Continual Reassessment Method Research Articles

The Safety and Efficacy of Salvage Stereotactic Radiation Therapy in Patients with Intraprostatic Tumor Recurrence After Previous External Radiation Therapy: Phase 1 Results from the GETUG-AFU 31 Study

BackgroundThere is no consensus on the best local salvage treatment for prostate cancer recurrence after primary external beam radiotherapy. Prospective data on stereotactic body radiation therapy (SBRT) are very scarce. ObjectiveTo determine the optimal dose regimen for salvage SBRT. Design, setting, and participantsThe present report concerns the phase 1 part of the GETUG-AFU 31 multicenter open-label study. The main inclusion criteria were histologically proven biochemical recurrence, clinical stage T1-T2 upon relapse, multiparametric magnetic resonance imaging data, prostate-specific antigen (PSA) level ≤10 ng/ml prior to salvage SBRT, PSA doubling time >10 mo, and an International Prostate Symptom Score of ≤12. InterventionFive or six fractions of 6 Gy were delivered using focal SBRT. Outcome measurements and statistical analysisDose-limiting toxicity (DLT) was defined as grade ≥3 gastrointestinal or genitourinary tract toxicity, or any grade 4 toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03) occurring in the first 18 wk following treatment initiation. A time-to-event continual reassessment method was used to select the dose regimen. Results and limitationsTwenty-one patients were treated (median [interquartile range] age: 76.8 yr [72.2–80.8]), including 12 at 6 × 6 dose level. No DLT was observed. The acute grade 2 genitourinary tract toxicity rate was 19%. With a median follow-up of 12.3 mo, the estimated cumulative incidence of late grade 2 genitourinary toxicity was 41.2% (95% confidence interval: 18.1–63.1%). No grade >2 genitourinary toxicity and no grade ≥2 gastrointestinal toxicity were reported. All treated patients were alive and relapse free at the last follow-up. ConclusionsA 6 × 6 Gy dose regimen was selected for our phase 2 study of salvage SBRT. With a short follow-up period, the level of toxicity appears to be acceptable. Patient summaryThere is no consensus on the best local treatment for patients with local relapse after radiotherapy for prostate cancer. Prospective data are very scarce. Our early phase trial allowed us to recommend six fractions of 6 Gy using high-precision radiotherapy for further studies.

Hybrid continuous reassessment method with overdose control for safer dose escalation

ABSTRACT Phase 1 oncology studies focus on safety of novel treatments and identifying a dose associated with acceptable toxicity level. Various model-based designs have been proposed for guiding dose escalation and estimating maximum tolerated dose in dose-finding studies. However, these methods are either excessively conservative or imprudent by allowing overly toxic doses. Transparent and easy to implement model-assisted designs have also received increasing attention but require pre-set rules including perceived dose levels. Therefore, we propose a hybrid model-based design that has a high probability to select MTD with a good balance of overdose control by disentangling in two separate models, which is flexible and easy to implement. Extensive simulations show the model to have real promise.

Riluzole for treating spasticity in patients with chronic traumatic spinal cord injury: Study protocol in the phase ib/iib adaptive multicenter randomized controlled RILUSCI trial.

Satisfactory treatment is often lacking for spasticity, a highly prevalent motor disorder in patients with spinal cord injury (SCI). Low concentrations of riluzole potently reduce the persistent sodium current, the post-SCI increase in which contributes to spasticity. The repurposing of this drug may therefore constitute a useful potential therapeutic option for relieving SCI patients suffering from chronic traumatic spasticity. RILUSCI is a phase 1b-2b trial designed to assess whether riluzole is a safe and biologically effective means of managing spasticity in adult patients with traumatic chronic SCI. In this multicenter double-blind trial, adults (aged 18-65 years) suffering from spasticity after SCI (target enrollment: 90 participants) will be randomly assigned to be given either a placebo or a recommended daily oral dose of riluzole for two weeks. The latter dose will be previously determined in phase 1b of the study by performing double-blind dose-finding tests using a Bayesian continuous reassessment method. The primary endpoint of the trial will be an improvement in the Modified Ashworth Score (MAS) or the Numerical Rating Score (NRS) quantifying spasticity. The secondary outcomes will be based on the safety and pharmacokinetics of riluzole as well as its impact on muscle spasms, pain, bladder dysfunction and quality of life. Analyses will be performed before, during and after the treatment and the placebo-controlled period. To the best of our knowledge, this clinical trial will be the first to document the safety and efficacy of riluzole as a means of reducing spasticity in patients with chronic SCI. The clinical trial, which is already in progress, was registered on the ClinicalTrials.gov website on August 9, 2016 under the registration number NCT02859792. Assistance Publique-Hôpitaux de Marseille.

