Optimal Biological Dose Research Articles

Statistical and practical considerations in planning and conduct of dose-optimization trials.

The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In addition, practical considerations for selecting an appropriate design and planning and executing the trial are discussed. The article also presents freely available software tools that can be utilized for designing and implementing dose-optimization trials. The approaches and their implementation are illustrated through real-world examples.

Abstract C084: iExplore: A phase I study of mesenchymal stem cell derived exosomes with KrasG12D siRNA for metastatic pancreas cancer patients harboring the KrasG12D mutation

Abstract Introduction The safety, target engagement, and benefit of iExosomes, short interfering RNA targeting KrasG12D encapsulated within exosomes and intravenously administered, were explored in patients with advanced pancreatic cancer harboring a KrasG12D mutation. Methods The initial phase I protocol was a conventional 3+3 design with three escalating dose levels (levels 1-3) of iExosomes, defined as exosomal protein levels and containing equal amounts of siRNA. Lack of toxicity at the highest dose level subsequently guided protocol amendment to an adaptive design exploring further dose escalation, with one patient treated at each additional dose level (levels 4-6). The highest dose level safely tolerated would be considered the optimal biological dose (OBD). Treatments were administered over three consecutive 14-day cycles. Blood was collected from all patients to assess changes in KrasG12D circulating DNA in response to treatment. Pre and post treatment biopsies were obtained from patients treated at dose levels 4-6 to evaluate target engagement, including changes in phosphorylated ERK levels by immunohistochemistry. Results Twelve patients received multiple iExosome treatments at specified dose levels, and none experienced any related adverse events of any grade. No dose limiting toxicities were observed, and the OBD was determined to be 28.8 mg of iExosome protein, administered in 6 infusions. Levels of circulating KrasG12D DNA decreased over the course of therapy. Levels of phosphorylated ERK in tumor biopsies decreased while on treatment, dropping to undetectable levels in higher dose levels. Clinically, the best response observed was stable disease as per RECISTv1.1 criteria in three patients, one each at dose levels 1-3. Conclusions iExosome therapy targeting KrasG12D is a safe and well-tolerated treatment for metastatic pancreatic cancer. Decrease in levels of circulating KrasG12D DNA and suppression of downstream Kras signaling phosphorylated ERK in tissue biopsies support effective target engagement of iExosomes in patients. Considering preclinical studies that indicate iExosome treatment enhances immune mediated anti-tumor responses, a future trial design will explore iExosomes at the OBD in combination with immune checkpoint inhibition for the treatment of pancreatic cancer. Citation Format: Brandon G. Smaglo, Valerie S. LeBleu, J. Jack Lee, Anirban Maitra, Raghu Kalluri, Katy Rezvani, Luisa M. Solis Soto, Mark Hurd, Indreshpal Kaur, Mayela C. Mendt Vilchez, Michelle L. Kirtley, Stacy L. Shaftoe, Maria Pia Morelli, Michael J. Overman, Dan Zhou, Robert A. Wolff, Janet Tu, Jason A. Willis, Ryan W. Huey, Michael S. Lee, Priya R. Bhosale, Suzanne W. Dworsky, Li Xu, Shubham Pant, Elizabeth J. Shpall. iExplore: A phase I study of mesenchymal stem cell derived exosomes with KrasG12D siRNA for metastatic pancreas cancer patients harboring the KrasG12D mutation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C084.

Adaptive phase I-II clinical trial designs identifying optimal biological doses for targeted agents and immunotherapies.

Targeted agents and immunotherapies have revolutionized cancer treatment, offering promising options for various cancer types. Unlike traditional therapies the principle of "more is better" is not always applicable to these new therapies due to their unique biomedical mechanisms. As a result, various phase I-II clinical trial designs have been proposed to identify the optimal biological dose that maximizes the therapeutic effect of targeted therapies and immunotherapies by jointly monitoring both efficacy and toxicity outcomes. This review article examines several innovative phase I-II clinical trial designs that utilize accumulated efficacy and toxicity outcomes to adaptively determine doses for subsequent patients and identify the optimal biological dose, maximizing the overall therapeutic effect. Specifically, we highlight three categories of phase I-II designs: efficacy-driven, utility-based, and designs incorporating multiple efficacy endpoints. For each design, we review the dose-outcome model, the definition of the optimal biological dose, the dose-finding algorithm, and the software for trial implementation. To illustrate the concepts, we also present two real phase I-II trial examples utilizing the EffTox and ISO designs. Finally, we provide a classification tree to summarize the designs discussed in this article.

The Backfill i3+3 Design for Dose-Finding Trials in Oncology

We consider a formal statistical design that allows simultaneous enrollment of a main cohort and a backfill cohort of patients in a dose-finding trial. The goal is to accumulate more information at various doses to facilitate dose optimization. The proposed design, called Bi3+3, combines the simple dose-escalation algorithm in the i3+3 design and a model-based inference under the framework of probability of decisions (POD), both previously published. As a result, Bi3+3 provides a simple algorithm for backfilling patients to lower doses in a dose-finding trial once these doses exhibit safety profile in patients. The POD framework allows dosing decisions to be made when some backfill patients are still being followed with incomplete toxicity outcomes, thereby potentially expediting the clinical trial. At the end of the trial, Bi3+3 uses both toxicity and efficacy outcomes to estimate an optimal biological dose (OBD). The proposed inference is based on a dose-response model that takes into account either a monotone or plateau dose-efficacy relationship, which are frequently encountered in modern oncology drug development. Simulation studies show promising operating characteristics of the Bi3+3 design in comparison to existing designs.

