HDR) single-channel vaginal cuff brachytherapy (VCB).A retrospective review of patients treated with HDR VCB from 2012 to 2021 for medically operable endometrial cancer at a single institution was conducted. Dog ears, defined as tissue at the apex extending at least 10 mm from the brachytherapy applicator were identified on CT simulation images. Fisher exact test and a multivariate logistic regression model evaluated the association between factors of interest with treatment failure. Vaginal cuff failure free survival (VCFFS) was calculated from first brachytherapy to vaginal cuff recurrence (VCR).A total of 219 patients were reviewed. In this sample, 57.5% of patients met criteria for having dog ears. In total, 13 patients (5.9%) developed a VCR. There was no statistically significant difference in the rate of VCR between patients with and without dog ears (7.1% vs. 4.3%, p = 0.56). There was a trend toward increased risk of recurrence with higher grade histology identified in the multivariate logistic regression model (p = 0.085). The estimated 3-year probability of VCFFS was 86%.Vaginal apex dog ears are prevalent but are not found to statistically increase the risk of VCR after VCB in our single institution experience. However, while local failure remains low in this population, we report an absolute value of over twice as many VCRs in patients with dog ears, indicating that with improved dog ear characterization this may remain a relevant parameter for consideration in treatment planning.

Venous thromboembolism (VTE) is a known complication of malignancy. While brain tumors in general predispose to VTE, the incidence in primary central nervous system lymphoma (PCNSL) is poorly characterized. We sought to characterize incidence, risk factors, management, and outcome of VTE in PCNSL Retrospective study of 78 PCNSL patients from 2/1/2002 to 4/1/2020 at the University of Virginia 31% (24/78) of patients developed VTE. 12.8% (10/78) had deep venous thrombosis (DVT) alone, 11.5% (9/78) isolated pulmonary embolism (PE) and 6.4% (5/78) both. The median time from PCNSL diagnosis to VTE was 3 months. In a univariate competing risks analysis, previous VTE (p

Background/aims This article describes the proposed design of a phase I study evaluating the safety of ceramide nanoliposome and vinblastine among an initial set of 19 possible dose combinations in patients with relapsed/refractory acute myeloid leukemia and patients with untreated acute myeloid leukemia who are not candidates for intensive induction chemotherapy. Methods Extensive collaboration between statisticians and clinical investigators revealed the need to incorporate several adaptive features into the design, including the flexibility of adding or eliminating certain dose combinations based on safety criteria applied to multiple dose pairs. During the design stage, additional dose levels of vinblastine were added, increasing the dimension of the drug combination space and thus the complexity of the problem. Increased complexity made application of existing drug combination dose-finding methods unsuitable in their current form. Results Our solution to these challenges was to adapt a method based on isotonic regression to meet the research objectives of the study. Application of this adapted method is described herein, and a simulation study of the design’s operating characteristics is conducted. Conclusion The aim of this article is to bring to light examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying changing design conditions.

Indoleamine 2-3 dioxygenase 1 (IDO1) expression may contribute to immunologic escape by melanoma metastases. However, a recent clinical trial failed to identify any clinical benefits of IDO1 inhibition in patients with unresectable metastatic melanoma, and prior characterizations of IDO1 expression have predominately studied primary lesions and local metastases, generating uncertainty regarding IDO1 expression in distant metastases. We hypothesized that IDO1 expression in such lesions would be low and correlated with decreased overall survival (OS). Metastases from patients (n=96) with stage IIIb to IV melanoma underwent tissue microarray construction and immunohistochemical staining for IDO1. Th1-related gene expression was determined quantitatively. Associations between OS and IDO1 expression were assessed with multivariate models. Of 96 metastatic lesions, 28% were IDOpos, and 85% exhibited IDO1 expression in

This study aims to identify the strongest predictor of postoperative hypocalcemia following thyroid surgery.Study of patients who underwent total/completion thyroidectomy. No patients received postoperative calcium supplementation. Demographic and perioperative data were collected including preoperative baseline parathyroid hormone (PTH) levels, PTH levels at 30 min and 6 h post-excision, and 18 h post-excision calcium levels.Of 124 patients studied, 20.2% developed temporary hypocalcemia (Ca 8.5 mg/dL at 18 h post-excision). In multivariate analyses, absolute PTH levels at 30 min and 6 h post-excision as well as change in PTH from baseline at 30 min and 6 h post-excision were statistically significantly associated with postoperative hypocalcemia. Per 10 units decrease in PTH from baseline at 30 min post-excision, the risk of developing temporary hypocalcemia increases by 17%.Absolute PTH levels and change in PTH from baseline at 30 min and 6 h post-excision predict hypocalcemia after total or completion thyroidectomy.