Phase I Study of Safety and Pharmacokinetics of RO7297089, an Anti-BCMA/CD16a Bispecific Antibody, in Patients with Relapsed, Refractory Multiple Myeloma

IntroductionThis phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of RO7297089, an anti-BCMA/CD16a bispecific antibody.MethodsRO7297089 was administered weekly by intravenous infusion to patients with relapsed/refractory multiple myeloma. The starting dose was 60 mg in this dose-escalation study utilizing a modified continual reassessment method with overdose control model.ResultsOverall, 27 patients were treated at doses between 60 and 1850 mg. The maximally administered dose was 1850 mg due to excipients in the formulation that did not allow for higher doses to be used. The maximum tolerated dose was not reached. The most common adverse events irrespective of grade and relationship to the drug were anemia, infusion-related reaction, and thrombocytopenia. Most common treatment-related grade ≥ 3 toxicities were ALT/AST increase and reduced lymphocyte count. Pharmacokinetic studies suggested non-linear pharmacokinetics and target-mediated drug disposition, with a trend of approaching linear pharmacokinetics at doses of 1080 mg and higher. Partial response was observed in two patients (7%), minimal response in two patients (7%), and stable disease in 14 patients (52%).ConclusionsRO7297089 was well tolerated at doses up to 1850 mg, and the efficacy data supported activity of RO7297089 in multiple myeloma. Combination with other agents may further enhance its potential as an innate immune cell engager in multiple myeloma.Trial RegistrationClinicalTrials.gov: NCT04434469; Registered June 16, 2020; https://www.clinicaltrials.gov/ct2/show/NCT04434469.

Concurrent dose-finding of a novel cancer drug with and without a second agent.

More complex research questions are being posed in early-phase oncology clinical trials, necessitating design strategies tailored to contemporary study objectives. This paper describes the proposed design of a Phase I trial concurrently evaluating the safety of a hematopoietic progenitor kinase-1 inhibitor (Agent A) as a single agent and in combination with an anti-PD-1 agent in patients with advanced malignancies. The study's primary objective was to concurrently determine the maximum tolerated dose (MTD) of Agent A with and without anti-PD-1 therapy among seven possible study dose levels. Our solution to this challenge was to apply a continual reassessment method shift model to meet the research objectives of the study. The application of this method is described herein, and a simulation study of the design's operating characteristics is conducted. This work was developed through collaboration and mentoring between the authors at the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) annual AACR/ASCO Methods in Clinical Cancer Research Workshop. The aim of this manuscript is to highlight 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 modern design conditions. Although the design is presented using an investigation of Agent A with and without anti-PD-1 therapy as an illustrative example, the approach described is not specific to these agents and could be applied to other concurrent monotherapy and combination therapy studies with well-defined binary safety endpoints.

Quasi-partial order continual reassessment method: Applying toxicity scores to cancer dose-finding drug combination trials

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.

Controlled amplification in oncology dose-finding trials

In oncology clinical trials the guiding principle of model-based dose-finding designs for cytotoxic agents is to progress as fast as possible towards, and identify, the dose level most likely to be the MTD. Recent developments with non-cytotoxic agents have broadened the scope of early phase trials to include multiple objectives. The ultimate goal of dose-finding designs in our modern era is to collect the relevant information in the study for final RP2D determination. While some information is collected on dose levels below and in the vicinity of the MTD during the escalation (using conventional tools such as the Continual Reassessment Method for example), designs that include expansion cohorts or backfill patients effectively amplify the information collected on the lower dose levels. This is achieved by allocating patients to dose levels slightly differently during the study in order to take into account the possibility that “less (dose) might be more”. The objective of this paper is to study the concept of amplification. Under the heading of controlled amplification we can include dose expansion cohorts and backfill patients among others. We make some general observations by defining these concepts more precisely and study a specific design that exploits the concept of controlled amplification.

