Evidence Of Clinical Activity Research Articles

Phase I studies of davoceticept (ALPN-202), a PD-L1-dependent CD28 co-stimulator and dual PD-L1/CTLA-4 inhibitor, as monotherapy and in combination with pembrolizumab in advanced solid tumors (NEON-1 and NEON-2)

BackgroundDavoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4...

Abstract PS12-09: Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated Phase 1b analysis from CAPItello-292

Abstract Background AKT pathway activation is implicated in endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance in patients (pts) with HR+/HER2– advanced breast cancer (ABC). In CAPItello-291, capivasertib (C, a potent inhibitor of all 3 AKT isoforms) + fulvestrant (F) significantly improved PFS versus placebo F in pts with aromatase inhibitor-resistant HR+/HER2– ABC. Simultaneous inhibition of AKT and CDK4/6 pathways may delay CDK4/6i resistance or re-sensitize tumors to ET plus CDK4/6i, leading to improved clinical outcomes. CAPItello-292 (NCT04862663) is an ongoing Phase 1b/3 study examining the efficacy and safety of C + CDK4/6i (palbociclib [P], ribociclib [R]) + F in HR+/HER2– ABC. The recommended Phase 3 dose (RP3D) of C+P+F has been determined (C 400 mg BID, 4 days on/3 days off, P 125 mg, F 500 mg). Here we report ongoing Phase 1b data on C+P+F and C+R+F. Methods: Phase 1b of CAPItello-292 uses a keyboard design (mTPI-2) with the following planned doses: C 200 mg, 320 mg, 400 mg; P 75 mg, 100 mg, 125 mg; R 200 mg, 400 mg, 600 mg; F is fixed at 500 mg every 28 days + loading dose on cycle 1 day 15. Starting doses for C+P+F were C 320 mg BID, 4 days on/3 days off, P 125 mg QD) for 21 days of each 28-day cycle. Starting doses for C+R+F (ongoing) are C 400 mg BID, 4 days on/3 days off, R 400 mg QD for 21 days of each 28-day cycle. Eligible pts have HR+/HER2− ABC and ≥1 prior ET in the advanced setting or disease recurrence within 12 months of completing (neo)adjuvant ET (HER2− defined as immunohistochemistry [IHC] 0, or 1-positive or IHC2-positive/in situ hybridization-negative). Prior use of CDK4/6i, selective estrogen receptor degraders, and chemotherapy is permitted in Phase 1b. Phase 1b primary objectives: assess safety/tolerability; confirm RP3D. Objective response and clinical benefit rates (24 weeks; RECIST v1.1) were also assessed. Results: At data cut-off (Apr 21, 2023), 40 pts (median age: 58.5 years [range 38–82]) who were heavily pre-treated (as follows: 82.5% [33/40] prior CDK4/6i; 47.5% [19/40] prior F; 70.0% [28/40] prior chemotherapy [median 1.5 lines]) were treated with C+P+F. No new dose-limiting toxicities (DLTs) were observed since determination of RP3D. The most frequent adverse events (AEs) occurring in >40% of pts were diarrhea (70.0% [28/40]; 1/28 grade [G] ≥3), neutropenia (55.0% [22/40]; 20/22 G≥3), fatigue, and nausea (both 42.5% [17/40]; all G1/2). Hyperglycemia occurred in 17.5% (7/40) pts (1/7 G3). No treatment-related deaths or new safety risks were identified. At the RP3D, the median (range) duration of exposure to C was 8.6 months (1.7–14.1); 5/8 pts with measurable disease at baseline had confirmed partial response (objective response rate: 62.5%, 95% confidence interval [CI] 24.5–91.5). Two additional pts had stable disease ≥7 weeks as a best objective response. At 24 weeks, the clinical benefit rate was 53.8% (7/13; 95% CI 25.1–80.8).Enrollment into C+R+F is ongoing: as of May 05, 2023, 8 pts had been dosed (6/8 pts had completed cycle 1). Based on clinical and safety review, the safety review committee has endorsed dose escalation to the highest dose level of R; no DLTs have been reported so far, although data are preliminary.Preliminary ctDNA analyses of pts treated with C+P/R+F will be presented. Conclusions: C+P+F was tolerable in heavily pre-treated pts with HR+/HER2– ABC at all dose levels; AEs were as expected, given the known safety profile of the individual treatments. Evidence of clinical activity has been observed in pts treated with the RP3D; data collection is ongoing. Preliminary safety analysis of C+R+F suggests no critical tolerability concerns; more pts and longer follow-up is required to characterize the safety of the combination. Updated data will be presented. Funding: AstraZeneca Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited) Citation Format: Erika Hamilton, Patrick Neven, Barbara Pistilli, Muralidhar Beeram, Virginia Borges, Mario Campone, José Luiz Miranda Guimarães, Theodoros Foukakis, Annette Raskov Kodahl, Peter Lau, Elgene Lim, Iwona Ługowska, Greg Rychlik, Christopher Gresty, Claire Miller, Roberto Sommavilla, Dhivya Sudhan, Hope Rugo. Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated Phase 1b analysis from CAPItello-292 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-09.

A phase 1, first-in-human, dose-escalation and expansion study of FX-909 in patients with advanced solid malignancies, including advanced urothelial carcinoma.

