Continuous Daily Dosing Research Articles

Development of a recombinant Lactobacillus plantarum oral vaccine expressing VP2 protein for preventing feline panleukopenia virus

Feline panleukopenia virus (FPV) represents a significant health threat to the kittens. While traditional vaccines administered via subcutaneous or intramuscular injection are effective, they can induce stress and adverse reactions. Moreover, unvaccinated kittens visiting veterinary clinics risk exposure to FPV, increasing their susceptibility to infection. Therefore, there is an urgent need for a safer, more gentle vaccination method with streamlined administration. In this study, we developed a recombinant L. plantarum NC8/VP2 expressing the VP2 protein of the prevalent Chinese FPV strain, FPV-251. Our results show that L. plantarum NC8/VP2 effectively colonizes the feline intestinal tract and induces high levels of neutralizing antibodies through oral administration. Kittens exhibited significant protection against FPV-251 infection and associated illnesses or fatalities after 30 days of continuous dosing. These results highlight the potential of recombinant L. plantarum NC8/VP2 as a novel oral vaccine for FPV, presenting a promising approach for disease prevention in domestic cats.

Roginolisib, an oral, highly selective and allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) in patients with uveal melanoma and advanced cancers.

9597 Background: The highly selective, oral allosteric modulator of PI3Kδ, roginolisib (IOA-244), blocks the activity of PI3Kδ-dependent signaling, in both tumor cells and Tregs. Methods: Continuous daily dosing of roginolisib at 10, 20, 40 and 80 mg in patients (pts) with pretreated solid tumours and Follicular Lymphoma (FL) were evaluated (Part A). Part B consists of a dose confirmation cohort in uveal melanoma (UM) pts of 2 parts, B.1 and B.2. Primary objective: safety of the anticipated biologically effective dose (BED). Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); RECIST 1.1 or Lugano-based responses; PFS and OS. Exploratory studies: phenotypic changes in circulating immune cells by mass cytometry (i.e., CyTOF); response assessments by radiomics; analysis of circulating protein signatures via Olink proteomics. Results: Part A Solid Tumour (completed): Sixteen pts were treated in 4 cohorts of 4 pts each. Pts characteristics: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%). Only Grade 1 and 2 AEs by CTCAE v.5 were observed, including 2 cases of transient (lasting < 24 hrs) diarrhoea and 2 of AST/ALT elevation. Part A FL Cohort (completed): 8 pts were treated at 20 mg (n=4) and 80 mg (n=4). Grade 3 toxicities were transient and observed in 2/8 (25%) pts. 2/4 pts (50%) at the 80 mg had PR as per Lugano criteria. Treatment-emergent adverse events (TEAEs) did not result in study drug discontinuation, immune-related toxicity, or dose-limiting toxicity in either the solid tumor or hematological patients. UM pts (Part A and Part B)>: 29 pts (Part A: 9 pts; Part B.1: 7 pts, Part B.2: 13 pts), of which 23 were treated at 80 mg QD (RP2D). Mean time on treatment: 10.7 mo (range: 1.5-39.6 mo). ORR (RECIST 1.1): PR: 1/29 (3%); SD: 21/29 (72%). Median OS for Part A: 20.8 mo (5/9 with 4 pts alive); Part B.1 20.1 (4/7 with 3 pts alive); Part B.2 not determined; 1-year OS rate: Part A 66.7%; Part B.1 71%; Part B.2 immature. Exploratory Investigations: At 3.7 mo (Cycle 5), there were 2 groups: one with SD (13/29; 45%) and the other with PD (16/29; 55%). At 6 mo, this split continued with 38% (11/29) showing SD and 62% having PD (18/29). Volumetric changes matched durable SDs while having higher sensitivity in the 15 analyzed patients. Interestingly, tumor burden reduction in mediastinal lymph nodes was indicative of SD and 70% of pts had volumetric spleen size reduction. Volumetric and radiomic changes were matched with peripheral changes in plasma proteins and immune cell changes. Conclusions: Roginolisib is well tolerated at 80 mg, demonstrates efficacy, and induces phenotypic changes in circulating immune cells. At the RP2D, the most robust anti-tumour activity was observed in FL (50% PR) and UM pts (3% PR; 72% SD). Clinical trial information: NCT04328844 .

Abstract PS17-06: A phase I trial of the PI3K inhibitor (PI3Ki) copanlisib and fulvestrant in combination with continuous or intermittent abemaciclib in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) metastatic breast cancer

Abstract Background: Activation of the phosphoinositide 3-kinase (PI3K) pathway is a prominent resistance mechanism to endocrine therapy and CDK4/6 inhibition (CDK4/6i) in ER+, HER2- breast cancer. There is reciprocal crosstalk between PI3K and cell cycle regulatory pathways. Triplet therapy that targets ER, CDK4/6, and PI3K prevents or delays disease progression in preclinical models of ER+, HER2- breast cancer. However, the toxicities of triplet therapy hinder its clinical development. Copanlisib (COP) is an intravenous (IV) PI3Ki with potent activity against α and δ isoforms. Intermittent high-dose PI3Ki is expected to be less toxic and more effective than continuous daily dosing. We set out to determine the recommended phase 2 dose (RP2D) for the COP/Fulvestrant (FUL)/Abemaciclib (ABE) combination. Methods: Eligible patients (pts) included men or women with ER+, HER2- metastatic breast cancer (MBC), with no more than 1 prior chemotherapy in the metastatic setting, and no limits on prior endocrine or targeted therapy. Prior FUL, CDK4/6i and PI3K/mTORi were allowed. Pts with HbA1c >8.5% were excluded. Pts received FUL 500 mg IM standard dosing and COP/ABE at assigned doses. Premenopausal women also received a GnRH agonist. Dose-limiting toxicity (DLT) was assessed during the first 28-day cycle. Adverse events (AEs) were graded according to NCI-CTCAE v5.0. Dose escalation/de-escalation was based on continual reassessment (CRM) and the RP2D was defined as the dose with the highest probability of the DLT rate within the acceptable 25~35%. Results: Between June 2020 and June 2023, 24 pts with ER+, HER2- MBC were enrolled. Table 1 shows the dose levels (DLs) and DLTs. The first 10 pts were enrolled to Part A on two consecutive DLs of COP (DL1: 45 mg IV D1 and D15, n=7; DL2: 45 mg IV D1, D8, and D15, n=3), with ABE fixed at 100 mg PO BID continuously. DL2a exceeded the maximum tolerated dose (MTD). DL1a was tolerable based on Cycle 1 AEs. However, during subsequent cycles, only 1 of the 7 pts in DL1a maintained the intended dose of ABE due to neutropenia, others reduced ABE to 50mg bid (n=5) or discontinued (n=1). This triggered a protocol amendment, adding Part B with ABE administered 5 days on and 2 days off (5-on/2-off) intermittent schedule. 14 pts were enrolled to Part B in 2 consecutive DLs of COP (DL1b: n=7; DL2b: n=7), the same as in Part A. ABE was fixed at 100 mg PO Bid 5-on/2-off. DL2b exceeded the MTD. DL1b was tolerable based on Cycle 1 AEs. In addition, in subsequent cycles, only 1 of 7 pts on DL1b required dose reduction of ABE to 50mg bid. RP2D is therefore defined as DL1b. Grade (G) 4 AEs were rare. The most common all cycle G3 AEs included transient hypertension (45%), rash (30%), anemia (25%), neutropenia (25%), and AST elevation (20%). As of 6/14/2023, 22 pts, with a median of 1 prior metastatic regimen (range 0-5), prior CDK4/6i in 18 (82%), liver mets in 8 (36%), and PIK3CA mutation in 8 (50%) of 16 pts with known mutation status, were evaluable for response. There were 5 partial responses and 3 stable diseases lasting for ≥24 weeks. Clinical benefit rate was 36.4% (8/22, 95%CI: 17.19% ~ 59.34%). Responses were observed in pts regardless of prior CDK4/6i, FUL, or PIK3CA mutation. Conclusion: COP/FUL/intermittent ABE can be safely administered with fair overall tolerability. Preliminary anti-tumor activity was observed, which will be further examined in the randomized phase II trial (NCT 03939897). Table 1 Dose-limiting Toxicities by Dose Level Citation Format: Cynthia Ma, Jingqin Luo, Jessica Moss, Maryann Kwa, Ritesh Parajuli, Katia Khoury, Emily Douglas, Ashley Frith, Caron Rigden, Foluso Ademuyiwa, Shana Thomas, Brittney Haas, Gerburg Wulf, Claire Dees, Rabih Said. A phase I trial of the PI3K inhibitor (PI3Ki) copanlisib and fulvestrant in combination with continuous or intermittent abemaciclib in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) metastatic breast cancer [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 PS17-06.