Pembrolizumab in Combination with Epigenetic Therapy Is Safe and Active in Heavily Treated Patients with Peripheral T-Cell Lymphoma (PTCL) and Cutaneous T-Cell Lymphoma (CTCL): Preliminary Results from the Embolden Trial

Background: Peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Our group previously demonstrated that combinations of epigenetic modifiers such as histone deacetylase inhibitors (HDACi), hypomethylating agents and pralatrexate produced potent synergy in pre-clinical models of PTCL, which produced compelling activity in early phase clinical studies. We have demonstrated that epigenetic modifiers, such as decitabine and 5-azacytidine (Marchi et al; Br. J. Haematol. 171, 2015) induces the expression of cancer testis antigens and established that pralatrexate acts as an immunomodulatory agent affecting genes involved in cytokine production, viral response and apoptosis. These pre-clinical data suggest a role for the incorporation of the immune-checkpoint inhibitor, pembrolizumab, to epigenetic backbones. Herein, we report on the differential clinical activity of adding the immune checkpoint inhibitor, pembrolizumab, to decitabine, pralatrexate, or the combination and we describe the role of cytokines as a biomarker of treatment response. Trial Design & Methods: This is a phase 1b study of pembrolizumab combined with pralatrexate alone (Arm A), with pralatrexate + decitabine (Arm B), or decitabine alone (Arm C) in patients with relapsed and refractory PTCL and CTCL. A standard 3+3 dose-escalation was applied in the doublet Arms (A and C) while a DLT-adapted partial order continual reassessment method (POCRM) for dose-finding with combinations of agents was applied in the triplet Arm (Arm B). We evaluated the cytokine profile using a Luminex-based immunoassay on serum samples obtained from trial patients on days 1, 8 and 15 during cycle 1 of treatment. Quantitative changes in 25 unique cytokines were evaluated, and these changes were correlated with clinical outcomes. Results: We enrolled 15 patients with six patients in Arm A, four in Arm B, and five in Arm C. All patients that received at least one dose of drug were evaluable for toxicity. One dose limiting toxicity (DLT) was observed in Arms A and B (grade 3 thrombocytopenia and febrile neutropenia, respectively). In Arm C, three DLTs were observed including one patient with grade 3 hyponatremia and rash; one patient with grade 4 thrombocytopenia, neutropenia, and anemia; and one patient with grade 4 neutropenia. There were no treatment related deaths. Nine patients out of 15 were evaluable for response at the time of this analysis. Of these nine evaluable patients, one achieved a complete remission (Arm B), two achieved partial remission (1 in Arm A, 1 in Arm B), one had stable disease (Arm C), and five experienced disease progression (2 in Arm A, 1 in Arm B, and 2 in Arm C). Interestingly, two of the three responses were seen in patients who received the triplet of pralatrexate, decitabine, and pembrolizumab (Arm B) and one response was seen in a patient treated with pralatrexate and pembrolizumab (Arm A). The serum cytokine profile revealed significant changes in only five of the 25 cytokines surveyed. Of the five cytokines, three pro-inflammatory cytokines, TNFα, MIP-3α and IL-10, measured at day 1 pre-treatment exhibited significantly higher levels (p= 0.0001, 0.0008 and 0.003 respectively) compared to healthy controls. Trial patients who responded to treatment (PR/CR) in either Arms demonstrated a decline in serum levels of TNFα and IL-10 by day 15 of cycle 1, whereas non-responders (PD/SD) showed stable to increased levels of both TNFα (Figure 1) and IL-10. Conclusion: These preliminary data suggest that the integration of pembrolizumab into an epigenetic backbone is safe and demonstrates encouraging responses in heavily pretreated patients with PTCL and CTCL. Pharmacodynamic data suggests that certain cytokines might have predictive value as biomarkers of disease response and progression. Interestingly, patients that responded (PR/CR) to the study drugs displayed a decline in cytokine levels, highlighting the prognostic implications of these cytokines. Additional pharmacodynamic studies, including flow cytometry of peripheral blood mononuclear cells, and pharmacokinetic studies are ongoing. Clinical trial registry NCT03240211. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

First-in-Human Phase I Trial of a ROR1 Targeting Bispecific T Cell Engager (NVG-111) in Combination with Ibrutinib or As Monotherapy in Subjects with Relapsed Refractory Chronic Lymphocytic Leukaemia (CLL) and Mantle Cell Lymphoma (MCL)

