Imetelstat Sodium (GRN163L), a Telomerase Inhibitor:
Tolerability, Pharmacokinetics and Pharmacodynamic Activity Using an
Intermittent Once Every Four Weeks Dosing Schedule in Patients With Advanced Solid Tumors
1
Ratain ,
M. J.
S.
L.
J.
N.F.
P.M.
1University of Chicago, Chicago, IL, USA; 2 Karmanos Cancer Institute, Detroit, MI, USA; 3Geron Corp, Menlo Park, CA, USA.
Telomeres
Results
Rational
• Purpose: Multiple doses and dosing schedules of imetelstat
were assessed in a Phase I study in patients with advanced solid
tumors. Endpoints included safety, tolerability and
pharmacokinetics.
• Initial Dosing: Weekly imetelstat
• TTAGGG hexa-nucleotide repeats that cap the ends of chromosomes
and prevent chromosomal fusion.1
• Shorten by 50-200 basepairs (bp) per cell division.2-3
• Critically short telomeres may cause growth arrest and senescence.4
• Telomere length is shorter in cancer cells than normal somatic cells.9
Telomerase
• Consists of at least two essential components, the RNA template
(hTR) and the catalytic subunit (hTERT).
• Counters telomere loss by the direct addition of TTAGGG repeats to
the chromosome ends.1
• Repressed in most somatic cells5 and downregulated in
hematopoietic and other somatic stem cells.6
Telomerase and cancer
• Telomerase activation and preservation of telomeres are required for
immortalization.7-8
• Telomerase is highly activated in cancer and cancer stem cells, which
have been shown to be sensitive to telomerase inhibition in several
models.9
 The dose-limiting toxicity (DLT) was thrombocytopenia,
often seen after the first 3 weeks
• Intermittent Dosing: Days 1 and 8 of a 21-day cycle
Figure 1. Imetelstat Sodium (GRN163L) Structure
5’ end
• Modified DNA oligonucleotide (13 nts + lipid)
• N3’→P5’ phosphoramidate backbone
 Improves binding affinity and
chemical/enzymatic stability
C16
• Palmitoyl (C16) lipid covalently attached to 5’
thio-phosphate of first nucleotide
 Improves in vivo potency (cell uptake,
 Hematologic toxicity observed but may be mitigated with the
intermittent dosing; other observed toxicities were mostly
mild.
 The 9.4 mg/kg dose using this intermittent schedule is
currently being tested in Phase II studies.
• Alternative Dosing Schedule: Once every 28-days
 The purpose of this regimen is to assess the effect of a
longer interval between doses on the onset and duration of
cytopenias after a single dose of imetelstat and to ascertain
the maximum tolerated dose.
 The current analysis includes 16 patients following
this dosing schedule.
• Design: Phase I, sequential cohort, 3+3 dose escalation,
multicenter trial
• Patient population: Adults with refractory advanced solid
tumors
 Major Inclusion criteria: Patients with malignancy that is
evaluable or measurable; refractory or not amenable to
standard therapy, Karnofsky status ≥70%, anticipated
life expectancy ≥3 months.
 Major Exclusion Criteria: Primary malignancy or active
metastasis
in
CNS;
Hematologic
malignancies;
Hemoglobin <9.0 g/dL; ANC <1,500 /mm3; Platelet
count <100,000 /mm3; significant serum chemistry
abnormality (bilirubin, AST, ALT, albumin, creatinine),
active uncontrolled bleeding/ bleeding diathesis, elevated
PT or aPTT.
3’ end
O
H
N
OH
O
S
NP linkage
Na
+
• Endpoints: Safety (primary), pharmacokinetics and efficacy
(secondary), pharmacodynamics of telomerase activity
(exploratory)
 Plasma samples were collected to test pharmacokinetic
effects
 Peripheral blood mononuclear cells (PBMC)
collected to further test pharmacodynamic effects.
were
• Dose Limiting Toxicity (DLT): Grade 4 non-hematologic
toxicity, grade 3 non-hematologic toxicity lasting >3 days or
not medically-controllable, grade 4 neutropenia lasting >5
days, ≥ grade 3 neutropenia associated with fever, grade 4
thrombocytopenia, inability to complete cycle 1 or treatment
delays of >2 weeks from next scheduled dose due to any
toxicity thought to be associated with study drug.
1
H.L.Kindler ,
• Sixteen patients received imetelstat on day 1 of a 28 day
cycle, up to the data cut-off of October 6, 2010.
• Intermittent dosing using an 11.7 mg/kg dose every 28 days ameliorated the dose limiting
Grade 3 and 4 thrombocytopenia occasionally observed with the more frequent dosing
schedule (see Figure 2) .
• The median age was 59.7 years (range 39-80) and the
sex distribution was equal.
11.7 mg/kg day 1 & 8 of 21 day cycle
Dosing and Disposition
• Sixteen (16) patients received at least 1 infusion of
imetelstat.
 3 patients in the 9.4mg/kg cohort
• One patient in the 11.7mg/kg cohort is currently in
treatment, and 12 of 15 patients discontinued the study
due to disease progression.