TPS709 Background: High Expression of Peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor-family transcription factor, drives the initiation and development of UC in luminal molecular subtype tumors. Genetic profiling of UC has identified recurrent oncogenic alterations in the PPARG transcriptional complex, including focal amplification, missense mutations, and fusions in the heterodimeric partner of PPARG, the retinoid X receptor alpha (RXRA). High levels of PPARG expression and recurrent oncogenic alterations are observed in other solid malignancies including colorectal, gastroesophageal, pancreatic and lung cancers. FX-909 is an oral, first-in-class, new molecular agent that specifically, potently, and covalently modifies PPARG to mediate basal and ligand-activated transcription. Treatment of genetically defined UC xenografts with FX-909 has shown an 84% tumor growth inhibition (TGI) at a dose expected to be equivalent to 50 mg dose in humans, which is the starting dose in this clinical study. Methods: FX-909-CLINPRO-1 (NCT05929235) is a first-in-human, multicenter, open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FX-909 given orally in patients with advanced solid malignancies. Patients enrolled in the trial must have ECOG performance status ≤2 and must be ≥ 18 years of age. Initially, FX-909 will be given once daily to patients with any advanced solid malignancy in a dose-escalation phase (Part A) utilizing a 3+3 design. Five dose cohorts of 3 to 6 patients are planned. At the time of submission, three patients are enrolled in Part A- cohort one, 50mg. Additional patients will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or evidence of clinical activity. Once a RP2D has been determined, a monotherapy expansion phase (Part B) will proceed in a Simon 2-stage design in patients with locally advanced (unresectable) or metastatic UC with measurable disease and tumors harboring defined genetic alterations in PPARG, RXRA and FGFR3 (Motley et al, 2022). In stage 1, up to 19 evaluable patients will be enrolled. If ≥4 objective responses are observed, enrollment will continue into Stage 2 with an additional 14 evaluable patients. One treatment cycle is 28 days. Dose expansion will evaluate the safety, PK/PD profile, and antitumor activity of FX-909 at the RP2D. Exploratory objectives include the evaluation patient selection biomarkers from tissue and blood samples. FX-909 clinical activity will be assessed using RECIST v1.1 criteria. The study is currently enrolling patients in the US. Clinical trial information: NCT05929235 .

Abstract B005: A phase 1 expansion cohort study evaluating the safety and efficacy of the CHK1 inhibitor LY2880070 with low-dose gemcitabine in metastatic pancreatic adenocarcinoma

Abstract Background: Combining gemcitabine with CHK1 inhibition has shown promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we report the findings from a phase I expansion cohort study (NCT02632448) investigating low-dose gemcitabine combined with the CHK1 inhibitor LY2880070 in patients with previously treated advanced PDAC. Methods: Patients with metastatic PDAC were treated with gemcitabine intravenously at 100 mg/m2 on days 1, 8, and 15, and LY2880070 50 mg orally twice daily on days 2–6, 9–13, and 16–20 of each 21-day cycle. Pre-treatment tumor biopsies were obtained from each patient for correlative studies and generation of organoid cultures for drug sensitivity testing and biomarker analyses. Results: Eleven patients with PDAC were enrolled in the expansion cohort between August 27, 2020 and July 30, 2021. Four patients (36%) experienced drug-related grade 3 adverse events. No objective radiological responses were observed, and all patients discontinued the trial by 3.2 months. In contrast to the lack of efficacy observed in patients, organoid cultures derived from biopsies procured from two patients demonstrated strong sensitivity to the gemcitabine/LY2880070 combination and showed treatment-induced upregulation of replication stress and DNA damage biomarkers, including pKAP1, pRPA32, and gamma-H2AX, as well as induction of replication fork instability. Conclusions: No evidence of clinical activity was observed for combined low dose gemcitabine and LY2880070 in this treatment refractory PDAC cohort. However, the gemcitabine/LY2880070 combination showed in vitro efficacy, suggesting that drug sensitivity for this combination in organoid cultures may not predict clinical benefit in patients. Citation Format: Brandon M. Huffman, Hanrong Feng, Kalindi Parmar, Junning Wang, Kevin Kapner, Bose Kochupurakkal, David Martignetti, Thomas Abrams, Leah Biller, Marios Giannakis, Kimmie Ng, Anuj Patel, Kimberly Perez, Harshabad Singh, Douglas Rubinson, Benjamin Schlechter, Elizabeth Andrews, Alison Hannigan, Stanley Dunwell, Zoe Getchell, Srivatsan Raghavan, Brian Wolpin, Alan D'Andrea, Andrew Aguirre, Geoffrey Shapiro, James Cleary. A phase 1 expansion cohort study evaluating the safety and efficacy of the CHK1 inhibitor LY2880070 with low-dose gemcitabine in metastatic pancreatic adenocarcinoma [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 B005.

