Continual Reassessment Research Articles

537MO First-in-human study of JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced cancers

PRMT5 regulates proteins important for tumorigenesis via symmetric arginine dimethylation (SDMA). JNJ64619178 is an oral, potent and selective PRMT5 inhibitor that demonstrates efficacy in multiple tumor models. Here, we present a phase I study of JNJ64619178 in adults with advanced solid tumors and non-Hodgkin lymphoma (Part 1). Dose escalation was supported by a modified continual reassessment method. Patients (pts) received JNJ64619178 either intermittently (14 days on/7 days off) or once daily (QD) on a 21-day cycle. Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy were evaluated to identify the recommended phase II doses (RP2D). Fifty-four pts were enrolled as of 17 Mar 2020. The most common tumor types were adenoid cystic carcinoma (ACC; 20%), prostate cancer (15%), and uveal melanoma (13%). Median age was 59 (range 28-82), and median number of prior systemic therapies was 3 (range 0-11). Dosing ranged from 0.5 mg to 4 mg intermittently, and from 1 mg to 2 mg QD. Median treatment duration was 1.5 mo (range 0.4-22.4). The only dose-limiting toxicity observed was thrombocytopenia, at 3 and 4 mg intermittently and 2 mg QD. Fifty-one pts (91%) experienced treatment-related adverse events (TRAE), the most common being thrombocytopenia (52%), anemia (41%), nausea (39%), fatigue (32%), dysgeusia (30%), asthenia (24%), and diarrhea (20%). Grade 3/4 TRAEs in >1 pt were thrombocytopenia (20%), anemia (17%), and neutropenia (6%). Thirty pts (56%) had dose interruptions or reductions due to AE. JNJ64619178 plasma Cmax and AUC were linearly dose-proportional. Robust target engagement, as measured by plasma SDMA, was achieved even with intermittent dosing. A confirmed partial response (RECIST) was observed in ACC, and 7 pts (13%) with ACC, prostate cancer, salivary gland carcinomas, and other tumor types had stable disease >6 mo. Two provisional RP2Ds were selected: 1.5 mg intermittently and 1 mg QD. JNJ64619178 demonstrated manageable toxicity and preliminary evidence of antitumor activity at selected dose levels. Intermittent dosing maintains target inhibition. Assessment of two provisional RP2Ds is ongoing.

Abstract CT150: A first-in-human phase I study of the OX40 agonist GSK3174998 (GSK998) +/- pembrolizumab in patients (Pts) with selected advanced solid tumors (ENGAGE-1)