The primary endpoint of most dose-finding cancer trials is patient toxicity, and the primary goal is to identify the maximum tolerated dose (MTD), that is, the highest dose that falls below or within a pre-specified toxicity tolerability threshold. Conventionally, dose-finding methods have utilized a binary toxicity endpoint based on whether or not a patient experiences a dose limiting-toxicity (DLT). Improving upon this, in recent years several methods have been developed for modeling toxicity scores, a novel continuous endpoint designed to more precisely estimate patient toxicity burden. Separately, drug-combination trials have become increasingly prevalent, and due to added complexities regarding estimating 'true' dose ordering and potential for more complex patient toxicity profiles, provide an ideal setting which may benefit from the improved precision of toxicity scores. In this paper, we merge two frameworks based on the Continual Reassessment Method (CRM) - the Quasi-CRM and the Partial Order CRM (POCRM) - to propose a novel approach for modeling toxicity scores in a combination-trial setting. We demonstrate that utilizing toxicity scores has the potential to greatly improve correct dose-selection over a variety of trial scenarios. We further present a simple adaptation to the toxicity-score model to control for potential over-dosing issues such that it adheres to the conventional DLT definition and will, at worst, perform equivalently to that of the traditional binary DLT framework. We demonstrate that extending toxicity scores to the combination-trial setting offers potential for improvement over the conventional binary endpoint models.

BackgroundTertiary lymphoid structures (TLS) are ectopic lymphoid organs that are localized near tumors and other sites of inflammation, and are commonly believed to support antitumor immunity. We previously published studies that show that most desmoplastic melanomas contain TLS, and that TLS in cutaneous metastatic melanomas varied widely in maturation state, in proportions of proliferating T and B cells, and in markers of B cell function, including AID and CD21. Thus, we hypothesized that there may be diversity in TLS function, or immunologic activity, among melanomas. To address this hypothesis, we evaluated TLS in primary desmoplastic melanomas (DM), and non-desmoplastic melanomas (non-DM) for markers of cell proliferation which are indicative of early immune activity.MethodsDM and non-DM tumor specimens, which included primary melanomas (PM), and cutaneous metastatic melanomas (CMM), were evaluated for TLS by multiplex Immunofluorescence histology, by staining for CD20, CD8, PNAd, Ki67, FoxP3, and DAPI. Lymphoid aggregates were identified in 20x spectrally unmixed images by visual inspection and identified as TLS if possessing organized T-cell and B-cell regions in addition to high endothelial venule-like vasculature (PNAd+). TLS were identified in 30 out of 64 screened (48%) CMM, 4/4 non-DM PM, and 8 out of 11 screened (73%) DM. Immune cells localized in TLS were enumerated using Halo software (Indica Labs). Mann-Whitney tests were used for statistical assessments.ResultsDM commonly contain a dense network of fibroblasts and associated stroma, which are not typical for other non-DM (PM and CMM). TLS in DM are located throughout the tumors, intratumorally, in sharp distinction from the peritumoral location of TLS in non-DM. Furthermore, when compared to TLS of non-DM (PM and CMM), TLS of DM contain increased densities of CD20+ B cells (PM p=0.007; CMM pConclusionsRecently published studies have identified tumor-associated fibroblasts as the likely initiating cells for TLS formation in murine melanomas. The intratumoral location of TLS in DM puts them in close proximity to the dense fibroblasts and desmoplastic stroma in these tumors, which may be responsible for their intratumoral location. The increased density of B and T cells, and higher proportion of proliferating (Ki67+) B cells, in DM than in non-DM, suggests that there may be greater immune activation, increased germinal center maturation, or less regulation in TLS of DM.Ethics ApprovalApproval was obtained for these studies under IRB protocol #’s 10598 and 19694.

Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton's tyrosine kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib (IBR) has shown synergy in preclinical MCL models. Prior MCL studies of the combination show promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual reassessment method of 6 combinations of IBR (280 mg, 420 mg, and 560 mg by mouth daily) and VEN (max dose of 200 mg and 400 mg by mouth daily). Eligible participants were not previously exposed to BTKi and not high risk for tumor lysis syndrome (TLS). VEN, initiated first at 100 mg, then at 20 mg by mouth daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level assigned. Combination treatment continued for six 28-day cycles. Thirty-five participants were enrolled and treated. One TLS event occurred with starting dose of 100 mg VEN; no TLS was seen with 20 mg. The optimal dosing combination was considered to be VEN 200 mg and IBR 420 mg with an overall response rate (ORR) of 93.8% (95% CI: 73.6% to 99.7%) and DLT incidence of 6.2% (95% CI: 0.3% to 26.4%). ORR for all arms was 82.3% (28/34; 95% CI: 65.5% to 93.2%) with a complete response (CR) rate of 42.4% (14/33; 95% CI: 25.5% to 60.8%). A participant was not allocated to IBR 560 mg and VEN 400 mg. ORR benefit was not seen with higher dosing combinations and toxicity was higher; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560.

Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.

Immunotherapy and chemotherapy combinations have proven to be a safe and efficacious treatment approach in multiple settings. However, it is not clear whether approved doses of chemotherapy developed to achieve a maximum tolerated dose are the ideal dose when combining cytotoxic chemotherapy with immunotherapy to induce immune responses. This trial of a modulated dose chemotherapy and Pembrolizumab, with or without a second immunomodulatory agent, uses a Bayesian design to select the optimal treatment combination by balancing both safety and efficacy of the chemotherapy and immunotherapy agents within each of two cohorts. The simulation study provides evidence that the proposed Bayesian design successfully addresses the primary study aim to identify the optimal dose combination for each of the two independent patient cohorts. This conclusion is supported by the high percentage of simulated trials which select a treatment combination that is both safe and highly efficacious. The proposed trial was funded and was being finalized when the sponsoring company decided not to proceed due to negative findings in another patient population. The proposed trial design will continue to be relevant as multiple chemotherapy and immunotherapy combinations become the standard of care and future research will require evaluating the appropriate doses of various components of multiple drug regimens.

BackgroundWe performed a clinical trial to evaluate safety and immunogenicity of a novel long peptide vaccine administered in combinations of incomplete Freund’s adjuvant (IFA) and agonists for TLR3 (polyICLC) and TLR7/8 (resiquimod). We hypothesized that T cell responses to minimal epitope peptides (MEPs) within the long peptides would be enhanced compared with prior vaccines with MEP themselves and that T cell responses would be enhanced with TLR agonists, compared with IFA alone.MethodsParticipants with resected stage IIB-IV melanoma were vaccinated with seven long melanoma peptides (LPV7) from tyrosinase, gp100, MAGE-A1, MAGE-A10, and NY-ESO-1, each containing a known MEP for CD8+ T cells, plus a tetanus helper peptide (Tet) restricted by Class II MHC. Enrollment was guided by an adaptive design to one of seven adjuvant combinations. Vaccines were administered at weeks 1, 2, 3, 6, 9, 12 at rotating injection sites. T cell and IgG antibody (Ab) responses were measured with IFN-gamma ELIspot assay ex vivo and ELISA, respectively.ResultsFifty eligible participants were assigned to seven study groups, with highest enrollment on arm E (LPV7+Tet+IFA+polyICLC). There was one dose-limiting toxicity (DLT) in Group E (grade 3 injection site reaction, 6% DLT rate). All other treatment-related adverse events were grades 1–2. The CD8+ T cell immune response rate (IRR) to MEPs was 18%, less than in prior studies using MEP vaccines in IFA. The CD8+ T cell IRR trended higher for IFA-containing adjuvants (24%) than adjuvants containing only TLR agonists (6%). Overall T cell IRR to full-length LPV7 was 30%; CD4+ T cell IRR to Tet was 40%, and serum Ab IRR to LPV7 was 84%. These IRRs also trended higher for IFA-containing adjuvants (36% vs 18%, 48% vs 24%, and 97% vs 60%, respectively).ConclusionsThe LPV7 vaccine is safe with each of seven adjuvant strategies and induced T cell responses to CD8 MEPs ex vivo in a subset of patients but did not enhance IRRs compared with prior vaccines using short peptides. Immunogenicity was supported more by IFA than by TLR agonists alone and may be enhanced by polyICLC plus IFA.Trial registration numberNCT02126579.

