Monotherapy In Subjects Research Articles

A first-in-human, phase 1, dose escalation study of SGR-2921 as monotherapy in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

TPS6590 Background: Cell division cycle 7-related protein kinase (CDC7) is a cell cycle kinase that maintains DNA replication by phosphorylation and activation of the minichromosome maintenance protein 2 and 4 (MCMs), components of the replicative DNA helicase. Due to the CDC7's central role in maintaining replication fork integrity, chemical inhibition of CDC7 can ultimately lead to cancer cell death. SGR-2921 is an oral, small molecule inhibitor of CDC7. Preclinical studies demonstrate that SGR-2921 has potent anti-proliferative activity in AML cell lines representative of difficult to treat patient populations, agnostic of serious mutations (including those with p53 mutations), BTK resistance, and multiple prior lines of treatment. This anti-tumor activity has also been demonstrated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) AML models. Methods: This is a phase 1, FIH, open-label, single-agent, two-arm, dose escalation study (NCT#05961839) designed to evaluate safety and tolerability and identify the recommended phase 2 dose (RP2D) of SGR-2921 as monotherapy in subjects with relapsed or refractory (R/R) AML, high risk (HR) MDS, or very high risk (VHR) MDS. The study utilizes an accelerated titration design with single patient cohorts that transitions to a 3+3 design once a single Grade 2 event is observed. This is a multicenter global study (US, Spain and France). SGR-2921 will be administered orally, once daily, utilizing a 5-day on and 9-day off dosing schedule over a 28-day cycle. A maximum of 144 patients will be enrolled into dose escalation and exploratory cohorts. To evaluate the effect of CYP3A4 inhibition on SGR-2921 exposure, subjects will be enrolled into one of two staggered, parallel study treatment arms, according to concomitant administration with (Arm B) or without (Arm A) azole antifungals that are strong CYP3A4 inhibitors. A single dose PK run-in will be required for subjects enrolled into the first 3 cohorts of each treatment arm. Subjects will be treated at increasing doses of SGR-2921 until the maximum tolerated dose (MTD) is exceeded. A RP2D will be selected from one of the tolerable dose levels. Key study inclusion criteria include: Age ≥ 18 years of age; Life expectancy ≥ 8 weeks; Confirmed diagnosis of R/R AML or HR and VHR MDS; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Key study exclusion criteria include: Active malignancies not related to AML or MDS within two years prior to the first dose or requiring ongoing treatment; active CNS leukemia; QTcF ≥470 msec. The primary objectives are to evaluate the safety and tolerability of SGR-2921 as monotherapy and to identify the RP2D. Secondary objectives include evaluating SGR-2921 pharmacokinetics and investigating preliminary antitumor activity. Clinical trial information: NCT05961839 .

ADU-1604, a novel CTLA-4 blocking antibody, to modulate pharmacodynamic markers in patients with PD1 relapse/refractory melanoma.

9552 Background: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a negative regulator of T-cell responses, also known as an immune checkpoint. The clinical relevance of CTLA-4 blockade was demonstrated by the approval of ipilimumab for the treatment of melanoma, both in the adjuvant as well as metastatic settings. ADU-1604 is a humanized hIgG1 CTLA-4 antagonist antibody. ADU-1604 binds a unique epitope on CTLA-4 demonstrating, in contrast to ipilimumab full blockade of both CD80 and CD86 interactions. In vitro and in vivo ADU-1604 demonstrates at least as potent efficacy as compared to ipilimumab, was well tolerated in non-human primates and demonstrated enhanced immunogenicity against hepatitis B vaccine in non-human primates. Methods: This is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of ADU-1604 given as monotherapy in subjects with advanced-stage, relapsed/refractory melanoma who relapsed or were refractory to a prior anti-PD-1/PD-L1 therapy. Main endpoints are safety of ADU-1604 monotherapy, pharmacokinetics, pharmacodynamics (upregulation of ICOS and Ki-67 on circulation CD4+ T cells and ALC, CD4+ and CD8+ T cells) as well as preliminary clinical efficacy. 20 subjects received escalating doses of ADU-1604 IV (25, 75, 225, 450 mg flat dose) Q3W. In the dose expansion part up to 20 additional patients will be treated with 225 mg dose to confirm recommended Phase 2 dose (RP2D). Safety and preliminary efficacy of ADU-1604 monotherapy in PD1 relapsed/refractory melanoma patients will be evaluated. The study was initiated in June 2022. Results: ADU-1604 was demonstrated to have a typical pharmacokinetic behavior for a human IgG1 antibody and similar exposure was observed as described for ipilimumab. Administration of ADU-1604 in cycle 1 and 2 showed a dose-dependent modulation of ICOS and Ki-67 on circulating CD4+ T cells. Similarly, in cycles 3 and 4 a dose-dependent increase of ALC and CD4+ and CD8+ T cells was detected. Notably, no DLTs across the 25, 75, 225 and 450 mg dose level have occurred. Of the patients treated at 225 and 450 mg dose levels (N=6 at 225 mg and N=6 at 450 mg), two Grade 2 severe adverse events (both immune-related enterocolitis) and two Grade 3 AESIs (ALT elevation and immune-related gastritis) suggesting that ADU-1604 has a relatively mild safety profile. Two patients at 225 mg and one patient at 450 mg demonstrated clinical efficacy. Conclusions: ADU-1604 Phase 1 dose-escalation data indicates clinical activity in line with what has been observed with other CTLA-4 blocking antibodies. Importantly, no DLTs and very limited safety signals were reported during the study. Dose expansion at 225 mg dose is ongoing in subjects with advanced-stage, relapsed/refractory melanoma who relapsed or were refractory to a prior anti-PD-1/PD-L1 therapy. Clinical trial information: 2021-002623-38 .