Abstract Background: OX40 is a costimulatory receptor transiently expressed on the surface of activated T cells and some innate immune cells (e.g. NK cells). OX40 agonists have been shown to increase antitumor immunity and improve tumor-free survival in preclinical models, demonstrating increased efficacy when given in combination with a PD-1 inhibitor. GSK998 is a humanized IgG1 agonistic OX40 monoclonal antibody. Methods: ENGAGE-1 (NCT02528357) is a Phase 1 dose escalation study evaluating safety, PK, PD, and clinical activity of GSK998 (0.003-10 mg/kg IV Q3W) alone (Part 1) and in combination with pembrolizumab 200 mg IV Q3W (Part 2) in pts with previously treated advanced solid tumors: non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck, renal cell carcinoma, melanoma (MEL), bladder cancer, soft tissue sarcoma (STS), triple-negative breast cancer, and MSI-high colorectal carcinoma. Dose escalation used a continuous reassessment method and 4-week DLT period. Results: A total of 138 pts were enrolled (45 Part 1, 96 Part 2; 3 crossed over from Part 1). Two DLTs occurred in Part 2 only (G3 non-malignant pleural effusion 0.03 mg/kg; G1 myocarditis 10 mg/kg); MTD was not established. Most common (≥10%) treatment-related AEs (mostly G1-2) were diarrhea, fatigue (Part 1) and fatigue, nausea (Part 2). GSK998 demonstrated target engagement in the periphery as evidenced by PK and receptor occupancy (RO); a dose of 0.3 mg/kg was the threshold for linear PK & peripheral RO saturation over the 3-wk dose interval and was selected for further clinical evaluation in MEL, STS, and NSCLC in Part 2 expansion. Clinical responses and SD ≥24 weeks were observed in both PD-1/L1 naïve and experienced pts: Part 1 (1 PR, 1 SD; both 0.3 mg/kg) and Part 2 (2 CR, 7 PR, 9 SD; 0.01-3 mg/kg); Part 2 clinical responses were not correlated with baseline tumor PD-L1 expression levels; including one MEL pt with PD-L1 TPS=0 who progressed on prior CTLA-4/PD-1 treatment and had a CR (>18mo). Overall, peripheral and tumor expression of OX40 was low (<2% total cells in tumor were OX40 +ve). MultiOmyxTM data from tumor biopsies suggested increased NK/decreased Treg involvement in some responders. Conclusions: GSK998 +/- pembrolizumab was well tolerated, with evidence of target engagement; monotherapy clinical activity was limited. While combination responses may not be significantly greater than expected for pembrolizumab alone, responses were observed in some PD-1/L1 experienced pts and some with low PD-L1 expression. Given the low OX40 expression observed and preclinical evidence that increased expression improves activity of OX40 agonism, ongoing clinical evaluation of GSK998 will assess whether concurrent immune-stimulation or immunogenic cell death impacts OX40 expression and increases the efficacy of this agent. Combinations with TLR4 and ICOS agonists and an anti-BCMA antibody-drug conjugate are ongoing. Citation Format: Sophie Postel-Vinay, Vincent K. Lam, Willeke Ros, Todd M. Bauer, Aaron R. Hansen, Daniel C. Cho, F. Stephen Hodi, Jan H.M. Schellens, Jennifer K. Litton, Sandrine Aspeslagh, Karen A. Autio, Frans L. Opdam, Meredith McKean, Neeta Somaiah, Stephane Champiat, Mehmet Altan, Anna Spreafico, Osama Rahma, Elaine M. Paul, Christoph M. Ahlers, Helen Zhou, Herbert Struemper, Shelby A. Gorman, Maura Watmuff, Kaitlin M. Yablonski, Niranjan Yanamandra, Michael J. Chisamore, Emmett V. Schmidt, Axel Hoos, Aurélien Marabelle, Jeffrey S. Weber, John V. Heymach. A first-in-human phase I study of the OX40 agonist GSK3174998 (GSK998) +/- pembrolizumab in patients (Pts) with selected advanced solid tumors (ENGAGE-1) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT150.

A Bayesian Adaptive Design in Cancer Phase I Trials Using Dose Combinations with Ordinal Toxicity Grades.

We propose a Bayesian adaptive design for early phase drug combination cancer trials incorporating ordinal grade of toxicities. Parametric models are used to describe the relationship between the dose combinations and the probabilities of the ordinal toxicities under the proportional odds assumption. Trial design proceeds by treating cohorts of two patients simultaneously receiving different dose combinations. Specifically, at each stage of the trial, we seek the dose of one agent by minimizing the Bayes risk with respect to a loss function given the current dose of the other agent. We consider two types of loss functions corresponding to the Continual Reassessment Method (CRM) and Escalation with Overdose Control (EWOC). At the end of the trial, we estimate the MTD curve as a function of Bayes estimates of the model parameters. We evaluate design operating characteristics in terms of safety of the trial and percent of dose recommendation at dose combination neighborhoods around the true MTD by comparing this design to the one that uses a binary indicator of DLT. The methodology is further adapted to the case of a pre-specified discrete set of dose combinations.

Abstract A21: Time-to-event Bayesian optimal interval design to accelerate phase I pediatric oncology trials

Abstract Late-onset toxicity is common for novel molecularly targeted agents and immunotherapy. It causes major logistic difficulty for existing adaptive phase I trial designs, which require the observance of toxicity early enough to apply dose escalation rules for new patients. The same logistic difficulty arises when the accrual is rapid. We propose the time-to-event Bayesian optimal interval (TITE-BOIN) design to accelerate phase I trials by allowing for real-time dose assignment decisions for new patients while some enrolled patients’ toxicity data are still pending. Similar to the rolling six design, the TITE-BOIN dose escalation/de-escalation rule can be tabulated before the trial begins, making it transparent and simple to implement, but is more flexible in choosing the target DLT rate and has higher accuracy to identify the MTD. Compared to the more complicated model-based time-to-event continuous reassessment method (TITE-CRM), the TITE-BOIN has comparable accuracy to identify the MTD but is simpler to implement with substantially better overdose control. A numerical study shows that the TITE-BOIN design supports continuous accrual, without sacrificing patient safety or the accuracy of identifying the MTD, and therefore has great potential to accelerate early-phase drug development. Note: This abstract was not presented at the conference. Citation Format: Ying Yuan, Ruitao Lin, Daniel Li, Lei Nie, Katherine Warren. Time-to-event Bayesian optimal interval design to accelerate phase I pediatric oncology trials [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A21.