400  
300
200




• Systemic exposure of imetelstat increased with dose (range of 4.8 to 11.7
mg/kg) after a 2-hour IV infusion with T1/2 ranging from 3.6 to 5.2 hours (data
not shown).
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







100














0
2
4


–










Gr1



8
10
Gr2
Gr3
Gr4


  
 
6
14
12
16
18
Weekly
Imetelstat
AUC
(μg/mL*hr)
• Seven patients in the 11.7 mg/kg cohort received 2 or
more doses, and 4 of 7 experienced dose delays, which
were primarily due to hematological toxicity.
• No dose delays occurred in the 9.4mg/kg cohort.
• Two patients in the 11.7 mg/kg cohort discontinued
imetelstat following an infusion reaction.
• Due to dose delays in cycle 2 and hematological toxicity,
the maximum administered dose was 11.7 mg/kg. This
dose and schedule is also being tested in Phase II studies.
600
500
800 –
exposure
is based on 15
–
mg/kg tiw dosing in
mice, which was
400 –
associated with both
a ≥50% inhibition
–
of telomerase in
tumors and a
0 –
concomitant
inhibition of tumor
growth.



300  





 
 
 


200  


100



























 
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























 


4
6














 










Gr1

Gr2
Gr3
Gr4

0
Screen
2
8
• No significant toxicity was observed at 9.4 mg/kg.
 Non-hematological adverse events ≥ Grade 3: intestinal obstruction, bile duct
obstruction, blood creatinine increased, bronchitis, cholangitis, diffuse large B-cell
lymphoma, headache, hyperglycemia, hypersensitivity/ infusion reaction, hypertension,
hyponatremia, and pituitary tumor benign.
 All were assessed as unrelated to imetelstat except one infusion-related reaction in the
11.7 mg/kg cohort.
• Two patients experienced an infusion reaction, both in the 11.7 mg/kg cohort, including a
Grade 3 reaction classified as a dose limiting toxicity (DLT) and a Grade 1 reaction.
• As previously observed with other dosing schedules, transient (<24hr) prolongation of aPTT
occurred without clinical sequelae in 12/16 (75%) of patients.
• Cytopenias were observed in both dose groups, which were mostly Grade 1-2 in severity.
See Table 1.
ι
4.8









ι
7.5
ι
9.4






10
12
14
16
18
20
• Cytopenias are delayed in onset and may still
delay the administration of the next dose
even using a once every 28 day schedule.
The periodicity of the cytopenias is consistent
with an effect on the hematopoietic
progenitor population which known to
express telomerase.
• Pharmacodynamic (PD) evidence of target
inhibition has been observed in selected
patient tissues.
• A once every 28 day schedule presents a
reasonable alternative to the intermittent
dosing schedule of Day 1 and 8 every 21
days, although the dose intensity per cycle is
less. This schedule is currently being tested
in ongoing Phase II studies.


ι
6.0
ι
11.7
Imetelstat Dose (mg/kg)
• Peripheral blood mononuclear cells (PBMC) from whole blood were collected pre- and
24h after a single dose of imetelstat on cycle-1 day-1 and analyzed for telomerase
activity using the TRAP assay (Telomere Repeat Amplification Protocol).
Figure 4: Inhibition of telomerase activity in peripheral blood
mononuclear cells 24 hours after a single dose of imetelstat
Weeks
• The dose-limiting toxicity is neutropenia and
thrombocytopenia.

Pharmacodynamics: Telomerase Activity
1500 –
Safety
• Imetelstat infusions were generally well tolerated.