Zinpentraxin Alfa Reduces Myelofibrosis in a JAK2-V617F Mouse Model of Myeloproliferative Neoplasms

Background: Myeloproliferative neoplasms (MPNs) are clonal disorders of the hematopoietic stem cell (HSC), caused by somatic mutations in JAK2, MPL or CALR . Myelofibrosis, characterized by increased deposition of reticulin and/or collagen fibers, is found in advanced stages of MPN. Pentraxin-2 (PTX2, serum amyloid P component/SAP) belongs to the family of short pentraxins and acts as an inhibitor of fibrocyte differentiation and modulator of macrophage polarization. Zinpentraxin alfa (PRM-151, ZPN), a recombinant form of human PTX2, was reported to reduce myelofibrosis in a retroviral model of MPN driven by MPL-W515L (Verstovsek S et al, J Exp Med 2016). ZPN has also been investigated as monotherapy and in combination with ruxolitinib (RUX) in a phase 2 clinical study in patients with myelofibrosis (NCT01981850; Verstovsek S et al, Haematologica 2023). Evidence of clinical activity and tolerable safety as monotherapy and in combination with RUX was shown in that open-label, non-randomized trial. Here, we examined the effects of ZPN alone or in combination with RUX in a mouse model of MPN driven by Cre-inducible expression of human JAK2-V617F (Tiedt R et al, Blood 2008). Methods: To obtain sufficient numbers of mice for drug testing, bone marrow cells from JAK2-V617F mice were transplanted into lethally irradiated C57BL/6 recipients (Kubovcakova L et al., Blood 2013), and groups of 6 mice were sacrificed at 16, 20, and 24 weeks to determine the histological grade of reticulin fibrosis. 24 weeks post transplantation, grade 1-2 fibrosis was confirmed in these satellite mice and treatment was initiated. During treatment, weight and complete blood counts were monitored (n=8 mice per group). At terminal work-up, spleen weight and fibrosis grade were determined, along with flow cytometry of bone marrow and peripheral blood, single cell RNA sequencing of bulk bone marrow, and proteomics analysis by mass spectrometry of bone marrow and plasma. Additionally, we characterized the plasma pharmacokinetics (PK) in these mice following single IP (10 mg/kg) administration of ZPN. Results: Systemic exposure after IP administration was confirmed in each animal (T max at 4 h, C max 27.9 ug/mL,AUC 0-48 381 h*ug/mL). No weight loss or mortality were observed in ZPN monotherapy cohorts, and the slight weight loss observed in RUX treated animals was not potentiated by the addition of ZPN. A trend towards lower platelet, monocyte and total leukocyte counts was observed for ZPN treatment groups compared to vehicle controls (Figure 1A). RUX alone largely normalized hemoglobin values, while ZPN alone or in combination with RUX had less effect on hemoglobin. Terminal work-up showed grade 1-2 fibrosis in the vehicle group, whereas reticulin fibrosis decreased in the majority of mice with ZPN monotherapy or in combination with RUX (Figure 1B). ZPN monotherapy did not reduce spleen weight. Single cell RNA sequencing and proteomics analyses are currently being analyzed and data will be shown. Conclusion: ZPN treatment in a JAK2-V617F mouse model of MPN with myelofibrosis was well tolerated as monotherapy and in combination with RUX. A reduction in the grade of myelofibrosis was observed in all ZPN treatment groups. ZPN showed promising trends in reducing platelet and monocyte counts, while the decrease in hemoglobin by RUX was in part prevented in combination with ZPN.

Trial in Progress: Phase 1 Trial Evaluating the Safety and Tolerability of Odronextamab in Combination with Cemiplimab in Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Background and Significance CD20×CD3 bispecific antibodies (bsAbs) have emerged as an important immunotherapeutic approach for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). These agents have shown compelling efficacy in indolent B-NHL, with the CD20×CD3 bsAb odronextamab demonstrating 75% complete response (CR) rates and encouraging durability of responses (median duration of response [DoR], 20.5 months) in heavily pretreated patients with R/R follicular lymphoma in the ELM-2 study (Kim TM, et al. ASH. 2022). In comparison, patients with R/R diffuse large B-cell lymphoma who were treated with odronextamab in the same study demonstrated a CR rate of 31%, and median DoR was 10.2 months (Kim WS, et al. ASH. 2022). These data indicate an unmet need for treatment strategies that can improve the depth and durability of responses in patients with aggressive R/R B-NHL. Combination therapy with drugs that complement the mechanism of action of CD20×CD3 bsAbs may provide an opportunity to address this unmet need. Cemiplimab is a human immunoglobulin G4 (IgG4) monoclonal antibody directed against programmed cell death protein 1 (PD-1), blocking PD-1- and programmed cell death ligand 1 (PD-L1)-driven inhibitory T-cell signaling. Combining odronextamab and cemiplimab provides an attractive therapeutic opportunity to improve anti-tumor efficacy while restricting T-cell exhaustion, and preliminary results for this combination provided proof of concept, with evidence of clinical activity and manageable tolerability in patients with B-lymphoid malignancies (n=12; Topp MS, et al. ASH. 2017). Here, we investigate whether the addition of cemiplimab to odronextamab can improve the depth and durability of response in patients with previously treated aggressive B-NHL. Study Design and Methods This is a Phase 1, open-label, multicenter, dose-escalation and -expansion study that will take place at up to 28 sites globally (NCT02651662). Intravenous (IV) odronextamab is administered in 21-day cycles, initially as monotherapy and with step-up dosing during Cycle (C) 1 to mitigate the risk of cytokine release syndrome (Figure). Full-dose odronextamab is administered on Day (D) 1, D8 and D15 of C2-C4, and then on D15 of each cycle during maintenance (C5 onwards) until disease progression or treatment discontinuation. IV cemiplimab starts on C2D15 at the specified dose level (DL1-DL7) and is administered on D15 of subsequent cycles. The dose-limiting toxicity (DLT) period is 28 days from the start of cemiplimab administration. At the end of dose escalation, a regimen will be selected for further investigation in dose expansion. Approximately 60 patients will be enrolled. Patients will be aged ≥18 years with aggressive CD20+ B-NHL that is R/R after ≥2 lines of systemic therapy containing an anti-CD20 antibody and an alkylating agent. Patients must have measurable disease, Eastern Cooperative Oncology Group performance score (ECOG PS) ≤1, and adequate bone marrow and organ function. Exclusion criteria include primary central nervous system lymphoma, prior allogeneic stem cell transplantation, autoimmune disease, prior adverse events from anti-PD-1/PD-L1 therapy, and uncontrolled infections. Primary endpoints are safety, tolerability, DLTs, and to determine the recommended Phase 2 dose of the combination regimen of odronextamab and cemiplimab. Secondary endpoints include pharmacokinetics, immunogenicity, and preliminary anti-tumor activity (overall response rate, CR rate, and DoR, according to the Lugano classification). There are no formal hypotheses for this study and analyses will be descriptive in nature.

