Signs Of Efficacy Research Articles

Abstract 4078: WTX-712, a conditionally active IL-21 INDUKINETM molecule, induces a strong anti-tumor phenotype through a differentiated mechanism

Abstract Despite great strides seen recently in the development of immunotherapies such as immune checkpoint inhibitors (ICI), many patients do not respond or acquire resistance, highlighting a need for alternative immunotherapies. As potent immunomodulators, cytokines have been explored as treatments for cancer, but their use has been limited due to toxicity and poor pharmacokinetics (PK). One of these key cytokines, interleukin 21 (IL-21), is a pluripotent cytokine that activates anti-tumor T cell responses, induces B cell activation, and promotes generation and maintenance of germinal centers and tertiary lymphoid structures. IL-21 acts on a broader range of cells and does not induce vascular leak syndrome compared to IL-2, another common-gamma chain family member. Half-life extended IL-21 (IL-21-HLE) drives robust anti-tumor activity in several syngeneic tumor mouse models. Of particular interest, IL-21-HLE showed superior anti-tumor activity compared to IL-2-HLE in the EMT-6 and Renca models, both of which are highly resistant to anti-PD-1/PD-L1 treatment. Although IL-21-HLE and IL-2-HLE induced a similar frequency of tumor infiltrating CD8+ T cells, IL-21-HLE treatment led to higher polyfunctionality in CD8+ T cells than IL-2-HLE treatment. Of note, IL-21-HLE induced greater amounts of effector cytokines, Granzyme B and perforin, than IL-2-HLE. Transcriptomic analysis revealed that IL-21 drives upregulation of a type I IFN signature in the tumor promoting an anti-tumorigenic microenvironment. Clinical activity of IL-21 has been hampered by poor PK and adverse events at dose levels associated with signs of efficacy. To overcome these limitations Werewolf Therapeutics has developed WTX-712, an IL-21 INDUKINETM molecule, which contains wild-type human IL-21, an inactivation domain, and a half-life extension domain tethered together by protease sensitive linkers. In preclinical studies with mouse syngeneic tumor models, WTX-712 is inactive in the periphery, and wild-type IL-21 is selectively released within the tumor, resulting in anti-tumor efficacy with an expanded therapeutic window compared to IL-21-HLE. Anti-tumor efficacy was linked to expansion and activation of tumor infiltrating CD8 T cells with increased polyfunctionality. We will show additional mechanistic data evaluating the effect of WTX-712 dosing on immune populations, including tumor spatial profiling using different models. Citation Format: Jenna M. Sullivan, Pamela A. Aderhold, Heather R. Brodkin, Celesztina Nagy-Domonkos, Kyriakos Economides, Daniel J. Hicklin, Nesreen Ismail, Yuka Lewis, Cynthia Seidel-Dugan, William M. Winston, Andres Salmeron. WTX-712, a conditionally active IL-21 INDUKINETM molecule, induces a strong anti-tumor phenotype through a differentiated mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4078.

A phase II clinical trial of toripalimab combined with neoadjuvant chemoradiotherapy in locally advanced esophageal squamous cell carcinoma (NEOCRTEC1901)

To evaluate the efficacy and safety of toripalimab combined with neoadjuvant chemoradiotherapy (NCRT) for locally advanced esophageal squamous cell carcinoma (ESCC). In this single arm, phase II trial, 44 ESCC patients were enrolled from December 2019 to July 2021at Sun Yat-sen University Cancer Center (Guangzhou, China). All patients received concurrent radiotherapy (44Gy in 20 fractions), chemotherapy (paclitaxel 50mg/m2 and cisplatin 25mg/m2 on days 1, 8, 15, and 22), and toripalimab (240mg on days 1 and 22). Within 6-8 weeks of neoadjuvant treatment, patients underwent surgery. The results of the study patients were compared with those of 86 matched patients between July 2015 and March 2022. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoints were treatment-related adverse events and R0 rates. This trail was registered with ClinicalTrails.gov, NCT04006041. All patients received neoadjuvant treatment, and 42 completed esophagectomy. Of the 42 patients, 21 (50%; 95% CI 35-65) achieved pCR and 2 (5%) patients were ypT0N+. The R0 resection rate was 98% (41/42). Nine (20%) of 44 patients had grade 3/4 adverse events. Among the perioperative complications (n=42), anastomotic leakage occurred in five cases (12%), tracheal fistula in three cases (7%), and postoperative death in one case (2%) due to tracheal fistula. Compared with the control cohort, the pCR rate of the study group was higher but without significant difference (50% vs. 36%, P=0.19). Toripalimab combined with NCRT failed to show significantly better pCR rate than historical data. Nevertheless, considering the signs of efficacy and acceptable safety of this regimen, further evaluation in phase III randomized trials might be warranted. National Natural Science Foundation of China.

Safety and efficacy of Sleeping Beauty TCR-T cells targeting shared KRAS and TP53 mutations expressed by solid tumors in first-in-human phase 1 study.