An Optimal Dose Finding Study of N-Acetylcysteine in Patients with Myeloproliferative Neoplasms

Background and Significance: The major clinical issues that impact myeloproliferative neoplasm (MPN) patients are thromboses, debilitating symptoms such as itching and fatigue, and progression to acute leukemia. There are no available therapies that address all three of these issues. We have found that N-acetylcysteine (N-AC), an anti-oxidant with an established safety profile, protects animal MPN models from thrombosis and extends survival. Moreover, N-AC is known to reduce inflammation and protect cells from DNA damage, properties which are likely to be beneficial for reduction in symptoms and prevention of leukemia, respectively. We are performing a Phase I/II optimal biological dose (OBD) finding study. Our goals with this initial dose finding study are 1) to identify a dose which has a signal of efficacy (based on reduction in MPN symptom burden) without excessive toxicity and 2) to explore biological correlates of oxidative stress, inflammation, and thrombosis. Study Design and Methods: We have obtained an IND, IRB approval and opened for recruitment in January 2022 (NCT05123365). Nine patients have been enrolled. This is a single center study performed at University of California, Irvine. We are recruiting patients with all types of classic Ph-neg myeloproliferative neoplasms (ET, PV, MF). Patients must be symptomatic with an MPN symptom score (MPN-TSS) of ≥ 10. Patients on interferon-alpha or JAK inhibitors are excluded, however all other MPN directed therapies are allowed. We are using a Simple Toxicity and Efficacy Interval (STEIN) design for phase I/II trials which identifies the OBD based on both safety and efficacy. In contrast, the conventional 3+3, continuous reassessment method (model based Bayesian method) or Bayesian optimal interval designs for phase I dose finding study determine the maximum tolerable dose (MTD) solely on toxicity. The STEIN design is simple, robust and does not have strict assumptions. We will accrue patients in up to 9 cohorts of size 3 for a total of up to 27 patients. Three dose levels will be evaluated (600mg BID, 1200mg BID, 1800mg BID). Patients receive N-AC for a total of 8 weeks. For efficacy, the MPN symptom score (MPN-TSS) is assessed daily from the time of enrollment for 7 days before starting treatment to quantify the mean baseline symptom score and daily for 7 days during the last week of treatment (days 50-56) to assess the mean final symptom score. The desired target efficacy outcome is achievement of more than 30% reduction of MPN-TSS from baseline. Patients are monitored for toxicity with adverse event queries and labs including complete blood counts (CBC) and comprehensive metabolic panel (CMP) at weeks 1, 3, 6, 8, and 12 (week 12 is 30 day post-treatment follow-up). Dose-limiting toxicity (DLT) is defined as hematologic and non-hematologic toxicity, grade 3 or more according to The Common Terminology Criteria for Adverse Events (CTCAE Version 5), reported from the day of starting N-AC through the follow up period. N-AC possesses anti-oxidant, anti-inflammatory, and anti-thrombotic properties. Quantifying biologic measures of these features of N-AC at each dose level will help identify the specific mechanism(s) by which N-AC may be inducing benefit in MPN patients. At week 1 (immediately before initiating treatment) and Week 8 (last week of treatment) biological samples will be used for biological correlates. Plasma will be frozen within 2 hours of draw for metabolomics, multiplex cytokine array, and assessment of neutrophil extracellular trap (NET) formation by citrullinated histone H3 (H3Cit). We will also collect a stool sample at week 1 and week 8 to explore any changes in the gut microbiome.

Englumafusp Alfa (CD19-4-1BBL) and Glofitamab Combination in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL): Biomarker Results from a Phase I Dose-Escalation Trial

Background: Englumafusp alfa is an antibody-like fusion protein that simultaneously targets CD19 on B cells and 4-1BB on T cells and other immune cells. In the presence of a T-cell receptor signal and strictly dependent on CD19 crosslinking, englumafusp alfa co-stimulates T cells via 4-1BB agonism that boosts T-cell effector functions and prevents T-cell anergy. An ongoing Phase I dose-escalation study (NCT04077723) is investigating the safety, efficacy, pharmacokinetics, and pharmacodynamics (PD) of intravenous administration of englumafusp alfa in combination with glofitamab in patients (pts) with R/R NHL. We recently presented preliminary clinical data demonstrating promising clinical activity and good tolerability in R/R NHL (Hutchings et al, ICML 2023). Here, we report preliminary peripheral blood (PB) and tissue biomarker analyses to demonstrate mechanisms of action (MoA), dose relationship, and baseline features associated with response. Methods: Exploratory biomarker analyses included data from 84 pts with indolent or aggressive NHL (aNHL) dosed with 0.36-75mg englumafusp alfa, starting on Cycle 2 Day 8 (C2D8) and followed by combination with the fixed target dose of glofitamab (30mg), once every 3 weeks, from C3D1 for up to 12 cycles. Immune profiling of PB by flow cytometry and plasma cytokines analysis by ELLA were performed. Circulating tumor DNA (ctDNA) dynamics were evaluated by the Avenio NHL CAPP-Seq assay (Stokowski et al, ASH 2022) at C3D1, C5D1, and the end of 12-cycle treatment (EoT) in patients with aNHL. Baseline tumor biopsies (n=65) were analyzed by immunohistochemistry/immunofluorescence assays. On-treatment (OT) PD changes during the first five cycles of treatment were evaluated and compared to historical glofitamab monotherapy PD data generated in a phase I/II study (NCT03075696). Results: Englumafusp alfa in combination with glofitamab induced PD changes in PB at all tested doses. Specifically, in a dose-dependent manner, englumafusp alfa in combination with glofitamab limited the PB expansion of fully differentiated PD1+ CD8+ effector memory T cells re-expressing CD45RA (Temra), previously shown to expand dose-dependently following glofitamab monotherapy (Broeske et al, Blood Advances 2022). Additionally, the combination also resulted in a significant PB expansion of the activated (HLA-DR+) and effector memory CD8+ T (T EM) cells, and the ratio of T EM to central memory and naïve CD8+ T cells compared to glofitamab monotherapy. Furthermore, we detected no significantly added cytokine release with the combination to that previously observed with glofitamab monotherapy, in line with the clinically observed safety profile. Preliminary analysis of ctDNA dynamics showed that at C3D1 33% (18/55), at C5D1 40% (15/38), and at EoT 53% (9/17) of the pts had no detectable ctDNA. Notably, 61% of pts with aNHL who achieved complete metabolic response (CMR) had no detectable ctDNA at any OT visit. Our preliminary analysis also indicated a significant (p=0.03) association between the observed OT expansion of CD8+ T EM cells and the extent of decrease in ctDNA levels (mean mutant molecules per milliliter) at EoT relative to baseline. Finally, we observed ~60% of pts with low tumor infiltrating CD8+ T cells (<500 cells/mm 2 CD8+) and a more aggressive disease (>5000 cells/mm 2 proliferative (Ki67+) tumor cells) at baseline, both poor outcome correlates of glofitamab monotherapy, achieved a CMR with higher doses of englumafusp alfa. Conclusions: In this study, we demonstrated the MoA of englumafusp alfa in R/R NHL and key PD effects in combination versus glofitamab monotherapy that will support optimal biological dose finding. Furthermore, the observed association between expansion of T EM cells in PB and changes in ctDNA dynamics at EoT, albeit preliminary, supports ctDNA as a marker for depth and durability of response. Overall, our PD and biomarker observations so far strengthen the rationale of combining glofitamab with englumafusp alfa to drive long-term responses in this heavily pre-treated NHL patient population. Acknowledgments: This study was sponsored by F. Hoffmann-La Roche Ltd. The authors would like to thank the patients who participated in this trial, their families, and their caregivers. Special thanks also to Daria Rukina, Iva Lelios, Philip Knuckles, Kat Reyskens, Grigori Singovski, and Joanne Hayward for their contributions to this work.