Abstract CT161: First-in-human study of ENPP1 inhibitor, SR-8541A, for the treatment of solid tumors

Abstract Purpose: Compelling evidence suggests that careful and therapeutically relevant activation of the STING (STimulator of INterferon Genes) pathway is vital to elicit potent anti-cancer innate immune responses. STING is widely expressed and targeting it directly poses many challenges, including systemic activation of interferon. Therefore, alternative approaches to activate STING in a controlled manner may generate a better therapeutic response in cancer patients. Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) is the direct negative regulator of the STING pathway that hydrolyzes 2’3’ cGAMP, the direct activator of STING. Highest levels of 2′3′ cGAMP can be found in tumors and recent evidence suggests that 2′3′ cGAMP acts locally, as a paracrine immune transmitter. Recent studies have also reported elevated ENPP1 expression in metastatic tumors. We hypothesize that inhibiting ENPP1 with a small molecule inhibitor may produce superior outcomes by activating STING in the tumor microenvironment. We have developed SR-8541A, a highly selective and potent inhibitor of ENPP1. Our initial work to support the development of SR-8541A consisted of pharmacodynamics studies, bioanalytical development, pharmacokinetics (PK) and non-GLP toxicology studies in three species, a GLP repeat dose dog telemetry study, and 28-day GLP toxicology studies in rats and dogs including toxicokinetic (TK) analyses. Here we report initial findings from our ongoing first in human, phase I trial of SR-8541A in advanced metastatic solid tumors. Methods: This study is evaluating the safety, tolerability, and pharmacokinetics (PK) of SR-8541A administered orally as a monotherapy in subjects with solid tumors which are refractory to standard therapeutic options, or for which there are no standard therapeutic options (NCT06063681). The primary objective of the study is to characterize the safety, tolerability, DLTs, maximum tolerated dose and RP2D and schedule for future studies of SR-8541A. Secondarily, the study aims to evaluate the PK and efficacy per RECIST of SR-8541A. SR-8541A is administered orally in 28-day cycles and is following an accelerated titration dose (ATD) escalation. Blood samples are being collected for PK assessment, target engagement, and biomarker assessment. Results: Sample analysis from a subject treated with SR-8541A (5 mg) in the ATD portion of the study is ongoing. No treatment-related adverse events have been reported. No dose-limiting toxicities occurred during the 28-day DLT period. Plasma drug levels collected for the PK show cMAX concentrations in the projected therapeutic dose range. Biomarker assessment is ongoing and will be included in the presentation. The SR-8541A dose has escalated and the study is currently enrolling at the 10 mg dose. Conclusions: The first evaluated dose of SR-8541A has shown to be safe and well tolerated. Pharmacokinetic data shows strong oral bioavailability and supports escalation in the phase I trial and continued assessment of SR-8541A in the clinic. Citation Format: Alexis S. Weston, Trason Thode, Monil Shah, Amanda Seiz, Jonathan Northrup, Srinivas Kasibhatla, Mohan Kaadige, Sunil Sharma. First-in-human study of ENPP1 inhibitor, SR-8541A, for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT161.

A First-in-Human, Phase 1, Dose Escalation Study of Sgr-2921 As Monotherapy in Subjects with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Background Cell division cycle 7-related protein kinase (CDC7), or DBF4-dependent CDC7 kinase (DDK), is a cell cycle kinase that maintains DNA replication by phosphorylation and activation of the minichromosome maintenance protein 2 and 4 (MCMs), components of the replicative DNA helicase. Due to the central role of CDC7 in maintenance of the replication fork integrity, chemical inhibition of CDC7 kinase can ultimately lead to cancer cell death. SGR-2921 is an oral, small molecule inhibitor of CDC7. Preclinical studies demonstrate that, among all cell lines tested, SGR-2921 has the most potent anti-proliferative activity in AML. Potent antitumor activity has also been demonstrated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) AML models. This antitumor response is observed in animal models representative of difficult to treat patient populations and appears to be agnostic of serious mutations (including those with p53 mutations and FLT3 mutations), BTK resistance, and multiple prior lines of treatment. Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk (HR) or very high-risk (VHR) myelodysplastic syndrome (MDS) have low response rates and poor overall survival. Considering the potent preclinical activity of SGR-2921 in AML and MDS models, coupled with the high unmet medical need in this population, SGR-2921 is being evaluated in patients with R/R AML and HR/VHR MDS. Study Design and Methods This is a phase 1, FIH, open-label, single-agent, two-arm, dose escalation study (NCT#05961839) designed to evaluate safety and tolerability and identify the recommended phase 2 dose (RP2D) of SGR-2921 as monotherapy in subjects with R/R AML, HR MDS, or VHR MDS. The study utilizes a hybrid accelerated titration design with single patient cohorts that transitions to a 3+3 design once a single Grade 2 event or DLT is observed. This is a multicenter global study (US, Spain and France) with an estimated study recruitment start date in October, 2023. SGR-2921 will be administered orally, once daily, utilizing a 5-day on and 9-day off dosing schedule over a 28-day cycle. Up to a maximum of 144 patients will be enrolled in the dose escalation and exploratory cohort phase of the study. To evaluate the effect of CYP3A4 inhibition on SGR-2921 exposure, subjects will be enrolled into one of two staggered, parallel study treatment arms, according to concomitant administration with (Arm B) or without (Arm A) azole antifungals that are strong CYP3A4 inhibitors at time of first dose. Safety and tolerability must be demonstrated in treatment Arm A, at the first two dose levels before initiating treatment Arm B. A single dose PK run-in will be required for subjects enrolled into the first 3 cohorts of each treatment arm. Subjects will be treated at increasing doses of study drug until all dose levels have been investigated or any dose level is found to exceed the maximum tolerated dose (MTD). A RP2D will be selected from one of the tolerable dose levels which will not exceed the MTD (see Figure 1 for study design). Key study inclusion criteria include: Age ≥ 18 years of age; Life expectancy ≥ 8 weeks; Confirmed diagnosis of R/R AML or HR and VHR MDS; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Key study exclusion criteria include: Active malignancies not related to AML or MDS within two years prior to the first dose or requiring ongoing treatment; Clinical evidence of central nervous system (CNS) or pulmonary leukostasis; ≥ Grade 3 disseminated intravascular coagulation, or active CNS leukemia; QT interval corrected for heart rate per Fridericia's formula ≥470 msec during screening ECG. The study primary objectives are to evaluate the safety and tolerability of SGR-2921 as monotherapy and identify RP2D including MTD. Secondary objectives include evaluating the pharmacokinetics (PK) of SGR-2921 and investigating preliminary antitumor activity (composite complete remission rate, objective response rate, duration of response, etc.).