A Phase I Expansion Cohort Study Evaluating the Safety and Efficacy of the CHK1 Inhibitor LY2880070 with Low-dose Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma.

Combining gemcitabine with CHK1 inhibition has shown promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we report the findings from a phase I expansion cohort study (NCT02632448) investigating low-dose gemcitabine combined with the CHK1 inhibitor LY2880070 in patients with previously treated advanced PDAC. Patients with metastatic PDAC were treated with gemcitabine intravenously at 100 mg/m2 on days 1, 8, and 15, and LY2880070 50 mg orally twice daily on days 2-6, 9-13, and 16-20 of each 21-day cycle. Pretreatment tumor biopsies were obtained from each patient for correlative studies and generation of organoid cultures for drug sensitivity testing and biomarker analyses. Eleven patients with PDAC were enrolled in the expansion cohort between August 27, 2020 and July 30, 2021. Four patients (36%) experienced drug-related grade 3 adverse events. No objective radiologic responses were observed, and all patients discontinued the trial by 3.2 months. In contrast to the lack of efficacy observed in patients, organoid cultures derived from biopsies procured from two patients demonstrated strong sensitivity to the gemcitabine/LY2880070 combination and showed treatment-induced upregulation of replication stress and DNA damage biomarkers, including pKAP1, pRPA32, and γH2AX, as well as induction of replication fork instability. No evidence of clinical activity was observed for combined low-dose gemcitabine and LY2880070 in this treatment-refractory PDAC cohort. However, the gemcitabine/LY2880070 combination showed in vitro efficacy, suggesting that drug sensitivity for this combination in organoid cultures may not predict clinical benefit in patients.

Circulating and intratumoral immune determinants of response to atezolizumab plus bevacizumab in patients with variant histology or sarcomatoid renal cell carcinoma

Abstract Background Renal cell carcinoma of variant histology (vRCC) encompasses approximately 20% of RCC diagnoses. Due to a poor understanding of the different biologies of vRCCs, there is currently no standard of care for this type of tumor and guidelines are extrapolated from clear-cell RCC trials. A phase II trial of atezolizumab plus bevacizumab in patients with vRCC or sarcomatoid differentiation had an acceptable safety profile and evidence of clinical activity, particularly in tumors with positive PD-L1 expression or sarcomatoid differentiation. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with vRCC, or any RCC histology with sarcomatoid differentiation, enrolled in this phase II trial of atezolizumab and bevacizumab. Methods We used patient data and biospecimens (blood and tumor) from a prospective phase-II clinical trial of the anti-PD-L1 antibody atezolizumab and the anti-VEGF-A antibody bevacizumab in patients with metastatic RCC with variant histology and/or sarcomatoid differentiation (NCT02724878). Blood samples were collected at baseline, prior to therapy (C1D1: cycle one day one), and on-treatment, following two cycles of therapy (C3D1: cycle three day one). Plasma was assayed for the levels of soluble factors (e.g., cytokines and growth factors), and peripheral blood mononuclear cells (PBMCs) were immunophenotyped using flow cytometry. In addition, formalin-fixed, paraffin-embedded (FFPE) archival or pre-treatment study tumor biopsies were analyzed by immunohistochemistry and immunofluorescence for enrolled subjects with available biospecimen. Baseline demographics, clinical characteristics, and treatment outcomes, including progression-free survival (PFS), overall survival (OS), and clinical benefit, were collected, and analyzed from the trial database. This study was approved by each participating institution's institutional review board, and all patients provided written informed consent. We used R (version 4.1.1) to carry out our analyses. We assessed the relationships between biomarker variables were analyzed using Pearson correlations and hierarchical clustering using Euclidean distance. All biomarker variables were Z-score normalized. We calculated an inflammatory module, the systemic inflammation score (SIS), which corresponds to the average score of the five highly correlated inflammatory cytokines: MIP-1b, IL-1, MCP-1, IL-6, and IL-13. We applied pair-wise Wilcoxon tests to evaluate the association of biomarkers with clinical benefit groups and log-rank-tests and univariate Cox regression models to evaluate the relationship of biomarkers with PFS and OS. Results With the exception of two angiogenic cytokines (VEGF-A and Angiopoietin 2) that were more abundant in patients with non-sarcomatoid tumors, baseline circulating cytokines (plasma) had similar distributions between sarcomatoid and non-sarcomatoid subgroups. Baseline circulating inflammatory cytokines were highly correlated with one another, forming an “inflammatory module” that was increased in IMDC-poor risk patients and was associated with worse PFS (p=0.028) and with resistance to therapy (p=0.033). At baseline, an elevated circulating VEGF-A level was associated with a lack of response (p=0.03) and worse PFS (p=0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (p=0.01) and improved overall survival (p=0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+ PD-L1+ (HR:0.62[0.49-0.91], p=0.016) and CD8+ PD-L1+ T cells (HR:0.59[0.39-0.87], p=0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (p=0.028). We observed similar trends for all of these results in different subgroups according to sarcomatoid status and histology. Conclusions Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab. Furthermore, they provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.