Abstract 3217: Discovery of novel inhibitors of the epigenetic regulator Kat6a histone acetyl transferase and characterization of their anti-tumor activity

Abstract KAT6A and its paralog KAT6B are histone acetyltransferases (HATs) which direct chromatin structural rearrangement and subsequent changes in gene transcription through acetylation of histones, primarily specific lysine residues on histone H3. KAT6A is modified in cancer, including genomic amplification, overexpression, mutation, as well as genetic rearrangement, resulting in the production of fusion proteins. Dysregulation of this MYST family member and its acetyl transferase activity is known to drive gene expression and tumorigenic progression in cancers. An inhibitor of KAT6A and KAT6B entered phase 1 clinical trials (NCT04606446). With continuous daily dosing, durable partial responses were seen in estrogen-receptor positive (ER+) breast cancer patients who had progressed on a prior endocrine therapy and CDK4/6 inhibitor. In that study, evidence of dose dependent pharmacodynamics (H3K23Ac inhibition) was observed in peripheral blood mononuclear cells and paired tumor biopsies (Sommerhalder, ASCO2023). Isosterix has developed a series of structurally diverse small molecule KAT6A-selective inhibitors which engage at the active site in the acetyl CoA substrate binding pocket. Lead compounds are selective for KAT6A and have significant potency and cellular activity in a variety of assays; they inhibit KAT6A-mediated histone acetylation in a biochemical assay as well as pharmacodynamic dose-dependent inhibition of histone acetylation in the breast cancer tumor cell line ZR-75-1. These compounds reduce cell viability of ZR-75-1 in 10 days with continuous compound administration, confirming the dependence of this cell line on KAT6A acetyl transferase activity for proliferation and cell cycle progression. Lead inhibitors are orally bioavailable with excellent pharmacokinetic properties in rodents. They demonstrate dose-dependent anti-tumor efficacy with minimal weight loss with continuous daily dosing in mouse xenograft tumor models. Inhibitors against this novel epigenetic target demonstrate the potential for efficacy in not only ER+ breast cancer but also other tumor indications which exhibit transcriptional induction dependent on KAT6A-directed chromatin remodeling. Selection of a lead candidate is planned for early 2024 with IND enabling studies to follow. Citation Format: Leslie J. Holsinger, Roopa Rai, Rahul R. Nagawade, Benoy K. Pal, Samir G. Pawar, Krishna Anand Putta, Somashekar S.C., Mahaboobi Jaleel, Jianhong Wang, Alison L. Hannah. Discovery of novel inhibitors of the epigenetic regulator Kat6a histone acetyl transferase and characterization of their anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3217.

Abstract A094: Preclinical characterization of HMPL-415, a second-generation SHP2 inhibitor

Abstract Background: Oncogenic activation of the RAS/MAPK signaling pathway is one of the leading causes for driving a variety of cancers. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) functions downstream of multiple RTKs, and integrates growth factor signals to promote RAS activation, making it an attractive drug target for cancers harboring oncogenic alterations in RAS/MAPK pathway. Herein, we present the preclinical characterization of HMPL-415, a highly potent, selective and non-competitive SHP2 inhibitor, discovered and being currently developed in phase I clinical trial (NCT05886374) by HUTCHMED. Methods: The inhibition of HMPL-415 on the full length and catalytic domain of SHP2 was detected by a biochemical DIFMUP pseudosubstracte-fluorgenic assay. For selectivity, HMPL-415 was assessed against a panel of 413 kinases and 21 phosphatases by Eurofins. The modulation of HMPL-415 on RAS/MAPK signaling cascades was evaluated by western blot. In vitro anti-proliferation activity was measured by CellTiter-Glo luminescent assay. Multiple human xenograft tumors with RAS/MAPK pathway activation were applied in immune-deficient mice to investigate the anti-tumor activity of HMPL-415. Results: In vitro, HMPL-415 displayed higher potency in enzyme (5 fold) and cellular target inhibition (> 20 fold) compared to first-generation SHP inhibitor TNO155. It strongly inhibited full length of human SHP2 with an IC50 of 0.4 nM, while had no inhibitory activity up to 10 µM against the catalytic domain of SHP2. In NCI-H358 (KrasG12C), NCI-H508 (class Ⅲ BRAFG596R), and NCI-H1838 (NF1N184fs) cells, HMPL-415 inhibited p-ERK with IC50s of 1~3 nM, and significantly suppressed downstream molecules p-RSK and p-S6. Through inhibition of RAS/MAPK signaling pathway, HMPL-415 robustly inhibited cell proliferation in a panel of human cancer cell lines with KRAS G12C/V, BRAF class Ⅲ, NF1 loss of function (LOF), RTK mutations or KRAS amplification (median GI50 =1 nM) compared to cell lines harboring KRAS G12D, G13 or Q61 mutations (median GI50 >1 µM), indicating a dependence on specific KRAS nucleotide-cycling for anti-tumor effect. Furthermore, the selectivity across panels of 413 kinases and 21 phosphatases revealed that HMPL-415 should have a low off-target risk. In vivo, oral administration of HMPL-415 showed prolonged and high tumor exposure and sustained inhibition on RAS/MAPK signaling after repeat dosing. In human xenograft models carrying KRAS, BRAF class Ⅲ, NF1LOF, and EGFR alterations, HMPL-415 dose-dependently induced tumor growth inhibition at continuous daily doses that were well tolerated. Tumor regression was observed in most tumor models tested at the dose of 3 mg/kg/day, which demonstrated much superior anti-tumor activity than that of TNO155 at 30 mg/kg/day. Conclusion: HMPL-415 is a highly potent, selective and non-competitive SHP2 inhibitor that demonstrates strong anti-tumor activity in vitro and in vivo, supporting further clinical evaluation. Citation Format: Jia Hu, Jun Ni, Zhihu Gao, Xiaoqing Liu, Hui Zhang, Pan Wang, Min Cheng, Guanglin Wang, Zeyu Zhong, Jian Wang, Yang Sai, Na Yang, Weiguo Qing, Yongxin Ren, Michael Shi, Weiguo Su. Preclinical characterization of HMPL-415, a second-generation SHP2 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A094.