First-in-Human Dose-Escalation and -Expansion Trial with Sirpα Antibody BYON4228 in R/R B-Cell NHL

Introduction: Blocking of the immune checkpoint CD47-SIRPα promotes myeloid cell-mediated innate as well as adaptive immunity towards tumor cells. Antibodies in development are either directed against CD47 or SIRPα and in combination with tumor-targeting antibodies, checkpoint inhibitors, chemotherapeutics or other agents. The humanized SIRPα antibody BYON4228 (van Helden et al (2023) JITC 11: e006567) has been designed with three distinguishing characteristics compared to other CD47- or SIRPα-directed therapies which makes BYON4228 potentially best-in-class: 1.High specificity for SIRPα and no binding to SIRPγ on T cells which enables maximal contribution of T cells and therefore maximal anti-tumor immune response; 2.Silenced Fc backbone (IgG1-L234A/L235) which potentially results in reduced toxicity as confirmed in nonclinical studies showing no anemia or neutropenia in monkey; 3.Binding to both allelic forms of SIRPα (α 1 and α BIT) covering a broad patient population. Phase 1 clinical trial design: BYON4228.001 (NCT05737628) is the first-in-human clinical trial of BYON4228, in combination with rituximab, in relapsed or refractory (R/R) B-cell Non-Hodgkin's lymphoma (NHL). Part 1 (dose escalation) evaluates the safety, tolerability and Pharmacokinetics (PK) of, and receptor occupancy by BYON4228 to determine the maximum tolerated dose (MTD) or optimal biological dose (OBD) if the MTD is not reached, and recommended dose for expansion (RDE). A 28-day flat dose escalation schedule starting at 7 mg will be followed in a standard 3+3 design. Notably, only 1 cycle BYON4228 monotherapy will be given in each patient before combining with rituximab (375 mg/m 2 first cycle weekly administration; thereafter every 4 weeks for a total of 6 cycles). In part 2 (cohort expansion) BYON4228 + rituximab combination therapy will be given from cycle 1 onwards to further evaluate safety and efficacy in up to 24 additional diffuse large B cell lymphoma (DLBCL) patients and up to 24 patients with either marginal zone lymphoma (MZL) or follicular lymphoma (FL). This trial design of only 1 cycle monotherapy and swiftly moving into combination therapy not only allows to investigate PK and safety of BYON4228 but also efficacy of combination treatment with rituximab in a relevant therapeutic setting. Enrollment is ongoing in The Netherlands, United Kingdom, Italy and Spain since June 2023. Key inclusion criteria include, for part 1: B-cell NHL expressing CD20 by immunohistochemistry (IHC) or flow cytometry, R/R to at least 2 prior lines of therapy; for part 2, cohort A: Histologically confirmed DLBCL expressing CD20 R/R to front-line therapy, or second-line salvage regimens; for part 2, cohort B: Histologically confirmed MZL or FL (Grade 1-3a) expressing CD20, R/R to at least 2 prior lines of therapy. Autologous or allogeneic hematopoietic cell transplantation and autologous CAR-T cell therapy are allowed as prior lines. Key exclusion criteria include prior treatment with CD47- or SIRPα- targeting agents at any time; other anticancer therapy including investigational agents within 2 weeks or within at least 4 times the elimination half-life; Burkitt's lymphoma; history of active auto-immune disorders, active infections or uncontrolled systemic disease. Tumor response is determined according to Lugano and LYRIC criteria. An extensive biomarker program in the peripheral blood and bone marrow is included in the trial.

Covalent-103: A Phase 1, Open-Label, Dose-Escalation, and Dose-Expansion Study of Bmf-500, an Oral Covalent FLT3 Inhibitor, in Adults with Acute Leukemia (AL)