2547 Background: Solid tumors present driver mutations in KRAS, TP53, and EGFR genes on their surface in the context of human leukocyte antigen (HLA) molecules to T-cell receptors (TCRs) expressed by T cells. Non-viral genetic engineering of patient T cells with the Sleeping Beauty transposon/transposase system can generate driver mutation-reactive TCR-T cells. Methods: This is a first-in-human phase 1/2 study of autologous Sleeping Beauty TCR-T cell therapy for patients with non-small cell lung (NSCLC), colorectal, endometrial, pancreatic, ovarian and bile duct cancer whose tumors contain at least one of the targeted driver mutations in KRAS, TP53, and EGFR. The primary objective of the phase 1 portion is to define the incidence of dose-limiting toxicities (DLTs) and the maximum tolerated dose or recommended phase 2 dose to be explored in disease specific cohorts during phase 2. Dose levels of 0.1-1 x 1010 (DL1), 1-7 x 1010 (DL2) or 7-15 x 1010 (DL3) TCR-T cells are being explored. Any of the six tumor types or 12 TCRs within the library can be used for the Phase 1 portion of the trial. Results: As of February 14, 2023, three patients have been treated with Sleeping Beauty TCR-T cells on this study. The first was a 34 year old female with stage IV mucinous adenocarcinoma NSCLC refractory to chemotherapy and immunotherapy who received DL1 (0.9 x 1010 TCR-T cells) targeting KRASG12D and HLA-A*11:01, second was a 54 year old female with stage IVA chemotherapy resistant colorectal cancer who received DL2 (6.4 x 1010 TCR-T cells) targeting p53R175H and HLA-A*02:01 and the third was a 60 year old male with stage IV pancreatic cancer refractory to chemotherapy who received DL2 (5.8 x 1010 TCR-T cells) targeting KRASG12V and HLA-A*11:01. Overall, a manageable safety profile with no unexpected adverse events, DLTs or immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. Patients 1, 2 and 3 had cytokine release syndrome grades 2, 3 and 1, respectively, that were self-limiting or resolved with standard management and anti-IL-6 antibody in the case of Patient 2. Best overall responses were partial response for Patient 1 with six month progression-free survival, stable disease for Patient 2 and progressive disease for Patient 3. Persistence of TCR-T cells was observed in all patients at last follow-up and out to 6 months in the case of Patient 1. Acceleration to DL3 is under consideration based on a continued manageable safety profile. Conclusions: This is the first-in-human experience administering Sleeping Beauty TCR-T cells. Signs of efficacy, safety and persistence of TCR-T cells was observed. Thus, this treatment has promise for patients with solid tumors expressing shared mutations in driver genes. The trial is actively enrolling new patients and treating at one of the two highest dose levels. Clinical trial information: NCT05194735 .

Neoadjuvant checkpoint inhibitor immunotherapy for resectable mucosal melanoma.

Neoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in patients with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting. We hypothesize that neoadjuvant CPI is a safe and feasible approach for patients with resectable MM. Under an institutionally approved protocol, we identified adult MM patients with resectable disease who received neoadjuvant anti-PD1 +/- anti-CTLA4 between 2015 to 2019 at our institution. Clinical information include age, gender, presence of nodal involvement or satellitosis, functional status, pre-treatment LDH, tumor mutation status, and treatment data was collected. Outcomes include event free survival (EFS), overall survival (OS), objective response rate (ORR), pathologic response rate (PRR), and grade ≥3 toxicities. We identified 36 patients. Median age was 62; 58% were female. Seventy-eight percent of patients received anti-PD1 + anti-CTLA4. Node positive disease or satellite lesions was present at the time of treatment initiation in 47% of patients. Primary sites of disease were anorectal (53%), urogenital (25%), head and neck (17%), and esophageal (6%). A minority of patients did not undergo surgery due to complete response (n=3, 8%) and disease progression (n=6, 17%), respectively. With a median follow up of 37.9 months, the median EFS was 9.2 months with 3-year EFS rate of 29%. Median OS had not been reached and 3-year OS rate was 55%. ORR was 47% and PRR was 35%. EFS was significantly higher for patients with objective response and for patients with pathologic response. OS was significantly higher for patients with pathologic response. Grade 3 toxicities were reported in 39% of patients. Neoadjuvant CPI for resectable MM is a feasible approach with signs of efficacy and an acceptable safety profile. As there is currently no standard approach for resectable MM, this study supports further investigations using neoadjuvant therapy for these patients.

