TGFβR1 Kinase Inhibitor Galunisertib, LY2157299 H 2 0 Derived from Prud homme GJ 1 ; Flavell RA, et al. 2 Drug Discovery Platform: Cancer Angiogenesis and Tumor Microenvironment/Immuno-Oncology
A Phase 2 Study of LY2157299 in Patients With Hepatocellular Carcinoma* Hepatocellular carcinoma (HCC) not amenable to curative surgery Known HCC with fibrolamellar or mixed histology Child-Pugh class A or B7 (parts A and B) or Child-Pugh class A (part C) Presence of clinically relevant ascites Part A: Serum alpha-fetoprotein (AFP) 1.5 upper limit of normal (ULN) Part B: Serum AFP <1.5 ULN Received more than one line of systemic treatment (parts A, B, and D); or received previous systemic treatment (part C) Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Moderate or severe cardiac disease Known hypersensitivity to sorafenib or its excipients (part C) Adequate hematologic, hepatic, and renal function Serious illness or medical condition(s) (part D) Parts A and B: Received sorafenib and has progressed, was intolerant to sorafenib, or is ineligible for sorafenib treatment Part C: No previous systemic treatment Part D: Received sorafenib and has progressed, was intolerant to sorafenib, is ineligible for sorafenib treatment (at the investigator s discretion), or has not received prior systemic treatment (at the investigator s discretion) on this clinical trial [NCT01246986]. Parts A, B, and D: Discontinued sorafenib for at least 2 weeks * This clinical trial is being conducted globally. Part A: Randomization 1:1; elevated serum AFP Cohort 1 : 80 mg galunisertib PO BID Cohort 2 : 150 mg galunisertib PO BID Part B : Serum AFP normal 150 mg galunisertib PO BID Part C: Cohort 1: 80 mg galunisertib PO BID + 400 mg sorafenib PO BID Cohort 2: 150 mg galunisertib PO BID + 400 mg sorafenib PO BID Expansion cohort: 80 mg or 150 mg galunisertib PO BID + 400 mg sorafenib PO BID Part D: Cohort 1: 80 mg galunisertib PO BID + 8 mg/kg ramucirumab Cohort 2: 150 mg galunisertib PO BID + 8 mg/kg ramucirumab Time to progression Galunisertib dose is administered for the first 14 days of a 28-day cycle. Sorafenib dose is administered for 28 days of a 28-day cycle. Ramucirumab is administered intravenously on days 1 and 15 of a 28-day cycle. 2 3
A Phase 1b/2 Dose-Escalation and Cohort-Expansion Study of the Safety, Tolerability, and Efficacy of a Novel Transforming Growth Factor-Beta Receptor I Kinase Inhibitor (Galunisertib) Administered in Combination With Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors (Phase 1b) and in Recurrent or Refractory Non-small Cell Lung Cancer, Hepatocellular Carcinoma, or Glioblastoma (Phase 2)* Phase 1b Dose escalation of galunisertib + nivolumab For phase 1b: Must have advanced refractory solid tumors in any line of therapy History of a serious cardiac condition within 6 months prior to enrollment, such as unstable angina pectoris, congestive heart failure New York Heart Association class 3/4, or uncontrolled hypertension For phase 2: - Recurrent or refractory non-small cell lung cancer (NSCLC; any histology), hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein 200 ng/ml, or glioblastoma (primary) - Disease progression or was refractory or intolerant to one prior line of therapy and has refused currently approved second-line therapy Documented major electrocardiogram abnormalities (not responding to medical treatments) Echocardiogram abnormalities, such as heart valve function defect For NSCLC: Prior lines of therapy must include a platinum-based therapy Conditions consistent with predisposition for aneurysms For HCC: Evidence of interstitial lung disease or active, noninfectious pneumonitis - Received one prior line of therapy with sorafenib or has progressed or been intolerant to sorafenib for participants not eligible for transarterial chemoembolization - Child-Pugh class A only on this clinical trial [NCT02423343]. - Participants may have any viral status (hepatitis B, C, or none) with a viral load <100 IU/mL * This clinical trial is being conducted globally in partnership with Bristol-Myers Squibb. - Participants with hepatitis B must be on a nucleoside analog reverse transcriptase inhibitor For glioblastoma (GB): Previous first-line therapy with at least radiotherapy and temozolomide, except for participants with O6-methylguanine-DNA methyltransferase (MGMT) unmethylated newly diagnosed GB. Participants with MGMT unmethylated newly diagnosed GB may have received radiation therapy only Adequate organ function Safety and tolerability of galunisertib in combination with nivolumab Phase 2 Galunisertib + nivolumab (NSCLC, HCC, or glioblastoma) Safety of combination therapy Galunisertib is administered PO BID for the first 14 days of a 28-day cycle. Nivolumab is administered intravenously (IV) every 2 weeks for two cycles. Galunisertib is administered PO BID for the first 14 days of a 28-day cycle. Nivolumab is administered IV every 2 weeks of a 28-day cycle. Participants continue study treatment until discontinuation criteria are met. 4 5
