4540 Background: In TiNivo-2, the addition of Nivo to Tivo did not prolong progression-free survival (PFS) relative to Tivo alone (Choueiri, Lancet 2024). To assess study outcomes in the context of contemporary treatment sequencing, a subset of pts treated in the 2L who failed 1L Ipi/Nivo or VEGFR-TKI/ICI therapy was evaluated. Methods: Pts were randomized 1:1 to receive Tivo once daily for 21/28 days at either 1.34mg alone or at 0.89 mg with Nivo at 480 mg by IV on day 1 of each 28-day cycle. We characterized PFS, objective response rate (ORR), and best percentage change from baseline in tumor size in two cohorts consisting of pts who did not previously receive adjuvant therapy and who progressed in 1L on Ipi/Nivo, or VEGFR-TKI/ICI therapy. Results: Among the 153 eligible 2L pts, 70 (46%) previously received Ipi/Nivo and 83 (54%) previously received a VEGFR-TKI/ICI regimen (TKI/ICI): axitinib/pembrolizumab (54.2%), cabozantinib/nivolumab (25.3%), axitinib/avelumab (12.0%), and lenvatinib/pembrolizumab (8.4%). Overall, the median follow-up was 11.6 months. More pts with lung metastasis and age <65 years were in the Tivo arm than in the Tivo+Nivo arm in both cohorts. In the Ipi/Nivo cohort, median PFS was 9.2 months (95% CI, 4.5-NR) with Tivo and 9.3 months (95% CI, 7.3-15.3) with Tivo+Nivo. ORR was 32.4% (95% CI, 18.0%-49.8%) with Tivo and 24.2% (95% CI, 11.1%-42.6%) with Tivo+Nivo. In the TKI/ICI cohort, median PFS was 7.4 months (95% CI, 3.7-9.3) with Tivo and 3.9 months (95% CI, 2.1-5.7) with Tivo+Nivo. ORR was 22.0% (95% CI, 10.6%-37.6%) with Tivo and 9.5% (95% CI, 2.7%-22.6%) with Tivo+Nivo. Target tumor size reduction from baseline was observed in both arms (Table). More pts had target tumor reductions (≥30% or ≥50%) in the Tivo arm than in the Tivo+Nivo arm in both cohorts. Of 7 pts with target tumor reduction of ≥50% from Tivo, 6 (85.7%) and 1 (14.3%) were previously treated with axitinib and cabozantinib, respectively. Conclusions: In this TiNivo-2 subgroup analysis, Tivo monotherapy at 1.34 mg daily showed activity in pts who previously received a contemporary 1L mRCC regimen. At this dose of Tivo, substantial tumor size reduction was observed, both after Ipi/Nivo and VEGFR-TKI/ICI regimens. There appeared to be no benefit with the addition of Nivo to Tivo in this context, akin to the results of the parent trial. Clinical trial information: NCT04987203 . Best percentage change in target tumor size. Best % Change from Baseline Prior Treatment ≥30% Reduction ≥50% Reduction Tivo TKI/ICI 30.5% 19.4% Ipi/Nivo 44.4% 27.8% Tivo+ Nivo TKI/ICI 17.5% 2.5% Ipi/Nivo 33.3% 12.1%

Tivo is a potent and highly selective VEGFR inhibitor designed to optimize VEGF blockade and minimize off-target toxicities. In TiNivo-2, patients with mRCC who had previous exposure to ICI, were randomized to receive study treatment as 2 L or 3 L with Tivo alone at 1.34 mg, or at 0.89 mg in combination with the ICI nivolumab (nivo).[1] The addition of nivo to tivo in second line (2 L) or third-line treatment (3 L) did not improve outcomes, and tivo monotherapy showed activity as a 2 L treatment in the post ICI setting. In TIVO-3, randomized patients had at least two previous systemic treatments and received tivo or sorafenib. We carried out a safety review of tivozanib monotherapy in these 2 randomized trials in the context of populations that had been previously exposed to VEGFR-TKI and ICI treatment. The safety profile of tivo monotherapy was evaluated in these two phase 3 trial cohorts that consisted of the tivo monotherapy arms of TiNivo-2 (N = 171), and TIVO-3 (N = 173).[2] Patient baseline characteristics of the two tivo monotherapy cohorts showed some differences, most notably in the distribution of previous exposure to VEGFR target therapy and ICIs: in TIVO-3, exposure to two prior VEGFR-TKI was 45%, to prior ICI plus VEGFR-TKI was 27%, and to a prior VEGFR-TKI plus other agent was 28%. Whereas inTiNivo-2, exposure to prior ICI was 100% (71% as the most recent line of therapy), while exposure to VEGFR-TKI was: none 31%, one 56% and two 13%. Additionally, 94% of TIVO-3 participants were white, compared with 62% of those in TiNivo-2. The incidence of grade 3-4 TEAEs and serious AEs was lower in TiNivo-2, however there was consistency in the incidence of any cause TEAEs, as well as those leading to death or treatment modifications in both cohorts (Table 1). For TEAEs ≥Grade 3, hypertension was the most common, occurring in approximately 20% of patients in each cohort; while the incidence of all other TEAEs ≥Grade 3 was lower, they also occurred at similar rates in each cohort (Table 1). Here, results show that tivo has a manageable safety profile across phase 3 trials. The better tolerability of tivo in the TiNivo-2 study vs TIVO-3 is driven in part by more patients enrolled in the earlier lines of treatment (2 L).1. Choueiri et al. Lancet 20242. Rini et al. Lancet Oncol 2020

