loxo-101, a selective pan-trk inhibitor for patients … dizziness and anemia; no study drug related...
TRANSCRIPT
Abstract
• Rearrangements in NTRK1, NTRK2, and NTRK3 that lead to constitutively-active TRKA, TRKB, and TRKC receptors are oncogenic and prevalent in a wide array of tumor types, including lung adenocarcinoma, thyroid, head and neck cancer, glioblastoma, and others
• NTRK1 and NTRK3 fusions with various partner genes have been described in 2-3% of papillary thyroid carcinomas and are mutually exclusive of other known oncogenic mutations
• LOXO-101 demonstrates potent and highly-selective inhibition of TRKA, TRKB, and TRKC over other kinase- and non-kinase targets
• LOXO-101 demonstrated robust inhibition of tumor growth in xenograft models, acceptable pharmaceutical properties, and safety in nonclinical models
• LOXO-101 was generally well tolerated with the most common adverse events being Grade 1 and 2 fatigue, dizziness and anemia; no study drug related SAEs have been reported; the MTD has not yet been reached
• As of 29 June 2015, one patient with a known LMNA-NTRK1 fusion has shown a dramatic and sustained response after treatment at 100mg BID
Summary
Study Objectives
To determine the safety of oral LOXO-101, including dose-
limiting toxicity (DLT), in adult patients with an advanced solid
tumor, characterize the pharmacokinetic (PK) properties, and to
identify the maximum tolerated dose (MTD) and/or the
appropriate dose of LOXO‑101 for further clinical investigation.
LOXO-101 is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in nonclinical models.
LOXO-101
Introduction: The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3, respectively), and their neurotrophin ligands regulate growth, differentiation and survival of neurons. Gene rearrangements resulting in mis-expression of fusion products that include the TRK kinase domain have been observed in diverse tumor types and may contribute to tumorigenesis (Vaishnavi, Cancer Discov 5:25, 2015). NTRK1 and NTRK3 fusions with various partner genes have been described in 2-3% of papillary thyroid carcinomas and are mutually exclusive of other known oncogenic mutations (TCGA, 2014 and data on file). LOXO-101 is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in preclinical models. Methods: We are performing a Phase 1, multicenter, open-label, 3+3 dose-escalation study of LOXO-101 to assess safety and tolerability. Results: Data from 15 patients evaluated across 3 dose cohorts were reviewed. LOXO-101 was generally well tolerated with the most common adverse events being Grade 1 and 2 fatigue, dizziness and anemia. Pharmacokinetic assessment demonstrated that maximum plasma concentrations of LOXO-101 were reached 30-60 minutes following dosing. Exposure increased in approximate proportion with dose and was similar on Day 1 and Day 8 of repeated dosing in all subjects, and biologically relevant plasma levels have been achieved. Conclusions: LOXO-101 is well tolerated at doses for which biologically relevant plasma levels are achieved. The activity of LOXO-101 will be assessed in thyroid cancer patients with NTRK gene fusions in ongoing studies.
LOXO-101 is highly selective for TRKA, TRKB, and TRKC
• No inhibition of >200
other kinases at 1000
nM
• Weak inhibition of TNK2
(IC50 > 1000 nM)
• >100-fold selective for
other kinases
• 1,000-fold selective for
>75 non-kinase targets
(A) LOXO-101 caused inhibition of tumor growth at doses of 20 to 200 mg/kg/day; (B) Inhibition of tumor growth was associated with dose-dependent reduction in pTRKA and pERK
Time (Days)
Tum
or V
olum
e (m
m3)
0 7 14 21
0
1000
2000
3000
10 mg/kg BID
20 mg/kg QD
30 mg/kg BID
60 mg/kg QD
100 mg/kg BID
200 mg/kg QD
Vehicle Control
LOXO-101 Treatment
A
0
50
100
0.01
0.1
1
10
Dose of LOXO-101 (mg/kg, PO)
pTR
KA
or
pER
K(P
erce
nt o
f C
ontr
ol, m
ean±
SEM
)
Concentration of LO
XO
-101 in Plasm
a andTum
or (µ g/mL or
µ g/g, mean
± SEM)
pTRKApERK
Vehicle 10
Plasma Level (µg/mL)Tumor Level (µg/g)
20 60 200
B
Methods