Abstract LB_A13: Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer

Abstract Background: The MCT inhibitor CYT-0851 potently inhibits MCT1, has activity against MCT4, and blocks lactate transport resulting in cell death in glycolytic cancer cells. In an in vitro CRISPR screen, thymidylate synthetase was a significant hit in 2 resistant cell models, sensitizing them to CYT-0851. Follow-up in vitro combination studies showed that CYT-0851 synergized with 5-FU to inhibit cancer cell growth. Monotherapy clinical activity of CYT-0851 has been reported previously in lymphoma and solid tumors. In the phase 1 dose escalation trial of CYT-0851 plus cape, 400 mg was identified as the recommended phase 2 dose. In three phase 2 trials, cape had a RECIST response rate of 5-8% in ovarian cancer. Methods: An expansion cohort of 10 patients (pts) with platinum resistant advanced ovarian cancer were treated with CYT-0851, 400 mg QD in combination with cape, 1000 mg/m2 PO BID x 14 days every 21 days and were evaluable. One additional pt treated at the 300 mg dose level was evaluable and added to the analysis. The primary objective was safety, and secondary objectives were pharmacokinetics and preliminary anti-tumor activity by RECIST. Results: As of Aug 21, 2023, 11 pts were treated and evaluable, 9 white, 1 African American black, and 1 American Indian or Alaskan native, with a median age of 64 (range 52-76). Median prior therapies were 6 (range 2-14). All but one had 3 or more prior therapies. Median CYT-0851 dose compliance with continuous daily dosing was 99% (range 91– 100%). There were no treatment discontinuations or CYT-0851 dose reductions for treatment related adverse events. 7 pts (64%) experienced a treatment-related adverse event, all were Grade 1-2. There were no grade 3+ treatment related adverse events. The most common related AEs were fatigue reported in 5 pts (46%), and decreased appetite, diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome and vomiting, each reported in 2 patients (18%). Exposure of CYT-0851 in combination with capecitabine exhibits dose proportional behavior and was similar between combination therapy and monotherapy. One pt had a confirmed PR with progression on day 294, and 2 additional pts achieved a PR that has not been confirmed yet, with treatment ongoing on day 113 and 41. 7 pts had SD, and one patient PD as best response. The disease control rate was 91%. 5 Pts discontinued for progressive disease with a median of 133 days of treatment (range 43-300), and 2 withdrew consent on days 131-134. 4 patients continue therapy on days 42,47,106, and 113. Median PFS was 170 days (95% CI 79-NA). Conclusions: The oral outpatient combination of CYT-0851 and cape has demonstrated an acceptable safety and tolerability profile without any unanticipated toxicities at clinically active doses. The disease control rate of 91% and unconfirmed response rate of 27% in refractory platinum resistant ovarian cancer is promising and warrants further exploration. Furthermore, this regimen should be evaluated in other tumor types commonly treated with 5-FU, including breast and colorectal cancer. Citation Format: Elizabeth Swisher, Gerald Steven Falchook, Pamela N. Munster, Nina Beri, Kathleen N. Moore, Timothy A. Yap, David R. Spigel, Susan Doleman, William D. Bradley, Thomas J. O'Shea, Markus F. Renschler, Ryan C. Lynch. Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A13.

Phase 1b/2 Trial of Enasidenib in Lower-Risk MDS and Nonproliferative CMML without Isocitrate Dehydrogenase Type 2 Mutations

Introduction: Enasidenib is an FDA approved selective-inhibitor of mutant IDH2 ( mIDH2) enzyme commonly found in acute myeloid leukemia (AML). Previous studies found enasidenib unexpectedly improved red blood cell and platelet transfusion needs in mIDH2 AML patients without a reduction in AML disease burden (Pollyea DA, et al. Leukemia 2019; 33(11):2575-2584; DiNardo CD, et al. Lancet Oncol 2021; 22(11):1597-1608). We subsequently demonstrated enasidenib robustly enhanced human erythropoiesis from umbilical cord-blood and bone marrow-derived CD34+ hematopoietic progenitor cells independent of IDH2 status and the oncometabolite R-2-hydroxyglutarate (R-2-HG), thus prompting us to investigate enasidenib as an erythropoiesis-stimulating agent (Dutta R, et al. J Clin Invest 2020; 130(4):1843-1849). Aim: To evaluate the safety, tolerability, and efficacy of daily enasidenib in patients with lower-risk MDS or nonproliferative CMML without IDH2 mutations. Methods: In this ongoing two-part phase 1b/2 single-center, investigator-initiated, open-label trial, patients with a diagnosis of IDH2 wildtype lower risk MDS and nonproliferative CMML self-administered continuous daily dosing of enasidenib. Two dose levels were planned at 100mg and 200mg daily for Cohort A and B, respectively based on a standard 3 x 3 dose escalation schema. All patients were evaluated for adverse events (AEs) to determine dose-limiting toxicities (DLTs) and establish the recommended phase 2 dose (RP2D). Patients were screened in a consecutive manner to reduce selection bias by the investigators and all consents were translated into participant's native language to ensure full understanding and voluntary participation. Eligible patients are 18 years or older, ECOG ≤3, negative for IDH2 mutation, have adequate organ function, and symptomatic anemia (hemoglobin <10.5g/dL). Other causes such as iron/nutritional deficiencies and bleeding were ruled out during screening. Prior treatment with ESA, G-CSF, and luspatercept was allowed with a 30-day washout period. Each cycle is 28 days. Patients were evaluated by the PI on Day 1 (±3 days), and laboratory evaluation was conducted every 15 ±3 days. Results: Seven patients were enrolled between July 6, 2022 and December 21, 2022 with three patients in Cohort A receiving 100mg and 4 patients in Cohort B receiving 200mg (Table 1A). No DLTs were seen during the first 6 cycles of treatment. One treatment was discontinued due to the need for treatment of vasculitides related to a new diagnosis of VEXAS made during cycle 2 of the trial (unrelated to study drug). Another patient discontinued treatment after 1 cycle to pursue allogeneic stem cell transplant. All patients experienced at least one treatment-related adverse event (TRAE) which were limited to grade 1 or 2. TRAEs noted were consistent with those previously reported with enasidenib use (Stein EM, et al. Lancet Haematol 2020; 7(4):e309-e319), most commonly hyperbilirubinemia observed in 6 patients (85.7%), nausea in 4 patients (57.1%), and rash (inflammatory dermatoses, previously well-described) in 5 patients (71.4%) (Table 1B) (Parisi R, et al. Leuk Res 2022; 123:106970). No grade 3 or higher TRAE were observed. Two patients (28.7%) experienced a Grade 3 adverse event of pneumonia. Four patients developed an infection (57.1%) with only one requiring a hospitalization. One grade 4 event occurred (duodenal hemorrhage) in a patient with history of duodenal ulcers and concurrent aspirin use. As above, a patient in Cohort A was diagnosed with VEXAS syndrome after enrollment and experienced a complicated course of vasculitis and opportunistic infections in the setting of high dose steroid use. Interestingly, one newly diagnosed patient in the 200mg Cohort B without prior growth factor or ESA is enjoying a sustained trilineage improvement with increase of absolute neutrophil count, hemoglobin, and platelets from baseline (10 cycles at the time of data cutoff of June, 16, 2023). Conclusions: Enasidenib at 200mg dose was safe and well tolerated in patients with lower-risk MDS. Thus far, one patient has seen trilineage improvement in blood counts and continues on study. The Phase 2 portion of the study is ongoing to further characterize safety and evaluate for efficacy to improve anemia and decrease transfusion needs.