Preliminary results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with metastatic BRAF V600E mutated colorectal cancer (CRC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers).

3557 Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) has dramatically worse survival than non-BRAF V600E mutated CRCs, and novel therapies are needed. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. The combination of a BRAF plus EGFR inhibitor (EC) is approved for the treatment of pts with BRAF V600E mCRC; however, only 20% of pts experience an objective response. ERAS-007 alone or in combination with EC showed promising in vitro and in vivo activity in BRAF V600E CRC models to support the combinatorial clinical benefit of ERAS-007+EC in BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety and tolerability of escalating doses of ERAS-007 + EC in pts with BRAF V600E CRC. Prior BRAF inhibitor and EGFR inhibitor treatment is neither required nor excluded to be enrolled in this study. Results: As of 30 November 2022, 12 patients were dosed with ERAS-007 twice daily-once a week (BID-QW) (75 and 100 mg; n = 10) or once daily once a week (QW) (150 mg; n = 2) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion once every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥20% of pts were fatigue (50%), headache (42%), constipation, diarrhea, nausea, dermatitis acneiform (33% each), and vomiting (25%). No TEAEs led to ERAS-007 discontinuation or death. Grade ≥3 TEAEs were reported in 3 pts (25%). Grade ≥3 treatment-related AEs reported in ≥ 2 patients (17%) include hypertension, headache, confusional state, and skin toxicity. Three pts (25%) died due to disease progression. No DLTs were reported. Out of 4 efficacy evaluable EC naïve pts, one confirmed partial response (PR) and one unconfirmed PR were observed. Evaluation of PK is ongoing and preliminary data will be presented. Conclusions: ERAS-007+EC in pts with BRAF V600E CRC shows acceptable preliminary safety/tolerability and evidence of clinical activity. The highest dose of ERAS-007 evaluated and cleared by the safety review committee to date is 100 mg BID-QW when combined with EC. Observed PK, toxicity, and preliminary activity support continued evaluation of this combination in pts with BRAF V600E CRC. Clinical trial information: NCT05039177 .

Abstract CT160: Phase 1b/2a clinical trial of the oral BET inhibitor PLX2853 as monotherapy for ARID1A mutated gynecologic cancers and in combination with carboplatin for platinum resistant ovarian cance

Abstract The Bromodomain and Extra-Terminal (BET) Domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all 4 BET family members (BRD2, BRD3, BRD4, and BRDT). PLX2853 development is continuing at Opna Bio as OPN-2853. Clinical experience with PLX2853 monotherapy in subjects with heavily pretreated solid tumors and lymphoma showed signs of activity. The current study (NCT04493619) was designed as a multicenter, open-label trial with two parallel arms: (1) a phase 2a study of PLX2853 monotherapy in advanced gynecological malignancies with a known ARID1A mutation and (2) a phase Ib/2a combination study of PLX2853 plus carboplatin in platinum resistant OC. The primary objective of the Ib portion of the study was safety and tolerability, with the primary objective of both phase 2a portions being efficacy. In the monotherapy arm, up to 6 patients were treated at 80 mg PLX2853 daily in a safety lead-in, with progression to phase 2a using a Simon 2-stage design if dose limiting toxicities (DLTs) were observed in fewer than 33% subjects. In Stage 1, 6 additional subjects (N=12 total) were planned, with progression to stage 2 if two or more patients responded in stage 1. The combination arm included an escalation phase Ib. Three to six evaluable subjects were planned for each group, with dose escalation pending less than 33% DLT rate. The combination arm defined by the phase 1b portion of the study continued to a planned phase 2a Simon 2 stage design similar to that described for the monotherapy arm. 34 of 37 enrolled patients were evaluable with data from at least 1 post-baseline response (14 monotherapy, 20 combination therapy). Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a partial response (PR) with progression-free survival of 278 days, 5 (35.7%) had stable disease (SD) and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable OC patients on the PLX2843 + carboplatin combination, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD. This study in a larger cohort of gynecologic cancer patients confirmed the safety profile of the agent and demonstrated the feasibility of combination with carboplatin. While these results did not meet the pre-specified response criteria, evidence of clinical activity nevertheless highlights the rationale for further exploration of BRD4 inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway, frequently activated in these cancers. Citation Format: Elizabeth M. Swisher, Linda R. Duska, Erika P. Hamilton, Amit M. Oza, Gini Fleming, Oladapo O. Yeku, Alexander I. Spira, Debra L. Richardson, Robin Guo, Jackie Walling, Kerry Inokuchi, Dmitriy Zamarin. Phase 1b/2a clinical trial of the oral BET inhibitor PLX2853 as monotherapy for ARID1A mutated gynecologic cancers and in combination with carboplatin for platinum resistant ovarian cance [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 CT160.