801P Neoadjuvant checkpoint inhibitor immunotherapy (IMT) for resectable mucosal melanoma (MM)

Neoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients (pts) with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in pts with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting. We hypothesize that neoadjuvant CPI is a safe and feasible approach for pts with resectable MM. Under an institutionally approved research protocol, we identified adult MM pts with resectable disease who received neoadjuvant anti-PD1 +/- anti-CTLA4 between 2015 to 2019 at our institution. Clinical information include age, gender, presence of nodal involvement or satellitosis, functional status, pre-treatment LDH, tumor mutation status, and treatment data was collected. Outcomes include event free survival (EFS), overall survival (OS), objective response rate (ORR), pathologic response rate (PRR), and grade ≥3 toxicities were assessed. We identified 36 pts. Median age was 62; 58% were female. 78% of pts got anti-PD1 + anti-CTLA4. Node-positive disease or satellite lesions was present in 47% of pts. Primary sites of disease were anorectal (53%), urogenital (25%), head and neck (17%), and esophageal (6%). A minority of pts did not undergo surgery due to complete response (n=3, 8%) and disease progression (n=6, 17%), respectively. With a median follow up of 37.9 months, the median EFS was 9.2mo with 3-year EFS rate of 29%. Median OS had not been reached and 3-year OS rate was 55%. ORR was 47% and PRR was 35%. EFS was significantly higher for pts with objective response and for pts with pathologic response. OS was significantly higher for pts with pathologic response. Grade 3 toxicities were reported in 39% of pts. Neoadjuvant CPI for resectable MM is a feasible approach with signs of efficacy and an acceptable safety profile. As there is currently no standard approach for resectable MM, this study supports further investigations using neoadjuvant therapy for these pts.

EP08.01-015 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Anti-oxMIF Antibody ON203 in Malignant Solid Tumors

Macrophage migration inhibitory factor (MIF) is often described as a pleiotropic cytokine whose overexpression is associated with tumor aggressiveness, metastases, and poor prognoses. Due to its ubiquitous nature, MIF is considered an unsuitable target for therapeutic intervention. However, presence of a disease-related isoform of MIF, oxidized MIF (oxMIF), has been specifically found in tumor tissue, including tissue from patients with non-small cell lung cancer (NSCLC). A first-generation anti-oxMIF monoclonal antibody (mAb) was able to demonstrate an acceptable safety profile and signs of efficacy in a Phase 1 clinical trial in patients with malignant solid tumors, seven of which were patients with NSCLC.

A phase II/III, randomized, open-label, multicenter study of BI 907828 compared to doxorubicin in the first-line treatment of patients with advanced dedifferentiated liposarcoma (DDLPS): Brightline-1.

TPS11586 Background: The standard of care in the first-line treatment of patients (pts) with unresectable/metastatic DDLPS is doxorubicin, despite only moderate efficacy and many associated adverse events (AEs). BI 907828 is a mouse double minute 2 (MDM2)–p53 antagonist that binds to MDM2 and blocks its interaction with p53, leading to p53 stabilization, TP53 target gene induction, cell-cycle arrest and apoptosis in TP53 wild-type tumor cells. In a Phase I study, BI 907828 monotherapy demonstrated a manageable safety profile and preliminary signs of efficacy, particularly in pts with DDLPS (Gounder et al, ESMO 2021). Methods: NCT05218499 is a Phase II/III, randomized, open-label, international, multicenter study (̃125 sites) that aims to evaluate whether BI 907828 is superior to doxorubicin in the first-line treatment of advanced/metastatic DDLPS. In the Phase II part, ≤180 pts will be randomized 1:1:1 to receive BI 907828 30 mg or 45 mg orally every 3 weeks (q3w), or doxorubicin 75 mg/m2 intravenously q3w to a maximum cumulative dose of 450 mg/m2. Main inclusion criteria include: ≥18 years of age; histologically proven advanced/metastatic, unresectable DDLPS; positive MDM2 immunohistochemistry or amplification; ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. Exclusion criteria include a known TP53 gene mutation and prior systemic therapy for liposarcoma. In the experimental arm, treatment will continue until disease progression, unacceptable AEs, or consent withdrawal. Pts who receive doxorubicin may cross-over to receive BI 907828 after confirmed progressive disease. The primary endpoint is progression-free survival (PFS; based on blinded independent central review), defined as the time from randomization to tumor progression (RECIST v1.1) or death from any cause, whichever occurs first. Secondary endpoints are objective response (OR), duration of OR, overall survival, disease control, and pt-reported health-related quality of life. In Phase II, an interim analysis (based on the totality of safety and PK/PD data) will be used to select the optimal BI 907828 dose. Subsequently, an interim futility analysis will be performed after ̃56 PFS events using a log-rank test stratified by the extent of disease (locally advanced vs metastatic). If the selected BI 907828 dose passes the futility boundary, the trial will proceed to Phase III. In the Phase III part, ≥120 additional pts will be randomized 1:1 to receive the selected BI 907828 dose or doxorubicin. The primary PFS analysis will be performed after ̃92 and ̃65 PFS events in pts enrolled before and after the interim futility analysis, respectively, using a weighted inverse normal method combining one-sided p-values from a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05218499.