A comparison of phase I dose-finding designs in clinical trials with monotonicity assumption violation.

In oncology, new combined treatments make it difficult to order dose levels according to monotonically increasing toxicity. New flexible dose-finding designs that take into account uncertainty in dose levels ordering were compared with classical designs through simulations in the setting of the monotonicity assumption violation. We give recommendations for the choice of dose-finding design. Motivated by a clinical trial for patients with high-risk neuroblastoma, we considered designs that require a monotonicity assumption, the Bayesian Continual Reassessment Method, the modified Toxicity Probability Interval, the Bayesian Optimal Interval design, and designs that relax monotonicity assumption, the Bayesian Partial Ordering Continual Reassessment Method and the No Monotonicity Assumption design. We considered 15 scenarios including monotonic and non-monotonic dose-toxicity relationships among six dose levels. The No Monotonicity Assumption and Partial Ordering Continual Reassessment Method designs were robust to the violation of the monotonicity assumption. Under non-monotonic scenarios, the No Monotonicity Assumption design selected the correct dose level more often than alternative methods on average. Under the majority of monotonic scenarios, the Partial Ordering Continual Reassessment Method selected the correct dose level more often than the No Monotonicity Assumption design. Other designs were impacted by the violation of the monotonicity assumption with a proportion of correct selections below 20% in most scenarios. Under monotonic scenarios, the highest proportions of correct selections were achieved using the Continual Reassessment Method and the Bayesian Optimal Interval design (between 52.8% and 73.1%). The costs of relaxing the monotonicity assumption by the No Monotonicity Assumption design and Partial Ordering Continual Reassessment Method were decreases in the proportions of correct selections under monotonic scenarios ranging from 5.3% to 20.7% and from 1.4% to 16.1%, respectively, compared with the best performing design and were higher proportions of patients allocated to toxic dose levels during the trial. Innovative oncology treatments may no longer follow monotonic dose levels ordering which makes standard phase I methods fail. In such a setting, appropriate designs, as the No Monotonicity Assumption or Partial Ordering Continual Reassessment Method designs, should be used to safely determine recommended for phase II dose.

GUIP1: a R package for dose escalation strategies in phase I cancer clinical trials

BackgroundThe main objective of phase I cancer clinical trials is to identify the maximum tolerated dose, usually defined as the highest dose associated with an acceptable level of severe toxicity during the first cycle of treatment. Several dose-escalation designs based on mathematical modeling of the dose-toxicity relationship have been developed. The main ones are: the continual reassessment method (CRM), the escalation with overdose control (EWOC) method and, for late-onset and cumulative toxicities, the time-to-event continual reassessment method (TITE-CRM) and the time-to-event escalation with overdose control (TITE-EWOC) methods. The objective of this work was to perform a user-friendly R package that combines the latter model-guided adaptive designs.ResultsGUIP1 is an R Graphical User Interface for dose escalation strategies in Phase 1 cancer clinical trials. It implements the CRM (based on Bayesian or maximum likelihood estimation), EWOC and TITE-CRM methods using the dfcrm and bcrm R packages, while the TITE-EWOC method has been specifically developed. The program is built using the TCL/TK programming language, which can be compiled via R software libraries (tcltk, tkrplot, tcltk2). GUIP1 offers the possibility of simulating and/or conducting and managing phase I clinical trials in real-time using file management options with automatic backup of study and/or simulation results.ConclusionsGUIP1 is implemented using the software R, which is widely used by statisticians in oncology. This package simplifies the use of the main model-based dose escalation methods and is designed to be fairly simple for beginners in R. Furthermore, it offers multiple possibilities such as a full traceability of the study. By including multiple innovative adaptive methods in a free and user-friendly program, we hope that GUIP1 will promote and facilitate their use in designing future phase I cancer clinical trials.

Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples

BackgroundAwareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples.MethodsThe TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant’s dose and subsequently declare the maximum tolerated dose.We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies.ResultsIn setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians’ time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion.ConclusionModel-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice.

A phase 1 trial of the safety, tolerability and biological effects of intravenous Enadenotucirev, a novel oncolytic virus, in combination with chemoradiotherapy in locally advanced rectal cancer (CEDAR)

BackgroundChemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation.MethodsEligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for ‘proof-of-concept’ and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years.DiscussionChemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies.Trial registrationClinicalTrial.gov, NCT03916510. Registered 16th April 2019.