Background: FLT3 mutations occur in 25-35% of patients with AML and are associated with poor prognosis. FLT3 mutations are most frequently the result of an internal tandem duplication (ITD) of amino acids in the juxtamembrane region of FLT3 or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased incidence of relapse, shorter duration of remission, and decreased disease-free and overall survival. BMF-500 is a novel orally bioavailable, highly potent and selective covalent inhibitor of FLT3 including wildtype (WT), ITD, TKD, as well as a variety of additional resistance-conferring mutations such as the gatekeeper F691. BMF-500 has demonstrated high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing capacity despite drug washout (Law et al., ASH 2022 Abstract 2756). BMF-500 has shown sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML. Study Design: COVALENT-103 (NCT05918692) is an open-label, non-randomized, multicenter, first-in-human Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of twice daily oral BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3 mutations. The trial has 2 arms that will undergo dose escalation in parallel: Arm A (without) and Arm B (with) concomitant use of a moderate or strong CYP3A4 inhibitor. Utilizing an accelerated titration design (ATD), doses of BMF-500 will be escalated in single-subject cohorts until 1 subject experiences either a Grade 2 or higher related-adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 +3” design. Patients with WT FLT3 AL may be enrolled, up to a limit of 33% per arm. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data. Patients must be refractory, relapsed or must have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care therapies, including HSCT. Participants with FLT3-mutant AML must have received treatment with a FLT3 inhibitor approved for treatment of relapsed or refractory FLT3-mutant AML. Key inclusion criteria include ECOG PS ≤ 2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease involvement, clinically significant cardiovascular disease, and WBC count >50,000/µL (uncontrollable with cytoreductive therapy). Objectives: The primary objective of the study is to evaluate safety and tolerability and to determine the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-500 oral monotherapy based on evaluation of available PK/ PD, safety and efficacy data. Secondary objectives include characterization of the pharmacodynamics and pharmacokinetics of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or the NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. Endpoints include best overall response rate (ORR), complete remission (CRc), duration of response (DOR), relapse-free survival (RFS) and overall survival (OS). The study was initiated in July 2023 and will enroll ~110 participants at approximately 30 sites.

Generalized Likelihood Ratios for Designing Dose Optimization Studies of Targeted Therapies

Dose optimization studies of new therapeutic agents aim to identify one or more promising doses for further evaluation in subsequent studies. Traditionally, dose optimization has focused on finding the maximum tolerated dose (MTD), assuming that drug activity and efficacy generally increase with increasing dose. For modern targeted agents, the dose-activity relationship is often non-monotone and such that activity starts to plateau or even decline before reaching the MTD. Finding the optimal biological dose (OBD) for a targeted agent requires considering both toxicity and activity in dose optimization. This article proposes a new design for finding the OBD that utilizes generalized likelihood ratios (GLRs) to measure statistical evidence regarding key scientific questions on toxicity and activity. This GLR-based design requires no parametric modeling assumptions and only assumes that the dose-toxicity relationship is monotone and that the dose-activity relationship follows a two-sided isotonic regression model. Compared with existing designs that operate under similar assumptions, the GLR-based design is more general and more flexible, and performs competitively in simulation experiments where drug activity starts to plateau or decline before reaching the MTD.

Safety and efficacy of P2Et extract from Caesalpinia spinosa in breast cancer patients: study protocol for a randomized double blind phase II clinical trial (CS003-BC)

BackgroundChemotherapy in breast cancer is effective but can generate significant toxicity and lead to tumor resistance. Joint treatment with standardized plant extracts can be an alternative to improve the response and allow an effective activation of the antitumor immune response that favors recovery in the short and long term. The P2Et extract of Caesalpinia spinosa presents antitumor activity in cells and animal models of breast cancer, improves the tumor microenvironment, and induces activation of the specific immune response against the tumor and is synergistic when used together with anthracyclines, which makes it a good candidate for evaluation in patients.MethodsConducted at a single center, this phase II study is a randomized, double-blind, placebo-controlled trial aimed at assessing the safety and efficacy of P2Et extract in patients diagnosed with stage II and III breast cancer, who are eligible for neoadjuvant treatment. The study aims to determine the safety profile at the previously established optimal biological dose from phase I trial while investigating various efficacy outcomes. These outcomes include improvements in quality of life, immunomodulation, metabolic profile, microbiome, as well as clinical indicators such as tumor reduction, disease-free survival, and pathological response, assessed at different stages of the treatment regimen.DiscussionTreatment with the P2Et extract in breast cancer patients is hypothesized to enhance overall well-being, positively influencing their quality of life, while also triggering an antitumor immune response and enhancing immune infiltration. These combined effects have the potential to contribute to improved long-term survival outcomes for patients receiving the phytomedicine alongside neoadjuvant chemotherapy treatment.Trial registrationThis trial was registered in the US National Library of Medicine with identifier NCT05007444. First Registered August 16th, 2021. Last Updated: August 9th, 2022.

Local continual reassessment methods for dose finding and optimization in drug-combination trials.

Due to the limited sample size and large dose exploration space, obtaining a desirable dose combination is a challenging task in the early development of combination treatments for cancer patients. Most existing designs for optimizing the dose combination are model-based, requiring significant efforts to elicit parameters or prior distributions. Model-based designs also rely on intensive model calibration and may yield unstable performance in the case of model misspecification or sparse data. We propose to employ local, underparameterized models for dose exploration to reduce the hurdle of model calibration and enhance the design robustness. Building upon the framework of the partial ordering continual reassessment method, we develop local data-based continual reassessment method designs for identifying the maximum tolerated dose combination, using toxicity only, and the optimal biological dose combination, using both toxicity and efficacy, respectively. The local data-based continual reassessment method designs only model the local data from neighboring dose combinations. Therefore, they are flexible in estimating the local space and circumventing unstable characterization of the entire dose-exploration surface. Our simulation studies show that our approach has competitive performance compared to widely used methods for finding maximum tolerated dose combination, and it has advantages over existing model-based methods for optimizing optimal biological dose combination.

AIPAC-003: A randomized, double-blind, placebo-controlled phase 3 trial testing eftilagimod alpha (soluble LAG-3) in patients with HER2-neg/low metastatic breast cancer receiving paclitaxel, following an open-label dose optimization.