A Phase 1 Study of the Oral CDK9 Inhibitor Voruciclib in Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL) or Acute Myeloid Leukemia (AML)

Background: The anti-apoptotic protein Mcl-1 contributes to the pathophysiology of certain B-cell malignancies and AML, and dependence on Mcl-1 is associated with resistance to venetoclax. Efforts to target Mcl-1 through direct inhibition have faced challenges due to cardiovascular toxicities. Voruciclib, a potent oral CDK9 inhibitor (CDK9i), was shown to indirectly downregulate Mcl-1 protein levels and synergize with venetoclax in preclinical models in lymphoid and myeloid malignancies. In solid tumors, voruciclib maximum tolerated dose (MTD) was defined as 350 mg with continuous daily dosing, and 600 mg when used on days 1-14 on a 21-day cycle. This phase 1 study is the first to evaluate the safety, dose-limiting toxicities (DLT), preliminary efficacy, pharmacokinetics, and pharmacodynamics of voruciclib in R/R hematologic malignancies (NCT03547115). Methods: Patients (pts) with relapsed B-cell NHL, CLL, or AML aged ≥18 years who had ECOG performance status ≤1, disease progression after standard therapies, adequate hepatic and renal function, and no prior CDK9i were eligible. The study followed a 3+3 design and DLTs were assessed in Cycle 1. Voruciclib was administered daily continuously at a starting dose of 50 mg on a 28-day cycle (Cohort I). After 2 DLTs were observed at 100 mg in AML pts, dosing was changed to daily on days 1-14 on a 28-day cycle (Cohort II). Also, pts with prior allogeneic transplant were excluded and dose escalation (100, 150, 200 mg) proceeded separately in AML and B-cell malignancies. Disease response was assessed by investigators using the Lugano, 2008 iwCLL, and 2017 ELN criteria. Results: 40 pts were enrolled: 21 AML, 19 NHL (9 DLBCL, 3 CLL, 3 MCL, 3 FL and 1 MZL). Cohort I enrolled 16 pts, 8 each at 50 mg and 100 mg. Cohort II enrolled 24 pts (17 AML and 7 B-cell malignancies), including 6 at 100 mg, 7 at 150 mg, and 11 at 200 mg. Dose escalation in Cohort II did not reach the MTD and was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition. Median age was 70 years (range 40-90), 72.5% of pts were ≥65 years, and 77.5% had ECOG performance status = 1. Pts had a median of 3 prior therapies (range, 1-8). Median duration on drug was 5 weeks (range 1-22). Drug-related serious adverse events (AEs) were reported in Cohort I only. Two pts with AML had a DLT of Grade (Gr) 3 interstitial pneumonitis at 100 mg; both had had allogeneic transplant and active graft versus host disease, one of whom also had a concurrent Gr 3 differentiation syndrome. One pt with DLBCL at 50 mg had Gr 3 hypoxemic respiratory failure in Cycle 4. In Cohort II, no DLTs were observed and there were no non-hematologic Gr 3-5 drug-related AEs. In the overall population, the most common AEs were diarrhea (30%), nausea (25%), anemia (22.5%), fatigue (22.5%), constipation (17.5%), dizziness (15%) and dyspnea (15%) [Table 1). One pt with AML had Gr 3 hyperbilirubinemia. There was no evidence of drug-related neutropenia in pts with NHL. No significant cardiovascular AEs were observed. One pt with AML in Cohort I achieved a morphologic leukemia-free state. At 200 mg, 5 of 10 AML pts (50%) had stable disease. Voruciclib pharmacokinetics was dose proportional, mean accumulation ratio was 2.4, mean T max was 4 hours, and at 200 mg, steady state C max was 925 ng/mL and mean C trough was 442 ng/mL (~1 microM). Analysis of Mcl-1 protein expression in normal lymphocytes by flow cytometry showed a trend of decrease in on-treatment samples compared to pre-treatment. Consistent with this, RNA-Seq analysis of 3 paired CLL samples confirmed rapid (after 6 hours) downregulation of Mcl-1 mRNA transcript in the malignant B-cells. Furthermore, scRNA-Seq analysis of 2 longitudinal AML samples demonstrated downregulation of MYC transcriptional program and oxidative phosphorylation in circulating AML blasts, both evident 24 hours after start of voruciclib and ongoing at C1D15. Conclusions: Voruciclib at doses up to 200 mg administered on 14 consecutive days on a 28-day cycle was well tolerated, with no DLTs observed, and no cardiovascular toxicities. There was no significant myelosuppression in pts with B-cell malignancies. As the safety profile suggested non-overlapping toxicities with venetoclax, the study is now evaluating voruciclib in combination with venetoclax in pts with R/R AML to exploit dual inhibition of Bcl-2 and Mcl-1.

Phase 1/1b study of SY-5609, a selective and potent CDK7 inhibitor, in advanced solid tumors and in 2L/3L pancreatic ductal adenocarcinoma (PDAC) in combination with gemcitabine +/- nab-paclitaxel.