Background/aims: Dose feasibility is a challenge that may arise in the development of adoptive T cell therapies for cancer. In early-phase clinical trials, dose is quantified either by a fixed or per unit body weight number of cells infused. It may not be feasible, however, to administer a patient’s assigned dose due to an insufficient number of cells harvested or functional heterogeneity of the product. The study objective becomes to identify the maximum tolerated dose with high feasibility of being administered. This article describes a new dose-finding method that adaptively accounts for safety and feasibility endpoints in guiding dose allocation. Methods: We propose an adaptive dose-finding method that integrates accumulating feasibility and safety data to select doses for participant cohorts in early-phase trials examining adoptive cell immunotherapy. We sequentially model the probability of dose-limiting toxicity and the probability of feasibility using independent beta-binomial models. The probability model for toxicity borrows information across all dose levels using isotonic regression, allowing participants infused at a lower dose than his or her planned dose to contribute safety data to the dose-finding algorithm. We applied the proposed methodology in a single simulated trial and evaluated its operating characteristics through extensive simulation studies. Results: In simulations conducted for a phase I study of adoptive immunotherapy for newly diagnosed glioblastoma, the proposed method demonstrates the ability to identify accurately the feasible maximum tolerated doses and to treat participants at and around these doses. Over 10 hypothesized scenarios studied, the percentage of correctly selecting the true feasible and maximum tolerated dose ranged from 50% to 90% with sample sizes averaging between 21 and 24 participants. A comparison to the only known existing method accounting for safety and feasibility yields competitive performance. Conclusion: We have developed a new practical adaptive dose-finding method to assess feasibility in early-phase adoptive cell therapy trials. A design that incorporates feasibility, as a function of the quantity and quality of the product manufactured, in addition to safety will have an impact on the recommended phase II doses in studies that evaluate patient outcomes.

This paper studies the notion of coherence in interval-based dose-finding methods. An incoherent decision is either: (i) a recommendation to escalate the dose following an observed dose-limiting toxicity, or (ii) a recommendation to de-escalate the dose following a non-dose-limiting toxicity. In a simulated example, we illustrate that the Bayesian optimal interval method and the Keyboard method are not coherent. We generated dose-limiting toxicity outcomes under an assumed set of true probabilities for a trial of n = 36 patients in cohorts of size 1, and we counted the number of incoherent dosing decisions that were made throughout this simulated trial. Each of the methods studied resulted in 13/36 (36%) incoherent decisions in the simulated trial. Additionally, for two different target dose-limiting toxicity rates, 20% and 30%, and a sample size of n = 30 patients, we randomly generated 100 dose-toxicity curves and tabulated the number of incoherent decisions made by each method in 1000 simulated trials under each curve. For each method studied, the probability of incurring at least one incoherent decision during the conduct of a single trial is greater than 75%. Coherency is an important principle in the conduct of dose-finding trials. Interval-based methods violate this principle for cohorts of size 1 and require additional modifications to overcome this shortcoming. Researchers need take a closer look at the dose assignment behavior of interval-based methods when using them to plan dose-finding studies.