TPS1120 Background: Eftilagimod alpha (efti), a soluble LAG-3 protein, acts as an MHC class II agonist that enhances immunity by mediating antigen presenting cell and CD8 T-cell activation. Data from a randomized, phase 2b trial of efti plus paclitaxel compared to placebo plus paclitaxel in patients (pts) with HR+ HER2– metastatic breast cancer (MBC) (AIPAC; NCT02614833) showed sustained pharmacodynamic activity that was linked to improved overall survival (OS) in the efti arm. AIPAC-003 is a randomized, double-blind, placebo-controlled phase 3 trial testing efti plus paclitaxel in HER2-neg/low MBC pts, including an initial open-label dose optimization lead-in (DOL) component to determine the optimal biological dose (OBD) of efti in this combination. Methods: Enrolment for the DOL will begin in March 2023 in max. 66 pts. Primary endpoints (EP) in the DOL include safety and tolerability of 90 mg vs 30 mg efti and defining the OBD of efti in combination with weekly paclitaxel. Determination of the OBD will be based on the totality of safety and tolerability data together with overall response rate (ORR) and pharmacodynamic marker (CD8+ T cells, absolute lymphocyte count) data. In the Phase 3 component approx. 771 pts are randomized to receive either paclitaxel + efti or paclitaxel + placebo in a double-blinded fashion. The primary EP for the proposed Phase 3 is OS. Key secondary EPs include progression free survival and ORR by RECIST 1.1, quality of life and safety. Pts will receive paclitaxel (80 mg/m2 I.V. on D1, 8 and 15 in a 4-week cycle), followed by efti or placebo (DOL: 30 or 90 mg efti; Phase 3: OBD of efti or placebo) S.C. on D1 and 15 in a 4-week cycle for up to 12 months. Key inclusion criteria: Pts with either a) HR+ and HER2-neg/low and endocrine therapy-resistant MBC or b) TNBC not eligible for anti-PD-1-based therapy. Pts must have measurable disease, ECOG PS 0-1 and no prior chemo for metastatic disease.

Harnessing the power of tumor-infiltrating lymphocytes: A first-in-human study of GT201 as monotherapy in advanced solid tumors.

2551 Background: Genetically engineered TIL has shown features such as prolonged memory that can improve therapeutic efficacy in tumor mouse models. GT201 is an engineered TIL that expresses a membrane-bound IL-15 (mbIL-15), and preclinical studies have demonstrated enhanced antitumor reactivity. A phase 1 study was initiated to evaluate the preliminary safety of GT201 and to identify Optimal Biological Dose (OBD) suitable for monotherapy expansion. Methods: The dose-escalation study (using TITE-BOIN design) intended to enroll patients (pts) with advanced treatment-refractory solid tumors. Once the OBD is identified, a monotherapy expansion phase will be opened for patients with various solid tumors. Enrolled patients were preconditioned with a nonmyeloablative (NMA) lymphodepletion regimen and treated by autologous infusion of the GMP-grade G201 cell product, followed with supportive low dose IL-2 administration. Results: As of January 17, 2023, the dose-escalation study enrolled 4 pts, all of whom were female with a median age of 52.6 years. The median number of infused TIL cells was 5.3E+09. All pts experienced TRAEs, with the majority being grade 1 or 2. The most common grade 3/4 TRAEs were lymphopenia (100%), leukopenia (25%) and neutropenia (25%), which were related to the NMA regimen. No dose-limiting toxicities (DLTs) or TIL-related grade ≥3 TRAEs were observed. Median time on study was 17 wks (6–30 wks). One pt with highly treatment-refractory cervical cancer experienced a confirmed partial response (PR) after 16 wks that was durable for 30 wks (RECIST 1.1). Two pts (cervical cancer and melanoma) experienced disease stabilization, while another malignant melanoma pt experienced progressive disease. Despite varying doses of TILs (5.0E+09 to 1.40E+10) and IL-2 (up to 3.0E+05 IU/kg), all patients receiving GT201 therapy showed robust T cell expansion post-infusion, with higher doses of IL-2 leading to more rapid TIL expansion. GT201 TILs could be detected in patients after one month post-infusion, indicating promising activation and long-term persistence of the infused TILs. Based on safety, tolerability, PKs, and preliminary efficacy, a TIL dose of 1.0E+10 and an IL-2 dose of 3.0E+05IU/kg was selected as the OBD for the study. Conclusions: The results of the first-in-human study of GT201, a mIL-15 expressed on TILs, demonstrate promising preliminary findings as a monotherapy in pts with advanced cancers. The administration of GT201 was associated with robust T cell expansion, as well as prolonged persistence of infused TILs. Results of mbIL-15 expressed TIL demonstrates that GT201 has good tolerability with encouraging preliminary antitumor activity as a monotherapy. Further investigations, including correlative biomarker analyses and updated safety and clinical outcome data, will be presented at the meeting. Clinical trial information: NCT05430360 .

Safety and efficacy of CRISPR-based non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells in patients with relapsed or refractory Non-Hodgkin's lymphoma: a first-in-human phase I study.

Thus far, all approved chimeric antigen receptor (CAR)-T products are manufactured using modified viruses, which increases the risk of tumorigenesis, costs and production time. We aimed to evaluate the safety and efficacy of a kind of virus-free CAR-T cells (PD1-19bbz), in which an anti-CD19 CAR sequence is specifically integrated at the PD1 locus using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, in adults with relapsed/refractory (r/r) B cell non-Hodgkin's lymphoma (B-NHL). This single-arm phase I dose-escalation clinical trial evaluated PD1-19bbz in adult patients with r/r B-NHL from May 3rd 2020 to August 10th 2021. The patients were recruited and treated at the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Patients underwent leukapheresis and lymphodepleting chemotherapy before PD1-19bbz infusion. After the dose-escalation phase including three cohorts: 2×106/kg, 4×106/kg, 6×106/kg with three patients at each dose level, the optimal biological dose was determined to be 2×106/kg, which was then applied to an extended cohort of nine patients. The primary endpoint was the incidence of dose-limiting toxicities (DLT). The secondary endpoint was the response and survival. This trial was registered at www.clinicaltrials.gov as #NCT04213469. Twenty-one patients received PD1-19bbz infusion. Among all treated patients, 19 (90%) patients were diagnosed with stage III or IV disease. Meanwhile, 19 (90%) were stratified as intermediate risk or worse. Of note, four participants had >50% programmed death ligand-1 (PD-L1) expression in pre-treatment tumour sample, including two with extremely high levels (∼80%). There was no DLT identified. Fourteen patients had low-grade (1-2) cytokine release syndrome and two patients received tocilizumab. Four patients experienced immune effector cell-associated neurotoxicity syndrome of grade 1-2. The most common adverse events were hematologic toxicities, including anaemia (n=6), lymphocyte count decreased (n=19), neutrophil count decreased (n=17), white blood cell count decreased (n=10), and platelet count decreased (n=2). All patients had objective response and 18 patients reached complete response. At a median follow-up of 19.2 months, nine patients remained in remission, and the estimated median progression-free survival duration was 19.5 months (95% confidence interval: 9.9-infinity), with the median overall survival not reached. In this first-in-human study of non-viral specifically integrated CAR-T products, PD1-19bbz exhibited promising efficacy with a manageable toxicity profile. A phase I/II trial of PD1-19bbz in a larger patient cohort is underway. National Key R&D Program of China, National Natural Science Foundation of China, Key Project of Science and Technology Department of Zhejiang Province, Shanghai Zhangjiang National Independent Innovation Demonstration Area, Key Projects of Special Development Funds.