3080 Background: SY-5609 is an oral, highly selective and potent noncovalent inhibitor of CDK7, a key regulator of cell cycle progression and transcription. In this Phase 1 FIH study (NCT04247126), the single agent (SA) continuous daily dosing (CDD) regimen maximum tolerated dose (MTD) was 3 mg/day. Subsequently, enhanced tolerability was demonstrated using an intermittent 7 day on/7 day off (7/7) schedule at higher dose levels (Sharma 2021). SY-5609 preclinical data and early clinical activity provided the rationale for evaluating SY-5609 + gemcitabine (gem) +/- nab-paclitaxel (np) in PDAC. Herein, we present data from the ongoing SA dose escalation and SY-5609 + gem +/- nab-paclitaxel (np) safety lead-ins (SLIs). Methods: The 7/7 schedule was used to further evaluate SA escalation in pts with select solid tumors. In the PDAC combination SLIs, SY-5609, starting with a dose of 4 mg, is escalated using the 7/7 schedule in combination with biweekly gem (1000 mg/m2) +/- np (125 mg/m2). Evaluations included safety, clinical activity (RECIST v1.1), PK, and induction of peripheral blood PD marker POLR2A (Papadopoulos 2020). Results: As of 13 Jan 2023, 87 pts have been enrolled (70 SA, 14 SY-5609 + gem, 3 SY-5609 + gem/np), including 30 pts across the 4, 5, 6, 7, and 10 mg SA 7/7 cohorts included in the safety summary. MTD for the 7/7 schedule has not been reached. The 15 mg SA cohort is now enrolling. Most SA 7/7 AEs were low-grade; AEs included (>20%) nausea, diarrhea, fatigue, anorexia, and thrombocytopenia. No new safety signals were observed in the SY-5609 4 mg and 5 mg + gem and SY-5609 4 mg + gem/np cohorts; 1 pt (SY-5609 5 mg + gem) had a DLT of Gr3 diarrhea. The 10 mg + gem cohort is now enrolling. Most SY-5609 + gem +/- np AEs were low grade. AEs in the SLIs were consistent with the safety profile of either SY-5609 or gem +/- np and included (>20%) fatigue, anorexia, nausea, abdominal pain, and constipation. In the SA cohorts (response-evaluable, n=29), 100% (3/3) of pts in the 10 mg 7/7 cohort had stable disease (SD) as the best response, compared to 19% (5/26) SD rate in 4 to 7 mg SA 7/7 cohorts. Disease control rate in the combination SLIs (response-evaluable, n=11) was 45% (5/11), including 1 confirmed partial response (4 mg + gem) in a patient with liver metastases who had a reduction in CA 19-9 from 60,357 U/mL to 968 U/mL, and SD in 4 pts (3 in 5 mg + gem, 1 in 4 mg + gem/np). SA and SLI PK data support an emerging exposure-activity relationship. POLR2A PD marker data from SA and SLI cohorts correlate with exposure. Conclusions: To date, intermittent dosing of SY-5609 on the 7/7 schedule has acceptable tolerability alone and in combination with gem +/- np. Encouraging preliminary clinical activity and the emerging exposure-activity relationship supports the ongoing escalation of SY-5609 in SA and combination SLI cohorts; updated results will be presented. Clinical trial information: NCT04247126 .

First-in-human (FIH) phase I dose escalation study (part A) of the first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) roginolisib in patients with advanced cancer and dose confirmation in uveal melanoma (part B).

3110 Background: The highly selective oral allosteric modulator of PI3Kδ, roginolisib (IOA-244), blocks the activity of PI3Kδ -dependent signalling, in both tumour cells and Tregs. Methods: Part A explored the continuous daily dosing of roginolisib at 10, 20, 40 and 80 mg in patients (pts) with solid tumours and Follicular Lymphoma (FL). Part B consists of dose confirmation cohorts, including uveal melanoma (UM) pts. Primary objective: safety of the anticipated biologically effective dose (BED), or the recommended phase 2 dose (RP2D). Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); RECIST 1.1. or Lugano-based responses; PFS and OS. Exploratory studies: phenotypic changes in circulating immune cells by Cytometry by Time of Flight (CyTOF); response assessments by radiomics; analysis of circulating protein signatures via Olink proteomic. Results: Part A Solid Tumour (completed): Sixteen pts were treated in 4 cohorts, each with 4 pts. Pts characteristics: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%). Only Grade 1 and 2 AEs by CTCAE v5 were observed, including 2 cases of transient (lasting < 24 hrs) diarrhoea and 2 of AST/ALT elevation. Part A FL Cohort (completed): 8 pts were treated at 20 mg (n=4) and 80 mg (n=4). Grade 3 toxicities were transient and observed in 2/8 (25%) pts. 2/4 pts (50%) at the 80 mg had PR as per Lugano criteria. Neither in the solid tumour nor in the haematology pts treatment-emergent adverse events (TEAE) led to study drug discontinuation, immune related toxicity, or a Dose Limiting Toxicity. Subgroup evaluation: UM pts (Part A and Part B): 24 pts (Part A: 9 pts; Part B ongoing: 15 pts), of which 18 pts treated at 80 mg QD (RP2D). Mean time on treatment: 8.6 mo (range: 1.0-27.9 mo). ORR (RECIST 1.1): PR: 1/20 (5%); SD: 16/20 (80%). Median OS for Part A: 20.8 mo (5/9 with 4 pts alive); Part B: not determined; 1-year OS rate: Part A 66.7%; Part B: ongoing. Exploratory Investigations: Radiomics-based evaluation of CT images in pts with solid tumors assessed each metastatic organ, detecting mixed responses; peripheral proteomic evaluation detected changes in several cytokines and chemokines; CyTOF detected reduction in circulating Tregs associated with increased activated effector CD8+ T cells. Conclusions: Roginolisib is well tolerated at the 80 mg dose, shows signs of efficacy and induces phenotypic changes in the circulating immune cells. As best response at the RP2D, the most robust anti-tumour activity was observed in FL (50% PR) and UM pts (5% PR; 80% SD). Clinical trial information: NCT04328844 .

A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer

BackgroundThis was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737.MethodsPatients with advanced solid tumours enrolled in dose-escalation cohorts and received SRA737 monotherapy orally on a continuous daily (QD) dosing schedule in 28-day cycles. Expansion cohorts included up to 20 patients with prospectively selected, pre-specified response predictive biomarkers.ResultsIn total, 107 patients were treated at dose levels from 20–1300 mg. The maximum tolerated dose (MTD) of SRA737 was 1000 mg QD, the recommended Phase 2 dose (RP2D) was 800 mg QD. Common toxicities of diarrhoea, nausea and vomiting were generally mild to moderate. Dose-limiting toxicity at daily doses of 1000 and 1300 mg QD SRA737 included gastrointestinal events, neutropenia and thrombocytopenia. Pharmacokinetic analysis at the 800 mg QD dose showed a mean Cmin of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen.ConclusionsSRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy.Clinical trial registrationClinicaltrials.gov NCT02797964.

Sunitinib versus imatinib dose escalation after failure of imatinib standard dose in patients with advanced Gastrointestinal stromal tumors – a real-world multi-center study

BackgroundWhether to escalate imatinib dosage or directly switch to sunitinib in gastrointestinal stromal tumors (GISTs) failing on standard dose 400 mg/d of imatinib is still controversial. MethodsWe evaluated progression-free survival (PFS), overall survival (OS), and time to sunitinib failure (TTSF) of patients selecting imatinib dose escalation or directly switching to sunitinib after the failure of imatinib 400 mg/d therapy from 3 tertery referring centers between January 2008 to December 2016. ResultsA total of 240 patients receiving sunitinib (37.5 mg continuous daily dose or 50 mg 4 weeks on with 2 weeks off) for at least 8 weeks were examined. After failure on imatinib 400 mg/d, 100 (49.3%) patients had dose escalation to 600 mg or 800 mg per day (IM group, imatinib group), and 103 (50.7%) directly switched to sunitinib (SU group, sunitinib group). The PFS in the SU and IM groups was 12 months and 5.0 months (P < 0.001), respectively. TTSF or OS in both groups was not statistically significantly different. ConclusionsAfter the progression of imatinib standard-dose treatment in recurrent/metastatic GISTs, the PFS of patients directly switching to sunitinib was significantly longer compared with the PFS of patients with imatinib dose escalation. However, when the patients continued with sunitinib therapy after the failure of IM dose escalation, TTSF and OS in the IM group were similar to those in the SU group. Further exploration of the characteristics of the population benefiting from imatinib dose escalation are warranted.