Background: HDAC inhibitors (HDACi) upregulate thymidine phosphorylase resulting in enhanced conversion of capecitabine to active 5-fluorouracil and in synergistic anti-proliferative effects. HDACi's down regulate thymidine synthase and may prevent resistance to fluoropyrimidines. Entinostat is a well-tolerated class I HDACi in phase III trials for metastatic breast cancer. Specific Aims: The primary objective is to determine the maximum tolerated dose combination (MTDC) of entinostat and capecitabine in participants with metastatic breast cancer. It is hypothesized that entinostat and capecitabine is a synergistic, safe, and tolerable combination. An expansion phase will assess the safety of the MTDC from Part A in participants with high risk breast cancer after neoadjuvant therapy. The expansion phase will generate a preliminary estimate of disease-free survival. Exploratory objectives include estimates of the association of volume of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) with the presence of residual disease and if it decreases following treatment with the combination of entinostat and capecitabine. Trial Design: The dose escalation phase (Part A) will accrue participants with metastatic breast cancer using an adaptive design to determine the MTDC. The starting doses will be entinostat 3mg po weekly and capecitabine 800mg/m2 po bid, 14 days on and 7 days off with 21 day cycles. Patients will be monitored for toxicity and adverse events. The MTDC is defined as the dose combination with DLT rate closest to the target DLT rate of 25%. The expansion phase (Part B) will accrue breast cancer participants with residual invasive disease after neoadjuvant therapy starting at the MTDC estimated in Part A. The adaptive modeling design will be used in Part B to establish the MTDC in this patient population. Participants will be treated with the MTDC for a total of 8 cycles. Blood samples will be obtained from all enrolled patients in the expansion phase prior to the start of adjuvant treatment with entinostat and capecitabine so that ctDNA and CTCs can be measured as correlative studies. Measurements will be repeated at the end of the eighth cycle. Eligibility Criteria: Part A: Dose Escalation Phase: Stage IV breast cancer patients; Receptor Status: hormone receptor positive or negative, triple negative patients; Age: 18 year and older Part B: Expansion Phase: Stage I-III high risk breast cancer patients; Completed at least four cycles of neoadjuvant taxane or anthracycline based chemotherapy; Residual invasive disease (ypT1a or greater) or known positive lymph nodes (ypN0(itc) or greater); Receptor Status: hormone receptor positive or negative, triple negative patients; Age: 18 years and older Statistical Methods: The trial is designed to determine the MTDC, defined by acceptable toxicity of the combination, for two study populations. A Bayesian adaptive design is being used to guide accrual decisions based on the occurrence of DLTs, and the minimum follow-up period for determination of escalation is 3 weeks. Accrual: Maximum target accrual is 55 participants. Accrual is estimated at 1-2 participants per month. Contact Info: Trish Millard, MD tas9g@virginia.edu Citation Format: Millard TA, Wages NA, Petroni GR, Brenin CM, Dillon PM. A pilot study of the combination of entinostat with capecitabine in metastatic and high risk breast cancer after neoadjuvant therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-05-01.

Venous thromboembolism (VTE) is a known complication of malignancy. While brain tumors in general predispose to VTE, the incidence in primary central nervous system lymphoma (PCNSL) is poorly characterized. We sought to characterize incidence, risk factors, management, and outcome of VTE in PCNSL METHOD: Retrospective study of 78 PCNSL patients from 2/1/2002 to 4/1/2020 at the University of Virginia RESULTS: 31% (24/78) of patients developed VTE. 12.8% (10/78) had deep venous thrombosis (DVT) alone, 11.5% (9/78) isolated pulmonary embolism (PE) and 6.4% (5/78) both. The median time from PCNSL diagnosis to VTE was 3 months. In a univariate competing risks analysis, previous VTE (p 0.001), impaired ambulation (p = 0.035), baseline hemoglobin 10 g/dL (p = 0.025) and history of diabetes mellitus (type 1 or 2) (p = 0.007) were associated with increased VTE risk. 34.8% were anticoagulated acutely with heparin (8/23) or 65.2% LMWH (15/23), and 25.0% (6/24) received warfarin, 41.7% (10/24) LMWH, and 33.3% (8/24) DOACs long-term. One adverse event was attributable to anticoagulation (arm hematoma with hemoglobin decrease). Five patients received IVC filters with concomitant oral anticoagulation; one experienced IVC thrombosis after anticoagulation discontinuation. Six of the 24 patients experienced recurrent VTE, four while anticoagulated.Patients with PCNSL are at high risk of VTE, most of which accrues in the first few months. History of VTE, diabetes mellitus (type 1 or 2), impaired ambulatory status, or hemoglobin 10 g/dL may predispose patients to this complication. While optimal management is uncertain, anticoagulation prevented recurrent VTE in most patients without intracranial bleeding.