Background: NVG-111 is a first in class, humanized, tandem scFv, ROR1xCD3 bispecific T cell engager that mediates potent killing of ROR1+ tumor by engaging an epitope on the Frizzled domain of ROR1 and redirecting T cell activity via the CD3 binder that has been engineered for lower cytokine release. Methods: This multi-center, open-label, phase I study is evaluating NVG-111 in relapsed/refractory CLL and MCL subjects who have received ≥2 prior systemic therapies. An adaptive trial design was used for dose escalation, starting with accelerated dose titration (ATD) followed by a Bayesian continual reassessment method with overdose control. Each patient received at least one dose of NVG-111, administered as a continuous intravenous infusion (cIV) over 21 days followed by 7 days off drug (=1 cycle). NVG-111 was administered in combination (cohorts 1-4) with ibrutinib to patients who had achieved a stable or partial response to >1 year of ibrutinib therapy, or as monotherapy in patients who had progressed after BTKi / BCL2 (cohort 4b). Measurable residual disease (MRD) was assessed using a flow cytometric method with sensitivity 1e4 (MRD4). Mesoscale discovery electrochemiluminescence assay (MSD-ECLA) was used for pharmacokinetic analysis of NVG-111. Serum cytokine levels were determined using a human high sensitivity cytokine A premixed magnetic Luminex assay. Primary endpoints consisted of safety, tolerability and determination of maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D). Additional end-points included overall response rates as well as duration of response. Results: As of July 2022, 10 subjects (8 males and 2 females, median age 60 years) had been enrolled to the study; three into single subject ATD cohorts, 3 into 30 µg/day flat dosing cohort (cohort 4) and 4 into cohort 4b that entailed a step-up dosing of NVG-111 in cycle 1 only; (first week cycle 1: 3 µg/day, second week, cycle 1: 10 µg/day and week 3, cycle 1: 30 µg/day dose). Eight subjects had CLL and 2 MCL. cIV was well tolerated. Adverse events (AEs) were largely limited to week 1 of cycle 1 and all were reversible. The most common AEs were Grade 1 or 2 nausea (70%), headaches (60%), and fatigue (50%) and thrombocytopenia (30%). Grade 1/2 cytokine release syndrome (CRS) was observed in (40%) of subjects. Grade 3 dose limiting toxicities occurred in two subjects consisting of immune effector cell-associated neurotoxicity syndrome-like symptoms (ICANS) in one (cohort 4) and ALT and AST elevation (cohort 4b) in the other. Both subjects recovered upon stopping NVG-111. Average steady-state serum concentration (Cavg.ss) of NVG-111 in serum of patients who received a 10µg/day and 30µg/day dose were 168-288pg/mL and 425-610pg/mL respectively. This was in line with the predicted drug levels from the single species allometric scaling. Evidence of T cell activation was observed in all evaluable subjects (9/10) with cytokine levels at the 30µg/day dose level being: TNFα, 21±6pg/ml; IL6, 206±178pg/ml; IFNɣ, 7±4pg/ml; and IL10, 47±21pg/ml. Objective clinical responses were observed in 66% of subjects and included 2 MRD4 negative clinical remissions (CR). These two subjects remained in MRD4 negative CRs at 6 months after completion of treatment. Conclusion: Early data shows that NVG-111 is generally well tolerated with a predictable and manageable safety profile. Promising evidence of efficacy was observed which appears to be durable in two subjects with MRD4 negative CR. Dose escalation is ongoing in combination or as monotherapy to determine the MTD/RP2D.

Implementation of the Time-to-Event Continuous Reassessment Method Design in a Phase I Platform Trial Testing Novel Radiotherapy-Drug Combinations-CONCORDE.

CONCORDE is the first phase I drug-radiotherapy (RT) combination platform in non-small-cell lung cancer, designed to assess multiple different DNA damage response inhibitors in combination with radical thoracic RT. Time-to-event continuous reassessment method (TiTE-CRM) methodology will inform dose escalation individually for each different DNA damage response inhibitor-RT combination and a randomized calibration arm will aid attribution of toxicities. We report in detail the novel statistical design and implementation of the TiTE-CRM in the CONCORDE trial. Statistical parameters were calibrated following recommendations by Lee and Cheung. Simulations were performed to assess the operating characteristics of the chosen models and were written using modified code from the R package dfcrm. The results of the simulation work showed that the proposed statistical model setup can answer the research questions under a wide range of potential scenarios. The proposed models work well under varying levels of recruitment and with multiple adaptations to the original methodology. The results demonstrate how TiTE-CRM methodology may be used in practice in a complex dose-finding platform study. We propose that this novel phase I design has potential to overcome some of the logistical barriers that for many years have prevented timely development of novel drug-RT combinations.