AB0356 TARGETING THE RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLAST VIA CYCLIN DEPENDENT KINASE INHIBITION (TRAFIC): A PHASE 1B STUDY TO DETERMINE THE MAXIMUM TOLERATED DOSE OF SELICICLIB FOR REPURPOSING IN RHEUMATOID ARTHRITIS

Background:Current rheumatoid arthritis (RA) therapeutics target immune inflammation and are subject to ceiling effects, with non-response observed in a third of recipients together with low remission rates. Synovial fibroblasts (SFs) are stromal cells not yet targeted in RA, whose hyperplastic and proliferative properties drive inflammation and tissue destruction. Seliciclib (R-roscovitine) is an orally available cyclin-dependent kinase (CDK) inhibitor that suppresses SF proliferation and ameliorates inflammatory arthritis in rodents.Objectives:To determine the maximum tolerated dose (MTD) of seliciclib in patients with active RA despite anti-TNF, with or without background conventional disease modifying anti-rheumatic drugs (cDMARDs). Safety and pharmacokinetics (PK) were also evaluated.Methods:A restricted, one-stage Bayesian continual reassessment method (CRM) determined MTD based on a target dose-limiting toxicity (DLT) probability of 35%. RA patients (DAS28 ≥3.2) were recruited sequentially to cohorts of 3 subjects each. Cohort 1 received 400mg seliciclib daily for 4 consecutive days each week for 4 weeks, added to existing therapy. Each subsequent cohort received a dose determined by the toxicity-based CRM algorithm, calculated upon conclusion of the previous cohort. Safety was assessed through adverse event (AE) monitoring. Associations with relevant PK parameters were sought.Results:15 anti-TNF recipients were enrolled, 10 of whom were also taking cDMARDs (median DAS28 4.9). Application of the CRM algorithm prompted one dose increment during the study (to 600mg for cohort 2), but reversion to 400mg for subsequent cohorts (Figure 1A). After treatment of 5 cohorts, 400mg was determined the MTD, with a DLT probability of 0.35 (CI 0.18-0.52; Figure 1B). 6 patients experienced DLTs, of which two were classified as serious AEs (SAEs) in keeping with the safety profile of seliciclib; these are summarised in Table 1. Of 43/65 total AEs reported at any dose that didnotcontribute to a DLT, 26 were possibly, probably or definitely related to seliciclib; 19 of these 26 were mild, 7 moderate and none severe. The most frequent AE was mild nausea. No relationship of safety and/or tolerability with concomitant cDMARD use or PK was seen.Table 1.Characteristics of patients who developed HZ at initiation of baricitinibDLTSeliciclib dose (mg)Doses receivedContributing AEsContributing SAEsDescriptionOutcomeA1400830Constipation, N+V, liver injury; fatigue.Resolved2600430Constipation, N+V.Resolved3600101BFever, N+V, renal injury.Resolved4400831BConstipation, N+V, jaundice, liver injury.Resolved5400840Fever, dizziness, liver injury.Resolved6400890Dizziness, N+V, liver injury, bilirubin rise.Persistent AST riseConclusion:The MTD of seliciclib has been defined for RA. No unexpected safety concerns were identified to preclude ongoing evaluation in patients, which focuses on clinical, radiological and biological indicators of efficacy.Disclosure of Interests:Arthur Pratt Grant/research support from: Pfizer, GlaxoSmithKlein, Stefan Siebert Grant/research support from: BMS, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Michael Cole: None declared, Deborah Stocken: None declared, Stephen Kelly: None declared, Muddassir Shaikh: None declared, Amy Cranston: None declared, Miranda Morton: None declared, Jennifer Walker: None declared, Sheelagh Frame Employee of: Cyclacel Ltd., Wan-fai Ng: None declared, Chris Buckley Consultant of: Janssen, Pfizer, GSK, Galapagos, Gillead, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Andrew Filer: None declared, John D Isaacs Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche

Immune activation in first-in-human anti-macrophage antibody (anti-Clever-1 mAb; FP-1305) phase I/II MATINS trial: Part I dose-escalation, safety, and efficacy results.