Abstract P1-18-34: Solti-1507 IPATHER - A phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with pertuzumab and trastuzumab (HP) in patients with HER2-positive (HER2+) advanced breast cancer (ABC) and a PIK3CA mutation (mut): Results from the first safety cohort

Abstract Background The combination of HP and a taxane increases progression-free survival (PFS) and overall survival (OS) in patients with HER2+ ABC. PIK3CA mut can occur in 30-35% of HER2+ tumors, independently of hormone receptor (HR) status. In an exploratory analysis from CLEOPATRA, patients with a tumor harboring a PIK3CA mut had a shorter PFS. The AKT inhibitor IPAT blocks the PI3K/AKT pathway and has activity in PI3K/AKT-altered tumors. Patients and Methods IPATHER (NCT04253561) is an open-label, single-arm, phase Ib study to evaluate the safety and preliminary efficacy of IPAT plus HP in patients with HER2+ ABC with a PIK3CA-mut (detected in tissue or plasma ctDNA in a Central Laboratory) who are candidates to receive maintenance HP after taxane discontinuation in the first line setting for a reason different to progressive disease. The primary objective is to characterize the safety and tolerability of IPAT in combination with HP, and to identify a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The study has two phases: a dose safety phase and a dose expansion phase. MTD is defined as the highest dose level at which ≤1 of 6 subjects experience a dose-limiting toxicity (DLT) during the first 28 days of treatment. DLT during first 28 days of therapy is defined as grade ≥3 diarrhea lasting more than 72 hours, grade ≥2 diarrhea lasting more than 5 days, and other non-hematologic or hematologic toxicities that are ≥ grade 3 and probably or definitely related to study therapy. Given the low risk for overlapping toxicities, the first cohort of the dose safety phase tested IPAT at 400 mg orally once daily D1-21 q28d and standard dose HP. Dose level -1 and -2 of IPAT were 300 mg and 200 mg in case dose de-escalation was needed. Loperamide was given as prophylaxis for diarrhea. In HR-positive tumors, endocrine therapy could be started after the DLT period. Here, we present the results of the dose safety phase of IPATHER. Results A total of 6 female patients with PI3KCA-mut/HER2+ ABC were included in the first dose safety cohort. Median age was 52 (41-78), most patients had ECOG 0 (66.6%), and 50% were postmenopausal. Five out of six patients (83.3%) had HR-negative tumors and visceral metastases. Patients received a median of 6 treatment cycles (range 4-7) with taxane plus HP. At the time of the data cut-off (28/02/2021), all the patients remained on treatment. Median follow up is 4 months (range 2-12). Treatment was well tolerated with no DLTs or grade 3/4 adverse events (AEs) observed during the DLT period or the rest of treatment period (Table 1). The most common treatment-related AEs were diarrhea (N=5, [83.3%]) and nausea (N=2,[33.3%]), mostly grade 1. There was no dose reduction and diarrhea was controlled with prophylactic loperamide. A partial response (PR) was observed in one patient, and 5 had stable disease. Of note, the addition of IPAT to HP in the patient with a PR deepened the response achieved during the induction phase with chemotherapy plus HP. Conclusion IPAT 400 mg orally once daily D1-21 q28d in combination with HP is well tolerated and has shown preliminary signs of efficacy. Given the favourable safety profile, the dose expansion phase testing IPAT 400 mg in combination with HP has started and will include 19 additional patients. Table 1.Adverse Events during treatment period related with study treatment (IPAT and/or HP).Adverse EventN AEsN patientsGrade 1Grade 2% (N=6)Diarrhea55 (83%)5083%Nausea32 (33%)2033Vomiting21 (17%)1017Anemia11 (17%)1033Lymphopenia11 (17%)1033Gastroesophageal reflux11 (17%)0117Dyspepsia11 (17%)1017Hyporexia11 (17%)1017 Citation Format: Mafalda Oliveira, Eva Ciruelos, Serafín Morales, Joaquín Gavilá, Vanesa Quiroga, Estela Vega, Javier Salvador Bofill, Alexandra Cortegoso, Fernando Henao, Pablo Tolosa, Jordi Canes, Patricia Villagrasa, Xavier Gonzalez Farré, Tomás Pascual, Cristina Saura. Solti-1507 IPATHER - A phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with pertuzumab and trastuzumab (HP) in patients with HER2-positive (HER2+) advanced breast cancer (ABC) and a PIK3CA mutation (mut): Results from the first safety cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-34.