Concurrent Olaparib and Radiotherapy in Patients With Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with radiotherapy in patients with TNBC would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear. To assess the safety and tolerability of PARP inhibition with olaparib used concurrently with radiotherapy in patients with TNBC with residual disease after neoadjuvant chemotherapy. This phase 1 prospective dose-escalation trial (Olaparib and Radiation Therapy for TNBC [RadioPARP] trial) using a time-to-event continual reassessment method was performed from September 2017 to November 2019, with follow-up until November 2021. Participants had an incomplete pathologic response after neoadjuvant chemotherapy or unresectable TNBC despite previous neoadjuvant chemotherapy, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ functions. Olaparib was administered orally in the form of tablets and given at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily). Olaparib therapy was started 1 week before radiotherapy and was continued concomitantly with radiotherapy. After breast-conserving surgery, a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed for patients younger than 60 years. After radical mastectomy or for unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall (after mastectomy) or to the whole breast (for unresectable tumors). Regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy in cases of node-positive disease. Main outcomes were the safety and tolerability of PARP inhibition with radiotherapy for early-stage, high-risk TNBC. Secondary outcomes included overall survival (OS) and event-free survival (EFS). Among the 24 patients included in the trial (100% female; median age, 46 years [range, 25-74 years]), no dose-limiting toxic effects were observed, and olaparib was escalated to 200 mg twice daily without reaching the maximum tolerated dose. No late treatment-related grade 3 or greater toxic effect was observed, and the maximum observed treatment-related toxic effects at the 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in 1 patient (4.2%). Three-year OS and EFS were 83% (95% CI, 70%-100%) and 65% (95% CI, 48%-88%), respectively. Homologous recombination status was not associated with OS or EFS. The findings of this phase 1 dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk TNBC is well tolerated and should continue to be evaluated in further clinical trials. ClinicalTrials.gov Identifier: NCT03109080.

Concurrent Olaparib with Radiotherapy in Patients with Triple Negative Breast Cancer: Final Results of the RADIOPARP Phase 1 Trial

<h3>Purpose/Objective(s)</h3> Preclinical studies have demonstrated that triple-negative breast cancer (TNBC) cells are sensitive to PARP inhibitors when used as radiosensitizers. Combining PARP-inhibitors with radiotherapy in TNBC patients may consequently enhance the biological effectiveness of the irradiation ultimately leading to improved locoregional control. We aimed to establish the appropriate dosing and safety profile of Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients with residual disease after neoadjuvant chemotherapy. <h3>Materials/Methods</h3> RADIOPARP (NCT03109080) was a prospective phase I dose-escalation trial establishing the tolerance profile of Olaparib combined with breast radiotherapy in high-risk early TNBC patients. Inclusion criteria were resected TNBC with non-complete pathological response after neoadjuvant chemotherapy, or unresectable TNBC despite prior neoadjuvant chemotherapy. Olaparib was started seven days before irradiation and continued during radiotherapy. A time-to-event continual reassessment method was used to increase Olaparib through four increasing dose levels (50mg, 100mg, 150mg or 200mg twice a day) with a 25% maximum probability rate of dose-limiting toxicities (DLT). Radiotherapy delivered 50 Gy to the breast or the chest wall, with or without lymph node irradiation. Toxicities were graded according to CTCAE (version 4.03). Homologous recombination (HR) proficiency status was genetically determined based on shallow whole genome sequencing. <h3>Results</h3> Twenty-four TNBC patients were enrolled between 09/2017 and 11/2019. Olaparib was escalated to 200 mg twice a day without DLT and the MTD was not reached. With a median follow-up of 34 months, no late treatment-related grade ≥ 3 toxicity was observed, and the maximum observed treatment-related toxicities were limited to grade 2 breast pain (n=2), fibrosis (n=2), deformity (n=1) and telangiectasia (n=1). Three-year OS and EFS were 83% [95% CI: 70%-100%] and 68% [51%-91%], respectively. HR proficiency status was not associated with OS and EFS. <h3>Conclusion</h3> Olaparib used as a radiosensitizer in combination with breast radiotherapy in TNBC patients was well-tolerated. The MTD was not reached, and no significant late toxicity was reported. For future trials evaluating the anti-tumor efficacy of this combination, an Olaparib dose of 200 mg twice a day should be considered.

