uzansertib (INCB53914) / Incyte - LARVOL DELTA

Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914 Alone or in Combination With Standard-of-Care Agents in Patients With Advanced Hematologic Malignancies. (PubMed, Clin Lymphoma Myeloma Leuk) - P1/2 | "INCB053914 was generally well tolerated as monotherapy and in combinations; TEAEs were most commonly ALT/AST-elevated. Limited responses were observed with combinations. Future studies are needed to identify rational, effective combination strategies."

Combination therapy • Journal • Metastases • P1/2 data • Acute Myelogenous Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Renal Disease

Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914 Alone or in Combination With Standard-of-Care Agents in Patients With Advanced Hematologic Malignancies (Clin Lymphoma Myeloma Leuk) - P1/2 | N=97 | NCT02587598 | Sponsor: Incyte Corporation | "Parts 1/2 (n=58): 6 patients experienced dose-limiting toxicities (DLTs), most commonly aspartate aminotransferase/alanine aminotransferase-elevated (AST/ALT; each n=4). Fifty-seven patients (98.3%) had treatment-emergent adverse events (TEAEs), most commonly ALT-elevated and fatigue (36.2% each); 48 (82.8%) had grade ≥3 TEAEs, most commonly anemia (31.0%); 8 (13.8%) had grade ≥3 ALT/AST-elevated TEAEs. Parts 3/4 (n=39):...Two complete responses were observed (1 with incomplete count recovery). For INCB053914+ruxolitinib (MF; n=17), no DLTs occurred; 3 patients achieved best reduction of >25% spleen volume at week 12 or 24."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Study of INCB053914 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=97; Terminated; Sponsor: Incyte Corporation; Completed ➔ Terminated

Trial termination • Oncology • Solid Tumor

Study of INCB053914 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=97; Completed; Sponsor: Incyte Corporation; Active, not recruiting ➔ Completed

Trial completion • Oncology • Solid Tumor • BCL2

A Safety and Tolerability Study of INCB053914 in Combination With INCB050465 in Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1b; N=9; Completed; Sponsor: Incyte Corporation; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN. (PubMed, Blood Adv) - "Significantly, low nanomolar INCB053914 enhances the efficacy of ruxolitinib to inhibit the neoplastic growth of primary MPN patient cells, and INCB053914 antagonizes ruxolitinib persistent myeloproliferation in vivo. These findings support the notion that INCB053914, which is currently in clinical trials in patients with advanced hematologic malignancies, in combination with ruxolitinib may be effective in MPN patients, and they support the clinical testing of this combination in MPN patients."

Combination therapy • Journal • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Oncology • Polycythemia Vera • Solid Tumor • Thrombocytosis

INCB053914 and Pomalidomide With Dexamethasone for Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1; N=0; Withdrawn; Sponsor: Medical College of Wisconsin; N=18 ➔ 0; Trial completion date: Jul 2023 ➔ Jul 2024; Initiation date: Jul 2020 ➔ Jul 2021; Not yet recruiting ➔ Withdrawn; Trial primary completion date: Jul 2022 ➔ Jul 2023

Clinical • Enrollment change • Trial completion date • Trial initiation date • Trial primary completion date • Trial withdrawal • Hematological Malignancies • Multiple Myeloma • Oncology

INCB053914 (Pan-PIM Kinase Inhibitor) and Pomalidomide With Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1; N=18; Not yet recruiting; Sponsor: Medical College of Wisconsin

Clinical • New P1 trial • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

Study of INCB053914 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=97; Active, not recruiting; Sponsor: Incyte Corporation; Recruiting ➔ Active, not recruiting; N=270 ➔ 97

Clinical • Enrollment change • Enrollment closed • Oncology • Solid Tumor • BCL2

A Safety and Tolerability Study of INCB053914 in Combination With INCB050465 in Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1b; N=9; Active, not recruiting; Sponsor: Incyte Corporation; Recruiting ➔ Active, not recruiting; N=25 ➔ 9

Clinical • Combination therapy • Enrollment change • Enrollment closed • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Safety and Tolerability Study of INCB053914 in Combination With INCB050465 in Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1b; N=25; Recruiting; Sponsor: Incyte Corporation; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Study of INCB053914 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=270; Recruiting; Sponsor: Incyte Corporation; Trial completion date: Jan 2020 ➔ Jan 2021; Trial primary completion date: Jan 2020 ➔ Jan 2021

Clinical • Trial completion date • Trial primary completion date • BCL2

RNA-Seq analysis reveals that spring viraemia of carp virus induces a broad spectrum of PIM kinases in zebrafish kidney that promote viral entry. (PubMed, Fish Shellfish Immunol) - "To elucidate the potential role of the 16 overexpressed Pim kinases in the infectivity of SVCV, we used three different pan-PIM kinase inhibitors (SGI-1776, INCB053914 and AZD1208), and different experiments were conducted both in vitro and in vivo. Moreover, zebrafish Pim kinases seem to facilitate viral entry into the host cells because when ZF4 cells were pre-incubated with the virus and then were treated with the inhibitors, the protective effect of the inhibitors was abrogated. Although more investigation is necessary, these results show that pan-PIM kinase inhibitors could serve as a useful treatment for preventing the spread of viral diseases."

Journal

A Basket Study of Novel Therapy for Untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes (ABNL-MARRO) (clinicaltrials.gov) - P1/2; N=159; Not yet recruiting; Sponsor: Michael Savona; Trial completion date: Nov 2024 ➔ Apr 2024; Initiation date: Oct 2019 ➔ Jan 2020; Trial primary completion date: Nov 2023 ➔ Apr 2023

Clinical • Trial completion date • Trial initiation date • Trial primary completion date

Abnl Marro: An International Cooperative Trial for Patients with MDS/MPN Overlap Syndromes (ASH 2019) - "The novel agents combined with ASTX727 are: a selective JAK1 inhibitor itacitinib, pan PIM inhibitor INCB053914 and LSD1 inhibitor, INCB059872. This design yields a type I error rate of 0.05 and power of 80% when the true response rate is 55%. The probability of early termination and expected sample size of any arm is 64% and 25 pts, respectively, assuming low (35% RR) efficacy Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will establish the ABNL MARRO infrastructure that leverages the expertise of the MDS/MPN international working group (IWG) for future prospective studies; will forge innovative scientific research that will improve our understanding of pathogenetic etiologies; and will inform the clinical application of diagnosis, risk stratification tools, and response assessments in MDS/MPNs."

Clinical

Bromodomain and Extra Terminal Domain (BET) Inhibitors Sensitize Chronic Myelomonocytic Leukemia (CMML) to PIM Inhibition Via Downregulation of Mir-33a (ASH 2019) - "Surprisingly, we identified that PIM1 was increased following treatment with INCB54329, other BETi, or a JQ1-derived PROTAC (Fig...Consistent with this, isogenic SKM1 leukemia cells engineered to overexpress PIM1 were resistant to INCB54329 and were more sensitive to INCB53914 versus controls cells...Collectively, these studies established BET and PIM inhibition as a novel and potent combination therapy for CMML that is mediated by miR-33a-dependent upregulation of PIM1(Fig. 1E)."

A Basket Study of Novel Therapy for Untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes (ABNL-MARRO) (clinicaltrials.gov) - P1/2; N=159; Not yet recruiting; Sponsor: Michael Savona

Clinical • New P1/2 trial