Phase I Study of Tq-B3101 in Pediatric Patients with Relapsed/Refractory Anaplastic Lymphoma Kinase Positive Anaplastic Large Cell Lymphoma

Background Anaplastic large cell lymphoma (ALCL) accounts for 10-30% of childhood lymphomas, and 90% of pediatric and adolescent patients (pts) are Anaplastic Lymphoma Kinase positive ALCL (ALK+ ALCL). The results of ADVL0912 (NCT00939770) and A8081013 (NCT01121588) studies suggest that the ALK inhibitor crizotinib has good efficacy and safety in the treatment of ALK+ALCL. The recommended pediatric dose of crizotinib is 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. TQ-B3101 is a novel kinase inhibitor for ROS1, ALK, and c-MET kinases. After oral administration, TQ-B3101 undergoes deacetylation to form crizotinib. In animal models, TQ-B3101 significantly inhibited the phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2) in ALK downstream signaling pathway in tumor tissue, with a longer inhibition time and stronger inhibition compared to equimolar crizotinib. This study aimed to explore the safety and efficacy of TQ-B3101 in pediatric patients with ALK+ ALCL. Methods TQ-B3101-II-02 is an open-label, single-arm, phase I dose escalation and pharmacokinetic study. Eligible pts were 10 to 18 years of age with relapsed/refractory (R/R) ALK+ALCL. We used a 3+3 design to determine the maximum tolerated dose (MTD). The dose levels to be investigated were 200mg BID, 250mg BID, and 300mg BID. Dose-limiting toxicities (DLT) were defined in cycle one (28-day) as any grade 4 hematologic toxicity or any grade 3 non-hematologic toxicity, except for alopecia and electrolyte disturbances that resolved within 3 days. The primary endpoints were safety and pharmacokinetics (PK). Secondary endpoints included overall response rate (ORR), progression free survival (PFS), and overall survival (OS). Responses were evaluated by investigators per the 2014 Lugano classification based on positron emission tomography/computed tomography (PET/CT) scans. This trial was registered at www.clinicaltrials.gov as # NCT04306887. Results All seven patients enrolled were evaluable for toxicities and response, with four males/three females, a median age of 12 years (range, 10-14 years), a median weight of 40.0 kg (range, 32.9-68.0 kg), a median height of 152.0 cm (range, 143.5-169.5 cm), and a median body surface area (BSA) 1.27 m2 (range, 1.15-1.73 m2). Three patients, three patients, and one patient with ALCL were treated at doses of 200mg, 250mg, and 300mg, respectively. The majority of patients (57.1%) had a median Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 1. Two patients had a refractory disease and five had relapsed disease. Histological diagnosis of ALK-positive ALCL was confirmed by immunohistochemistry. The area under the curve (AUC)(0-t) of the three dose groups after the first administration were 492 ± 285, 606 ± 288, and 914 μg/L*h, respectively, and the AUC(0-t) after the last administration was 2311 ± 997, 3749 ± 407, 3311 μg/L*h. The in vivo exposure of deacetylated metabolites generated after a single dose was lower than that of crizotinib, and after 28 days of continuous dosing, the in vivo exposure was similar to that of crizotinib (BSA-adjusted dose). The most frequently reported treatment-related adverse events (TRAEs) were hypothyroidism (n = 6), vomit (n = 6), reduced neutrophil count (n = 6). Four pts (57.1%) had grade 3-4 TRAEs. No treatment-related death and DLTs were observed. The ORR was 100%, with four patients achieving complete response (CR) and three patients achieving a partial response (PR). The median time to respond was 1.9 months (range 1.8, 2.0). Six pts had a ≥ 60% tumor reduction. As of the cut-off date of July 22, 2022, the four pts with CR received TQ-B3101 beyond 20 cycles (range, 20-34 cycles) and remained progression-free at 18.7 to 27.9 months. The three pts with PR progressed after 3 to 4 cycles of treatment and discontinued TQ-B3101. One patient voluntarily withdrew from the study. All seven patients were still alive, with the longest survival time of more than 32 months. Conclusion Our preliminary results suggest that TQ-B3101 has significant clinical activity in children with R/R ALK+ ALCL. Responses were durable and ongoing, and treatment was well tolerated. Further investigation is warranted to find the MTD and confirm the efficacy of TQ-B3101. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final Overall Survival, Safety, and Quality of Life Results From a Phase 2 Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced NSCLC

IntroductionCrizotinib provided meaningful clinical benefit in the initial analysis of a phase 2 study in East Asian patients with advanced ROS1-positive NSCLC (NCT01945021). Nevertheless, overall survival (OS) data were immature. Here, we present the final OS, quality of life (QoL), and safety data after an additional 3 years of follow-up. MethodsIn this phase 2, open-label, single-arm trial, East Asian patients with ROS1-positive advanced NSCLC who had received less than or equal to three systemic therapies previously were treated with crizotinib 250 mg twice daily on a continuous daily dosing schedule in 28-day cycles. The OS (secondary end point) was analyzed for the total population, by country, and by number of previous chemotherapy regimens. QoL and safety were also evaluated. ResultsWith a median duration of follow-up of 56.1 months, the median OS was 44.2 months (95% confidence interval: 32.0–not reached) for the total population (N = 127). Differences in median OS were observed among individual countries and with number of previous regimens. The improvement in QoL found in the previous analysis was maintained with the extended follow-up. Treatment-related adverse events led to crizotinib dose reductions or permanent treatment discontinuations in 17.3% and 2.4%, respectively, of the patients. ConclusionsThis is the largest trial of an ALK/ROS1 inhibitor to treat patients with ROS1-positive advanced NSCLC and provides a new benchmark for OS in East Asian patients. The QoL and safety profile with long-term follow-up were consistent with previous reports and support the continued use of crizotinib in the treatment of patients with ROS1-positive advanced NSCLC.