461 Background: TIVO is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) approved in the US for treatment of patients with RCC following ≥2 prior systemic therapies. The approved TIVO monotherapy starting dose is 1.34 mg once daily on days (D) 1-21 Q28D, with allowable dose modifications to manage adverse events. In the randomized TiNivo-2 trial, the addition of NIVO 480 mg to TIVO 0.89 mg D1-21 Q28D (lower dose of TIVO was studied given assumed risk of hypertension [HTN]) did not improve outcomes compared with TIVO 1.34 mg D1-21 Q28D. There was a trend toward worse progression-free survival (PFS) in the combination arm. Methods: Using a predeveloped population pharmacokinetic (PK) model, existing ER models based on Tivo-1 and Tivo-3 studies were augmented to characterize the relationship between TIVO at clinically relevant exposures and central reviewer–based PFS, tumor size (TS) reduction, and safety endpoints. TiNivo-2 trial results were integrated to update the PK and ER models for PFS (Cox proportional hazard), TS (sum of longest diameters longitudinal model), and HTN (logistic regression) and to simulate the ER-based risk/benefit profile of TIVO. Results: The visual predictive check of the PK model on TiNivo-2 PK data confirmed that the dose-proportional TIVO PK is unaffected by concurrent NIVO. The PFS range of 5.6-9.7 months and TS reduction models, with a range of −7.02% to −23.8%, showed a significant relationship with TIVO exposure (Table). Concurrent NIVO did not add discernible benefit to TIVO at the dose of 0.89 mg. An ER modeling analysis between maximum concentration and HTN showed that the predicted HTN incidence was similar between TIVO 1.34 mg and TIVO 0.89 mg (41.3% vs 38.8% for any-grade HTN; 23.8% vs 21.5% for grade ≥3 HTN). An effect term for NIVO in the ER model for HTN was nonsignificant. Conclusions: The efficacy ER models predicted that TIVO 1.34 mg would provide greater antitumor activity than the 0.89-mg dose, while the predicted HTN incidence (any grade and grade ≥3) was comparable at the 0.89- and 1.34-mg doses. The TIVO monotherapy dose selection of 1.34 mg is important, based on the ER analysis and its safety profile. The results from the TiNivo-2 data set further confirmed that re-challenge with immunotherapy does not add benefit and optimal dosing of TKI provides the highest clinical benefit. Clinical trial information: NCT04987203 . Efficacy endpoint TIVO average concentration, ng/mL n Observed value,combined studies (range) PFS 13.9-38.4 192 5.6 months PFS 38.4-47.9 191 7.3 months PFS 47.9-62.0 191 9.1 months PFS 62.0-177 191 9.7 months CFB TS 13.9-38.4 176 −7.02% (−16% to 1.93%) CFB TS 38.4-47.9 173 −11.7% (−21.3% to −2.05%) CFB TS 47.9-62.0 185 −17.3% (−26.4% to −8.27%) CFB TS 62.0-177 183 −23.8% (−33.5% to −14.1%) CFB, change from baseline.

Abstract BACKGROUND Cholesterol in the brain is derived wholly from de novo biosynthesis as the blood-brain barrier prevents uptake from the circulation. The overexpression of cholesterol synthesis genes is associated with decreased survival in glioblastoma (GBM), suggesting that gliomas may be sensitive to the inhibition of cholesterol biosynthesis. DSP-0390 is an investigational small molecule that inhibits EBP, a key enzyme in cholesterol biosynthesis. Preclinical studies demonstrated antitumor activity of DSP-0390 in orthotopic xenograft GBM models. METHODS This phase I dose escalation study aims to assess the safety, PK, PD, and preliminary antitumor activity of oral DSP-0390 monotherapy for recurrent HGG (NCT05023551). Key eligibility criteria include histologically confirmed grade III or IV glioma (WHO 2016); treatment with ≥ 1 prior therapy; no treatment options beyond standard of care; KPS ≥ 70. RESULTS As of 9 May 2023, 24 patients (37.5% women) were enrolled across 6 dose levels (20 mg QD to 240 mg QD) with a median age of 51 years (range 24-76) including 17 (70.8 %) with GBM, 3 (12.5%) with anaplastic astrocytoma and 2 (8.3%) with anaplastic oligodendroglioma. Ten patients (41.7%) had IDH mutant tumors. Four patients (16.7%) were on stable dose of corticosteroids at baseline, of which 2 were able to discontinue or dose reduce the corticosteroid while on DSP-0390. There were no reported DLTs. The most common treatment-related TEAEs included grade 1 or 2 nausea (7 patients [29.2%]) and alanine aminotransferase increased (6 patients [25.0%]). Only one grade 3 related AE (dry skin) was noted. Two patients with IDH mutant grade 3 glioma had tumor reduction and remain on DSP-0390 for ≥ 9 months. Dose dependent changes in PK and PD were observed. CONCLUSIONS DSP-0390 has been well tolerated to date with dose escalation ongoing. A dose response relationship was observed between PK and PD biomarkers.