Abstract 57: First-in-human CAR T targets MUC1 transmembrane cleavage product

Abstract Purpose: To develop a MUC1-targeted CAR T that recognizes the growth factor receptor form, MUC1*, does not bind full-length MUC1, hits a wide range of solid tumor cancers, binds to little or no normal tissues, and effectively kills tumor cells. Methods: Because MUC1 is expressed on normal epithelial tissues, we needed to develop an antibody that would only bind to the aberrant, cancerous form - MUC1*. MUC1* (muk1 star) is the transmembrane portion that remains after MUC1 is enzymatically cleaved and the bulky tandem repeat domain is shed from the cell surface. MUC1* is a growth factor receptor that is activated by ligand-induced dimerization of its truncated extracellular domain. Via a novel screen we identified antibodies that bind to a specific conformation within the ectopic epitope that is created when MUC1 is cleaved to MUC1* by enzymes secreted by the tumor microenvironment. This set of antibodies competitively inhibit the binding of onco-embryonic growth factor NME7AB to the cancerous form of MUC1*. We incorporated one of these cancer-specific antibodies into a CAR T. Results: huMNC2-CAR44 is in a 1st-in-human clinical trial [NCT04020575] for metastatic breast cancers, currently being performed at the Fred Hutchinson Cancer Research Center. Our IND-enabling studies showed that huMNC2-scFv bound robustly to 95% of breast cancer tissues, 83% ovarian cancers, 78% pancreatic cancers and 71% of lung cancer tissues, but showed little to no binding to normal tissues. In co-culture experiments, huMNC2-CAR44 T cells did not kill MUC1* negative cells, even if they expressed full-length MUC1, and the presence of MUC1* negative cells did not elicit a cytokine response from the CAR T cells. In vivo, huMNC2-CAR44 T cells inhibited or completely obliterated a variety of MUC1* positive solid tumors in NSG mice (n≥400). The human CD8+ huMNC2-CAR44 T cells expanded in animals as tumors shrunk, whereas the untransduced T cells did not. Clinical trial was slowed by COVID-19, as Seattle was the first hotbed of the virus. Thus far, there have been no serious adverse events attributed to the CAR T therapy. Even at the lowest dosage, patients have had robust CAR T cell expansion and have also had measurable signs of efficacy. Conclusions: MUC1* is the predominant form of MUC1 on cancerous tissues. Antibodies that bind to a specific conformation within the ectopic growth factor binding site in the MUC1* extra cellular domain are tumor selective. CAR T cells incorporating these antibodies are highly effective against solid tumors in animals. Robust staining of cancerous tissues and minimal to no staining of normal tissues predicts a large therapeutic window for huMNC2-CAR44 T cell dosing. Early patient responses appear to fulfill the predictions of the IND-enabling studies. We have now developed a cryopreservation formulation which enables shipping frozen product to additional clinical sites for bedside thaw and infusion. The trial is currently enrolling patients. Citation Format: Cynthia Bamdad, Andrew K. Stewart, Pengyu Huang, Benoit J. Smagghe, Scott T. Moe, Tyler E. Swanson, Thomas G. Jeon, Danica M. Page, Trevor J. Grant, Jennifer M. Specht. First-in-human CAR T targets MUC1 transmembrane cleavage product [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 57.

A Phase 1-2 Dose-Escalation and Cohort- Expansion Study of eFT508, a Selective, Orally Bioavailable Inhibitor of MNK1 and MNK2, in Patients with Hematological Malignancies

IntroductionDysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple hematological and solid tumors. eFT508, a potent and highly selective small molecule inhibitor of MNK-1 and 2, blocks activation of eIF4E, a key regulator of mRNA translation, and thereby selectively regulates translation of a small set of mRNAs. Significant anti-tumor activity has been observed in preclinical models of diffuse large B-cell lymphoma (DLBCL), particularly in tumor models that have a mutation in MyD88. In addition to direct antitumor activity, eFT508 triggers an anti- tumor immune response and enhances responses to checkpoint inhibitors in preclinical models.The current study is a first-in-human dose escalation and cohort expansion trial of eFT508 in patients with advanced hematological malignanciesMethodsUsing a 3+3 dose escalation schema, cohorts of 3-6 patients (pts) with performance status 0-1, adequate bone marrow, hepatic and renal function and advanced hematological tumors of mainly B cell origin were treated with eFT508 administered orally once daily at a starting dose of 300 mg. A study in pts with solid tumors had previously shown that a dose of 450 mg once daily was well tolerated and based on a pharmacodynamic assay was associated with a degree of target engagement sufficient for maximal efficacy in preclinical models. Efficacy evaluations were performed every 6 weeks.Results6 pts (4 male, 2 female, median age 65 years, range 32-79 years) were treated; 3 at 300 mg daily and 3 at 450 mg daily using an oral suspension of eFT508. 3 pts had DLBCL, 1 had Waldenström macroglobulinemia (WM), 1 had Hodgkin lymphoma (HL) and 1 had follicular lymphoma (FL). The mean number of prior therapies was 4 (range 2-7). Two patients had relapsed after autologous stem cell transplant.The most common adverse events occurring in ≥ 2 pts irrespective of causality, were Grade 1 or 2 unless specified. These included fatigue (n=5), constipation (n=3), hypercalcemia (n=3 with 2 patients experiencing grade 3 toxicity), gastroesophageal reflux (n=2), nausea (n=2) and upper respiratory tract infection (n=2). One of the cases of grade 3 hypercalcemia, felt to be possibly drug related in a patient treated at 450 mg, resolved after a single infusion of zoledronateIn 6 pts evaluated for PK, eFT508 was bioavailable and rapidly absorbed, with a median Tmax of 3 hours and a mean T1/2 of 9.7 hours. Minimal accumulation was observed between Days 1 and 15 in 4 evaluable pts, with a mean accumulation factor of 1.3-fold determined for AUC0-24. Target engagement is being assessed with a pharmacodynamic assay measuring P-eIF4E in peripheral blood cells. In addition, a set of circulating cytokines (including IL-6, IL-8, IL-10, CXCL10 and TNFα) are being measured throughout treatment as MNK1/2 have been shown to regulate cytokine production.Preliminary signs of efficacy were observed with 3 of the 6 pts experiencing stable disease. These included a 32 year old patient with classical HL who had relapsed following multiple lines of chemotherapy, autologous transplant, brentuximab and immune checkpoint inhibition who was treated with 300 mg daily of eFT508. He experienced rapid resolution of B symptoms (fever and night sweats) and at a 6 week scan had a 30% reduction in measurable nodal disease. This nodal reduction was maintained at 12 weeks but a new bone lesion was observedA pt with WM treated at the 450 mg dose level had a reduction in M protein of 22% and remains on treatment for 102 daysA pt with rituximab refractory FL treated at 300 mg remains on treatment with stable disease (6% reduction in tumor volume) for 156 daysConclusionsPreliminary data suggest that eFT508 has acceptable safety and pharmacological activity at the tested dose levels. Dosing has now switched to a capsule formulation that will be used to determine a recommended phase 2 dose. Expansion cohorts for more formal evaluation of efficacy will follow. Updated results will be presented at the ASH meeting. DisclosuresGopal:Seattle Genetics: Consultancy, Research Funding. Ramchandren:Curis: Consultancy; Gilead Sciences: Consultancy; Seattle Genetics: Consultancy; Janssen: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Patel:Gilead: Speakers Bureau; Exelixis: Speakers Bureau; Medivation: Speakers Bureau; Genentech: Speakers Bureau; BMS: Speakers Bureau. Miller:Sunesis Pharmaceuticals, Inc: Consultancy; PRONAI Therapeutics, Inc: Consultancy, Equity Ownership; Presage Biosciences, Inc: Consultancy; FLX Bio, Inc: Consultancy; EpiThany, Inc: Consultancy, Equity Ownership; Acerta Pharma, LLC: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cleveland BioLabs, Inc: Employment, Equity Ownership; Oncternal Therapeutics, Inc: Consultancy, Equity Ownership; LAM Therapeutics, Inc: Consultancy, Equity Ownership; eFFECTOR Therapeutics, Inc: Consultancy, Equity Ownership; Zucero Pty Ltd: Consultancy. Goel:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Chiang:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Webster:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Sperry:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Vallner:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Casseday:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Barton:eFFECTOR THERAPEUTICS: Employment, Equity Ownership.

Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib.

Different target exposures with sunitinib have been proposed in metastatic renal cell carcinoma (mRCC) patients, such as trough concentrations or AUCs. However, most of the time, rather than therapeutic drug monitoring (TDM), clinical evidence is preferred to tailor dosing, i.e., by reducing the dose when treatment-related toxicities show, or increasing dosing if no signs of efficacy are observed. Here, we compared such empirical dose adjustment of sunitinib in mRCC patients, with the parallel dosing proposals of a PK/PD model with TDM support. In 31 evaluable patients treated with sunitinib, 53.8% had an empirical change in dosing after treatment started (i.e., 46.2% decrease in dosing, 7.6% increase in dosing). Clinical benefit was observed in 54.1% patients, including 8.3% with complete response. Overall, 58.1% of patients experienced treatment discontinuation eventually, either because of toxicities or progressive disease. When choosing 50–100 ng/mL trough concentrations as a target exposure (i.e., sunitinib + active metabolite N-desethyl sunitinib), 45% patients were adequately exposed. When considering 1200–2150 ng/mL.h as a target AUC (i.e., sunitinib + active metabolite N-desethyl sunitinib), only 26% patients were in the desired therapeutic window. TDM with retrospective PK/PD modeling would have suggested decreasing sunitinib dosing in a much larger number of patients as compared with empirical dose adjustment. Indeed, when using target trough concentrations, the model proposed reducing dosing for 61% patients, and up to 84% patients based upon target AUC. Conversely, the model proposed increasing dosing in 9.7% of patients when using target trough concentrations and in 6.5% patients when using target AUC. Overall, TDM with adaptive dosing would have led to tailoring sunitinib dosing in a larger number of patients (i.e., 53.8% vs. 71–91%, depending on the chosen metrics for target exposure) than a clinical-based decision. Interestingly, sunitinib dosing was empirically reduced in 41% patients who displayed early-onset severe toxicities, whereas model-based recommendations would have immediately proposed to reduce dosing in more than 80% of those patients. This observation suggests that early treatment-related toxicities could have been partly avoided using prospective PK/PD modeling with adaptive dosing. Conversely, the possible impact of model-based adapted dosing on efficacy could not be fully evaluated because no clear relationship was found between baseline exposure levels and sunitinib efficacy measured at 3 months.

Optimal dose selection in oncology biologics development: Need for a paradigm shift.