Abstract A07: BTM 3566, a novel activator of the mitochondrial stress response promotes robust therapeutic responses in vitro and in vivo in diffuse large B-cell lymphoma

Abstract Relapsed/refractory diffuse large B-cell lymphomas (r/r-DLBCL) are a therapeutic challenge as they are highly heterogeneous both clinically and molecularly, which imposes a pressing need to develop novel therapies to improve outcomes in patients independently of the molecular subtype. We describe here BTM-3566, a first-in-class, orally active compound with activity against DLBCL. BTM-3566 induces apoptosis and complete cell killing in DLBCL lines a with an IC50 of ~200 – 500 nM. Responsive DLBCL cell lines include ABC, GCB, and double-hit and triple-hit lymphoma type. Pharmacokinetic studies in mice showed suitability for once daily dosing, with &amp;gt; 50% oral bioavailability and ~6 hours of serum half-life. In xenograft models using the double-hit DLBCL line SU-DHL-10, BTM-3566 treatment resulted in complete response in all tumor-bearing animals and durable remission in 50% of animals with no tumor growth occurring for 2 weeks after dose cessation. Expansion studies into human DLBCL PDX models harboring a range of high-risk genomic alterations demonstrated response in 100% of the lines with complete response in 6 of 9 PDX models tested. Dose scheduling studies indicate that 7 days of continuous dosing is sufficient to induce tumor regression and maintenance of a complete response. The therapeutic activity of BTM-3566 is related to a novel effect on mitochondrial proteostasis and a robust induction of the ATF4 ISR. Of the four eIF2α -kinases in the human genome we determined that HRI was uniquely required for BTM-3566 activity in DLBCL. HRI is activated by mitochondrial-related stress resulting in activation of the mitochondrial protease OMA1. Molecular analysis revealed that BTM-3566 activates OMA1, leading to induction of the ATF4 ISR pathway and apoptosis in DLBCL cell lines. Deletion of OMA1 reduces the ability of BTM-3566’s to induce apoptosis in DBLCL. Substrates of OMA1 include the dynamin OPA1 and DELE1, a protein recently shown to signal mitochondrial dysfunction through activation of HRI kinase and ATF4. Transfection of BJAB cells with a cleavage resistant OPA1 mutant has no effect on BTM-3566 induced apoptosis. In contrast, DELE1 KO suppresses BTM-3566 mediated apoptosis. BTM-3566 activates OMA1 without acting as a classical mitochondrial toxin. Instead, BTM-3566 induces OMA1 activity through a novel mechanism regulated by the mitochondrial protein FAM210B. FAM210B expression is negatively correlated with response to BTM-3566, and overexpression of FAM210B blocks OMA1 activation and causes complete resistance to BTM-3566 induced apoptosis. Taken together, these data support a novel antitumor mechanism in DLBCL, where BTM3566 induces mitochondrial stress, activating the OMA1-DELE1-HRI-eIF2a-ATF4 pathway leading to apoptosis and tumor regression. An Investigational New Drug application for BTM3566 in B-cell malignancies will be submitted in Q2 2022 with initiation of first in human clinical trials planned for fall 2022. Citation Format: Adrian Schwarzer, Matheus Oliveira, Marc-Jens Kleppa, Andy Anantha, Alan Cooper, Mark Hannink, Todd Hembrough, Jedd Levine, Michael Luther, Michael Stocum, Linsey Stiles, Marc Liesa-Roig, Matthew Kostura. BTM 3566, a novel activator of the mitochondrial stress response promotes robust therapeutic responses in vitro and in vivo in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A07.

Continuous sunitinib schedule in advanced platinum refractory thymic epithelial neoplasms: A retrospective analysis from the ThYmic MalignanciEs (TYME) Italian collaborative group

BackgroundThymic epithelial tumors (TETs) are rare diseases, with diverse clinical behaviour and prognosis. Intermittent dosing sunitinib represents the gold-standard systemic treatment following platinum-based chemotherapy. To ensure more homogeneous drug exposure, continuous daily dosing (CDD) sunitinib is utilised in other malignancies; however, no data exist in patients with TETs. MethodsWe retrospectively examined data from patients with platinum-resistant TETs receiving CDD sunitinib 37.5 mg between 1 May 2017 and 31 May 2022 within the Italian collaborative group for ThYmic MalignanciEs. Primary end-points were median progression-free survival, overall response rate (ORR), median duration of response and major treatment-related adverse events. ResultsA total of 20 consecutive patients (12 thymic carcinoma [TC], 6 B3, and 2 B2 thymoma) were evaluated. Among the 19 patients evaluable for response, ORR was 31.6% (95% CI, 12.5%–56.5%). Among patients with TC, one complete response, four partial responses, and four stable diseases were observed (ORR 41%).The overall median progression-free survival was 7.3 months (95% CI, 4.5–10.3): 7.3 months (95% CI, 4.4–NA) within patients with thymoma and 6.8 months (95% CI, 2.8–10.3) in patients with TC; median duration of response was 10.3 months (95% CI, 2.8–NA). CDD was associated with a manageable toxicity profile. Six patients (30%) experienced >G2 toxicity, nine required dose reduction and three discontinued treatment due to adverse events. ConclusionsCDD sunitinib showed a relevant antitumor activity and confirmed a good toxicity profile. Similar effectiveness and a better toxicity profile as compared with intermittent dosing historical data suggest that this schedule should be considered.

SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy

Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC50 value of 0.36 nM and exhibited more than 2855-fold selectivity over the closely related Ubiquitin-activating enzyme (UAE). It is worth noting that treatment with SOMCL-19-133 prominently inhibited Cullin neddylation and delayed the turnover of a panel of Cullin-RING ligases (CRLs) substrates (e.g., Cdt1, p21, p27, and Wee1) at lower effective concentrations than that of MLN4924, subsequently caused DNA damage and Chk1/Chk2 activation, and thus triggered cell cycle arrest and apoptosis. Moreover, SOMCL-19-133 exhibited potent antiproliferative activity against a broad range of human tumor cell lines (mean IC50 201.11 nM), which was about 5.31-fold more potent than that of MLN4924. In vivo, oral delivery treatments with SOMCL-19-133, as well as the subcutaneous injection, led to significant tumor regression in mouse xenograft models. All of the treatments were well tolerated on a continuous daily dosing schedule. Compared with MLN4924, SOMCL-19-133 had a 5-fold higher peak plasma concentration, lower plasma clearance, and a 4-fold larger area under the curve (AUClast). In conclusion, SOMCL-19-133 is a promising preclinical candidate for treating cancers owing to its profound in vitro and in vivo efficacy and favorable pharmacokinetic properties.

P1116: SAFETY, PHARMACOKINETIC (PK), PHARMACODYNAMIC (PD) AND ACTIVITY OF THE HIGHLY SELECTIVE PHOSPHOINOSITIDE 3-KINASE INHIBITOR DELTA (PI3KΔ) INHIBITOR IOA-244 IN PATIENTS WITH FOLLICULAR LYMPHOMA (FL)