3097 Background: The scavenger receptor CLEVER-1 mediates the clearance of “unwanted” self-components and is highly expressed on tumor associated macrophages (TAMs). CLEVER-1 expression is associated with immunotherapy resistance and poor survival in several cancers. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflammatory cytokine secretion and antigen presentation reactivating CD8 T cell responses with robust anti-tumor activity. Targeting CLEVER-1 could therefore overcome the immunosuppressive tumor microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody. Methods: The MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients (pts) with advanced cancers including immunotherapy-refractory melanoma, cholangiocarcinoma, hepatocellular carcinoma, ovarian cancer, colorectal (CRC), and pancreatic ductal adenocarcinoma. Part 1 consisted of a dose escalation phase; 30 pts (median age 65, range 30-81) were enrolled to examine 5 dose levels (0.1, 0.3, 1.0, 3.0, 10 mg/kg), to determine the optimal dose of FP-1305 for Parts 2 and 3. Two-stage time-to-event continual reassessment method (TITE-CRM) was utilized for the dose escalation in Part 1. Pts received 1-8 cycles (median 3) of FP-1305 Q3w. FP-1305 was well tolerated without dose-limiting toxicities. A consistent increase in blood NK cells, CD8/CD4 T cell ratio, B cells and a decrease in regulatory T cells was demonstrated. FP-1305 dosing led to the activation (CD25+) and Th1 skewing (CXCR3+) of T cell populations including increase in effector CD8 T-cells with downregulation of several inhibitory immune checkpoint molecules (PD-1, PD-L1, CTLA-4, and LAG3). Increased circulating IFNɣ levels were detected, with the highest levels in a heavily pretreated metastatic, microsatellite stable (MSS) colorectal cancer patient leading to a partial tumor response (-52%). FP-1305 is the first macrophage checkpoint inhibitor candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. FP-1305 represents a novel treatment option to provoke immune response especially in non-inflamed tumors. Full safety, pharmacokinetic and efficacy results of MATINS trial (Part 1) will be presented for the first time in a final late breaking abstract. Clinical trial information: 2018-002732-24 .

Radium-223 (Rad) and niraparib (Nira) treatment (tx) in castrate-resistant prostate cancer (CRPC) patients (pts) with and without prior chemotherapy (chemo).

5540 Background: Despite multimodality txs such as surgery, radiotherapy, hormonal tx and chemo, metastatic CRPC (mCRPC) prognosis remains poor. Research suggests PARP-1 is a key regulator of androgen receptor (AR) signaling and transition to lethal CRPC. Nira is a safe, potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in CRPC, and Rad is an alpha particle emitter. Addition of PARP inhibition may further enhance the clinical benefit of Rad. Nira has a favorable safety profile however, data on safety, tolerability and efficacy of Nira plus radiotherapy is limited. We hypothesize that targeting the PARP-1/AR axis in combination with radiation is safe and will improve mCRPC management. Methods: This is a phase (ph) Ib dose finding study (NCT03076203) of pts with progressive mCRPC using Time-to-Event Continual Reassessment Method (TITE-CRM). The primary objective is to determine the optimum ph II dose of Nira plus Rad (55 kBq/kg of body weight) in pts with and without prior chemo. Secondary endpoints include PSA reduction at 12 weeks (wks) and radiographic progression-free survival at 6 months. Pts enrolled to one of three dose levels of Nira (100, 200, and 300 mg PO daily). After completing 6 cycles of Rad, pts continued on Nira alone until objective progression, tx intolerance or pt decision. TITE-CRM identifies the maximum tolerated dose (MTD) based on toxicities observed over 12 wks of tx. Results: Between Oct 2017 and Jan 2020, 30 pts were enrolled (15 per stratum). Median age was 70 years; ECOG performance status was 0. The MTD of Nira was 100 mg in the chemo-exposed arm and 200 mg in the chemo-naïve arm. 19 Grade ≥ 3 adverse events were possibly related to tx: lymphocyte count decrease (n = 4, 13%), neutrophil count decrease (n = 3, 10%), anemia (n = 3, 10%), hypertension (n = 3, 10%), platelet count decrease (n = 2, 7%), creatinine increase (n = 1, 3%), hydronephrosis (n = 1, 3%), nausea (n = 1, 3%), white blood cell count decrease (n = 1, 3%). Tx duration and PSA response are shown in the table. Conclusions: Nira plus Rad was determined to be safe and tolerable. The MTD of Nira was identified and is pending ph II investigation. Managed by: Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Scientific Affairs and Bayer Healthcare Pharmaceuticals, Inc Clinical trial information: NCT03076203 . [Table: see text]