Abstract BACKGROUND Cholesterol in the brain is derived wholly from de novo biosynthesis as the blood-brain barrier prevents uptake from the circulation. The overexpression of cholesterol synthesis genes is associated with decreased survival in glioblastoma (GBM), suggesting that gliomas may be sensitive to the inhibition of cholesterol biosynthesis. DSP-0390 is an investigational small molecule that inhibits EBP, a key enzyme in cholesterol biosynthesis. Preclinical studies demonstrated antitumor activity of DSP-0390 in orthotopic xenograft GBM models. METHODS This phase I dose escalation study aims to assess the safety, PK, PD, and preliminary antitumor activity of oral DSP-0390 monotherapy for recurrent HGG (NCT05023551). Key eligibility criteria include histologically confirmed grade III or IV glioma (WHO 2016); treatment with ≥1 prior therapy; no treatment options beyond standard of care; KPS ≥70. RESULTS As of 9 May 2023, 24 patients (37.5% women) were enrolled across 6 dose levels (20 mg QD to 240 mg QD) with a median age of 51 years (range 24-76) including 17 (70.8 %) with GBM, 3 (12.5%) with anaplastic astrocytoma and 2 (8.3%) with anaplastic oligodendroglioma. Ten patients (41.7%) had IDH mutant tumors. Four patients (16.7%) were on stable dose of corticosteroids at baseline, of which 2 were able to discontinue or dose reduce the corticosteroid while on DSP-0390. There were no reported DLTs. The most common treatment-related TEAEs included grade 1 or 2 nausea (7 patients [29.2%]) and alanine aminotransferase increased (6 patients [25.0%]). Only one grade 3 related AE (dry skin) was noted. Two patients with IDH mutant grade 3 glioma had tumor reduction and remain on DSP-0390 for ≥9 months. Dose dependent changes in PK and PD were observed. CONCLUSIONS DSP-0390 has been well tolerated to date with dose escalation ongoing. A dose response relationship was observed between PK and PD biomarkers.

Topic: 16. Myeloproliferative neoplasms - Clinical Background: The constitutively active PIM1 serine/threonine kinase is highly expressed in hematologic malignancies including myelofibrosis (MF) and has been shown to play a role in modulating the activity of the cytokine-induced PI3K/AKT and JAK-STAT pathways. Upregulation of inflammatory cytokines are thought to play a key role in the pathobiology of MF. In preclinical studies, TP-3654, a highly selective PIM1 kinase inhibitor, showed spleen size reduction and bone marrow (BM) fibrosis reversion in JAK2V617F murine MF models (Dutta A, 2021). Importantly, TP-3654 also showed reduction of cytokine response genes and serum TGF-β in progenitor cells and JAK2V617F murine MF model, respectively. TP-3654 is currently being evaluated in patients with MF previously treated with JAK inhibitors (NCT04176198). Aims: This Phase 1/2 study aims to identify MTD and/or RP2D and to evaluate safety and efficacy of oral TP-3654 monotherapy in patients with MF. In addition, the study aims to evaluate pharmacodynamic markers changes (cytokine profile, bone marrow fibrosis etc.) in MF patients treated with TP-3654. Methods: Key eligibility criteria for this study include primary or secondary MF; DIPSS intermediate- 1, 2 or high-risk MF; previously treated with or ineligible for JAK inhibitors; platelet count ≥25x109/L; splenomegaly (≥450 cm3 by imaging); and ≥2 measurable symptoms. Spleen volume reduction (SVR) evaluated by imaging, ≥50% total symptom score (TSS) improvement assessed by MFSAF v4.0, and cytokines assessed by multiplexed immunoassay of plasma. Results: As of 09 Feb 2023, 15 patients were enrolled across 5 dose levels from 480 mg QD to 720 mg BID. At baseline, median age 69 years (range, 61 to 77), spleen volume 1936 cm3 (range, 857 to 4408), total symptom score 18.6 (range, 4 to 62), platelet count 129 x109/L (range, 64 to 520), hemoglobin 9.7 g/dL (range, 5.9 to 13.7), and 5 patients required RBC transfusion. All patients had received prior treatment with at least one JAK inhibitor. Median duration of prior JAK inhibitors treatment was 12.8 months (range, 2.3 to 72.9). No DLTs occurred. The most common treatment-related adverse events (TRAEs) in ≥20% of patients included mild to moderate nausea, vomiting, and diarrhea. No hematological TRAEs reported. SVR observed in 8 of 10 evaluable patients treated for ≥12 weeks (median best change -13%, range -3% to -42%, 2 patients showed ≥35% SVR). TSS improvements observed in 9 of 10 evaluable patients (median best change -70%, range -31% to -100%, 6 patients showed ≥50% TSS response). Broad reductions in cytokines (e.g., IL-6, IL-8, IL-10, EN-RAGE) were observed after TP-3654 treatment. Cytokine modulation was observed as early as within the first 24 hours. At week 12 analysis, patients with higher cytokine reductions correlated with higher TSS improvement (Figure 1). BM fibrosis reduction from grade 3 to 2 was seen in one patient who also achieved spleen and symptoms responses and showed reductions in MF associated cytokines: IL6 (68%), IL12p40 (83%), MMP9 (56%), and EN-RAGE (68%), and is on active treatment for more than 18 months. Enrollment is ongoing, additional data will be presented. Summary/Conclusion: Preliminary cytokine data showed that TP-3654 monotherapy may prompt early cytokine changes that may correlate with symptoms response. In addition, preliminary data of TP-3654 in relapsed/refractory MF patients showed SVR, TSS improvement, and BM fibrosis reduction. In the dose ranges evaluated to date, TP-3654 has been well tolerated with no myelosuppressive TRAEs.Keywords: Myeloproliferative disorder, Idiopathic myelofibrosis, Myelofibrosis