Study Design Phase 1, multicenter, open-label, 3+3 dose-escalation and safety study, with expansion cohorts for TRK-selected patients Drug Treatment LOXO-101 administered either QD or BID doses for continuous 28-day cycles. Individual patients will continue daily LOXO-101 dosing until disease progression, unacceptable toxicity, or other reason for treatment discontinuation Pharmacokinetics LOXO-101 concentrations quantified in plasma by a validated LC-MS/MS on Days 1 and 8 of Cycle 1
Dose Escalation Relapsed/refractory
Solid Tumors Progressed on SOC
ECOG 0-2
TRK Fusion positive
TRK Mutation / Alteration
Locally Confirmed TRK Status
Phase I Dose Escalation Phase I Dose Expansion
3+3 Design
RP2D
LOXO-101, A Selective Pan-TRK Inhibitor for patients with TRK-alterations
Marcia Brose1, Todd M. Bauer2,3, Howard A. Burris, III2,3, Robert C. Doebele4, Anna F. Farago5, Alice T. Shaw5, Brian B. Tuch6, Michael C. Cox6, David S. Hong7 1University of Pennsylvania, Philadelphia, PA 2Sarah Cannon Research Institute, Nashville, TN; 3Tenessee Oncology, PLLC, Nashville, TN; 4University of Colorado, Aurora, CO; 5Massachusetts General Hospital, Boston, MA; 6Loxo Oncology, South San Francisco, CA; 7MD Anderson Cancer Center, Houston, TX
386
Selection of Identified TRK Fusions
Characterization of Trk Fusions in Papillary Thyroid Cancer
NTRK Gene Fusion Partner (N=13) NTRK1 IRF2BP2 (n=2), TFG (n=1), TPM3 (n=1),
SQSTM1 (n=1) & SSBP2 (n=1)
NTRK2 none
NTRK3 ETV6 (n=6) & RBPMS (n=1)
An analysis of publically-available TCGA gene expression data (RNA-Seq) from 513 papillary thyroid cancer tumors was
performed with Omicsoft’s OncoLand software. The analysis revealed 13 in-frame fusion transcripts putatively harboring the
full kinase domain of NTRK1, NTRK2 or NTRK3.
Dose- and Schedule-Dependent Inhibition of Tumor Growth and pTRKA in 3T3-TRKA Allografts
Dose- and Schedule-Dependent Inhibition of Tumor Growth in KM-12 Allografts
LOXO-101 caused inhibition of tumor growth at doses of 200 mg/kg/day in either single dose or split dosing
Baseline Characteristics
Characteristics Subjects (n=15) Median age (range), years 57, (38-76)
Sex Male 8
Female 7
Race White 12
Black 3
Tumor Type
Colorectal carcinoma 2
Head and neck (MASC, synovial sarcoma, squamous cell) 3 (1,1,1)
Lung (NSCLC, mesothelioma) 3 (2,1)
Appendiceal peritoneal carcinomatosis 1
Anal 1
Thyroid (follicular) 1
Thymus 1
Pancreatic 1
Melanoma 1
Soft tissue sarcoma 1
ECOG Status 0 7
1 8
Prior systemic anticancer therapy alone, n (%) 10 (67%)
Prior radiation and systemic anticancer therapy, n (%)* 4 (27%)
Median number of regimens (range)* 3 (0-6)
TRK-fusion positive 1 (LMNA-NTRK1 fusion soft tissue sarcoma)
*One patient received radiation therapy alone
Interim Results (Data as of 25 March 2015)
Seven SAEs were reported in four patients and were considered unrelated to study drug: pneumonia, bile duct obstruction, malignant neoplasm progression, pleural effusion, syncope
At the 100-mg BID dose level, one DLT occurred, delirium (Grade 3, deemed unrelated to study drug), which resolved within 72 hours; dose was reduced to 100 mg QD without recurrence
Summary of Treatment-Emergent Adverse Events
Dose: Total
(n=15)
Adverse Events (AEs)*
All Grades Grade 3-4
n (%) n (%) Fatigue 7 (47%) 1 (7%)
Dizziness 4 (27%) 0
Anemia 5 (33%) 2 (13%)
Constipation 3 (20%) 0
Dry mouth 3 (20%) 0
Diarrhea 2 (13%) 0
Nausea 2 (13%) 0
Vomiting 2 (13%) 0
Chills 2 (13%) 0
Pyrexia 2 (13%) 0
ALP increased 2 (13%) 0
Hyper-glycemia 2 (13%) 0
Hypokalemia 2 (13%) 0
Peripheral edema 2 (13%) 0
Syncope 2 (13%) 2 (13%)
Cough 2 (13%) 0
Rash 2 (13%) 0
AST increased 1 (7%) 1 (7%)
Delirium 1 (7%) 1 (7%)
Pneumonia 1 (7%) 1 (7%)
*Treatment-emergent adverse events (reported by > 10% of total subjects) or any Grade 3-4 events; patients were on study between 8 to 64 days
Study baseline Study cycle 3 day 1
LMNA-NTRK1 Fusion Soft Tissue Sarcoma Response (Scans as of 29 June 2015)
MP
Doebele et al, Cancer Discovery. July 2015. Published OnlineFirst July 27, 2015; doi: 10.1158/2159-8290.CD-15-0443
Study cycle 5 day 1