A Phase I, Open-label, Dose-finding Study to Assess the Safety, Tolerability, and Pharmacokinetics of PHI-101 in Patients With Platinum-Resistance/Refractory Ovarian Cancer

This study aims to assess the safety and tolerability of PHI-101 in patients with platinum-resistance/refractory ovarian, fallopian tubal, and primary peritoneal cancer. This study also evaluates the pharmacokinetics of PHI-101 and efficacy of PHI-101 during treating platinum-resistance/refractory ovarian, fallopian tubal, and primary peritoneal cancer.
PHI-101 is a CHK2 inhibitor that is a checkpoint kinase binding specifically to CHK2, rather than CHK1, and it inhibits the DDR system by inhibiting the ATM-CHK2 pathway, which is activated in response to DSBs. When a high-grade serous ovarian (HGSO) cancer cell line and various ovarian cancer cell lines (CAOV3, OVCAR3, SK-OV-03, and SW626) were treated with PHI-101 in a non-clinical study, the therapeutic effect of PHI-101 against ovarian cancer was demonstrated by a decrease in viability of ovarian cancer cells. In addition, a stronger growth inhibition effect was observed compared to that of treatment with olaparib or rucaparib alone, and a much stronger inhibition effect was observed when concomitantly used with paclitaxel, cisplatin, and topotecan. Based on the aforementioned results of the non-clinical studies, the potential of PHI-101 as a new treatment or concomitant cytotoxic chemotherapeutics for patients with ovarian cancer who are resistant to existing antineoplastic drugs was confirmed.

Start Date17 Dec 2020

Sponsor / Collaborator

Seoul National University Hospital

[+1]

NCT04842370

/ Unknown statusPhase 1IIT

A Prospective, Phase Ia/Ib, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the FLT3 Inhibitor, PHI 101, Alone in Subjects With Relapsed or Refractory Acute Myeloid Leukemia (AML)

The purpose of this study is to find out the maximum tolerable dose and safety of PHI-101, novel FLT3 inhibitor in the treatment of relapsed or refractory AML for patients who have received standard therapy or cannot tolerate standard therapy, and/or for whom no standard therapy exists.
There will be two parts to the study, which we will call Phase Ia and Phase Ib. Phase Ia is called the dose escalation. Approximately 20 to 24 patients are planned to be enrolled into Phase Ia. Phase 1a is conducted to determine the best dose and schedule of dosing of PHI-101 to be used in Phase 1b. There will be 5 different dose levels of PHI-101 given to patients in Phase Ia.
Phase Ib is called the dose expansion. Approximately 14-34 patients (approximately 14-17 patients in each of the 2 cohorts planned) of each cohort are planned in Phase Ib based on study design. Phase Ib is also being conducted to assess anti-leukemia response, changes in transfusion requirements, and safety of PHI-101 at the dose level identified during Phase Ia.

Start Date08 Jun 2020

Sponsor / Collaborator

Seoul National University Hospital

[+1]

100 Clinical Results associated with Pharos iBio Co., Ltd.

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05 Nov 2024·Blood

PHI-101, a Novel FLT3 TKI, Shows Clinical Efficacy in Relapsed/Refractory FLT3-Mutated AML

Author: Cheong, June-won ; Hong, Junshik ; Kim, Hee-Je ; Shin, Ho-Jin ; Im, Jeejin ; Nam, Ky-Youb ; Lee, Jeong-Ok ; Yoon, JeongHyeok ; Li, Li ; Lee, Yoo Jin ; Yoon, Sung-Soo ; Nguyen, Bao ; Han, June ; Lee, Je-Hwan ; Kim, Kyu-Tae ; Sung, Gi-Jun ; Clarey, Joseph ; Cho, Byoung-Sik ; Shin, Dong-Yeop ; Small, Donald ; Jang, Jun-Ho ; Ahn, Jae-Sook