2022 Background: ODE is an investigational cancer vaccine derived from Wilms tumor 1. WIZARD was a randomized, adaptive, phase 3 study to test ODE + bev vs bev in rGBM pts (NCT03149003). Patients were stratified prior to randomization based upon KPS [60 or 70] vs [80 to 100] and extent of resection at initial diagnosis. Patients with low KPS (e.g., 60) are generally underrepresented in clinical trials. Methods: Pts ≥18 years with GBM at first recurrence were enrolled. Overall survival (OS) was the primary endpoint; the key secondary endpoint was the 12-month OS rate. The primary and the key secondary endpoints were tested using 1-sided test with an overall significance level 2.5%. The Lan-DeMets error spending function based upon O’Brien-Fleming stopping boundaries was used to adjust the significance level for the interim and final analyses. Results: From April 2018 to Aug 2021, 217 pts were randomized 1:1; 109 to ODE + bev and 108 to bev. OS was analyzed after 185 events with a median follow-up of 31.8 months (mo). Pts at baseline had a median age of 60 years, 45.2% reported corticosteroid use, 29% had KPS 60 or 70, 7.8% had tumors that harbored IDH1 or 2 mutations, and the median tumor volume was 10,532 mm3. Baseline characteristics between treatment arms were balanced in the ITT and KPS subgroups. Pts with KPS 60 or 70 had more corticosteroid use, worse NANO scores, and larger tumor burden than those with KPS 80-100. The study did not meet its primary endpoint of OS by ITT (ODE + bev: 10.2 mo vs bev: 9.4 mo, 1-sided p-value: 0.2159). Pts with KPS 60 or 70 had longer OS when treated with ODE + bev (8.2 vs 6.3 mo, 45% death risk reduction, 1-side p value: 0.0119). Grade 1 or 2 injection site reaction was the most common TEAE in the ODE + bev arm. No clinically significant difference in safety was noted between KPS subgroups. Conclusions: The data in pts with KPS 60 or 70 suggested benefit with ODE + bev that was consistent across different endpoints and that warrants further validation. Clinical trial information: NCT03149003 . [Table: see text]

TPS11589 Background: Cyclin-dependent kinase 9 (CDK9) blockade inhibits tumor growth and progression by impairing the transcription of key oncogenes, such as myeloid cell leukemia-1 (MCL-1) and c-MYC. CDK9 overexpression has been observed in sarcoma patients (pts), and CDK9 has emerged as a potential therapeutic target in pts with sarcoma. TP-1287 is an investigational orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. In preclinical studies, TP-1287 has been shown to decrease MCL-1 expression and phosphorylation of RNA polymerase II (RPB1), and inhibit tumor growth in an Ewing sarcoma (EWS) mouse model. Phase 1 dose-escalation in solid tumors has completed and TP-1287 is being investigated in a dose expansion cohort in pts with EWS (NCT03604783). The design of the expansion part of the trial in pts with EWS is herein described. Methods: Up to thirty pts with EWS will be enrolled in this dose expansion cohort. Key eligibility criteria are age ≥18 years (≥12 years, if weight ≥40 kg); histologically confirmed locally advanced or metastatic unresectable EWS; received 1 to 5 prior lines of treatment including an anthracycline; one or more measurable tumors per the RECIST v1.1; ECOG performance status of ≤1; acceptable liver and renal function, and acceptable hematologic and coagulation status; no treatment with surgery, chemotherapy, or investigational therapy within 28 days or 5 half-lives. Eligible pts will be treated with oral TP-1287 monotherapy RP2D established from the dose escalation part (11 mg BID, continuous dosing in a 28-day treatment cycle) and will continue treatment until treatment-related adverse event or disease progression. Assessments will be performed on Day 1 and Day 15 of each cycle. Tumor response assessment will be done after Cycle 2 and at the end of every other cycle thereafter. The primary objectives are objective response rate (ORR) and clinical benefit rate (CBR) ; secondary objectives are median progression-free survival (PFS), PFS rate at 16-weeks and 24-weeks and safety; and exploratory objectives include evaluation of systemic exposure and pharmacodynamics. Safety data will be reviewed on an ongoing basis and a Bayesian approach will be used to assess the efficacy data. Statistical analysis for safety and efficacy parameters will be primarily descriptive in nature. EWS dose expansion cohort is currently recruiting in the United States. Clinical trial information: NCT03604783 .

Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, ineffective hematopoiesis, splenomegaly, and debilitating symptoms. PIM-1 expression is upregulated in MF hematopoietic cells supporting exploration of PIM-1 as a potential therapeutic target in MF. TP-3654 is a selective oral investigational PIM-1 kinase inhibitor.TP-3654 alone and in combination with ruxolitinib reduced spleen size and BM fibrosis in murine MF models (Dutta, 2021).

Introduction: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, ineffective hematopoiesis, splenomegaly, and debilitating symptoms. Expression of PIM-1 is significantly upregulated in MF hematopoietic cells, supporting exploration of PIM-1 as a potential therapeutic target in MF. TP-3654 is a highly selective oral investigational PIM-1 kinase inhibitor. When administered alone and in combination with ruxolitinib, TP-3654 reduced spleen size and BM fibrosis in JAK2V617F and MPLW515L murine MF models (Dutta, 2021). In addition, TP-3654 decreased cytokine response genes and serum TGF-b in progenitor cells and JAK2V617F mice, respectively. TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation. Methods: This Phase I/II study evaluates the safety and efficacy of TP-3654 monotherapy in patients with MF (NCT04176198). Key eligibility criteria include primary or secondary MF; intermediate or high-risk MF per DIPSS; previously treated with or ineligible for JAK inhibitor treatment; grade ≥2 BM fibrosis; platelet count ≥25x109/L; absolute neutrophil count ≥1x109/L; splenomegaly; and ≥2 measurable symptoms. The study aims to identify the maximum tolerated dose and/or recommended Phase II dose using a Bayesian logistic regression model (BLRM) with overdose control, and to assess clinical activity (spleen volume reduction [SVR], total symptom score [TSS] improvement, and BM fibrosis reduction), safety, pharmacokinetic, and pharmacodynamic markers in peripheral blood and BM biopsies. Results: As of 11 July 2022, 8 patients were enrolled across 5 dose levels in the dose escalation phase. At baseline, median age was 70 years (range, 61 to 77), median spleen volume was 2370 cm3 (range, 1189 to 4407), median total symptom score was 19 (range, 4 to 62), median platelet count was 120 x109/L (range 68 to 237), median hemoglobin was 10.1 g/dL (range, 5.9 to 13.7), and two patients were transfusion-dependent. All patients had received prior treatment with at least one JAK inhibitor. Median duration of prior JAK inhibitor treatment was 35 weeks (range, 13 to 269). Six patients had JAK2V16F mutation, 2 patients had CALR mutation. The median duration of TP-3654 treatment was 21 weeks (range, 1 to 45). No dose-limiting toxicities occurred. Treatment-related adverse events (TRAEs) occurring in >20% of patients included mild to moderate nausea, vomiting, and diarrhea. Grade ≥ 3 TRAEs included only 1 case of vomiting. No hematological TRAEs were reported. No discontinuation due to AE occurred. SVR was observed in 5 out of 6 evaluable patients (median best change -14%, range -3.2% to -35%) (Figure 1). Symptom improvement was observed in 5 out of 6 evaluable patients (median best change -70%, range -32 to -100%). A panel of cytokines were evaluated in plasma samples obtained at baseline and during TP-3654 treatment. Reductions in cytokines (TGF-b, IL-18, VEGF, RANTES, MMP-9, and TIMP-1) were observed after TP-3654 treatment (Figure 2). Patients with higher cytokine reductions correlated with higher reduction in total symptom score. Enrollment is ongoing, updated data will be presented. Conclusions: The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

History of thrombocytopenia was a major factor influencing ruxolitinib dose and was associated with history of anemia and neutropenia. Our findings underscore the need for more treatment options to manage myelofibrosis patients with thrombocytopenia.