In recent years, the landscape in clinical trial development has changed to involve many molecularly targeted agents, immunotherapies, or radiotherapy, as a single agent or in combination. Given their different mechanisms of action and lengths of administration, these agents have different toxicity profiles, which has resulted in numerous challenges when applying traditional designs such as the 3 + 3 design in dose-finding clinical trials. Novel methods have been proposed to address these design challenges such as combinations of therapies or late-onset toxicities. However, their design and implementation require close collaboration between clinicians and statisticians to ensure that the appropriate design is selected to address the aims of the study and that the design assumptions are pertinent to the study drug. The goal of this paper is to provide guidelines for appropriate questions that should be considered early in the design stage to facilitate the interactions between clinical and statistical teams and to improve the design of dose-finding clinical trials for novel anticancer agents.

BackgroundPeptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund’s adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.Participants and methodsAn adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry.ResultsForty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy.Conclusions6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.

Purpose The phase 1 portion of this multicenter, phase 1/2 study of hypofractionated (HypoFx) prostate bed radiation therapy (RT) as salvage or adjuvant therapy aimed to identify the shortest dose-fractionation schedule with acceptable toxicity. The phase 2 portion aimed to assess the health-related quality of life (QoL) of using this HypoFx regimen. Methods and Materials Eligibility included standard adjuvant or salvage prostate bed RT indications. Patients were assigned to receive 1 of 3 daily RT schedules: 56.6 Gy in 20 Fx, 50.4 Gy in 15 Fx, or 42.6 Gy in 10 Fx. Regional nodal irradiation and androgen deprivation therapy were not allowed. Participants were followed for 2 years after treatment with outcome measures based on prostate-specific antigen levels, toxicity assessments (Common Terminology Criteria for Adverse Events, v4.0), QoL measures (the Expanded Prostate Cancer Index Composite [EPIC] and EuroQol EQ-5D instruments), and out-of-pocket costs. Results There were 32 evaluable participants, and median follow-up was 3.53 years. The shortest dose-fractionation schedule with acceptable toxicity was determined to be 42.6 Gy in 10 Fx, with most patients (23) treated with this schedule. Grade 3 genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 3 patients and 1 patient, respectively. There was 1 grade 4 sepsis event. Higher dose to the hottest 25% of the rectum was associated with increased risk of grade 2+ GI toxicity; no dosimetric factors were found to predict for GU toxicity. There was a significant decrease in the mean bowel, but not bladder, QoL score at 1 year compared with baseline. Prostate-specific antigen failure occurred in 34.3% of participants, using a definition of nadir plus 2 ng/mL. Metastases were more likely to occur in regional lymph nodes (5 of 7) than in bones (2 of 7). The mean out-of-pocket cost for patients during treatment was $223.90. Conclusions We identified 42.6 Gy in 10 fractions as the shortest dose-fractionation schedule with acceptable toxicity in this phase 1/2 study. There was a higher than expected rate of grade 2 to 3 GU and GI toxicity and a decreased EPIC bowel QoL domain with this regimen. Future studies are needed to explore alternative adjuvant/salvage HypoFx RT schedules after radical prostatectomy.

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.

Existing methodology for the design of Phase I-II studies has been intended to search for the optimal regimen, based on a trade-off between toxicity and efficacy, from a set of regimens comprised of doses of a new agent. The underlying assumptions guiding allocation are that the dose-toxicity curve is monotonically increasing, and that the dose-efficacy curve either plateaus or decreases beyond an intermediate dose. This article considers the problem of designing Phase I-II studies that violate these assumptions for both outcomes. The motivating application studies regimens that are not defined by doses of a new agent, but rather a peptide vaccine plus novel adjuvants for the treatment of melanoma. All doses of each adjuvant are fixed, and the regimens vary by the number and selection of adjuvants. This structure produces regimen-toxicity curves that are partially ordered, and regimen-efficacy curves that may deviate from a plateau or unimodal shape. Application of a Bayesian model-based design is described in determining the optimal biologic regimen, based on bivariate binary measures of toxicity and biologic activity. A simulation study of the design's operating characteristics is conducted, and its versatility in handling other Phase I-II problems is discussed.