A phase 1 first-in-human study of GS-0189, an anti-signal regulatory protein alpha (SIRPα) monoclonal antibody, in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).

Signal regulatory protein alpha (SIRPα) is the receptor for cluster of differentiation (CD)47, a potent "don't eat me" signal for macrophages. Disruption of CD47-SIRPα signaling in the presence of prophagocytic signals can lead to enhanced phagocytosis of tumor cells, resulting in a direct antitumor effect; agents targeting this pathway have shown efficacy in non-Hodgkin lymphoma (NHL) and other tumor types. GS-0189 is a novel anti-SIRPα humanized monoclonal antibody. Here we report: (1) clinical safety, preliminary activity, and pharmacokinetics of GS-0189 as monotherapy and in combination with rituximab from a phase 1 clinical trial in patients with relapsed/refractory NHL (NCT04502706, SRP001); (2) in vitro characterization of GS-0189 binding to SIRPα; and (3) in vitro phagocytic activity. Clinically, GS-0189 was well tolerated in patients with relapsed/refractory NHL with evidence of clinical activity in combination with rituximab. Receptor occupancy (RO) of GS-0189 was highly variable in NHL patients; binding affinity studies showed significantly higher affinity for SIRPα variant 1 than variant 2, consistent with RO in patient and healthy donor samples. In vitro phagocytosis induced by GS-0189 was also SIRPα variant-dependent. Although clinical development of GS-0189 was discontinued, the CD47-SIRPα signaling pathway remains a promising therapeutic target and should continue to be explored.

Abstract 4533: Serum protein changes in patients with desmoid tumors responsive to the TBL1 inhibitor, tegavivint

Abstract Background: A Phase 1/2 clinical trial (NCT03459469) of the small molecule tegavivint in patients with desmoid tumors (DTs), demonstrated drug safety and tolerability with evidence of clinical activity. Transducin Beta-Like Protein 1 (TBL1) is a necessary co-activator for beta-catenin’s oncogenic activity. Wnt-activation promotes formation of a TBL1: beta-catenin complex that protects β-catenin from degradation in the nucleus and promotes Wnt-target gene activation. Tegavivint binds TBL1 preventing the interaction with beta-catenin, which results in nuclear beta-catenin degradation and inhibition of downstream transcription. For patients whose desmoid tumors responded to tegavivint we assayed changes in serum-based proteins, selected based on their cancer-related function and dysregulation by aberrant Wnt/beta-catenin signaling, to potentially identify suitable biomarkers that may be useful in future studies. Methods: Whole blood and tumor tissue was collected from desmoid patients before and after administration of tegavivint at dose levels ranging from 1 to 5 mg/kg administered via a 4-hour intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Collection timepoints were pre-dose and up 1 week (wk.) following the start of the infusion. Secreted protein levels were profiled in the serum using Luminex multiplex technology. Changes in protein levels were compared to the tegavivint pharmacokinetic (PK) profiles. Tissue samples were analyzed for gene expression changes. Results: Preliminary analyses demonstrated that the majority of tegavivint treated patients with an objective response to tegavivint showed a consistent and expected pattern in serum levels of known Wnt/beta-catenin regulated proteins. Decreases in levels of DKK1, FGF-2, MMP-1, PDGF-AA and VEGF-A and an increase in CCL5 levels were observed. In treated patient serum, protein level changes were detected as early as 2 hours (h) following the start of infusion and continued to progress in the predicted direction at 24 h. At the 5 mg/kg dose, all selected biomarkers remained decreased (or in the case of CCL5, increased) during the dosing interval, with a tegavivint half-life of 48.6 h and Cmin (trough value) 1 wk. post treatment above in vitro IC50 values. Gene expression changes were found in tumor tissue in comparing pre- to post-tegavivint treatment. Conclusion: A panel of beta-catenin regulated proteins and transcripts were identified as candidate pharmacodynamic biomarkers in patients whose desmoid tumor responded to tegavivint. Alterations in these serum proteins continued throughout the dosing interval and, for several proteins, a potential dose response correlation was observed. Further characterization of the relationship between tegavivint plasma levels, serum biomarkers, transcriptional changes and clinical responses in additional patients and time points will be presented. Citation Format: Stephen Horrigan, Kimberly R. Holloway, David Stenehjem, Casey Cunningham. Serum protein changes in patients with desmoid tumors responsive to the TBL1 inhibitor, tegavivint. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4533.