Exposure†






















–
†Target

400
1600 –
– Target
- Dosed and had platelets test done


–
1200 –
11.7 mg/kg day 1 of 28 day cycle


2000 –
20
Weeks
Dose Escalation




2400 –


Screen
• Patient weekly plasma AUC values were calculated, and individual values for
each dose group are shown in Figure 3.





 


• Plasma samples were obtained prior to and following imetelstat infusions for
determination of imetelstat concentration by a validated hybridization-ELISA
assay.
Figure 3. Weekly AUCinf in patients and in xenograft mice (dashed line)


 

• The once every 28 day dosing schedule is
well tolerated.
• The exposure in patients (AUC values at 7.5 mg/kg and above) is higher than
the exposure associated with tumor growth inhibition in xenograft models.
- Dosed and had platelets test done

600
500
Summary
Patient Pharmacokinetics
Figure 2. Platelet levels vs time with 11.7 mg/kg on different dosing schedules
• All patients received prior cytotoxic regimens (mean 4.1),
and 9 (56%) had prior radiation therapy.
2
LoRusso
Results
Platelet Levels
• Grade 3 or higher non-hematological adverse events were reported in 5/16 (31%) patients.
O P TAGGGTTAGACAA
13-base
aminoglycerol
complement of
thioRNA template
phosphate
region
linker
palmitoyl
group
• Treatment: Successive cohorts of a single dose of 9.4 or
11.7mg/kg imetelstat given by 2-hour IV infusion on day 1 of
a 28 day cycle, with delays up to 2 weeks allowed between
cycles.
1
M.L.Maitiland ,
Results
• Patients received a median of 2 (range 1-3) cycles prior to
disease progression.
Methods
3
Lin ,
Baseline Characteristics
 13 patients in the 11.7mg/kg cohort.
PK, biodistribution)
• Molecular Weight ≈4600
3
Go ,T.
 Allowed for plasma concentrations and exposures to be
achieved consistent with efficacy in the preclinical models.
Imetelstat: A Telomerase Inhibitor
• 5’palmitoylated 13-mer thio-phosphoramidate oligonucleotide
complimentary to the hTR template in telomerase.
• Inhibits telomerase by acting as a competitive inhibitor of the
enzyme.10
• Demonstrates telomerase inhibitory and cancer growth and
metastasis inhibitory effects in both in vitro and in vivo preclinical
models.10-13
3
Smith ,
Platelets (10^3/uL)
• Preservation of telomere length is crucial to cell survival and enabling
the unlimited replicative capacity of cancer cells.
• Telomerase is a promising target for novel cancer therapeutics.
• Imetelstat (GRN163L) is the only telomerase inhibitor in clinical
development.
Dose
1
Janisch ,
Platelets (10^3/uL)
Introduction
3
Kelsey ,
Acknowledgements
• The authors gratefully acknowledge Deena Gruver,
Shuling Hwang and Dianne Morfeld for their important
contributions and dedicated work throughout this study.
• The authors would like to acknowledge the patients and
their families who participated in this study and the
investigators and study coordinators who made this study
possible.
• Funding provided by Geron Corp.

1000 –
Table 1. Hematological adverse events by grade
Dose (mg/kg)
9.4
# of Patients
3
Thrombocytopenia
Grade 1
2
Grade 2
0
Grade 3 -4
0
Anemia
Grade 1
2
Grade 2
0
Grade 3-4
0
Neutropenia
Grade 1
0
Grade 2
0
Grade 3
0
Grade 4
0
11.7
13
12
1
0
Total
16
14
1
0
8
1
0
10
1
0
0
3
1
1
0
3
1
1
Percent
Telomerase
Activity
Change
50 –
References



0–

-50 –
-100 –


ι
6.0
ι
7.5










ι
9.4
ι
11.7



Imetelstat Dose (mg/kg)
*note single outlier with significant increase in post-treatment telomerase activity
• Significant inhibition of telomerase was observed at all dose levels above 7.5 mg/kg.
• Median telomerase inhibition for the 9.4 mg/kg group was 34.0% (p value 0.2891*).
• Median telomerase inhibition for the 11.7 mg/kg group was 48.0% (p value 0.0215).
• Overall median telomerase inhibition from 23 patients (cohorts 6.0 to 11.7mg.kg)
tested was 40.5% (p value 0.0106).
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Poster (#388) presented at the EORTC-NCI-AACR symposium on “Molecular
Targets and Cancer Therapeutics” in Berlin, Germany, 16-19 November 2010