Dose finding studies for therapies with late-onset toxicities: A comparison study of designs.

An objective of phase I dose-finding trials is to find the maximum tolerated dose; the dose with a particular risk of toxicity. Frequently, this risk is assessed across the first cycle of therapy. However, in oncology, a course of treatment frequently consists of multiple cycles of therapy. In many cases, the overall risk of toxicity for a given treatment is not fully encapsulated by observations from the first cycle, and hence it is advantageous to include toxicity outcomes from later cycles in phase I trials. Extending the follow up period in a trial naturally extends the total length of the trial which is undesirable. We present a comparison of eight methods that incorporate late onset toxicities while not extensively extending the trial length. We conduct simulation studies over a number of scenarios and in two settings; the first setting with minimal stopping rules and the second setting with a full set of standard stopping rules expected in such a dose finding study. We find that the model-based approaches in general outperform the model-assisted approaches, with an interval censored approach and a modified version of the time-to-event continual reassessment method giving the most promising overall performance in terms of correct selections and trial length. Further recommendations are made for the implementation of such methods.

1251P CHARIOT: A phase I dose escalation study combining ATR inhibitor Berzosertib with chemoradiotherapy in oesophageal cancer using time to event continual reassessment (TiTE-CRM) method: Results from A1 cohort (combination with palliative RT)

Berzosertib (M6220) is a selective ATR protein kinase inhibitor. Preclinical studies in esophageal cancer cell lines show that combining M6220 with cisplatin increased tumour cell kill in vitro and caused tumour growth delay in combination with radiation in vivo. The A1 cohort of CHARIOT (NCT03641547) tested the feasibility of combining Berzosertib with radiation in esophageal cancer. Primary objective: establish recommended phase II dose (RP2D) in combination with palliative RT; secondary objectives: safety, toxicity and efficacy.

1367P JNJ-70218902 (JNJ-902), a TMEFF2 x CD3 bispecific antibody, in prostate cancer: Initial results from a phase I dose escalation study

JNJ-902 is a bispecific antibody that engages TMEFF2–expressing tumor cells and CD3 on T cells. TMEFF2 is a unique prostate cancer lineage antigen with expression independent of androgen receptor signaling and retained throughout disease progression. In preclinical studies, JNJ-902 showed exposure-dependent pro-inflammatory responses, potent T cell-mediated cytotoxicity, and robust antitumor activity. This is a 2-part open-label, phase 1 study evaluating safety, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of JNJ-902 monotherapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). In Part 1 (dose escalation), a modified continual reassessment method was used to guide decision making in dose escalation and selection of the part 2 expansion dose. Subcutaneous JNJ-902 was administered with first dose given with corticosteroid premedication. Part 2 (dose expansion) will further evaluate safety and preliminary clinical activity of JNJ-902 at the part 2 expansion dose. As of April 6, 2022, 73 pts in Part 1 received at least one dose of JNJ-902 in 9 cohorts of ascending doses. Most common treatment-related AEs were fatigue (45%), decreased appetite (44%), injection site erythema (37%), anemia (33%), back pain (25%), and arthralgia (22%). Dose-limiting toxicity was reported in 2 pts (all Grade 3; 1 pt, fall-required hospitalization; 1 pt, orthostatic hypotension and syncope). Cytokine release syndrome was reported in 4 pts and resolved within 2–3 days. No deaths related to JNJ-902 were reported. Anti-drug antibody development was uncommon. PSA decline of 50% (PSA50) was observed in 8 pts and confirmed PR in 5 pts. JNJ-902 has linear PK over range of doses studied. JNJ-902 presented a tolerable safety profile at certain doses when PSA50 and RECIST responses were observed. JNJ-902 is being developed as a therapeutic option for mCRPC pts. Part 1 (dose escalation) is ongoing and Part 2 (dose expansion) of study will initiate once part 2 expansion dose is declared. Selection of part 2 expansion dosage is currently being adjusted and dose information will be presented.