A Phase 1, Open-Label, Multicenter, Dose-Escalation Study of Sgr-1505 As Monotherapy in Subjects with Mature B-Cell Malignancies

Background and Significance: MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a component of the MALT1-BCL10-CARD11 complex downstream from the Bruton Tyrosine Kinase (BTK) on the B-cell receptor signaling pathway. MALT1 is a key mediator of nuclear factor kappa B (NF-κB) signaling, which is the main driver of a subset of B-cell lymphomas. MALT1 is considered a potential therapeutic target for several subtypes of non-Hodgkin B-cell lymphomas and chronic lymphocytic leukemia (CLL), including tumors with acquired BTK inhibitor (BTKi) resistance. Constitutive activation of NF-κB is a molecular hallmark of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), and MALT1 may have utility as a treatment option for ABC-DLBCL. Furthermore, a MALT1 inhibitor (JNJ-67856633) showed efficacy in mature B cell malignancies from phase 1 studies (ref 1, 2). SGR-1505 is an oral potent small molecule allosteric inhibitor of MALT1 that inhibits MALT1 enzymatic activity and demonstrates anti-proliferative activity in BTKi-sensitive (OCI-LY10) and BTKi-resistant (OCI-LY3) ABC-DLBCL cell lines. SGR-1505 administered as a single agent and in combination with the approved Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, demonstrates tumorostatic and regressive antitumor activity in ABC-DLBCL cell line-derived and patient-derived xenograft models. These data suggest that SGR-1505-mediated MALT1 inhibition may expand therapeutic options for patients with selected B-cell lymphomas, supporting further evaluation of SGR-1505 in clinical trials. Study Design and Methods: SGR-1505-101 (NCT05544019) is a phase 1, multicenter trial of SGR-1505 as monotherapy in subjects with mature B-cell malignancies (figure 1). At present, the study is open to accrual at multiple investigative sites in the US with plans to expand to Europe. The primary objective is to evaluate safety and tolerability of SGR-1505 as monotherapy and to identify the maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary objectives are to evaluate the pharmacokinetic (PK) profile, food effect, drug-drug interaction, and preliminary anti-tumor activity of SGR-1505. Key inclusion criteria are: history of mature B-cell malignancy (including aggressive and indolent B-cell lymphomas, Waldenström macroglobulinemia, and CLL); measurable or detectable disease according to the applicable disease-specific classification system (Lugano, iwCLL, WWM6); Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Patients with indolent B-cell lymphomas or CLL must have an indication for treatment and not require immediate cytoreductive therapy. Subjects with symptomatic or active CNS involvement, and other conditions or laboratory findings placing them at increased risk to the use of an investigational drug are excluded. SGR-1505 is initially dose-escalated using an accelerated titration design in cohorts of 1-6 subjects, and at higher dose levels using a conventional 3+3 design.

Time Limited Exposure to a ROR1 Targeting Bispecific T Cell Engager (NVG-111) Leads to Durable Responses in Subjects with Relapsed Refractory Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL)