3093 Background: In oncology, the recommended phase 2 dose (RP2D) is typically selected from the first-in-patient (FIP) dose escalation and then carried forward to late stage trials. The RP2D is often informed by limited data from a relatively small number of patients. Further dose optimization in late stage trials is rare as these trials often evaluate only one dose/dosing regimen. Traditionally oncology development relied on establishing an MTD with the expectation this dose would ultimately provide an optimal benefit/risk profile. However, for biologics there are clear examples suggesting a need to reconsider this approach to dose selection during drug development. The present review attempts to evaluate the dose selection approaches for approved oncology biologics to identify opportunities for improved dose optimization of future oncology drugs. Methods: The dose selection steps for oncology biologics approved by the USFDA from 2010 to 2020 were reviewed. The primary focus of the review was RP2D selection based on early clinical data, doses tested in pivotal trials, exposure-response and dose justification for the proposed dose, and post-marketing requirements (PMR) or post-marketing commitments (PMC) related to dose optimization. Results: The dose selection process for a total of 22 biologics was analyzed. Among these, 17 (77%) did not identify MTD during the FIP trial, and 6 (27%) tested more than one dose in the registration trials. In the initial approval, 2 (10%) had PMR or PMC for further dose optimization. For majority of the biologics the dose justification was based on 1) receptor occupancy 2) biomarker response 3) early clinical activity and 4) target efficacious concentration based on xenograft data. The majority of biologics had shown a shallow exposure-response relationship in safety or efficacy end points which partly can be attributed to the common practice of testing single dose level in the registrational trial. The dose recommended in the FDA label appears to be highly correlated to the RP2D determined in FIP studies. Conclusions: Oncology biologics have heavily relied on pharmacodynamic, early signs of efficacy, and safety data from the limited number of patients in the FIP dose escalation to identify the dose for pivotal trials. In most cases, there have been no dose ranging or optimization based on the final therapeutic outcome. While integration of relevant biomarker, PK, and PD data for optimal dose selection is an important aspect, there is a need to change the paradigm to consider more robust dose optimization, especially in early stage development. Dose ranging assessments incorporating therapeutically relevant endpoints and adequate sample size should be considered, ideally prior to pivotal trials.

First Trial of a DARPin for Cancer Shows Promising Efficacy Signal

In a phase I trial, the DARPin MG0250 had an expected safety profile and early signs of efficacy.

A CD40 Agonistic Antibody Shows Signs of Efficacy in Pancreatic Cancer

Sotigalimab had manageable toxicity and an early efficacy signal in a phase Ib pancreatic cancer trial.

Oncolytic H-1 Parvovirus Enters Cancer Cells through Clathrin-Mediated Endocytosis.

H-1 protoparvovirus (H-1PV) is a self-propagating virus that is non-pathogenic in humans and has oncolytic and oncosuppressive activities. H-1PV is the first member of the Parvoviridae family to undergo clinical testing as an anticancer agent. Results from clinical trials in patients with glioblastoma or pancreatic carcinoma show that virus treatment is safe, well-tolerated and associated with first signs of efficacy. Characterisation of the H-1PV life cycle may help to improve its efficacy and clinical outcome. In this study, we investigated the entry route of H-1PV in cervical carcinoma HeLa and glioma NCH125 cell lines. Using electron and confocal microscopy, we detected H-1PV particles within clathrin-coated pits and vesicles, providing evidence that the virus uses clathrin-mediated endocytosis for cell entry. In agreement with these results, we found that blocking clathrin-mediated endocytosis using specific inhibitors or small interfering RNA-mediated knockdown of its key regulator, AP2M1, markedly reduced H-1PV entry. By contrast, we found no evidence of viral entry through caveolae-mediated endocytosis. We also show that H-1PV entry is dependent on dynamin, while viral trafficking occurs from early to late endosomes, with acidic pH necessary for a productive infection. This is the first study that characterises the cell entry pathways of oncolytic H-1PV.

Protocol of a prospective, multicentre phase I study to evaluate the safety, tolerability and preliminary efficacy of the bispecific PSMAxCD3 antibody CC-1 in patients with castration-resistant prostate carcinoma

IntroductionProstate cancer is the second most common cancer in men worldwide. When the disease becomes resistant to androgen-deprivation therapy, treatment options are sparse. To address the high medical need in...

Berzosertib Is Safe, with Signs of Efficacy against Advanced Solid Tumors

The ATR inhibitor berzosertib produced responses with or without the DNA-damaging agent carboplatin.

Abstract 3792: Imetelstat inhibits RNA-editing mediated myeloproliferative neoplasm stem cell self-renewal