Abstract PD13-12: PD13-12 Imlunestrant, an oral selective estrogen receptor degrader, in combination with abemaciclib with or without an aromatase inhibitor, in estrogen receptor-positive advanced breast cancer: Results from the phase 1a/b EMBER study

Abstract Background: Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties that result in sustained inhibition of estrogen receptor (ER)-dependent gene transcription and cell growth. Preclinically, imlunestrant has favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1-mutant models, along with enhanced efficacy when combined with abemaciclib. In dose escalation (Phase 1a) and dose expansion (Phase 1b) in the EMBER study, imlunestrant monotherapy was well tolerated with favorable safety, PK and encouraging antitumor activity in heavily pre-treated ER+, HER2- advanced breast cancer (aBC) patients (Jhaveri, ASCO 2022); imlunestrant recommended phase 2 dose (RP2D) was determined as 400mg QD. Here, we present the phase 1b dose expansion of imlunestrant with abemaciclib ± aromatase inhibitor (AI) in EMBER (NCT04188548). Methods: Phase 1b enrolled patients with ER-positive (ER+), HER2-negative (HER2-) aBC [shown prior endocrine therapy (ET) sensitivity or untreated de novo aBC; ≤1 prior therapies for aBC but must not have received a prior CDK4/6 inhibitor]. Patients were randomized, based on menopausal status and presence of visceral metastases, to receive imlunestrant + abemaciclib OR imlunestrant + abemaciclib + AI. Men and premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included safety and tolerability, PK, objective response rate (ORR) per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease), and clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) in patients enrolled ≥24 weeks prior to data cut. Results: As of 26 May 2022, 85 patients have received imlunestrant [n=80 at 400 mg (RP2D); n=5 at 800 mg] in combination with abemaciclib (150mg twice daily) ± AI. Forty-eight (56%) patients had visceral disease and 9% had at least 1 ESR1 mutation detected in ctDNA at baseline. Patients were predominantly (75%) ET pre-treated, 51% with an AI; and 8% and 5%, respectively, had received prior chemotherapy or fulvestrant, for aBC. The most common treatment-emergent adverse events were diarrhea (87%), nausea (58%), fatigue (45%), neutropenia (39%) and abdominal pain (34%). The majority of treatment-related AEs (TRAEs) were Grade 1 or 2, with Grade ≥3 TRAEs occurring in 36% of patients. Most common TRAEs at RP2D (400mg) were diarrhea (81%), nausea (45%), fatigue (33%) and neutropenia (35%). No patient discontinued treatment due to an AE. Dose reductions were required of both imlunestrant and abemaciclib in 6 (7%) patients and of either imlunestrant in 3 (4%) or abemaciclib in 22 (26%) patients. Preliminary efficacy is presented in Table 1. Conclusion: Imlunestrant in combination with abemaciclib ± AI showed acceptable safety and tolerability, comparable to the MONARCH 2 trial of fulvestrant + abemaciclib, along with evidence of clinical activity in ER+, HER2- aBC patients. These data suggest no additive toxicity of imlunestrant when administered in combination with abemaciclib, along with comparable clinical benefit to that observed in MONARCH 2. Further data will be presented at the meeting. The phase 3, EMBER-3 study is ongoing; evaluating imlunestrant, investigator’s choice ET, and imlunestrant + abemaciclib in ET pre-treated ER+, HER2- aBC patients (NCT04975308). Table 1. Preliminary efficacy in combination therapies in EMBER Citation Format: Komal Jhaveri, Hwei-Chung Wang, Cynthia Ma, Elgene Lim, Jessica J. Tao, Luis Manso, Jean-Yves Pierga, Ritesh Parajuli, Yolanda Jerez Gilarranz, Yen-Shen Lu, Muralidhar Beeram, Tim Larson, Ajay Dhakal, Roohi Ismail-Khan, Claudia Karacsonyi, Shanshan Cao, Cynthia Osborne, Shawn T. Estrem, Bastien Nguyen, Yujia Li, Eunice Yuen. PD13-12 Imlunestrant, an oral selective estrogen receptor degrader, in combination with abemaciclib with or without an aromatase inhibitor, in estrogen receptor-positive advanced breast cancer: Results from the phase 1a/b EMBER study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-12.

Selected Articles from This Issue

Highlights| January 17 2023 Selected Articles from This Issue Author & Article Information Online Issn: 1557-3265 Print Issn: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (2): 297. https://doi.org/10.1158/1078-0432.CCR-29-2-HI Related Content A commentary has been published: Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation A commentary has been published: Triple-Negative PAM50 Non-Basal Breast Cancer Subtype Predicts Benefit from Extended Adjuvant Capecitabine A commentary has been published: Intraperitoneal Monocytes plus IFNs as a Novel Cellular Immunotherapy for Ovarian Cancer: Mechanistic Characterization and Results from a Phase I Clinical Trial View more A commentary has been published: High-Sensitivity Mutation Analysis of Cell-Free DNA for Disease Monitoring in Endometrial Cancer View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record January 17 2023 Citation Selected Articles from This Issue. Clin Cancer Res 15 January 2023; 29 (2): 297. https://doi.org/10.1158/1078-0432.CCR-29-2-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Overall survival for advanced ovarian cancer remains poor, particularly for women with platinum-resistant disease. Green and colleagues report the bench to bedside development of a novel cytokine stimulated autologous monocyte therapy for advanced, platinum-resistant or -refractory ovarian cancer. Activated monocytes killed tumor cells in mice via a TRAIL-dependent pathway. Treatment was well tolerated and produced partial responses by RECIST criteria. These findings characterize the mechanism of a novel cellular immunotherapy for ovarian cancer, which is well tolerated with evidence of clinical activity in a heavily pretreated patient population. This therapy may serve as the backbone for a combination immunotherapy regimen incorporating additional agents targeting T-regulatory cells and/or myeloid-derived suppressor cells (MDSCs). Identifying predictive biomarkers that define the subset of triple-negative breast cancer (TNBC) deriving the most benefit from adjuvant capecitabine is necessary in clinical practice. In this hypothesis-testing study, Asleh and colleagues examined the capacity of candidate RNA biomarkers to... You do not currently have access to this content.