Background: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is absent or expressed at low levels in normal adult tissues but overexpressed in a range of malignancies including CLL and MCL. NVG-111 is a humanized first in class, tandem scFv, ROR1xCD3 bispecific T cell engager. NVG-111 mediates potent killing of ROR1 + tumors by engaging a unique epitope on the Frizzled domain of ROR1 and redirecting T cell activity via the CD3 binder engineered for attenuated cytokine release. Methods: In this phase 1, first-in-human, dose-escalation study (ClinicalTrials.gov identifier: NCT04763083), NVG-111 was evaluated in relapsed/refractory CLL and MCL subjects with an ECOG PS of 0-2 who received ≥2 prior lines of treatment including a Bruton tyrosine kinase inhibitor (BTKi). Bayesian continual reassessment method with overdose control was implemented to guide escalation over a dose range of 0.3-45ug/day. Each subject received at least one dose of NVG-111, administered as a continuous intravenous infusion (cIV) over 21 days followed by 7 days off drug (=1 cycle). NVG-111 was administered in combination (N=8) with ibrutinib to subjects who had achieved a partial response to >1 year of ibrutinib therapy, or as monotherapy in subjects that progressed after covalent BTKi/B-cell lymphoma 2 inhibitor (BCL2i) (N=4). Primary objective was safety, with the secondary objectives being efficacy (overall response rates [ORR], minimal residual disease (MRD) measured by ERIC-compliant flow cytometry and duration of response [DoR]). Serum cytokine levels were determined using a human high sensitivity cytokine premixed magnetic Luminex assay and T cell function was longitudinally evaluated using cytometry by time of flight (CyTOF) analysis. Results: Between May 2021 and July 2023 12 subjects (10 males and 2 females, median age 60 years) completed a maximum of 6 cycles of treatment with NVG-111 (median=3 cycles [range 1-6 cycles]). Pharmacokinetic and pharmacodynamic data demonstrated systemic NVG-111 exposure and exposure-dependent NVG-111 targeting of ROR1 on circulating tumor cells. Adverse events (AEs) related to NVG-111 occurred in 10 subjects (83%), with the most common being nausea (58%), headaches (67%), and fatigue (33%), majority of which were grade 1 or 2. Grade 1(71%) or 2(29%) cytokine release syndrome (CRS) occurred in 58% of subjects during week 1 of cycle 1 except in one subject who had a second grade 1 CRS in cycle 2. Grade 3 dose limiting toxicities (DLTs) occurred in three subjects (25%) consisting of transient elevation of liver enzymes (ALT and AST) in one subject dosed at 3ug/day, immune effector cell-associated neurotoxicity syndrome-like symptoms (ICANS) in one subject dosed at 30ug/day and headache in one subject dosed at 45ug/day. All AEs were fully reversible with no late emergent grade 3 or greater toxicities. Evidence of T cell activation was observed in all 12 subjects with peak cytokine levels at the 30µg/day dose levels (mean±SEM): TNFα, 43±17pg/ml; IL6, 566±541pg/ml; IFNɣ, 18±12pg/ml; and IL10, 103±56pg/ml. Furthermore, T cell profiling showed an increase in cytotoxic CD8 + T cell activation marker expression during each NVG-111 treatment cycle without evidence of T cell exhaustion. Efficacy was evaluable in 11 subjects with objective clinical responses observed in 55% (6/11), including two subjects with clear evidence of single agent activity. Amongst these, three CLL subjects were rendered MRD negative in peripheral blood and one MCL subject achieved complete metabolic response by the Lugano criteria. Two subjects had stable disease but in one of these subjects there was a >50% reduction in peripheral blood lymphocytosis and a 40% reduction in lymphadenopathy. Despite time limited exposure to NVG-111, the restricted mean survival time for DoR is currently 13.6 months (SEM 3.07), the median is not yet calculable with response ongoing in four subjects. The median progression-free survival currently is 18.7 months (95% CI 2.6 - not calculable). Conclusion: These data provide clinical proof of concept for selective targeting of ROR1 with a TCE leading to objective evidence of antitumor activity with encouraging response durability even in CLL patients known to have defective T cell function. The safety profile was consistent with the mechanism of action. Further evaluation of this promising molecule is ongoing.

SGR‐1505‐101: A PHASE 1, OPEN‐LABEL, MULTICENTER, DOSE‐ESCALATION STUDY OF SGR‐1505 AS MONOTHERAPY IN SUBJECTS WITH MATURE B‐CELL MALIGNANCIES

Background: MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a component of the MALT1-BCL10-CARD11 complex downstream from the Bruton Tyrosine Kinase (BTK) on the B-cell receptor signaling pathway. MALT1 is a key mediator of the nuclear factor kappa B (NF-κB) signaling, which is the main driver of a subset of B-cell lymphomas. MALT1 is considered a potential therapeutic target for several subtypes of non-Hodgkin B-cell lymphomas and chronic lymphocytic leukemia (CLL), including tumors with acquired BTK inhibitor (BTKi) resistance. In particular, constitutive activation of the NF-κB is a molecular hallmark of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), and MALT1 may have utility as a treatment option for ABC-DLBCL. SGR-1505 is an oral potent small molecule allosteric inhibitor of MALT1 that inhibits MALT1 enzymatic activity, and demonstrates anti-proliferative activity in ABC-DLBCL cell lines, both BTKi-sensitive (OCI-LY10) and BTKi-resistant (OCI-LY3). SGR-1505 administered as a single agent and in combination with the approved Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, demonstrates tumorostatic and regressive antitumor activity in ABC-DLBCL cell line-derived xenograft and patient-derived xenograft models. Aims: These data suggest that SGR-1505-mediated MALT1 inhibition has therapeutic potential and may expand therapeutic options for patients with selected B-cell lymphomas supporting further evaluation of SGR-1505 in clinical trials. Methods: SGR-1505-101 (NCT05544019) is a phase 1, multicenter trial of SGR-1505 as monotherapy in subjects with mature B-cell malignancies. At present, the study has been activated in 3 sites in the United States. The primary objective is to evaluate safety and tolerability of SGR-1505 as monotherapy and to identify the maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary objectives are to evaluate the pharmacokinetic (PK) profile, food effect, drug-drug interaction, and preliminary anti-tumor activity of SGR-1505. Key inclusion criteria are: history of mature B-cell malignancy (including aggressive and indolent B-cell lymphomas, Waldenström macroglobulinemia, and CLL); measurable or detectable disease according to the applicable disease-specific classification system (Lugano, iwCLL, WWM6); Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Patients with indolent B-cell lymphomas or CLL must have an indication for treatment and not require immediate cytoreductive therapy. Subjects with symptomatic or active CNS involvement, and other conditions or laboratory findings placing them at increased risk to the use of an investigational drug are excluded. SGR-1505 is initially dose-escalated using an accelerated titration design in cohorts of 1–6 subjects, and at higher dose levels using a conventional 3+3 design. Encore Abstract—previously submitted to EHA 2023 The research was funded by: Schrodinger Keywords: aggressive B-cell non-Hodgkin lymphoma, molecular targeted therapies, ongoing trials Conflicts of interests pertinent to the abstract. B. Yoo Employment or leadership position: Schrodinger Stock ownership: Schrodinger Z. Nie Employment or leadership position: Schrodinger Stock ownership: Schrodinger G. Krilov Employment or leadership position: Schrodinger Stock ownership: Schrodinger J. Tan Employment or leadership position: Schrodinger Stock ownership: Schrodinger H. Wright Employment or leadership position: Schrodinger Stock ownership: Schrodinger D. Weiss Employment or leadership position: Schrodinger Stock ownership: Schrodinger W. Yin Employment or leadership position: Schrodinger Stock ownership: Schrodinger K. Akinsanya Employment or leadership position: Schrodinger Stock ownership: Schrodinger

Factors Associated With Maintenance of Remission Following Change From Combination Therapy to Monotherapy in Patients With Rheumatoid Arthritis.