Abstract Background: Elevated expression of PIM kinases in various solid and hematologic malignancies is correlated with increased cell survival and reduced apoptosis, implicating inhibition of PIM kinases as attractive targets for disruptive therapy. TP-3654 is an oral, small molecule, investigational PIM kinase inhibitor with favorable selectivity against PIM-1 over other kinases. TP-3654 is currently being evaluated in a phase 1 first-in-human study in patients (pts) with advance solid tumors (NCT03715504). Methods: Pts with advanced metastatic, progressive, or unresectable solid tumors refractory or intolerant of established therapies were treated with TP-3654. Pts took TP-3645 orally once (QD) or twice (BID) daily in a 28-day dosing cycle until unacceptable toxicity or disease progression. Escalating dose levels of TP-3654 were evaluated using a 3+3 design. The primary objective was to determine maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included establishing the pharmacokinetic (PK) profile of oral TP-3654 and any evidence of antitumor activity. An exploratory objective was to study predictive biomarkers in tumor tissues and mechanism-based pharmacodynamic activity in peripheral blood mononuclear cells (PBMCs). Results: As of 31 May 2021, 22 pts were treated with TP-3654 at 480 mg QD (n=3), 720 mg QD (n=3), 1080 mg QD (n=4), 1440 mg QD (n=3), 720 mg BID (n=3), and 960 mg BID (n=6). Median age of 58 years (range: 20–72), 59% (13/22) pts male, and 86% (19/22) pts received ≥3 lines of prior therapy. Median treatment duration is 2 cycles (range: 0.1–24) and 6 pts received treatment for ≥4 cycles. Two pts remain on active study treatment. No DLT was observed. The most common treatment-emergent adverse events (TEAEs) reported in ≥20% of pts were vomiting, diarrhea, nausea, and abdominal pain. No related myelosuppressive AEs were reported. Fifty percent (11/22) of pts reported 18 Grade ≥3 TEAEs, of which only one (alanine aminotransferase increased) was considered related to TP-3654. No related, serious AEs were reported. Two TEAEs resulted in a fatal outcome (acute kidney injury, completed suicide); neither were related to TP-3654. Best response is stable disease (SD) in 67% (10/15) evaluable pts, SD for ≥ 16 weeks in 5 pts, best reduction of tumor size from baseline is -22%. TP-3654 plasma exposure increased with doses up to 1080 mg QD; the BID regimen at the 720 mg dose achieved greater plasma exposure than the 1440 mg QD dosing regimen. Reduced phosphorylation of PIM-1 downstream signal protein pBAD was observed in isolated PBMCs, predominantly in pts with prolonged clinical benefit. Conclusions: Preliminary data suggest that TP-3654 is tolerated as a monotherapy up to 960 mg BID in pts with heavily pretreated, relapsed, and refractory solid tumors. No DLT was observed and MTD was not reached. PK data indicate that the BID dose regimen achieved better plasma exposure than the QD regimen at higher doses. TP-3654 has shown target-specific inhibition of PIM-1 in pts. Updated data will be presented. Citation Format: Ignacio Garrido-Laguna, Patrick M. Dillon, Sujan Kabir, Jian Mei, Mark L. Wade, Huyuan Yang, Carl Stapinski, Jason M. Foulks, Steven L. Warner, Clifford Whatcott, Claudia Lebedinsky, Siqing Fu. Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654, a PIM kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P223.

4147 Background: Retrospective studies of phosphorylated STAT3 (pSTAT3, a regulator of gene expression) in cancer-lineage cells have suggested it is a biomarker of poor prognosis. We analyzed data from 3 phase 3 RCTs (BRIGHTER [T1; NCT02178956], CO.23 [T2; NCT01830621], CanStem111P [T3; NCT02993731]) to evaluate the prognostic impact of pSTAT3 on OS in GI cancer patients (pts). Methods: pSTAT3 was evaluated in archival tumor tissue from pts with gastric or gastroesophageal junction adenocarcinoma (T1), colorectal cancer (T2), or pancreatic cancer (T3) who received standard of care in the control arms (CTL) of their respective trials. pSTAT3 positive (+) or negative (−) status was determined by detecting pSTAT3 in both tumor and tumor microenvironment (TME) cells in a laboratory-developed immunohistochemistry (IHC) assay (T1; T2), later developed into the investigational pSTAT3 IHC D3A7 assay (Agilent Technologies, Inc.) (T3). The positivity cutoff requires a sample have both a TME score of 2 and ≥5% of tumor cells staining positively for pSTAT3. Pre-analytical variables (eg, specimen collection, handling, and processing), tumor indication, and slight differences in the assays used for each study may contribute to relative differences in evaluable rates between studies. In an exploratory analysis, OS was compared in pSTAT3+ vs pSTAT3− pts via an unstratified log-rank test. Results: In each study, intent-to-treat pts with evaluable pSTAT3 results were considered pSTAT3-evaluable. This abstract includes pSTAT3-evaluable pts randomized to the CTL arms (T1: n/N=248/357, 69.5%; T2: n/N=110/144, 76.4%; T3: n/N=243/569, 42.7%). Baseline characteristics are presented in the table. Median (m) OS was shorter in pts with pSTAT3+ tumors across all studies (T1 hazard ratio [HR]=1.32 [95% confidence interval (CI): 1.00, 1.74]; T2 HR=2.40 [1.50, 3.83]; T3 HR=1.08 [0.77, 1.50]). Conclusions: In pSTAT3-evaluable populations from 3 RCTs across GI cancers, CTL pts with pSTAT3+ (vs pSTAT3−) tumors had shorter mOS. These results suggest that pSTAT3 positivity may be a biomarker of poor clinical outcome. Clinical trial information: NCT02178956; NCT01830621; NCT02993731. [Table: see text]