The COVID-19 Pandemic and Rapid Implementation of Adolescent and Young Adult Telemedicine: Challenges and Opportunities for Innovation

PurposeThis study describes the rapid implementation of telemedicine within an adolescent and young adult (AYA) medicine clinic in response to the Coronavirus Disease 2019 (COVID-19) pandemic. While there are no practice guidelines specific to AYA telemedicine, observations made during this implementation can highlight challenges encountered and suggest solutions to some of these challenges. MethodsOver the course of several weeks in March, 2020, the Adolescent and Young Adult Medicine Clinic at the University of California San Francisco rapidly replaced most in-person visits with telemedicine visits. This required logistical problem-solving, collaboration of all clinic staff members, and continuous reassessment of clinical practices. This article describes observations made during these processes. ResultsTelemedicine visits increased from zero to 97% of patient encounters in one month. The number of visits per month was comparable with that one year prior. While there were limitations to the clinic’s ability to carry out health supervision visits, many general health, mental health, reproductive health, eating disorders, and addiction treatment services were implemented via telemedicine. Providers identified creative solutions for challenges that arose to managing general confidentiality issues as well as specific challenges related to mental health, reproductive health, eating disorders, and addiction care. Opportunities to implement and expand high-quality AYA telemedicine were also identified. ConclusionsThe COVID-19 pandemic is leading to widespread telemedicine implementation. While telemedicine seems to be feasible and acceptable for our clinic patients, unanswered questions remain regarding confidentiality, quality of care, and health disparities. Clinical guidelines are also needed to guide best practices for telemedicine in this patient population.

A surface-free design for phase I dual-agent combination trials.

In oncology, there is a growing number of therapies given in combination. Recently, several dose-finding designs for Phase I dose-escalation trials for combinations were proposed. The majority of novel designs use a pre-specified parametric model restricting the search of the target combination to a surface of a particular form. In this work, we propose a novel model-free design for combination studies, which is based on the assumption of monotonicity within each agent only. Specifically, we parametrise the ratios between each neighbouring combination by independent Beta distributions. As a result, the design does not require the specification of any particular parametric model or knowledge about increasing orderings of toxicity. We compare the performance of the proposed design to the model-based continual reassessment method for partial ordering and to another model-free alternative, the product of independent beta design. In an extensive simulation study, we show that the proposed design leads to comparable or better proportions of correct selections of the target combination while leading to the same or fewer average number of toxic responses in a trial.

Guidelines for Ambulatory Surgery Centers for the Care of Surgically Necessary/Time-Sensitive Orthopaedic Cases During the COVID-19 Pandemic

Guidelines for Ambulatory Surgery Centers for the Care of Surgically Necessary/Time-Sensitive Orthopaedic Cases During the COVID-19 Pandemic

Optimizing Hippocampal-Cortical Network Modulation via Repetitive Transcranial Magnetic Stimulation: A Dose-Finding Study Using the Continual Reassessment Method

Repetitive transcranial magnetic stimulation (rTMS) can cause potentially useful changes in brain functional connectivity (FC), but the number of treatment sessions required is unknown. We applied the continual reassessment method (CRM), a Bayesian, adaptive, dose-finding procedure to a rTMS paradigm in an attempt to answer this question. The sample size was predetermined at 15 subjects and the cohort size was set with three individuals (i.e., five total cohorts). In a series of consecutive daily sessions, we delivered rTMS to the left posterior parietal cortex and measured resting-state FC with fMRI in a predefined hippocampal network in the left hemisphere. The session number for each successive cohort was determined by the CRM algorithm. We set a response criterion of a 0.028 change in FC between the hippocampus and the parietal cortex, which was equal to the increase seen in 87.5% of participants in a previous study using five sessions. A ≥criterion change was observed in 9 of 15 participants. The CRM indicated that greater than four sessions are required to produce the criterion change reliably in future studies. The CRM can be adapted for rTMS dose finding when a reliable outcome measure, such as FC, is available. The minimum effective dose needed to produce a criterion increase in FC in our hippocampal network of interest at 87.5% efficacy was estimated to be greater than four sessions. This study is the first demonstration of a Bayesian, adaptive method to explore a rTMS parameter.

BRAINSTORM: A Multi-Institutional Phase 1/2 Study of RRx-001 in Combination With Whole Brain Radiation Therapy for Patients With Brain Metastases

To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume. Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01). The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response.