Some patients with rheumatoid arthritis (RA) who persist in remission may decide to stop their therapy. We evaluated baseline characteristics associated with remaining in remission or low disease activity (LDA) following medication withdrawal. The Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With Rheumatoid Arthritis (SEAM-RA) was a phase III, multicenter, randomized withdrawal, double-blind, controlled study in patients with RA on methotrexate (MTX) + etanercept (ETN). If remission (Simplified Disease Activity Index [SDAI] ≤ 3.3) was sustained through a 24-week run-in period, patients then entered a 48-week double-blind period and were randomized 2:2:1 to receive MTX monotherapy, ETN monotherapy, or continue combination therapy. Multivariate logistic regression analysis was performed to identify baseline factors associated with remission or LDA at the end of both periods. Of 371 patients enrolled, 253 entered the double-blind period. After adjusting for other factors, covariates associated with achieving SDAI remission at the end of the run-in period included younger age, longer duration of MTX treatment, and less severe clinical disease variables. Covariates associated with maintaining remission/LDA at the end of the 48-week double-blind period included lower patient global assessment of disease activity (PtGA), lower C-reactive protein, rheumatoid factor (RF) negativity, longer RA duration in the MTX arm, shorter duration of ETN treatment, and lower magnesium. These findings indicate patients with overall lower disease activity are more likely to remain in SDAI remission/LDA after switching from combination therapy to monotherapy. RF-negative status and lower PtGA scores were strongly associated with increased likelihood of remaining in remission/LDA with MTX or ETN monotherapy. (SEAM-RA; ClinicalTrials.gov: NCT02373813).

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.

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

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

Perampanel and childhood absence epilepsy: A real life experience.

ObjectivesThe aim of our study was to evaluate the effectiveness and tolerability of perampanel (PER) as first add-on and as second line monotherapy in subjects with childhood absence epilepsy.MethodsOur sample consisted of 20 patients with childhood absence epilepsy, aged between 8 and 10, already in therapy with a first antiseizure medication with incomplete seizure control. PER was added as first add-on in a dose ranging from 3 to 8 mg/die with 1- 2 mg/week increments. The patients that were seizure-free were shifted to a PER monotherapy. All patients underwent a standardized neuropsychological evaluation in order to assess non-verbal intelligence and executive functions before adding PER and after 6 months of drug therapy. All parents completed two questionnaires, in order to assess the emotional-behavioral problems and parental stress.Results15/20 patients responded to add-on PER and were seizure-free, in 3/20 patients we observed a reduction of seizure frequency <50%, and in the 2 remaining patients the add-on therapy with PER did not lead to a reduction in seizures frequency from baseline. The patients who were seizure-free were switched to PER monotherapy. 9/15 patients remained seizure-free in monotherapy with PER. In the first month of therapy with PER 2/20 patients (10%) reported mild, transient side effects of irritability, headache and dizziness, which did not lead to discontinuation of therapy. Adjunctive treatment with PER did not negatively affect non-verbal intelligence, executive functions, emotional/behavioral symptoms of children and parental stress levels.SignificanceOur clinical experience in real life showed that PER appears to be effective in the control of absence seizures in childhood absence epilepsy, with a favorable tolerability profile. PER would seem effective on absence seizures even in monotherapy. Further studies with larger samples, longer follow-up and controlled vs. placebo (or other first choice antiseizure medications) are needed to confirm our data.

Impact of clinical domains other than arthritis on composite outcomes in psoriatic arthritis: comparison of treatment effects in the SEAM-PsA trial

ObjectiveWe used the Study of Etanercept And Methotrexate in Combination or as Monotherapy in Subjects with Psoriatic Arthritis (SEAM-PsA) data set to examine the impact of presence of enthesitis, dactylitis,...

TiNivo-2: A phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor.

TPS4605 Background: Tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (aRCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile (Rini et al Lancet Oncol 2020). Tivozanib was approved by the FDA on March 10, 2021, for the treatment of patients with aRCC who had progressed on 2 or more prior systemic therapies. Tivozanib was combined with Nivolumab in the phase 1b/2 TiNivo trial (NCT03136627), showing an objective response rate of 56%, disease control rate of 96%, median PFS of 18.9 months and a tolerable safety profile (Albiges et al Ann Oncol. 2021). Methods: TiNivo-2 (NCT04987203) is a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following 1-2 lines of therapy including an immune checkpoint inhibitor. Eligibility criteria include age &gt;18 years, clear cell RCC, ECOG PS 0-1, and disease progression during or following at least 6 weeks of treatment with ICI for RCC. Subjects will be stratified by IMDC risk category and whether ICI was received in most recent line of treatment or not. Subjects will receive tivozanib 1.34 mg orally once daily for 21 consecutive days followed by 7 days off, on the monotherapy arm, and tivozanib 0.89 mg at the same schedule in addition to nivolumab 480mg intravenously every 4 weeks on the combination arm. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 for 2 years and every 12 weeks thereafter until disease progression is confirmed by independent radiology review (IRR). The primary objective is to compare the progression-free survival (PFS) of tivozanib in combination with nivolumab to tivozanib. A sample size of 326 subjects, with 191 events will provide at least 80% power to detect a 50% improvement in PFS, 12 mos v. 8 mos, as assessed by an IRR. Secondary endpoints include assessment of overall survival (OS), objective response rate (ORR), and duration of response (DoR), as well as safety and tolerability. Exploratory endpoints are to assess the quality of life (FKSI-DRS and EORTC QLQ C-30) and to investigate the pharmacokinetics of tivozanib. TiNivo-2 is actively enrolling and planning to open at 190 sites in the United States, and the European Union. Clinical trial information: NCT04987203.