Background: Myelofibrosis (MF) is characterized by bone marrow fibrosis (BMF) and ineffective extramedullary hematopoiesis resulting in splenomegaly and debilitating symptoms. An activating Janus kinase 2 (JAK2) mutation (V617F) has been frequently observed in MF. Ruxolitinib (a JAK1/JAK2 inhibitor) reduces splenomegaly and improves constitutional symptoms, but appears to offer a modest reduction of BMF. Patients with MF who are intolerant to JAK inhibitors or their components, or for whom JAK inhibitors have failed, have limited treatment options. The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine kinases are overexpressed in hematological malignancies. Because PIM kinase expression is regulated by JAK2 signaling, PIM kinase inhibition is a potential therapeutic target for JAK2 mutant-driven malignancies, such as MF. TP-3654, an investigational agent, has been shown to reduce proliferation and increase apoptosis in murine and human hematopoietic cells expressing the JAK2V617F mutation. TP-3654 alone reduced leukocytosis and spleen size in an in vivo murine model of JAK2V617F-induced MF, as well as an apparent reduction of BMF. A phase 1 study is being conducted to evaluate TP-3654 monotherapy in patients with MF. Study Design and Methods: This phase 1, multicenter, dose-escalation, open-label study is evaluating TP-3654 monotherapy in patients with MF who previously failed a JAK inhibitor or who are ineligible to receive ruxolitinib or fedratinib (NCT04176198). Primary objectives are to determine the incidence of dose-limiting toxicities (DLT) at escalated doses of TP-3654 and treatment emergent adverse events. Secondary objectives are to determine QT interval changes, establish the pharmacokinetic profile, and assess preliminary disease activity. Exploratory objectives are pharmacodynamic markers in peripheral blood and bone marrow biopsy samples. Eligible patients have a primary or secondary MF (post-polycythemia vera-MF/post-essential thrombocythemia-MF) based on the World Health Organization diagnostic criteria and intermediate-2 or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System; previously failed, or are ineligible to receive, treatment with a JAK inhibitor; grade ≥2 MF, as confirmed by BM biopsy ≤12 weeks prior to screening; have a platelet count >50x109/L, absolute neutrophil count ≥1x109/L, hemoglobin level ≥8 g/L, peripheral blood blast counts <10%, Eastern Cooperative Oncology Group performance status ≤2, life expectancy ≥3 months, and adequate renal and hepatic function; have spleen length ≥5 cm by palpation or spleen volume ≥450 cm3 by computerized tomography/magnetic resonance imaging, and show ≥2 measurable symptoms per the MF Symptom Assessment Form, version 4.0. Patients must not have received prior systemic antineoplastic therapy or any experimental therapy within 14 days or 5 half-lives before TP-3654; had major surgery ≤2 weeks before first study dose; have had splenic irradiation ≤6 months prior to screening; have acute myeloid leukemia or myelodysplastic syndrome; or had prior stem cell transplantation (SCT) or be eligible for allogeneic bone marrow or SCT. Enrollment of approximately 50 patients is planned. Patients will receive oral TP-3654. Dose-escalation will be performed using a Bayesian logistic regression model with escalation with overdose control. Adverse events occurring during the first cycle will be considered in the determination of the maximum tolerated dose (MTD). Dose escalation will continue until identification of the MTD or a suitable recommended phase 2 dose. This study is currently recruiting patients. Disclosures Lebedinsky: Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Anthony:Exact Sciences: Consultancy; Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Mohi:Tolero Pharmaceuticals Inc.: Research Funding. Yang:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Mei:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Braendle:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment.