MR-Guided Radiation Therapy With Concurrent Gemcitabine/Nab-Paclitaxel Chemotherapy in Inoperable Pancreatic Cancer: A TITE-CRM Phase I Trial

Ablative radiation therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) may limit concurrent chemotherapy dosing and usually is only safely deliverable to tumors distant from gastrointestinal organs. Magnetic resonance guided radiation therapy may safely permit radiation and chemotherapy dose escalation. We conducted a single-arm phase I study to determine the maximum tolerated dose of ablative hypofractionated radiation with full-dose gemcitabine/nab-paclitaxel in patients with BR/LA-PDAC. Patients were treated with gemcitabine/nab-paclitaxel (1000/125 mg/m2) x 1c then concurrent gemcitabine/nab-paclitaxel and radiation. Gemcitabine/nab-paclitaxel and radiation doses were escalated per time-to-event continual reassessment method from 40 to 45 Gy 25 fxs with chemotherapy (600-800/75 mg/m2) to 60 to 67.5 Gy/15 fractions and concurrent gemcitabine/nab-paclitaxel (1000/100 mg/m2). The primary endpoint was maximum tolerated dose of radiation as defined by 60-day dose limiting toxicity (DLT). DLT was treatment-related G5, G4 hematologic, or G3 gastrointestinal requiring hospitalization >3 days. Secondary endpoints included resection rates, local progression free survival (LPFS), distant metastasis free survival (DMFS), and overall survival (OS). Thirty patients enrolled (March 2015-February 2019), with 26 evaluable patients (2 progressed before radiation, 1 was determined ineligible for radiation during planning, 1 withdrew consent). One DLT was observed. The DLT rate was 14.1% (3.3%-24.9%) with a maximum tolerated dose of gemcitabine/nab-paclitaxel (1000/100 mg/m2) and 67.5 Gy/15 fractions. At a median follow-up of 40.6 months for living patients the median OS was 14.5 months (95% confidence interval [CI], 10.9-28.2 months). The median OS for patients with Eastern Collaborative Oncology Group 0 and carbohydrate antigen 19-9 <90 were 34.1 (95% CI, 13.6-54.1) and 43.0 (95% CI, 8.0-not reached) months, respectively. Two-year LPFS and DMFS were 85% (95% CI, 63%-94%) and 57% (95% CI, 34%-73%), respectively. Full-dose gemcitabine/nab-paclitaxel with ablative magnetic resonance guided radiation therapy dosing is safe in patients with BR/LA-PDAC, with promising LPFS and DMFS.

A semi-mechanistic dose-finding design in oncology using pharmacokinetic/pharmacodynamic modeling.

While a number of phase I dose-finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model-based. We propose a new framework for modeling the dose-response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting design is an extension of existing designs that make use of pre-specified summary PK information (such as the area under the concentration-time curve [AUC] or maximum serum concentration [Cmax ]). Our simulation studies show, with moderate departure from the hypothesized mechanisms of the drug action, that the performance of the proposed design on average improves upon those of the common designs, including the continual reassessment method (CRM), Bayesian optimal interval (BOIN) design, modified toxicity probability interval (mTPI) method, and a design called PKLOGIT that models the effect of the AUC on toxicity. In case of considerable departure from the underlying drug effect mechanism, the performance of the design is shown to be comparable with that of the other designs. We illustrate the proposed design by applying it to the setting of a phase I trial of a γ-secretase inhibitor in metastatic or locally advanced solid tumors. We also provide R code to implement the proposed design.

S207: EFFICACY AND SAFETY OF A THIRD GENERATION CD20 CART (MB-106) FOR TREATMENT OF RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA (FL)