D3S-001, a highly potent, selective, and differentiated covalent inhibitor of KRAS G12C: Human dose prediction and first‐in‐human (FIH) trial design.

e15087 Background: Effective inhibition of G12C mutated KRAS is believed to be critical for anti-tumor efficacy in KRAS-driven cancers. D3S-001 is a potent and highly differentiated KRAS G12C inhibitor, which demonstrates rapid and near complete target inhibition and strong anti-tumor activity in preclinical cell line and animal models [Preclinical characterization of D3S-001, a highly potent, selective, and differentiated covalent inhibitor of KRAS G12C, ASCO 2022 Abstract #378099]. The current study utilizes pharmacokinetic (PK) modeling to predict the extent of KRAS G12C target inhibition at the proposed clinical dose range. Methods: Allometric scaling and non-linear fixed effect modeling were used to predict human PK profiles from DMPK data in animals. Human in vivo target inhibition was calculated based on human PK predictions, free drug fraction and results from in vitro target engagement assay. A First-in-Human (FIH) study was designed to investigate D3S-001 monotherapy in subjects with advanced solid tumors having a KRAS G12C mutation. Six dose escalation cohorts will be investigated, starting from 50mg QD. Results: Based on a GLP toxicology study in dogs, the highest non-severely toxic dose (HNSTD) was determined to be 20 mg/kg/day. Per ICH S9, a 20 mg/kg/day dose in dog supports a FIH starting dose of 110 mg. To ensure an additional safety margin, a lower starting dose of 50 mg was proposed. At 50 mg QD, the predicted human exposure (Cmax 60 nM, Caverage 49 nM, Ctrough 31 nM) is expected to achieve ̃70% target inhibition at 2 hours after dosing. In NCI-H358 mouse xenograft model, this exposure is associated with 94% tumor growth inhibition (TGI). Safety margins based on Cmax and AUC comparing to dog HNSTD are 17-fold and 9-fold, respectively. At 100 mg QD, the predicted human exposure (Cmax 120 nM, Caverage 98 nM, Ctrough 63 nM) is expected to achieve ̃95% target inhibition. This exposure is associated with tumor regression of 72% in the NCI-H358 mouse xenograft model. At dose levels higher than 100 mg QD, predicted human exposures are expected to consistently achieve &gt;95% target inhibition starting 1 hour after dosing. These exposures are associated with deeper levels of tumor regression of 97%. Moreover, even at 400 mg QD, predicted human plasma concentrations are still below dog plasma concentration of 443 nM, Caverage at HNSTD. Conclusions: D3S-001 is predicted to achieve rapid and consistently efficacious KRAS G12C target inhibition in humans at proposed clinical dose range. This high degree of KRAS G12C inhibition over the dosing interval may translate into greater clinical benefit to patients with KRAS G12C mutations comparing with other clinical-stage KRAS G12C inhibitors. Clinical data from the FIH study will be evaluated and compared to preclinical predictions.

TiNivo-2: A phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor.

TPS405 Background: Tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (aRCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile (Rini et al. Lancet Oncol 2020; 21:95-104). Tivozanib was approved by the FDA on March 10, 2021, for the treatment of patients with aRCC who had progressed on 2 or more prior lines of therapy. Tivozanib was combined with Nivolumab in the TiNivo trial (NCT03136627), showing an objective response rate of 56%, disease control rate of 96%, median PFS of 18.9 months and a favorable safety profile (Albiges et al. Ann Oncol. 2021 Jan;32(1):97-102). Methods: TiNivo-2 (NCT04987203) is a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following 1-2 lines of therapy including an immune checkpoint inhibitor. Eligibility criteria include age &gt;18 years, clear cell RCC, ECOG PS 0-1, and disease progression during or following at least 6 weeks of treatment with ICI for RCC. Subjects will be stratified by IMDC risk category and whether ICI was received in most recent line of treatment or not. On both arms, subjects will receive Tivozanib 1.34 mg orally once daily for 21 consecutive days followed by 7 days off. In the combination arm, subjects will also receive Nivolumab 480mg intravenously every 4 weeks. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 for 2 years and every 12 weeks thereafter until disease progression is confirmed by independent radiology review. The primary objective is to compare the progression-free survival (PFS) of tivozanib in combination with nivolumab to tivozanib. A sample size of 326 subjects, with 191 events will provide at least 80% power to detect a 50% improvement in PFS, 12 mos v. 8 mos, as assessed by an IRR. Secondary endpoints include assessment of overall survival (OS), objective response rate (ORR), and duration of response (DoR), as well as safety and tolerability. Exploratory endpoints are to assess the quality of life (FKSI-DRS and EORTC QLQ C-30) and to investigate the pharmacokinetics of tivozanib. TiNivo-2 is actively enrolling and planning to open at 190 sites in the United States, and the European Union. Clinical trial information: NCT04987203.