Adct-602, a CD22 Targeting Antibody Drug Conjugate Bound to PBD Toxin in Adult Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: A Phase 1 Trial

Introduction: Outcomes of patients (pts) with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal. CD22 is expressed on lymphoblasts in >90% of pts with B-ALL and is an established therapeutic target. Inotuzumab ozogamicin is an approved CD22 targeting antibody for pts with R/R B-ALL; however, the toxin calicheamicin can lead to veno-occlusive disease (VOD) of the liver, especially after allogeneic SCT (allo-SCT). ADCT-602 is an antibody drug conjugate composed of a humanized monoclonal antibody directed against CD22 and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In preclinical studies, ADCT-602 demonstrated potent anti-tumor activity in mouse models of B-cell malignancies. We present here results from an ongoing phase 1/2 trial evaluating ADCT-602 in pts with R/R B-ALL (NCT03698552). Methods: This is an investigator-initiated phase 1/2 trial of ADCT-602 monotherapy in pts with R/R B-ALL. The primary objective of the phase 1 part is to assess the safety and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ADCT-602. The primary objective of phase 2 is to evaluate efficacy (CR/CRi rate). Eligible pts must be ≥18 years of age with R/R B-ALL with bone marrow blasts ≥5%. CD22 must be expressed in ≥20% blasts. Pts must have adequate organ function (creatinine ≤1.5 mg/dL; ALT and AST ≤2 times upper limit of normal (ULN), ≤5 times ULN if there is liver or bone involvement; total bilirubin ≤1.5 times ULN; LVEF ≥45%). A 3+3 dose-escalation design was used for phase 1. ADCT-602 was initially given IV once every 3 weeks; based on the PK data, the administration schedule was later amended to weekly infusions. Results: From November 2018 to July 2022, 21 pts (11 women, 10 men) with R/R B-ALL were enrolled and received treatment with ADCT-602. The median age was 39 years (range, 21-82) and pts had received a median of 5 (range, 2-9) prior therapies [inotuzumab ozogamicin 12/21 (57%); blinatumomab 18/21 (86%); venetoclax 12/21 (57%)]. A total of 8/21 (38%) had a prior CD19 CAR-T, including 1 pt who had both CD19 and CD22 CAR-T. Ten (10/21, 48%) pts had a prior allo-SCT, including 3 pts with 2 prior allo-SCT. The median pretreatment bone marrow blasts were 70% (range, 16-96). The median CD22 expression on blasts was 97% (range, 33.6-100). A total of 11 pts were treated in the Q3week schedule [30µg/kg, n=3; 60µg/kg, n=4; 90µg/kg, n=4]. As the PK data indicated rapid clearance of the antibody, the trial was amended to allow for weekly dosing. A total of 10 pts were treated at the weekly dose level [30µg/kg, n=3; 40µg/kg, n=4; 50µg/kg, n=3]. One pt (30µg/kg weekly dose level) had grade 4 thrombocytopenia possibly related to ADCT-602. One pt (50µg/kg weekly dose level) had a DLT of prolonged myelosuppression (marrow blast clearance without blood count recovery). No pt had VOD. Notably, all 3 pts treated at the 50µg/kg weekly dose level (a dose level expected to be close to RP2D) had evidence of anti-tumor activity (2 pts achieved MRD negative CR; one pt had bone marrow blast clearance). First pt at this dose level was a 26-yr-old with R/R B-ALL with PAX5-JAK2 fusion with 5 prior therapies including 2 CD19 CAR-T and an allo-SCT who achieved MRD negative CR and is receiving ongoing therapy in Cycle 5. Second pt at this dose level was a 66-yr-old with TP53- and KRAS-mutated B-ALL with 2 prior therapies including modified BFM regimen and blinatumomab who achieved MRD negative CR and is receiving ongoing therapy in Cycle 4. Third pt at this dose level was a 21-yr-old with TP53- and KRAS-mutated B-ALL with 4 prior therapies including inotuzumab and a CD19 CAR-T who had morphologic blast clearance without blood count recovery. Two additional pts treated at lower doses levels (1 each at 30µg/kg Q3week and 30µg/kg weekly schedule) achieved MRD negative CR. All responding pts had CD22 expression noted in >97% of the blasts by flow cytometry. Conclusions: In this phase 1 study in pts with very heavily pretreated R/R B-ALL with a median of 5 prior lines of therapy and high baseline bone marrow tumor burden, single-agent ADCT-602 was well tolerated with one pt with DLT noted at the 50µg/kg weekly dose level. Notably, all 3 pts treated at this dose level had evidence of clinical activity with 2/3 pts achieving MRD negative CR. Due to 1 pt with DLT at this dose level, this cohort is being expanded to treat 3 additional pts. This trial continues to accrue pts and updated data will be presented at the ASH meeting.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.