A Phase 1b Dose-Escalation and Cohort-Expansion Study of the Safety, Tolerability, and Efficacy of a Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor (Galunisertib) Administered in Combination With the Anti-PD-L1 Antibody Durvalumab (MEDI4736) in Recurrent or Refractory Metastatic Pancreatic Cancer* Part A Dose escalation of galunisertib + durvalumab Recurrent metastatic pancreatic adenocarcinoma Disease progression, or refractory or intolerant to no more than two prior systemic regimens for locally advanced or metastatic pancreatic cancer History of a serious cardiac condition within 6 months prior to enrollment (eg, unstable angina pectoris, congestive heart failure New York Heart Association class 3/4, or uncontrolled hypertension) Participants who have received prior neoadjuvant therapy and who now have metastatic disease must have received one of the following regimens for their metastatic disease prior to enrollment in this study: Electrocardiogram abnormalities (eg, cardiac arrhythmia, left bundle-branch block, or myocardial infarction within 6 months prior to enrollment) - FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) Echocardiogram abnormalities (eg, heart valve function defect or aneurysm) - Nab-paclitaxel/gemcitabine Conditions consistent with predisposition to aneurysms - TS-1 (tegafur gimeracil oteracil potassium) Interstitial lung disease or active, noninfectious pneumonitis - Liposomal irinotecan/5-fluorouracil/leucovorin Prior therapy with anti-pd-1, anti-pd-l1, anti-pd-l2, or anti-ctla4 antibody, or small molecules specifically targeting T-cell co-stimulation or checkpoint pathways (eg, CD137, GITR, TIM-3, and LAG CAR-T cells and vaccines) within 6 months prior to starting study treatment - Single-agent gemcitabine Safety and tolerability of galunisertib in combination with durvalumab Part B Dose confirmation of galunisertib + durvalumab (pancreatic cohort expansion) Prior treatment with a TGFβR1 kinase inhibitor Prior therapy with a monoclonal antibody within 28 days prior to starting study treatment or not recovered (grade 1 at baseline) from adverse events (except for fatigue or alopecia) due to agents administered more than 28 days earlier on this clinical trial [NCT02734160]. Safety of galunisertib in combination with durvalumab in patients with metastatic pancreatic cancer * This clinical trial is being conducted globally in partnership with AstraZeneca. 6 7
Target Molecule The transforming growth factor β (TGFβ) signaling pathway is complex and results in tumor suppressor or tumor-promoting activity depending on the cellular context in which the pathway is active. As many cancers progress to more aggressive disease states, the tumor suppressor arm of TGFβ signaling is lost and, instead, tumor cells proliferate. In contrast, TGFβ overexpression in advanced disease enhances tumor growth, suppresses the immune system, and exacerbates invasive and metastatic tumor cell behavior.3 TGFβ worsens immunosuppression by inhibiting cytotoxic cells such as CD8+ CTLs and NK cells and enhancing suppressive immune cells called T regulatory cells and myeloid-derived suppressor cells.2 Galunisertib (LY2157299 monohydrate) is a small molecule that has been shown in vitro to block TGFβ signaling.4-7 Clinical Development Galunisertib is being investigated in phase I clinical trials, including combination clinical trials in immuno-oncology, and in clinical trials in patients with glioblastoma, hepatocellular carcinoma, and pancreatic cancer. Study Schemas Not Available [NCT02304419] Early Development A Study of Galunisertib on the Immune System in Participants With Cancer [NCT02178358] Gastrointestinal Cancer A Study of LY2157299 in Participants With Advanced Hepatocellular Carcinoma [NCT02240433] Gastrointestinal Cancer A Study of LY2157299 in Participants With Unresectable Hepatocellular Cancer (HCC) [NCT01220271] Neurologic Cancer A Study Combining LY2157299 With Temozolomide-Based Radiochemotherapy in Patients With Newly Diagnosed Malignant Glioma References: 1. Prud homme GJ. Lab Invest. 2007;87(11):1077-1091. 2. Flavell RA, et al. Nat Rev Immunol. 2010;10(8):554-567. 3. Ikushima H, Miyazono K. Nat Rev Cancer. 2010;10(6):415-424. 4. Yingling JM, et al. Proc Amer Assoc Cancer Res. 2006;47. Abstract 250. 5. Rodón J, et al. Invest New Drugs. 2015;33(2):357-370. 6. Maier A, et al. Cell Oncol (Dordr). 2015;38(2):131-144. 7. Herbertz S, et al. Drug Des Devel Ther. 2015;9:4479-4499. ON98982 07/2016 PRINTED IN USA Lilly USA, LLC 2016. All rights reserved.