Phase I trial of WEE1 inhibition with chemotherapy and radiotherapy as adjuvant treatment, and a window of opportunity trial with cisplatin in patients with head and neck cancer: the WISTERIA trial protocol

IntroductionPatients with head and neck squamous cell carcinoma with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients...

A92 DOSE ESCALATION STUDY OF CYBERKNIFE® BOOST IN UNRESECTABLE LOCALLY ADVANCED PANCREATIC CANCER

Abstract Background Pancreatic cancer is the 4th deadliest cancer in Canada, with an overall 5-year survival of only 6%. Every year, approximately 4000 Canadians are diagnosed with pancreatic cancer, and only 10–15% of these patients have surgically resectable disease. No satisfactory treatment exists for patients with inoperable locally advanced pancreatic carcinoma. The best survival has been achieved using a combination of chemotherapy and radiotherapy. Conventional radiotherapy has inadequate local disease control as the therapeutic radiation dose to the tumour is limited by the sensitivities of surrounding tissues. Stereotactic body radiotherapy (SBRT) is a minimally invasive treatment technique that allows for ultra-high doses of radiation to be delivered to small areas. The CyberKnife® Robotic Radiosurgery System is a radiation unit designed to deliver SBRT. Fiducial markers placed by endoscopic ultrasound help direct the radiotherapy. It is hypothesized that a higher overall dose of radiation will result in higher rates of local control, and potentially improved survival. Aims The goal of this study is to establish the safety and feasibility of using stereotactic body radiotherapy boost technique via CyberKnife in treating unresectable locally advanced pancreatic cancer, as well as to determine the maximal tolerable radiation dose (MTD) of the SBRT boost that can be safely delivered. Methods This is a prospective single-arm, single-institution phase I Time-to-event Continual Reassessment Methodology (TITE-CRM) radiation dose escalation trial. This study enrolled patients aged 18–84 with pathologically confirmed pancreatic cancer who were determined to have surgically unresectable disease, with an ECOG ≤2. These patients were treated with SBRT prior to starting conventional radiotherapy, which consisted of a total dose of 45 Gy in 25 fractions over 5 weeks. Results Between 2012 and 2018, a total of 11 patients met the eligibility criteria of this study. Their ages ranged from 61 to 84 with a mean of 71.5 years, and they were 64% (7/11) male. At the time of this analysis, 10 of the 11 patients had passed away. The mean and median survival times were 413 days and 313 days, respectively. Three of the patients had significant complications attributed to the radiotherapy, 2 gastric outlet obstructions and 1 deep duodenal ulcer. The doses used ranged from 21 Gy in 3 fractions to 50 Gy in 5 fractions. Conclusions This phase 1, single arm study demonstrates that stereotactic body radiotherapy in the treatment of locally advanced, unresectable pancreatic cancer is technically feasible. When combined with conventional radiotherapy, this therapy is generally well tolerated, and can effectively deliver higher doses of radiation to pancreatic malignancies. Doses up to 50 Gy in 5 fractions were tolerated, with the most common dose being 21 Gy in 3 fractions. Funding Agencies National Pancreatic Cancer Canada Foundation

Phase I study of pasotuxizumab (AMG 212/BAY 2010112), a PSMA-targeting BiTE (Bispecific T-cell Engager) immune therapy for metastatic castration-resistant prostate cancer (mCRPC).

124 Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is a promising therapeutic target in mCRPC. Pasotuxizumab is a PSMA x CD3 BiTE immune therapy that mediates killing of tumor cells by T cells. Methods: NCT01723475 was a first-in-human, multicenter, dose-escalation study in patients (pts) with mCRPC refractory to standard therapy. Pts received continuous IV infusion of pasotuxizumab in cohorts of 3–4 pts. Dose-escalation followed a continuous reassessment methodology. The primary objective was to determine safety and maximum tolerated dose (MTD); secondary objectives included pharmacokinetics, biomarkers, and tumor response. Results: 16 pts were enrolled into 5 dosing cohorts (5 µg/d, n=3; 10 µg/d, n=4; 20 µg/d, n=3; 40 µg/d, n=4; 80 µg/d, n=2). All pts had ≥1 AE of any grade; most common were fever (94%), chills (69%), and fatigue (50%). 13 pts (81%) had ≥1 AE of grade ≥3; most common were decreased lymphocytes and infections (both 44%). No grade 5 AE occurred. A serious drug-related AE was reported for 1 pt (fatigue, 20 µg/d). No antidrug antibodies were observed. Recruitment was stopped before MTD was reached to allow initiation of a new study sponsored by Amgen. Antitumor activity as indicated by PSA serum level decline was dose dependent, with a mean best PSA change per dosing cohort vs baseline of +0.74% (5 µg/d), −17.9% (10 µg/d), −37.4% (20 µg/d), −42.5% (40 µg/d) and −54.9% (80 µg/d). PSA decreases ≥50% occurred in 3 pts (n=1 each in 20 µg/d, 40 µg/d, 80 µg/d cohorts). One long-term PSA responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter pt showed a complete regression of soft-tissue metastases and marked regression of bone metastases by PSMA-PET/CT, >90% reduction in PSA and alkaline phosphatase, and a significant and durable improvement in disease related symptoms. Conclusions: Pasotuxizumab had an acceptable safety profile and dose-dependent clinical activity in mCRPC pts. There were two long term responders in the dose escalation. This is the first clinical study showing that a BiTE immune therapy can be efficacious in solid tumors. Clinical trial information: NCT01723475.

