Download TGFβR1 Kinase Inhibitor - Lilly Oncology Pipeline USA

TGFβR1 Kinase
Inhibitor
Galunisertib, LY2157299 H20
Prud’homme GJ1; Flavell RA, et al 2
Drug Discovery Platform: Cancer Angiogenesis and Tumor Microenvironment/Immuno-Oncology
TGFβR1 Kinase Inhibitor Galunisertib, LY2157299 H2O
A Phase 2 Study of LY2157299 in Patients With Hepatocellular Carcinoma*
Key Inclusion Criteria
Key Exclusion Criteria
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• 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)
Please visit www.clinicaltrials.gov for more information
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§
Primary endpoint:
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.
The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory
approval and become commercially available for the uses being investigated.
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TGFβR1 Kinase Inhibitor Galunisertib, LY2157299 H2O
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†
Key Inclusion Criteria
Key Exclusion Criteria
• 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
Please visit www.clinicaltrials.gov for more information
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
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Primary endpoint:
Safety and tolerability of galunisertib
in combination with nivolumab
Phase 2
Galunisertib + nivolumab
(NSCLC, HCC, or glioblastoma)‡§
Primary endpoint:
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.
The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory
approval and become commercially available for the uses being investigated.
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TGFβR1 Kinase Inhibitor Galunisertib, LY2157299 H2O
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
Key Inclusion Criteria
Key Exclusion Criteria
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Primary endpoint:
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
Please visit www.clinicaltrials.gov for more information
on this clinical trial [NCT02734160].
Primary endpoint:
Safety of galunisertib in
combination with durvalumab
in patients with metastatic
pancreatic cancer
*This clinical trial is being conducted globally in partnership with AstraZeneca.
The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory
approval and become commercially available for the uses being investigated.
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TGFβR1 Kinase Inhibitor Galunisertib, LY2157299 H2O
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 hepatocellular carcinoma and pancreatic cancer.
Study Schemas Not Available
[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)
The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory
approval and become commercially available for the uses being investigated.
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.
ON99284
10/2016 PRINTED IN USA
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