Neoadjuvant chemotherapy and stereotactic body radiation therapy for borderline resectable pancreas adenocarcinoma: influence of vascular margin status and type of chemotherapy

BackgroundThe influence of chemotherapy type and vascular margin status after sequential chemotherapy and stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic cancer (BRPC) is unknown. MethodsA retrospective review was performed on BRPC patients treated with chemotherapy and 5-fraction SBRT from 2009 to 2021. Surgical outcomes and SBRT-related toxicity were reported. Clinical outcomes were estimated by Kaplan–Meier with log rank comparisons. ResultsA total of 303 patients received neoadjuvant chemotherapy and SBRT to a median dose of 40 Gy prescribed to the tumor–vessel interface and median dose of 32.4 Gyto 95% of the gross tumor volume. One hundred and sixty-nine patients (56%) were resected and benefited from improved median OS (41.1 vs 15.5 months, P < 0.001). Close/positive vascular margins were not associated with worse OS or FFLRF. Type of neoadjuvant chemotherapy did not influence OS for resected patients, but FOLFIRINOX was associated with improved median OS in unresected patients (18.2 vs 13.1 months, P = 0.001). ConclusionFor BRPC, the effect of a positive or close vascular margin may be mitigated by neoadjuvant therapy. Shorter duration neoadjuvant chemotherapy as well as the optimal biological effective dose of radiotherapy should be prospectively explored.

Abstract A003: COVALENT-102: A phase 1/1b dose finding study of BMF-219, an oral covalent menin inhibitor, in patients with metastatic non-small cell lung cancer (NSCLC), pancreatic cancer (PDAC), and colorectal cancer (CRC) with activating KRAS mutations

Abstract Background: BMF-219 is a selective covalent inhibitor of menin, a transcriptional regulator of oncogenic signaling pathways in multiple cancers, that inhibits the menin/MYC interaction and downregulates the expression of MYC and MYC target genes, including KRAS. Mechanism of Action (hypothesis): In addition to MYC disruption, inhibition of the Menin-MLL complex by BMF-219 alters JunD genomic function, a crucial factor for KRAS-driven tumorigenesis. Inhibition of the Menin-MLL complex suppresses expression of Rasgrf1, which is essential for generation of the active RAS-GTP conformation of KRAS, activation of downstream pathways, and tumorigenesis. Preclinically, BMF-219 shows sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 exerts pan-mutant KRAS anticancer activity that is independent of the specific KRAS-activating mutation. Methods: COVALENT-102 (NCT05631574) is a prospective, open-label, multicenter, dose finding study evaluating the safety, tolerability, and clinical activity of escalating doses of BMF-219 administered daily in patients with unresectable, locally advanced, or metastatic NSCLC (Cohort 1), PDAC (Cohort 2) &amp; CRC (Cohort 3) with activating KRAS mutations who have received standard therapy. All indications as a group will follow a 3+3 dose escalation design. BMF-219 will be administered orally daily as continuous therapy as 28-days treatment cycle until progression or intolerability/unacceptable toxicity. Following conclusion of the dose-escalation, each indication will enroll patients in expansion cohorts independently to obtain further safety and efficacy data. Eligible patients include those with any KRAS mutation &amp; (Cohort 1) stage IIIB/IV NSCLC with 2-4 prior lines of therapy including immune checkpoint inhibitors (ICI) &amp;/or platinum-based chemo ± bevacizumab with ECOG PS 0-2; (Cohort 2) stage III/IV PDAC with ≥ 1 prior line of therapy including either FOLFIRINOX or gemcitabine/nab-paclitaxel, ECOG PS 0-1; or (Cohort 3) stage III/IV CRC with ≥ 1 prior line of therapy including FOLFOX or FOLFIRI ± bevacizumab (prior ICI if MSI-H/dMMR), ECOG PS 0-2. Patients must have documented progression &amp; measurable disease as defined by RECIST 1.1. Patients with prior KRAS inhibitor exposure are eligible. Key exclusion criteria include symptomatic &amp;/untreated CNS metastasis, prior menin inhibitor therapy, and clinically significant cardiovascular disease. The primary objective is to determine the optimal biological dose (OBD)/recommended Phase 2 dose (RP2D) of BMF-219 monotherapy. Secondary objectives include further evaluation of safety &amp; tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and efficacy based on duration of response (DOR) &amp; disease control rate (DCR). Assessment of progression-free survival (PFS), overall survival (OS) &amp; time to response (TTR) are part of the exploratory endpoints. The first patient in the study is anticipated to be dosed in Q4 of 2022. Citation Format: Stacey A. Cohen, Christos Fountzilas, David Sommerhalder, Sandip Patel, Ai Benson, Kai He, Apar Ganti, Alex Spira, Bhagyashree (Kelshikar) Yadav, Alex Cacovean, Steve Morris, Tom Butler, David Hong. COVALENT-102: A phase 1/1b dose finding study of BMF-219, an oral covalent menin inhibitor, in patients with metastatic non-small cell lung cancer (NSCLC), pancreatic cancer (PDAC), and colorectal cancer (CRC) with activating KRAS mutations [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A003.