Purpose Radiation therapy is a well-established treatment for symptomatic bone metastases. Despite continued advances in both planning techniques and treatment delivery, the standard workflow has remained relatively unchanged, often requiring 1 to 3 weeks and resulting in patient inconvenience and delayed palliation. We developed an expedited method wherein computed tomography simulation, treatment planning, quality assurance, and treatment delivery are performed in 1 day. This prospective pilot clinical trial evaluates the safety, efficacy, and patient satisfaction of this rapid workflow. Methods and Materials Patients with 1 to 3 painful bone metastases were prospectively enrolled and treated with 1 fraction of stereotactic body radiation therapy, using a same-day Scan-Plan-QA-Treat workflow, termed STAT RAD, in a phase 1/2 dose escalation trial from 8 Gy to 15 Gy per fraction. Bone pain, opioid use, patient satisfaction, performance status, and quality of life were evaluated before and at 1, 4, 8, 12, 26, and 52 weeks after treatment. Outcomes and treatment-related toxicity were analyzed. Results A total of 49 patients were enrolled, and 46 patients with 60 bone metastases were treated per the protocol. Partial or greater pain response occurred in 50% of patients at 1 week, 75% of patients at 8 weeks, 68.7% of patients at 6 months, and 33.3% of patients at 12 months. There were 2 grade-3 toxicities, including 1 spinal fracture associated with disease progression and hyperbilirubinemia. Reirradiation was required in 16.7% of treated lesions at a median time to retreatment of 4.9 months. Most patient responses (78.6%) indicated that patients would choose this workflow again. Conclusions The results demonstrate that treating bone metastases with palliative stereotactic body radiation therapy via a single-fraction, patient-centric workflow is feasible and safe with doses up to 15 Gy. However, pain response decreased at 12 months and was associated with a 16.7% retreatment rate, which suggests that further dose escalation is warranted.

Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.

Purpose Operating characteristics for proposed clinical trial designs provide insight into performance regarding safety and accuracy, allowing the study team and review entities to determine the design's suitability to achieve the study's proposed objectives. Advances in cancer therapeutics have augmented the needs of early phase clinical trial design. Additionally, advances in research on early-phase trial design have led to the availability of a wide range of methods that show vast improvement over outdated approaches. Methods Three trials utilizing variations of the 3 + 3 decision rule are discussed. The protocols lacked detail, including operating characteristics and guidance for decision-making that deviated from the 3 + 3 decision rule and MTD determination. We provide a discussion of the statistical issues associated with each design and operating characteristics for the proposed design compared to alternatives better suited to achieve the aims of each trial. Results Our results illustrate how operating characteristics inform a design's safety and accuracy. Operating characteristics can unmask poor behavior, such as a high percentage of particiapnts exposed to overly toxic doses, a low probability of correctly identifying the MTD, and inappropriate early study termination. Conclusion Selection of early-phase trial design has significant implications on a trial's ability to meet its objectives. Operating characteristics are a necessary component in the design and review of a protocol, determining if the study's objectives can be achieved and documenting the study's scientific validity. Continued use of outdated approaches due to historical acceptance hinders scientific rigor and the effort to move effective agents through the drug development process.

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. Clin Cancer Res; 23(23); 7158–64. ©2017 AACR.

Background/aims: In evaluating the performance of Phase I dose-finding designs, simulation studies are typically conducted to assess how often a method correctly selects the true maximum tolerated dose under a set of assumed dose–toxicity curves. A necessary component of the evaluation process is to have some concept for how well a design can possibly perform. The notion of an upper bound on the accuracy of maximum tolerated dose selection is often omitted from the simulation study, and the aim of this work is to provide researchers with accessible software to quickly evaluate the operating characteristics of Phase I methods using a benchmark. Methods: The non-parametric optimal benchmark is a useful theoretical tool for simulations that can serve as an upper limit for the accuracy of maximum tolerated dose identification based on a binary toxicity endpoint. It offers researchers a sense of the plausibility of a Phase I method’s operating characteristics in simulation. We have developed an R shiny web application for simulating the benchmark. Results: The web application has the ability to quickly provide simulation results for the benchmark and requires no programming knowledge. The application is free to access and use on any device with an Internet browser. Conclusion: The application provides the percentage of correct selection of the maximum tolerated dose and an accuracy index, operating characteristics typically used in evaluating the accuracy of dose-finding designs. We hope this software will facilitate the use of the non-parametric optimal benchmark as an evaluation tool in dose-finding simulation.