Background:We investigated the clinical activity, PK, safety and resistance mechanisms of single-agent PHI-101 in patients (pts) with refractory/relapsed acute myeloid leukemia (R/R AML) with FLT3-ITD mutations.(NCT04842370)Study Design and Methods:PHI-101 was used in a range of once-daily (40-200 mg) regimens in a phase 1a, open label, dose-escalation expansion study in adult patients with R/R AML and in a phase 1b expansion study in adult patients with R/R FLT3 mutant AML. Study objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), characterize the safety and tolerability and pharmacokinetic/pharmacodynamic profile, and assess the preliminary antitumor activity of PHI-101. A total of 30 pts with a median age of 64 years (range = 22-81) were enrolled in the phase 1a/1b clinical trials. Participants had received a mean of 3.9 prior therapies (range = 1-9). The most commonly observed mutations were FLT3-ITD mutations (70.0%), followed by both FLT3-ITD and FLT3-TKD mutations (13.3%). Most pts (72.0%) with known FLT3 mutations had previously received FLT3 inhibitors including gilteritinib (66.7%).Results:A total of 30 pts were enrolled in the two treatment arms of which 21 pts were evaluable, 9 pts in arm A (dose escalation) and 12 pts in arm B (dose expansion). Clinical responses with PHI-101 (composite complete remission [CRc; including complete remission (CR), complete remission with incomplete hematological recovery (CRi), and morphologic leukemia-free state (MLFS)]), were observed in 33.3% of 21 evaluable pts (FLT3-WT pts:n=3, 0%; FLT3 mutated pts:n=18, 38.9%). The Phase 1a clinical trials of PHI-101 evaluated it for safety and tolerability at five dose levels from 40 mg to 200 mg. In total, 13 R/R AML pts were enrolled in phase 1a and no DLTs were reported from daily doses of PHI-101 for the 28-day cycle. Seven pts (53.8%) had received more than 3 prior anti-leukemic treatments in Phase 1a.The target recommended dose expansion (RDE) at 160 mg was determined based on several considerations, including the PIA test achieving >85% inhibition of phospho-FLT3, all available adverse events, PK data, and recommendation by the safety monitoring committee (SMC).PHI-101 therapy in Phase 1b resulted in a 50% CRc and 25% partial remission (PR) status among 12 evaluable R/R FLT3 AML pts (11 ITD, 1 ITD+D835). 75% of these patients had received prior FLT3 inhibitors (Gilteritinib (7), Midostaurin (3), Sorafenib (1), HM43239 (1)). Notably, 4 of the R/R pts who had received previous therapy with gilteritinib had clinical responses to PHI-101, including 1 CRi, 1 MLFS and 2 PR. One responder and another patient with stable disease with under 5% BM blasts were bridged to potentially life-saving transplant (HSCT). The common hematologic adverse events included febrile neutropenia, anemia, and thrombocytopenia. The common non-hematologic adverse events were elevations of ALT and AST. The recommended phase 2 dose will be 160 mg once-daily which resulted in Cmax and AUC0-24 plasma concentrations in Phase 1b of 259 ng/ml and 3,920 ng/ml at cycle 1 day 1.Conclusion:Once-daily dosing of single-agent PHI-101 had a distinct tolerability profile and showed excellent anti-tumor activity across FLT3i-pretreated and FLT3i-naïve patients with R/R FLT3 mutant AML.

22 Mar 2024·Cancer Research

Abstract 4657: PHI-501 is a novel potent next-generation pan-RAF/DDRs inhibitor, and overcomes resistance to RAF or MEK inhibitor in melanoma via dual inhibition of RAF and DDR1/2 signaling

Author: Han, June ; Kim, Sue Min ; Cho, Sungmin ; Nam, Ky-Youb ; Sung, Gi-Jun ; Shin, Sang Joon

AbstractBackground: The prevalent mutation of BRAF (~50%) and NRAS (~30%) in malignant melanomas has led to the aggressive development of RAF and MEK inhibitors as anticancer drugs. However, the major hurdle of targeted therapies for melanoma is resistance to RAF or MEK inhibitors, either intrinsic- or acquired- resistance. PHI-501 is an orally bioavailable and highly effective pan-RAF inhibitor. PHI-501 has dual inhibition activity against pan-RAF and discoidin domain receptor (DDR), a collagen-activated receptor tyrosine kinase. In this study, we evaluated the ability of PHI-501 to overcome drug-resistance to RAF or MEK inhibitors in melanoma harboring NRAS or BRAF mutations.Methods: Three drug-resistant cell lines were established by long-term treatment of belvarafenib in SK-MEL-2 (SK-MEL2BR) and each of dabrafenib and trametinib in SK-MEL-3 (SK-MEL3DR and SK-MEL3TR, respectively). RNA-seq of each resistant cell line and in-depth analysis of sequencing data was conducted, including GSEA. The anti-proliferative activity and signaling inhibition of PHI-501 were evaluated by CCK-8 assay and western blots. A long-term clonogenic assay was performed to confirm cell survival upon PHI-501 treatment. In vivo efficacy was evaluated in SK-MEL-3DR cell line xenograft models.Results: PHI-501 demonstrated significant anti-proliferative effects (GI50 < 1 µM, Mean GI50: 0.3 µM) in all 12 melanoma cell lines tested in this study. PHI-501 exerted cell growth inhibitory activities at least 3 to 50 times stronger than other RAF or MEK inhibitors in each of the resistance cell lines. Moreover, PHI-501 doses of less than 100 nM, significantly inhibited the colony formation of drug-resistant cells. Western blot revealed that PHI-501 retained strong inhibition of both ERK and AKT phosphorylation through downregulating pDDRs. In the SK-MER3DR xenograft mouse model, treatment of PHI-501 alone induced a rapid tumor reduction (TGI 72.1%), whereas the vehicle or dabrafenib did not display an anti-melanoma effect (TGI -7.4%). A comprehensive pathway analysis showed the TNFA-NFKB, IL6-JAK-STAT3, and KRAS signaling enriched in drug-resistant cells compared to the parental cells. PHI-501 treatment effectively downregulated those pathways in all three drug-resistant cells. In particular, PHI-501 downregulates the geneset in epithelial-mesenchymal transition (EMT) signaling more effectively in SK-MEL2BR, SK-MEL3DR, and SK-MEL3TR (Adjusted P=<.0001, and NES: -2.01, -1.72, -2.30, respectively).Conclusion: Novel pan-RAF/DDR dual inhibitor PHI-501 has greater anti-tumor activity in RAF or MEK inhibitor-resistant melanoma, which is through downregulation of MAPK signaling and EMT-related genesets and promoting apoptosis. These data support that the clinical development of PHI-501 for melanoma refractory to MAPK inhibitors.Citation Format: Sue Min Kim, Sungmin Cho, Gi-Jun Sung, Ky-Youb Nam, June Han, Sang Joon Shin. PHI-501 is a novel potent next-generation pan-RAF/DDRs inhibitor, and overcomes resistance to RAF or MEK inhibitor in melanoma via dual inhibition of RAF and DDR1/2 signaling [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 4657.