Optimal biological dose selection in dose-finding trials with model-assisted designs based on efficacy and toxicity: a simulation study

ABSTRACT With the emergence of molecular targeted agents and immunotherapies in anti-cancer treatment, a concept of optimal biological dose (OBD), accounting for efficacy and toxicity in the framework of dose-finding, has been widely introduced into phase I oncology clinical trials. Various model-assisted designs with dose-escalation rules based jointly on toxicity and efficacy are now available to establish the OBD, where the OBD is generally selected at the end of the trial using all toxicity and efficacy data obtained from the entire cohort. Several measures to select the OBD and multiple methods to estimate the efficacy probability have been developed for the OBD selection, leading to many options in practice; however, their comparative performance is still uncertain, and practitioners need to take special care of which approaches would be the best for their applications. Therefore, we conducted a comprehensive simulation study to demonstrate the operating characteristics of the OBD selection approaches. The simulation study revealed key features of utility functions measuring the toxicity-efficacy trade-off and suggested that the measure used to select the OBD could vary depending on the choice of the dose-escalation procedure. Modelling the efficacy probability might lead to limited gains in OBD selection.

Abstract CT110: Safety and anti-tumor activity of a novel Treg depleter RG6292, as a single agent and in combination with atezolizumab in patients with solid tumors

Abstract Background RG6292 is the first anti-human CD25 antibody developed to specifically deplete human Tregs while preserving IL-2R STAT5 signaling and Teff activity. Methods Patients with advanced/metastatic solid tumors and without standard treatment options were enrolled in dose escalation studies and received RG6292 i.v. Q3W as monotherapy (S1: NCT04158583) or in combination with atezolizumab 1200 mg Q3W (S2: NCT04642365) until disease progression or unacceptable toxicities to determine the maximum tolerated dose (MTD) and/or optimal biological dose, safety and preliminary clinical activity. DLT window was 4 weeks and dose increments were determined by a Bayesian-based continuous reassessment method (CRM) with overdose control. Adverse events (AEs) were graded by NCI CTCAE v5.0. Tumors were assessed by RECIST 1.1 every 8 weeks in the first year and then every 12 weeks. Results As of 27th May, 2022, 76 patients have been treated with RG6292 monotherapy (dose ranging from 0.3 - 165 mg). Six DLTs were reported, including rash, papular rash, rash macular-papular, AST elevation and ALT elevation. MTD is 165 mg. Seventy-five patients (99%) experienced at least one AE. The most common AEs were pruritus (32%), rash (29%) and fatigue (29%). Thirty-five patients (46%) experienced grade ≥ 3 AEs and 2 patients discontinued from study treatment due to AEs. Fourteen patients (18%) experienced grade ≥ 3 TRAEs. No AEs led to a fatal outcome. Median treatment duration was 43 days. Twenty-three patients have SD as best overall response. Forty-eight patients have been treated with RG6292 (dose ranging from 0.3 - 160 mg) in combination with atezolizumab. Two DLTs were reported, including immune system disorder and maculopapular rash. MTD has not been reached. Forty-seven patients (98%) experienced at least one AE. The most common AEs reported were pruritus (44%), rash (33%) and fatigue (33%). Twenty patients (42%) experienced grade ≥3 AEs and 2 patients discontinued from study treatment due to AEs. Five patients (10%) experienced grade ≥3 TRAEs. No AEs led to a fatal outcome. Median treatment duration was 54 days. Pruritus and rash were expected AEs and easily managed withtopical steroids or short course, low dose systemic steroids. Two patients have PR and 19 patients have SD as best overall response. Conclusion RG6292 is well tolerated and has a manageable safety profile as a single agent and in combination with atezolizumab. The preliminary safety and clinical activity from dose-escalation warrant further investigation of RG6292. Citation Format: Valentina Gambardella, Michael Ong, Maria Esperanza Rodriguez Ruiz, Jean-Pascal Machiels, Miguel Fernandez de Sanmamed, Josep Maria Tabernero, Anna Spreafico, Daniel J Renouf, Stephen J Luen, Rachel Galot, Bernard Doger de Speville Uribe, Emiliano Calvo Aller, Aung Naing, Samira Curdt, Eva Rossmann, Tamara Tanos, Kevin Smart, Maria Amann, Yuying Xie, Gabriel Schnetzler, Christophe Boetsch, Vaios Karanikas, Theresa Kolben, Linxinyu Xu, Kristoffer S Rohrberg. Safety and anti-tumor activity of a novel Treg depleter RG6292, as a single agent and in combination with atezolizumab in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT110.

Abstract CT096: Phase 1 study of RO7119929 (TLR7 agonist prodrug) in patients (pts) with advanced primary or metastatic liver cancers