Background In recent years, investigators have asserted that the 3 + 3 design lacks flexibility, making its use in modern early-phase trial settings, such as combinations and/or biological agents, inefficient. More innovative approaches are required to address contemporary research questions, such as those posed in trials involving immunotherapies. Design We describe the implementation of an adaptive design for identifying an optimal treatment regimen, defined by low toxicity and high immune response, in an early-phase trial of a melanoma helper peptide vaccine plus novel adjuvant combinations. Results Operating characteristics demonstrate the ability of the method to effectively recommend optimal regimens in a high percentage of trials with reasonable sample sizes. Conclusions The proposed design is a practical, early-phase, adaptive method for use with combined immunotherapy regimens. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of two small molecule inhibitors in relapsed/refractory mantle cell lymphoma.

Background: This article studies the notion of irrational dose assignment in Phase I clinical trials. This property was recently defined by Zhou and colleagues as a dose assignment that fails to de-escalate the dose when two out of three, three out of six, or four out of six patients have experienced a dose-limiting toxicity event at the current dose level. The authors claimed that a drawback of the well-known continual reassessment method is that it can result in irrational dose assignments. The aim of this article is to examine this definition of irrationality more closely within the conduct of the continual reassessment method. Methods: Over a broad range of assumed dose-limiting toxicity probability scenarios for six study dose levels and a variety of target dose-limiting toxicity rates, we simulated 2000 trials of n = 36 patients. For each scenario, we counted the number of irrational dose assignments that were made by the continual reassessment method, according to the definitions of Zhou and colleagues. For each of the irrational decisions made, we classified the dose assignment as an underdose assignment, a target dose assignment, or an overdose assignment based on the true dose-limiting toxicity probability at that dose. Results: Across eight dose-toxicity scenarios, there were a total of 181,581 dose assignments made in the simulation study. Of these assignments, 8165 (4.5%) decisions were made when two out of three, three out of six, or four out of six patients had experienced a dose-limiting toxicity at the current dose. Of these 8165 decisions, 1505 (18.4%) recommended staying at the current dose level and would therefore be classified as irrational by Zhou and colleagues. Among the irrational decisions, 41.2% were misclassified, meaning they were made either at the true target dose (17.9%) or at a true underdose (23.3%). The remaining 58.8% were made at a true overdose and therefore truly irrational. Overall, irrational dose assignments comprised Conclusion: Zhou and colleagues argue that the behavior of the continual reassessment method is disturbing due to its ability to make irrational dose assignments. These definitions are based on rules that mimic the popular 3 + 3 design, which should not be the benchmark used to construct guidelines for trial conduct of modern Phase I methods. Our study illustrates that these dose assignments occur very seldom in the continual reassessment method and that even when they do occur, they can often be considered sensible when accounting for all accumulated data in the study.

This article considers the problem of designing Phase I-II clinical trials with delayed toxicity and efficacy outcomes. The proposed design is motivated by a Phase I-II study evaluating all-trans retinoic acid (ATRA) in combination with a fixed dose of daratumumab in the treatment of relapsed or refractory multiple myeloma. The primary objective of the study is to identify a dose that maximizes efficacy and has an acceptable level of toxicity. The toxicity endpoint is observed in one cycle of therapy (i.e., 4 weeks) while the efficacy endpoint is assessed after 8 weeks of treatment. The difference in endpoint observation windows causes logistical challenges in conducting the trial, since it is not practical to wait until both outcomes for each patient have been fully observed before sequentially assigning the dose of a newly eligible patient. In order to avoid delays in treatment for newly enrolled patients and to accelerate trial progress, we generalize the time-to-event continual reassessment method (TITE-CRM) to bivariate outcomes. Simulation studies are conducted to evaluate the proposed method, and we found that the proposed design is able to accurately select doses that maximize efficacy and have acceptable toxicity, while using all available information in allocating patients at the time of dose assignment. We compare the proposed methodology to two existing methods in the area.