Abstract P1-19-27: Phase IB trial of ACY-1215 (ricolinostat) combined with nab-paclitaxel in metastatic breast cancer (MBC)

Abstract Background:HDAC6, a cytoplasmic histone deacetylase, impacts cell viability by influencing protein metabolism, microtubule dynamics, and chaperone function. ACY-1215 is an orally active, selective HDAC6 inhibitor. Preclinical studies have demonstrated ACY-1215 to have synergistic activity with taxanes. We have developed an algorithm (HDAC6 score) based on mRNA expression profiling to evaluate the HDAC6 activity of individual tumor samples. Methods: In this open-label phase Ib trial, patients (pts) received ACY-1215 PO daily for 21 days of each 28-day cycle with nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 until progression of disease or unacceptable toxicity. Entry criteria included men or women with any MBC subtypes. Measurable diseae was not required. The primary objective was to establish the maximum tolerated dose (MTD) of ACY-1215 with nab-paclitaxel. Dose escalation employed a time-to-event continual reassessment method (TITE-CRM) and the MTD was defined as the dose combination associated with a target probability of dose limiting toxicity (DLT) of 0.25.The TITE-CRM used an empirical dose-toxicity model (n=16 evaluable pts), starting at 120 mg to a maximum dose of 240 mg daily (qd). HDAC score was performed retrospectively on primary and/or metastatic tissue.Results:Seventeen pts were accrued between March 2016-Feb 2018; 16 were evaluable. Of evaluable pts, the median age was 57.5 years (range: 41-78), 14 were female (87.5%), 3 had triple negative MBC, and 13 hormone receptor (HR)+/HER2- MBC. The mean number of prior lines was 4 (range: 0-9). The first pt started at 120 mg qd, the second at 180 mg qd, and the rest at 240 mg qd. No DLTs were seen in the DLT window, and thus the MTD was not reached. Grade III events related to nab-paclitaxel included neutropenia (n=1), peripheral neuropathy (n=1), and 1 grade IV neutropenia. Grade III syncope related to ACY-1215 was observed in 2 pts. In the 16 evaluable pts, the following were best responses: 1 partial response (PR), 11 stable disease (SD), and 4 progressive disease (PD: 2 TNBC, 2 HR+/HER2-). One patient with SD remains on treatment since Feb 2018 (17 months). Median progression free survival (PFS) was 5.3 months [95% confidence interval (CI): 4.45-11.0]. In evaluable pts with accessible tissue (n=9), pts with high HDAC6 score (n=6: cutoff > -0.1) had a significantly improved PFS compared to low HDAC6 score (n=3, HR: 1.2-115, 6.6 months vs. 2.0 months, respectively p=0.01). Conclusions: ACY-1215 240 mg qd is safe and tolerable with weekly nab-paclitaxel. Clinical activity has been observed, with the majority of pts demonstrating SD and 1 with a PR. In this phase 1b trial, high HDAC6 score associates with longer PFS. HDAC6 score should be evaluated in larger trials as a predictor of response to HDAC6 inhibition. Citation Format: Kevin Kalinsky, Cody Chiuzan, Maika Onishi, Meghna S Trivedi, Melissa Accordino, Tizita Zeleke, Qingfei Pan, Sean Kelly, Erin Honan, Ruby Wu, Kathleen Fenn, Katherin D Crew, Dawn L Hershman, Matthew Maurer, Jiyang Yu, Jose Silva. Phase IB trial of ACY-1215 (ricolinostat) combined with nab-paclitaxel in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-27.