Background: Increased expression and neomorphic mutations of the histone methyltransferase EZH2 are often observed in cancer, leading to repression of genes associated with apoptosis and differentiation. High EZH2 expression and low expression of EZH2 target genes in mCRPC correlate with poor prognosis. CPI-1205 is a potent, reversible, cofactor-competitive small molecule inhibitor of EZH2. Preclinical studies revealed that prostate cancer models dependent on androgen receptor signaling (ARS) are sensitive to EZH2 inhibition, and that CPI-1205, when combined with novel ARS inhibitors, results in synergistic cell growth inhibition (Bradley 2018). Here we report preliminary results from the Phase Ib component. Methods: In this multicenter Phase Ib/II study, patients (pts) with mCRPC previously treated with a novel ARS inhibitor were enrolled in different cohorts exploring two regimens of oral CPI-1205 on a continuous 28-day cycle: 800 mg TID or 400 mg BID with cobicistat, a CYP3A4 inhibitor, combined with the standard dose of E (160 mg QD) or standard dose of A/P (1000 mg QD/5 mg BID). Prior chemotherapy was allowed. The primary objective in Phase Ib is to determine safety, a recommended Phase II dose, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 11/16/2018, 35 pts were enrolled in four cohorts (two cohorts of CPI-1205 + E; two cohorts of CPI-1205 + A/P) and were treated for ≥1 cycle. Age ranged from 55 to 90 years (median 72). 63% were ECOG 0 and 37% ECOG 1. 13 pts (37%) tested positive for ARV7. 21 pts (60%) had unfavorable circulating tumor cells (CTC) counts at baseline. 6 pts (17%) had prior taxane-based chemotherapy for mCRPC. 16 pts received CPI-1205 + E and 19 pts received CPI-1205 + A/P. Only 1 DLT (asymptomatic reversible ALT increase, Grade 4) was reported in the CPI-1205 + A/P + cobicistat. No serious AE related to the study drug was reported in any cohort. Overall, the commonly reported drug-related treatment-emergent adverse events (TEAEs ≥10%) were low-grade diarrhea (n= 11, 31%), fatigue and nausea (n= 9, 26% each), and decreased appetite (n=5, 14%). Grade ≥3 TEAEs were fatigue and elevated ALT (n=2, 6% each), and nausea, pruritus, hypokalemia, and muscular weakness (n=1, 3% each). 16 pts remain on treatment. Cases of PSA >80% reduction, CTC ≥30% reduction, and RECIST response were observed. Both CPI-1205 regimens resulted in significant target engagement (reduced H3K27me3 in PBMCs and CTCs). Patient sample analysis to maximize biomarker identification is ongoing. PK data will be presented. Conclusions: Both CPI-1205 800 mg PO TID and 400 mg PO BID plus cobicistat, combined with full doses of either E or A/P, are well tolerated, with acceptable safety. Encouraging clinical activity has been observed. CPI-1205 800 mg PO TID + E or A/P has been selected for phase 2 expansion, and patient enrollment is ongoing Citation Format: Mary-Ellen Taplin, Arif Hussain, Satish Shah, Neal D. Shore, William Jeffery Edenfield, Oliver A. Sartor, Luke T. Nordquist, Manish Agrawal, William Clark, David R. Wise, William K. Oh, Mark T. Fleming, James E. Butrynski, Gurkamal S. Chatta, Manojkumar Bupathi, Claudia Lebedinsky, Adrian Senderowicz, Jian Li, Gozde Colak, David Nash, Patrick Trojer, William D. Bradley, Jessica Piel, Emmanuel S. Antonarakis. Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT094.

TPS335 Background: EZH2 is frequently mutated and/or overexpressed in numerous cancers. High EZH2 expression is correlated with poor outcomes in prostate cancer patients (Varambally, 2002). EZH2 inhibition combines synergistically with anti-androgen therapies in preclinical models of advanced prostate cancer, suggesting epigenetic reprogramming as a pathophysiologic mechanism to enhance the combination therapy (Ku, 2017; Xiao 2018; Constellation, unpublished). CPI-1205 is a potent, selective, and cofactor-competitive inhibitor of wild type and mutant EZH2 catalytic activity, which demonstrates anti-proliferative effects in prostate and other cancer cell models. Methods: We present a Phase 1b/2 multicenter study of CPI-1205 combined with either E or A/P in patients with mCRPC, which includes phase 1 dose escalation, an expansion cohort in heavily pretreated patients (HPEC), and a randomized phase 2 study. Key eligibility criteria include progressive mCRPC in patients previously treated with a second-generation androgen inhibitor, ECOG 0-1, and measurable or non-measurable disease. During the phase 1b, patients will receive CPI-1205 continuously in 28-day cycles combined with the standard dose of either E (160mg PO once daily) or A/P (1000mg PO once daily/5 mg BID). The primary objective in Phase 1b is to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of CPI-1205 combined with either E or A/P. Secondary objectives include safety, pharmacokinetic and pharmacodynamic profiles, and anti-tumor activity. The HPEC arm, with Simon’s 2-stage design, may begin with the regimen that is deemed safe by the study safety committee. The primary endpoint of the HPEC arm is objective response rate (ORR) per PCWG3, with a requirement ≥ 1 measurable lymph node at baseline. Once RP2D is established, we will start a randomized Phase 2 trial of E or A/P combined with CPI-1205 vs. E or A/P alone. The co-primary endpoint includes PSA50 and composite response rate (either CTC 30% reduction or ORR per PCWG3). Patient accrual in US sites began in December 2017. Clinical trial information: NCT03480646.