Background: Follicular lymphoma (FL) is incurable and novel treatments with high efficacy and low toxicity are needed. Chimeric antigen receptor T-cells (CAR-T) targeting CD19 are effective, and axicabtagene ciloleucel is currently approved by FDA for treatment of patients (pts) with relapsed FL, but toxicities like cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may limit its use. MB-106 is a fully human 3rd-generation CD20-targeted CAR-T product with both 4-1BB and CD28 costimulatory domains. Aims: We present the results of the FL cohort from our ongoing phase I/II clinical trial investigating MB-106 for B-cell lymphoma/CLL. Methods: Pts with R/R B-cell malignancies including FL were eligible after confirmation of CD20 expression. Prior treatment with CD19 CAR-T is permitted. Lymphodepletion (LD) consists of cyclophosphamide (Cy) ± fludarabine (Flu). CAR-T cells are administered at one of 4 dose levels (DL): DL1: 3.3x105, DL2: 1x106, DL3: 3.3x106, DL4: 1x107 CAR T cells/kg. A continual reassessment method dose escalation design was used to find the maximally tolerated dose. CAR-T was infused in the outpatient setting except for the first pt of each dose cohort (overnight observation). Initial treatment response is assessed on day 28 and best response is reported here. CRS and ICANS are graded per ASTCT. Results: Between Dec 2019 and Dec 2021, 16 pts with FL were treated and had day 28 assessment. Median age was 61.5 years (range: 45 – 81). High-risk features included pts with progression of disease within 24 months of first-line chemotherapy (POD24) (n=11; 69%), history of histologic transformation (n=3; 19%), prior treatment with a CD19 targeted CAR-T (n=1; 6%). 6 pts (37.5%) had a PI3 kinase inhibitor. Median time between leukapheresis and LD was 15 days (range: 9-21) and 2 pts received bridging therapy with lenalidomide (1) and high-dose corticosteroids (1). All DLs were reached (DL0=1, DL1=1, DL2=4, DL3=7, DL4=2), with no dose-limiting toxicities. All CRS events were grade 1 (n=4; 25%) or grade 2 (n=1; 6%), with no grade ≥ 3 CRS events. There was no occurrence of ICANS of any grade. No pts had tumor lysis syndrome or Gr 3-4 infections. In the first 28 days, thrombocytopenia (Gr 3-4: 12.5%) and neutropenia (Gr 3-4: 94%) were common but there were no bleeding complications, and the rate of febrile neutropenia was 25%. Overall response (ORR) rate was 94% (15/16) and a complete response (CR) rate was 75% (12/16). Pts who received DL3 or DL4, had an ORR 100% and CR rate of 89%. The single patient who had previously been treated with a CD19 targeted CAR-T achieved a CR. With median follow-up of 10 months, one patient died, from complications of myelodysplastic syndrome (MDS) while still in remission; the MDS was attributed to the prior treatments (7 lines of chemo-based therapy and radioimmunotherapy). Most of the remissions are ongoing and 4 pts have relapsed during the follow-up median 7 months after treatment (range 3-10.5). CAR T cells were detectable by flow cytometry at last available timepoint (up to 2 years) for 15 of 16 patients. One patient had undetectable CAR T cells by day 201. Summary/Conclusion: Treatment with MB-106, a third generation CD20 targeting CAR-T, resulted in high ORR and CR rates and CAR-T persistence in FL pts and was associated with favorable safety profile with no occurrence of Gr 3 or Gr 4 CRS and no ICANS event of any grade. A multicenter trial for treatment of B-cell malignancies including FL will start enrollment in 2022.

The first-in-human phase I study of a brain penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas.

Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001. This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400mg twice daily. Dose escalation used a modified continual reassessment method. The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cut-off. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least one grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples. DS-1001 was well-tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).

Multi-stage dose expansion cohort (MSDEC) design with Bayesian stopping rule

ABSTRACT Phase I trial designs generally fall into three categories: algorithm-based (e.g., the classic 3 + 3 design), model-based (e.g., the continual reassessment method, CRM), and model-assisted designs that combine features of the first two (e.g., the Bayesian Optimal Interval, BOIN, design). The classic ‘3 + 3’ design continues to be the most frequently used design in phase I trials in finding maximum tolerated dose (MTD) due to its simplicity and feasibility, though many other model-based designs such as the Continual Reassessment Method (CRM) have also been proposed and used in various such as immunotherapies trials. The MTD based on three or six patients is not accurate, and dose-expansion cohorts (DEC) are increasingly used to better characterize the toxicity profiles of experimental agents. This article proposes a multi-stage dose-expansion cohort (MSDEC) hybrid frequentist-Bayesian design combining the power prior and the sequential conditional probability ratio test. In this design, results from the dose-escalation part are viewed and treated as historical data, and then are weighted and modeled through power prior. For safety monitoring, the Bayesian stopping rule is developed and the maximum sample size is calculated by a fixed-sample-size test with exact binomial computation. Simulation studies showed that MSDEC reduces the chance that a patient experiences a toxic dose. Power prior provides a reasonable prior for the Bayesian model because the degree of informativeness of the prior can be driven by the (“objective”) historical data rather than from expert opinion elicited on parameters in the model.