Background: IOA-244 is a highly selective inhibitor of PI3Kδ, and has a favourable safety and ADME profile in patients (pts) with solid malignancies. In pts with uveal melanoma, IOA-244 also reduced circulating Tregs counts at the biologically effective dose (BED) range. Aims: As part of the First-in-human (FiH) dose escalation study, pts with FL received IOA-244 at the BED range established in patients with solid malignancies to confirm its favourable safety and PK profile in pts with haematologic malignancies. Methods: IOA-244 was investigated in a two-part FIH study. Part A explored the continuous daily dosing of IOA-244 at 10, 20, 40 and 80 mg in pts with solid malignancies and at 20 mg and 80 mg in pts with FL. Part B consists of expansion cohorts of specific tumour indications, including pts with lymphoma. Primary objective: safety of the anticipated BED, or the recommended phase 2 dose (RP2D). Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); Lugano-based responses; PFS and OS Results: While Part A for solid malignancies have previously been reported (Di Giacomo et al 2021), we here report for the first time the safety, PK, PD and activity of pts with FL. This part of the study is still ongoing in patients with FL and is anticipated to be completed in 2022. Pts at the first cohort of 20 mg QD daily (4/4; 2 female and 2 males) had no DLT and no dose interruptions. Transient platelet reduction (G3) and AST/ALT elevation (G2) were observed in 1/4 pts, which improved while pt was on therapy. The PK and ADME profile was consistent with the ones observed in pts with solid malignancies. One patient had FL and DLBCL as prior co-primary malignancy with 7 prior lines of therapy. The other 3 pts had 1-3 prior lines of therapy. The best response was SD (1/3 pts) and all pts progressed after completing 2 cycles. LDH was initially elevated in 2/4 pts which subsequently decreased on therapy. 3/4 pts had low Treg counts at baseline. Additional pts are being recruited at the RP2D for solid malignancies, at 80 mg QD. Reference: Di Giacomo et al. Annals of Oncology (2021) 32 (suppl_7): S1428-S1457. 10.1016/annonc/annonc787 Summary/Conclusion: The PK and ADME profile of IOA-244 in pts with FL appears to match that in pts with solid malignancies. Additional pts at the 80 mg QD dose are expected to match the safety observed in pts with solid malignancies. In contrast to other PI3Kd inhibitors, IOA-244 is highly selective and may therefore target Tregs in pts with FL without off-target effects induced by inhibition of other PI3K isoenzymes.

Abstract 3327: Discovery and characterization of the potent, allosteric SHP2 inhibitor GDC-1971 for the treatment of RTK/RAS driven tumors

Abstract The non-receptor protein tyrosine phosphatase SHP2 (PTPN11) plays an important role in the regulation of RAS/MAPK signal transduction downstream of growth factor receptor activation. Loss of SHP2 activity suppresses tumor cell growth, making SHP2 a potential target for cancer therapy. Here we report the discovery of GDC-1971 (formerly RLY-1971), a highly potent, selective, and orally bioavailable small-molecule SHP2 inhibitor that stabilizes SHP2 in a closed, auto-inhibited conformation. GDC-1971 potently inhibits both wild-type SHP2 (IC50 &amp;lt;1nM) and the E76K activating mutant (IC50 &amp;lt;250nM) in biochemical assays. In standard 2-dimensional and anchorage-independent growth conditions, GDC-1971 inhibits cellular proliferation in models harboring receptor tyrosine kinases (RTKs), SHP2, NF1, KRAS, or BRAF mutations in a dose-dependent manner. GDC-1971 potently inhibits the proliferation of cellular models harboring KRAS G12C or G12A mutations (median IC50 &amp;lt;80 nM) compared to models harboring other KRAS G12, G13 or Q61 mutations (median IC50 &amp;gt;1 uM), indicating a link between KRAS GTP hydrolysis and SHP2 dependency. Despite this trend, some non-KRAS G12C or G12A cell lines harboring other KRAS mutations responded to GDC-1971 in vitro, suggesting some heterogeneity in RTK/SHP2 signaling dependence in subsets of other KRAS mutants. In vivo, GDC-1971 demonstrates dose-dependent RAS/MAPK pathway inhibition and induces significant tumor-growth inhibition in human xenograft models harboring EGFR and KRAS alterations at continuous daily doses that are well tolerated. Given the reported role of SHP2 as a critical mediator of resistance to targeted therapies, we assessed the activity of GDC-1971 combinations in multiple contexts. We observed increased suppression of the MAPK signaling cascade and anti-proliferation synergy when combining GDC-1971 with EGFR, ALK, and KRAS G12C inhibitors in vitro. The observed in vitro synergy translated to dramatic anti-tumor growth effects in vivo. GDC-1971 in combination with the KRAS G12C covalent inhibitor GDC-6036 resulted in significant regressions at doses well below those required for single agent activity in a KRAS G12C-mutant NSCLC xenograft model. In rodent and dog toxicology studies, GDC-1971 is well tolerated at exposures above those required to induce regression in xenograft models. The biochemical and cellular potency and favorable pharmaceutical properties of GDC-1971 support the further clinical development in RTK/MAPK pathway altered tumors using continuous daily dosing alone and in combination with other targeted agents, including the KRAS-G12C inhibitor GDC-6036 (clinical trial NCT04449874). Citation Format: Bret Williams, Alexander Taylor, Olivia Orozco, Christopher Owen, Elizabeth Kelley, Andre Lescarbeau, Kelley Shortsleeves, Randy Kipp, Vy Nguyen, Erin Brophy, Jeremy Wilbur, Yong Tang, David Lanzetta, Nigel Waters, Sherri Smith, Fabrizio Giordanetto, Paul Maragakis, Jack Greismann, Lindsay Willmore, Eric Therrien, Yang Xiao, Marie Evangelista, Luca Gerosa, Eva Lin, Mark Merchant, Alfonso Arrazate, Emily Chan, Pablo Sáenz-López Larrocha, Stefan Chun, Thomas Hunsaker, Gauri Deshmukh, Christine M. Bowman, David E. Shaw, Mark Murcko, Mahesh Padval, W Patrick Walters, James Watters, Donald A. Bergstrom. Discovery and characterization of the potent, allosteric SHP2 inhibitor GDC-1971 for the treatment of RTK/RAS driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3327.

ATRT-17. A phase II study of continuous low dose panobinostat in paediatric patients with malignant rhabdoid tumours and atypical teratoid rhabdoid tumours.

BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumours (MRT) and atypical teratoid rhabdoid tumours (ATRT) in pre-clinical models. We report results of the open label, phase II study of oral panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumour activity of low dose, continuous oral panobinostat as well as its associated toxicities. To assess the biological activity of low dose panobinostat by measuring histone H4 acetylation status in peripheral mononuclear cells (PMNC), and differentiation markers. METHODS: Following primary institutional standard of care induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2/day, with a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat at different dosing levels. Patients were monitored for toxicity; dose reductions were in decrements of 2mg/m2/day. RESULTS: A total of 13 patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled. The average age at enrollment was 3.6 years (range 0.8-6.8 years). The mean treatment duration was 206 days (13-344 days). Currently, six patients (42.9%) remain on study with a mean study duration of 531 days (range 13-895 days). 6/14 patients (42.9%) were removed due to disease progression at a mean study duration of 245 days (44-560 days). 2/14 patients (14.3%) withdrew due to toxicity. 12/14 patients (85.7%) required dose reductions. The main toxicities were thrombocytopaenia and leukopaenia (Grade III-IV). Real-time pharmacodynamic assessment of panobinostat, at a dose as low as 6mg/m2/day resulted in significant acetylation of histone H4 in PMNC. CONCLUSIONS: Treatment with low dose panobinostat is well tolerated in infants and children with MRT/ATRT, with significant acetylation of histone H4 in PMNC.