22 Mar 2024·Cancer Research

Abstract 7153: PHI-101 synergizes with chemotherapy and venetoclax in preclinical models of acute myeloid leukemia

Author: Sung, Gi-Jun ; Kim, Kyu-Tae ; Kim, Kyung-Ah ; Li, Li ; Small, Donald ; Han, June H. ; Nam, Ky-Youb ; Seale, Tessa ; Yoon, Jeong-Hyeok ; Hwang, Hee-sun ; Nguyen, Bao

AbstractFLT3 mutations are one of the most frequent genetic alterations in AML, resulting in poor prognosis. Although the development of FLT3 tyrosine kinase inhibitors (TKIs) provided new treatment options, patients with FLT3-mutant AML still suffer from high relapse rates when treated with FLT3 TKI alone. Accumulating evidence supports a combination treatment strategy to lower the recurrence rate. We have previously shown that PHI-101 demonstrated potent activity in various FLT3 mutant AML cell lines when used alone. Here we explore the use of PHI-101 in combination with other therapeutics in preclinical models of AML. We investigated the preclinical efficacy of the combination of PHI-101 with FDA-approved AML therapeutic agents in FLT3 mutant (MV4-11, Molm13, Molm14) and wild-type (THP-1) AML cell lines. Cell growth inhibition was assessed by CCK-8 and/or CellTiter-Glo assays. The Chou-Talalay method was used to calculate the combination index (CI) to test for synergy. Western blotting analysis was performed to explore the potential mechanisms underlying the combination effects. AML xenograft mouse models were used to assess the in vivo efficacy of PHI-101 combination therapy. Statistical comparisons included unpaired t-tests or one-way ANOVA. Combination treatment of PHI-101 with venetoclax or azacytidine showed strong synergistic effects on growth inhibition against both FLT3-ITD mutant (CI<0.3) and wild-type AML cells (CI <0.6). It is noteworthy that the FLT3-ITD homozygous cell line (MV4-11) showed especially strong synergism (CI <0.1). In the xenograft mouse model experiments, 14-day treatment with either PHI-101 alone or in combination with venetoclax or azacytidine showed significant suppression of tumor growth compared to venetoclax or azacytidine alone (in average tumor growth inhibition (TGI) 88.3% vs 8.6%)(p<0.05). In particular, PHI-101 3 mg/kg/day (mpk) with venetoclax 80mpk resulted in a stronger anti-tumor effect (TGI 94.2%) compared to PHI-101 (TGI 87.4%) or venetoclax alone (-9.6% of TGI) (p<0.05) even 21 days after stopping the treatment. In addition, PHI-101 treatment showed a survival advantage in AML animal models, and the combination with venetoclax led to significantly longer survival compared to the control groups. Our preclinical data showed that the combination of PHI-101 with venetoclax or azacytidine resulted in a highly effective anti-leukemic response against AML cells by inducing DNA damage, BCL-2 inhibition, and MCL-1 degradation. Additionally, treatment of mice with low-dose PHI-101 inhibited tumor regrowth and further potentiated venetoclax or azacytidine response in vivo. Our results suggest that the combination of PHI-101 and venetoclax or azacitidine may have the advantage of improving clinical responses in FLT3-ITD AML patients and offers a potential therapeutic option to treat patients with newly diagnosed or relapsed/refractory FLT3-mutant AML.Citation Format: Hee-sun Hwang, Gi-Jun Sung, Kyung-Ah Kim, Ky-Youb Nam, Kyu-Tae Kim, June H. Han, Jeong-Hyeok Yoon, Bao Nguyen, Li Li, Tessa Seale, Donald Small. PHI-101 synergizes with chemotherapy and venetoclax in preclinical models of acute myeloid leukemia [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 7153.

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