Abstract CT118: Preliminary data from Phase I first-in-human study of EOS884448, a novel potent anti-TIGIT antibody, monotherapy shows favorable tolerability profile and early signsof clinical activity in immune-resistant advanced cancers

Abstract TIGIT is an immunosuppressive mediator expressed by various immune cells in the microenvironment of most tumors. In preclinical models, targeting TIGIT with an FCγR-engaging antibody promotes an anti-tumor immune response. EOS884448 is designed to be a potent and highly selective fully human antagonist IgG1 antibody targeting TIGIT. This multicenter, first-in-human Phase I/IIa clinical trial (NCT04335253) is assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of EOS884448 monotherapy in subjects with advanced solid tumors. PD assessments were performed in peripheral blood with simultaneous determination of plasma PK. This report describes a preliminary analysis of the Phase I dose escalation part of the ongoing study with a data cut-off of December 15, 2020. Twenty-two adult participants with advanced solid malignancies have been treated with EOS884448 monotherapy. All subjects had at least 1 prior anti-cancer therapy. Cohorts of at least 3 participants were evaluated at doses of 20, 70, 200, 700 mg Q2W and 1400 mg Q4W administration. PK analyses indicated a dose-proportional increase of EOS884448 plasma exposures. PD evaluations revealed prolonged and maintained TIGIT occupancy over the dosing interval that correlated with significant depletion of suppressive Treg cells (CD4+CD25+CD127low) beginning at the lowest dose level. In terms of safety, 54 adverse events attributed to the investigational treatment were reported, 16 of which were considered immune-related. The most common (&amp;gt;10%) related adverse events (AEs) included Grade 1-2 rash and pruritus. No drug-related Grade 3-4 AEs and no dose-limiting toxicities were observed. Among the 20 patients who had at least one disease assessment, stable disease was observed in 8 participants, 4 of whom remain on therapy, and 1 partial response was observed in a patient with checkpoint inhibitor-refractory, BRAF-mutated melanoma. Overall, the early data from this Phase I trial show a manageable tolerability profile, a PK profile as expected for an IgG1 antibody, and evidence of immunomodulation with reductions in suppressive Treg cells beginning at the lowest dose tested. These observations correlate with early signs of clinical activity that will continue to be monitored in the ongoing trial. Further evaluation of EOS884448 as monotherapy and in combination with approved and investigational therapies is planned in both immune checkpoint-naïve and -refractory patients. Citation Format: Tom F.A. Van den Mooter, Ariane Migeotte, Christiane Jungels, Brant R. Delafontaine, Thi Lien-Anh Nguyen, Servane Warot, Clarise Truong, Olivier De Henau, Gregory Driessens, Joanne Lager, Sylvie Rottey, Jean-Pascal Machiels. Preliminary data from Phase I first-in-human study of EOS884448, a novel potent anti-TIGIT antibody, monotherapy shows favorable tolerability profile and early signsof clinical activity in immune-resistant advanced cancers [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 CT118.

Do Statins Enhance the Anti-Cancer Activity of Venetoclax?

▪Introduction: Venetoclax is an oral, small-molecule BCL-2 inhibitor capable of restoring apoptosis in susceptible cancers. It is approved in the US for treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with 17p deletion and in Europe for patients who are unsuitable for or who have failed B-cell receptor inhibitor (BCRi) therapy. It is also being evaluated in the broader CLL population and other hematologic malignancies. These diseases mostly afflict older patients, many of whom are treated with statins for high cholesterol. Aside from their cholesterol-lowering utility, statins have shown potential to induce apoptosis in various cancer cell lines, with evidence of synergism when combined with BCL-2 inhibition. On this background, post-hoc analyses of clinical trials in patients with CLL and multiple myeloma (MM) were undertaken to determine if statins have the potential to enhance the activity of venetoclax.Methods: Data from CLL subjects were pooled from 3 single-arm, open-label Phase 1 or 2 trials of venetoclax monotherapy in subjects with R/R disease: Study 1 (NCT01889186) enrolled subjects exclusively with 17p(del) CLL; Study 2 (NCT01328626) was a first-in-human, dose-escalation study in subjects with CLL/SLL and NHL; Study 3 (NCT02141282) enrolled CLL subjects previously treated with ibrutinib or idelalisib. MM data were from 2 single-arm, open-label Phase 1 studies in patients with R/R disease: Study 4 (NCT01794507) evaluated venetoclax in combination with bortezomib and dexamethasone (VenVd); Study 5 (NCT01794520) evaluated treatment with venetoclax monotherapy (Ven) or venetoclax plus dexamethasone (Vendex). Previously, it was reported that single-agent activity of venetoclax is almost entirely restricted to t(11;14) positive MM; therefore, analyses of response among subjects who received Ven or Vendex were limited to this subgroup. The following CLL endpoints were analyzed based on investigator assessment: overall remission rate (ORR), the composite complete remission (CR) rate (CR + CR with incomplete marrow recovery), progression free survival (PFS), and overall survival (OS). Odds ratios for ORR and CR were compared via Fisher exact test. PFS and OS were analyzed by Kaplan-Meier methodology. Multivariate analyses were conducted using Cox proportional hazard model (OS and PFS) and logistic regression model (ORR and CR) with implementation of a stepwise model selection procedure. For the MM studies, descriptive statistics were prepared based on investigator assessment for ORR, partial response (PR), and very good partial response (VGPR) or better. Exposure-response analyses have previously shown that higher exposures to venetoclax in CLL patients are associated with greater likelihood of CR and longer PFS; therefore, we also investigated the potential for statins to increase venetoclax exposures utilizing steady state pharmacokinetic sampling from Study 2.Results: In CLL studies, 22% of patients received a statin; statin users were more often male (79% vs. 67%), ≥65 years of age (73% vs. 54%), and enrolled at US sites (69% vs 46%). While the proportion of CLL subjects with any response (ORR) was similar for subjects with and without statin use (76% vs 75%), more statin users achieved CR, with cumulative CR rates of 26.7% vs. 15.2% in the pooled analysis. The unadjusted odds ratio (95% CI) for CR was 2.03 (1.099, 3.741; P=0.03) in favor of statin users, and the corresponding multivariable-adjusted odds ratio was 2.676 (1.338, 5.351; P<0.01). PFS and OS results were consistent with CR rates, with respective multivariable-adjusted hazard ratios of 0.61 (0.383, 0.956; P=0.03) and 0.50 (0.247, 1.007; P=0.05). The pharmacokinetic analysis showed no difference in venetoclax exposures between patients taking a statin versus those who did not. There were no unexpected safety observations in either group. The trend for improved response among statin-treated subjects was also present for the broad MM subject population treated with VenVd in Study 4 and t(11;14) positive MM subjects treated with Ven or Vendex in Study 5.Conclusions: Statins were associated with enhanced response to venetoclax in retrospective analyses of CLL and MM clinical trials. Given the post-hoc nature of these findings and lack of randomization, further evaluation in a prospective, randomized clinical trial is required to draw definitive conclusions. [Display omitted] DisclosuresRoberts:AbbVie: Employment, Equity Ownership. Xu:AbbVie: Employment, Equity Ownership. Jia:AbbVie: Employment, Equity Ownership. Agarwal:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership. Bellin:Abbvie: Employment, Equity Ownership. Lam:AbbVie: Employment, Equity Ownership.