Abstract Introduction: Myeloproliferative neoplasms (MPN) including blast crisis (BC) CML and myelofibrosis (MF) are characterized by the clonal proliferation of hematopoietic cell lineages, mostly in the marrow. BC CML gives rise to TKI resistant myeloid progenitors that activate Wnt/β-catenin signaling pathway. However, BCR-ABL TKI resistant BC CML exhibits a robust telomerase activity and presents at very low or undetectable level in normal cells, and telomerase plays a pivotal role in cancer cell growth and may serve as an ideal target for anticancer therapeutics. In addition, β-catenin had been reported to transcriptionally regulate human telomerase reverse transcriptase (TERT). Telomerase is composed of the enzymatic reverse transcriptase protein TERT and the RNA template TERC. Thus, we investigated the capacity of imetelstat, a telomerase inhibitor, which binds to the TERC subunit with high affinity to prevent self-renewal of malignant progenitors. Recent clinical trials showed early signs of efficacy in MF. But, it's role in selectively inhibiting leukemia stem cell (LSC) self-renewing in CML has not been elucidated. Methods and Results: Progenitors from BC CML were compared with chronic phase (CP) CML and primary normal samples, RNA-seq results revealed upregulation of TERT suggesting a role for TERT activation in BC CML progenitor transformation. Human MPN progenitor co-culture experiments revealed that combined treatment with dasatinib at 1 nM, and imetelstat at 1 or 5 uM significantly inhibited (p < 0.001, ANOVA) in vitro replating of BC CML compared with aged bone marrow progenitors. Also, imetelstat (5 mM) significantly reduced replating of MF compared with normal progenitor samples. Treatment of humanized MPN mouse models, established with 5 different BC CML and 4 different MF samples, at 30 mg/kg of imetelstat, three times a week for 4 weeks resulted in a significant reduction of malignant progenitors and human CD45+ cells (p < 0.001, t test) in BC CML, and a significant reduction of human CD45+ cells (p<0.01, t test) in MF in both marrow and spleen, when compared with vehicle controls. FACS analysis revealed a significant reduction of activated β-catenin protein in BC CML engrafted human progenitors after imetelstat treatment (p < 0.01, t test) compared with vehicle control. In addition, a significant inhibition of TERT (p = 0.03) and TERC (p = 0.02) was observed in BC CML LSC isolated from imetelstat treated mouse marrow when compared with vehicle control. Notably, imetelstat treatment spares normal human cells in humanized normal stem cell mouse models. Recent RNA-sequencing analysis showed an increase in ADAR1 expression during MPN progression, and our RNA-seq analysis demonstrated a decreased ADAR1 gene expression (p < 0.005) as well as overall adenosine to inosine editing rates as measured by edits per million reads (p <0.005) following imetelstat treatment of BC CML engrafted mice when compared to mismatch control. Conclusions: Niche responsive interactions between the telomerase complex and the Wnt/β-catenin self-renewal pathway sensitize β-catenin activated MPN progenitors to imetelstat treatment in both the in vitro co-culture and in vivo humanized MPN mouse models thereby providing a strong rationale for studies assessing eradication of malignant progenitors using imetelstat. Citation Format: Wenxue Ma, Larisa Balaian, Cayla Mason, Raymond Diep, Jessica Pham, Qingfei Jiang, Jeremy Lee, Sheldon Morris, Phoebe Mondala, Ping Chen, Thomas Whisenant, Mary Donohoe, Benjamin Heyman, Edward Ball, Fei Huang, Catriona Jamieson. Imetelstat inhibits RNA-editing mediated myeloproliferative neoplasm stem cell self-renewal [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3792.

Phase I, first-in-human study of AbGn-107, a novel antibody-drug conjugate (ADC), in patients with gastric, colorectal, pancreatic or biliary cancers.

e16771 Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in patients with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility included locally advanced or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). Dose limiting toxicities (DLT) were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 patients experienced Grade 3 or 4 neutropenia, all at higher dose levels, inc. 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs included grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. Based on safety profile and PK data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days). Six pts have demonstrated a minor response by RECIST (range, -1.3 to -21.1%); 4 pts (all PDA) have had durable dz control > 180 days. Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy in unselected pts with heavily pre-treated advanced GI cancers. Updated safety and efficacy data will be provided at the time of the meeting for the cohort expansion phase of this study (currently open across multiple sites in U.S. and Taiwan), in which subjects with G, CRC, PDA, and BIL cancers are pre-screened for high levels of AG-7 tumor expression. Clinical trial information: NCT02908451 .

The novel proautophagy anticancer drug ABTL0812 potentiates chemotherapy in adenocarcinoma and squamous nonsmall cell lung cancer.

Around 40% of newly diagnosed lung cancer patients are Stage IV, where the improvement of survival and reduction of disease-related adverse events is the main goal for oncologists. In this scenario, we present preclinical evidence supporting the use of ABTL0812 in combination with chemotherapy for treating advanced and metastatic Nonsmall cell lung adenocarcinomas (NSCLC) and squamous carcinomas. ABTL0812 is a new chemical entity, currently in Phase 1b/2a clinical trial for advanced squamous NSCLC in combination with paclitaxel and carboplatin (P/C), after successfully completing the first-in-human trial where it showed an excellent safety profile and signs of efficacy. We show here that ABTL0812 inhibits Akt/mTOR axis by inducing the overexpression of TRIB3 and activating autophagy in lung squamous carcinoma cell lines. Furthermore, treatment with ABTL0812 also induces AMPK activation and ROS accumulation. Moreover, combination of ABTL0812 with chemotherapy markedly increases the therapeutic effect of chemotherapy without increasing toxicity. We further show that combination of ABTL0812 and chemotherapy induces nonapoptotic cell death mediated by TRIB3 activation and autophagy induction. We also present preliminary clinical data indicating that TRIB3 could serve as a potential novel pharmacodynamic biomarker to monitor ABTL0812 activity administered alone or in combination with chemotherapy in squamous NSCLC patients. The safety profile of ABTL0812 and its good synergy with chemotherapy potentiate the therapeutic potential of current lines of treatment based on chemotherapy regimens, arising as a promising option for improving these patients therapeutic expectancy.