Abstract Background Agonists for TLR7, a major regulator of the innate immune response, have been tested in oncology across several nonclinical and clinical investigations due to their ability to stimulate T-cell mediated cancer cell killing. The orally available TLR7 agonist prodrug RO7119929 is converted to active drug predominantly in the liver. It was hypothesized to effectively reprogram the local immune microenvironment and thus enhance anti-tumor activity in liver tumors. Methods In this phase 1, first-in-human, open-label, dose-escalation study (NCT04338685), eligible pts had histologically confirmed advanced or metastatic primary liver cancers or solid tumors with predominant liver involvement. Pts received oral RO7119929 weekly in 3-week cycles in Part A (dose-escalation: Flat dosing [FD][A1], step-up dosing [SUD][A2] or FD with tocilizumab pre-treatment [A3]) and Part B (FD dose expansion with paired biopsies). Participants received treatment until disease progression, unacceptable toxicity or withdrawal. Primary endpoints were maximum tolerated dose (MTD) and/or optimal biologic dose and safety. Results At data cut-off (22 April 2022), 55 pts were enrolled (A1: n=27; A2: n=9; A3: n=1; B1: n=18). Median age: 58 years; 76% male; 51% Asian; 52% received ≥3 prior lines of therapy; 31% HCC as primary tumor type. Most pts discontinued treatment due to disease progression (75%). Among 17 HCC pts, a durable complete response was observed in one pt and 10 (59%) pts had stable disease. Treatment-related AEs were reported in 91% of pts, most common event was CRS (87%). Fever following drug administration was generally reported as CRS, and most CRS events were Grade 1 (fever). With FD, Grade 2 CRS occurred in 20 (44%) pts and Grade 3 CRS in 6 (13%) pts. With SUD, Grade 2 CRS occurred in one (11%) pt and no Grade 3 CRS was reported. The incidence and severity of CRS events was dose-dependent. Events generally had a predictable onset within 12h post-dosing. All events resolved, the majority within 1-2 days. CRS events of Grade 2/3 commonly occurred in Cycle 1, with later events rarely exceeding Grade 1. Increases in the TLR7-related peripheral pharmacodynamic (PD) biomarkers IFNα, ISG15 and IL6 were associated with higher doses, with particularly IL6 correlating with CRS severity. With SUD, high levels of IFNα and ISG15 levels were maintained while IL6 levels were reduced compared with FD. Pharmacokinetics (PK) of the active TLR7 agonist drug appeared linear (Cmax, AUC) and time-independent with a short effective t1/2 of approximately 5h on average. PK, PD and safety modeling-informed dose decisions. Conclusion CRS was identified as a dose-limiting safety risk, the incidence and severity of CRS appeared dose-dependent, and events were predictable and manageable. SUD reduced the risk of CRS whilst maintaining mode of action relevant PD effects. Combination therapy with a checkpoint inhibitor may be needed to leverage the pro-inflammatory potential of RO7119929 and further increase anti-tumor activity. Citation Format: Changhoon Yoo, Helena Verdaguer, Chia-Chi Lin, Camilla Qvortrup, Thomas Yau, Do-Youn Oh, Felix Lichtenegger, Izolda Franjkovic, Nicole Kratochwil, Juliana Bessa, Eva Rossmann, Elia Hall, Congqi Dai, Oliver Krieter, Audrey Yeo Te-Ying, Michael Cannarile, Christina Schiff, Bruno Sangro. Phase 1 study of RO7119929 (TLR7 agonist prodrug) in patients (pts) with advanced primary or metastatic liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT096.

Abstract CT265: Phase 1 dose-escalation study of SGN-TGT monotherapy in patients with advanced malignancies

Abstract Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T-cells and natural killer (NK) cells. TIGIT inhibits T and NK cell function by binding to CD155 and CD112. SEA-TGT is an investigational human, nonfucosylated monoclonal antibody directed against TIGIT, blocking TIGIT's interaction with CD155 and CD112. SGNTGT-001 (NCT04254107) is a phase 1, open-label, multicenter study of SEA-TGT in patients (pts) with advanced malignancies (solid tumors and lymphomas). In this abstract, we present data from the dose-escalation phase (Part A). Methods: Pts received SEA-TGT ranging from 0.01 to 6.0 mg/kg of body weight intravenously every 3 weeks (Q3W). The primary objectives were to evaluate the safety and tolerability of SEA-TGT and identify the maximum tolerated dose (MTD) or the recommended dose and schedule of SEA-TGT. The optimal biological dose was defined using the Clinical Utility Index. Secondary objectives included the evaluation of antitumor activity, pharmacokinetics (PK) and immunogenicity. Antitumor activity was based on Response Evaluation Criteria in Solid Tumors version 1.1 or the Lugano classification criteria with Lymphoma Response to Immunomodulatory Therapy Criteria. Results: From June 12, 2020, to October 5, 2022, 41 pts were enrolled (2, 4, 5, 11, 12, and 7 pts in the 0.01, 0.1, 0.3, 1, 3, and 6 mg/kg cohorts, respectively). Among the 39 pts who were treated 23 pts had solid tumors and 16 had lymphomas. The median number of prior therapies across all cohorts was 5. Treatment emergent adverse events of any grade were reported in 100% of pts, and treatment-related adverse events (TRAEs) of any grade were reported in 69.2%. TRAEs seen in ≥10% of the pts were infusion-related reaction (38.5%), chills (25.6%), pyrexia (17.9%), fatigue (12.8%), maculopapular rash (12.8%), and rash (10.3%). Seven pts (17.9%) reported TRAEs grade ≥3, and rash (5.1%) was the most frequently reported. No grade 4 or 5 TRAEs were reported. One dose-limiting toxicity, pruritic rash, was observed in 1 pt in the 6 mg/kg cohort, and MTD was not exceeded. Based on the PK and pharmacodynamic data, 1 mg/kg Q3W was selected as the optimal biological dose for the expansion cohorts. One partial response was observed in a pt with gastric cancer, and 2 partial metabolic responses were seen in a pt with Hodgkin’s lymphoma and a pt with diffuse large B-cell lymphoma. Conclusions: Overall, clinical data for SEA-TGT from the SGNTGT-001 trial suggest a manageable and tolerable safety profile. Preliminary antitumor activity warrants further clinical evaluation of SEA-TGT. SGNTGT-001 is ongoing and evaluating monotherapy and combination therapies. Citation Format: Elena Garralda Cabanas, Elisa Fontana, Honey Kumar Oberoi, Nataliya V. Uboha, Ecaterina E. Dumbrava, Emiliano Calvo, Giuseppe Curigliano, Diwakar Davar, Bridget K. Keenan, Vincent K. Lam, Sudhir Manda, Amitkuma Mehta, Anna Minchom, Alison Moskowitz, Ravi Paluri, Vincent Ribrag, Donald Richards, Lillian Siu, Paul Swiecicki, Trisha Wise-Draper, Jasmine Zain, Andres Forero-Torres, Ping Xu, Stephen Ansell. Phase 1 dose-escalation study of SGN-TGT monotherapy in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT265.