239-OR: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Four-Period, Crossover Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Three Dose Levels of PB201 as Monotherapy in Subjects with Type 2 Diabetes Mellitus

Background: PB201, a dual-acting glucokinase activator (GKA), increases glucose stimulated insulin secretion, promotes glycogen synthesis and reduces hepatic glucose output by targeting both pancreatic and hepatic glucokinase. As a partial GKA, PB201 maintains efficacy while mitigates risk of hypoglycemia.Methods: Totally 16 patients with T2DM were randomized to this 4-period crossover study. In each period, 1 of the 3 dose levels of PB201 (50/50mg, 100/50mg or 100/100 mg) or placebo was administrated before breakfast and lunch for 7 days. A 7 to 14-day washout separated each period. The primary endpoints were safety and PK profiles of PB201. Continuous glucose monitoring (CGM) system was also utilized. ClinicalTrials.gov NCT03973515.Results: PB201 demonstrated dose-proportional increases in AUClast and Cmax. Elimination half-life ranged from 8.01 to 9.55 hours across all doses. No sex effect was observed in PK parameters. PB201 also showed dose-related effect in PD responses and good glycemic control (Table 1). No hypoglycemia or other drug-related adverse events were reported.Conclusion: PB201 showed linear PK properties and provided efficient glycemic control in a dose-dependent manner. Meanwhile, it was safe and well tolerated by the subjects.View largeDownload slideView largeDownload slide DisclosureM. Xu: None. Pegbio study group: n/a.

A phase III study (APROMISS) of AL3818 (Catequentinib, Anlotinib) hydrochloride monotherapy in subjects with metastatic or advanced synovial sarcoma.

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

Abstract OT-29-01: Tenacity: A phase 2, multicenter, open-label, single-arm study of AL101 monotherapy in patients with notch-activated triple negative breast cancer

Abstract Background: There is an urgent need to identify new therapeutic strategies for triple-negative breast cancer (TNBC), a sub-type associated with poor prognosis. The Notch pathway is activated during mammary gland development and has been implicated as a key driver in breast cancer (Collu, 2007). The frequency of Notch mutations or gene rearrangements was reported at 5 to 16% in TNBC tumors and over-expression of Notch was associated with worse overall survival (Robinson, 2011; Stoeck, 2014; Wang, 2015). AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling. In preclinical models, AL101 exerts its antitumor activity through direct inhibition of cell proliferation and indirectly via inhibition of tumor angiogenesis. In TNBC patient-derived xenograft (PDX) tumor models, the presence of activating Notch mutations/fusions correlated with robust response to AL101 monotherapy (ASCO 2019, Abstr 1064). AL101 has been studied in three Phase 1 studies in more than 200 subjects with various cancers (ASCO 2018, Abstr 2515) and is currently being studied in a Phase 2 study for patients with Adenoid Cystic Carcinoma with Notch activating mutations (ACCURACY- NCT03691207). Preliminary data reported from this trial showed clear signs of clinical activity along with a favorable safety profile (ESMO 2019, Abstr 3568). Trial design: The TENACITY study is an open-label, international, multicenter, single arm Phase 2, Simon two-stage optimal design for targeted therapy study of AL101 monotherapy in subjects with Notch-activated recurrent or metastatic TNBC who have received ≤ 3 lines of prior therapy. Patients with stable, asymptomatic CNS metastases are eligible. Notch activation will be determined by Next Generation Sequencing (NGS) of tumor DNA/RNA to detect somatic mutations and gene rearrangements. Target enrollment is 67 subjects. The design will include a lead-in cohort of 6 subjects to ascertain safety of AL101, 6 mg weekly (QW). After the 6th subject completes 4 weeks of therapy, safety will be assessed and subsequent dosage of AL101 will be determined (continue at 6 mg QW versus reduction to 4 mg QW). The primary endpoint is overall response rate (ORR), based on RECIST v1.1 as assessed by the treating investigator. The study design has 80% power with type I error level of 5% to detect an ORR of 23%. Key Secondary endpoints include progression free survival, clinical benefit rate, duration of response, overall survival and quality of life. Study will open to enrollment in July 2020. For further information on this trial, email chen.d@ayalapharma.com or visit clinicaltrials.gov (NCT04461600). Citation Format: Tiffany A Traina, Erin F Cobain, Ella Evron, Chen Duksin, Gary Gordon. Tenacity: A phase 2, multicenter, open-label, single-arm study of AL101 monotherapy in patients with notch-activated triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-29-01.