Transcript Slide 1

Pharmacokinetic profile of the base-excision repair inhibitor
Methoxyamine-HCl (TRC102; MX) given as an one-hour intravenous infusion
with Temozolomide (TMZ) in the first in human phase 1 clinical trial.
Panos S. Savvides, Yan Xu, Lili Liu, Lisa Rogers, Smitha Krishnamurthi, Afshin Dowlati, Stanton L. Gerson
Seidman Cancer Center and CASE Comprehensive Cancer Center, Cleveland, OH.
Results: 23 patients have enrolled, in two cohorts. In cohort A
(patients with no-CNS disease), patients have enrolled in dose-levels
1 and 2 (TMZ 150 mg/m2/day, days 1-5 and MX 15 mg/m2 and 30
mg/m2 respectively). In cohort B (patients with CNS involvement)
enrollment started at a DL lower (in DL1, TMZ 100 mg/m2/day, days 15 and MX 15 mg/m2; for DL2 TMZ increased to 150 mg/m2/day, days
1-5 and MX remained 15 mg/m2 ). Demographic, toxicity and efficacy
data will be presented separately. The average half-life of MX
administered as an one-hour continuous infusion was 55.04 hours
(range: 12.2 - 100.3 hours, n = 20), statistically not different from halflife of MX administered as a five-day continuous infusion which was
45.1 hours (range: 32.1 - 68.8 hours, n = 6). PD results, performed on
22 patients, showed that administration of the combination of TMZ and
MX resulted in 10-40% reduction in detectable AP sites. Comet assay
results, performed on 20 patients revealed that the combination of
TMZ and MX induced a 2 to 3-fold higher levels of DNA strand breaks
compared to TMZ alone.
Conclusions: MX has a distinct PK profile in humans, corresponding
to a 10-fold increase in estimated half-life when compared to the halflife observed in dogs, which has allowed us to move to a convenient
one-hour infusion regimen for further development. PD demonstration
of MX’s biologic activity on patients’ mononuclear cells has been
demonstrated even at the lowest DL. Accrual to the trial is ongoing.
Cycle 1 (duration: 2 weeks)
Week1 Day1 Day2 Day3 Day4 Day5
TMZ
↓
MX
↔
Cycle 2 and subsequent (q 4 weeks)
Week1 Day1 Day2 Day3 Day4 Day5
TMZ
↓
MX
↔
↓
↓
↓
↓
DOSE-ESCALATION SCHEDULE (cohort A)
Dose
TMZ
MX
Dose Level
(mg/m2/day) x5days
(mg/m2)
Level -1
100
15
Level 1
150
15
Level 2
150
30
Level 3
150
60
Level 4
150
100
Level 5
150
150
Eligibility Criteria
●Histologically confirmed solid tumor; incurable
●Priorchemotherapy and/or radiation are allowed.
●Prior temozolomide treatment is not restricted.
●Age >18 years.
●ECOG performance status <2
●Life expectancy > 12 weeks.
●Patients must have normal organ and marrow
function
Patient # Half life
(h)
7
74.085
8
29.6
9
49.973
10
52.319
11
30.482
12
48.57
13
63.102
14
55.694
15
43.535
16
17
92.11
18
43.461
19
43.672
20
21
38.071
22
36.203
23
68.263
24
64.155
25
34.7
26
78.388
27
55.19
28
82.643
29
Cmax
(ng/mL)
AUC
(h*ng/mL)
Volume
(L/kg)
4.7
51.362
11.3
9.81
9.133
22.7
9.07
9.975
8.107
381.945
58.701
707.648
391.033
388.343
1289.31
552.133
648.292
408.526
76.519
538.773
38.424
52.506
51.188
13.58
54.093
47.512
44.315
10.15
15.3
8.957
774.351
1067.026
400.659
51.338
17.418
72.902
3
Typical PK profile:
TRC102 15mg/m2,
(Pt #13, cycle#1)
2.5
714.883
395.393
657.601
932.12
582.264
1564.373
370.45
775.47
29.9
48.03
56.66
35.745
55.305
41.946
59.71
43.563
MX
TMZ+MX
1.5
2
1.0
1.5
1
0.5
0.5
2.0
0
2h
0h
4h
24h
AP sites formed over time after a single dose of
TMZ and low levels of AP sites were detected in
cells treated with combination of TMZ and MX.
Comet Assay, Neutral conditions
(Detect DNA double strand breaks)
A
Comet Assay, Alkaline conditions
(Detect DNA single strand breaks)
B
4
4
16.3
8.66
7.937
11.2
19.35
29.2
9.2
27.2
2.0
TMZ
Tail length (arbitrary units)
Methods: This ongoing phase I dose-escalation trial investigates the
safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of
MX given as an one-hour intravenous infusion in combination with
TMZ. PD markers, including analysis of AP sites measured on DNA
extracted from patients’ mononuclear cells (PBMCs) as well as DNA
strand break determined by comet assay at multiple time points, are
included.
Pharmacokinetic Analyses
AP sites relative to control
Background: MX is the first base excision repair (BER) inhibitor
evaluated in humans. MX blocks the BER pathway by covalently
binding to apurinic/pymidinic (AP) sites in DNA. In several preclinical
studies, improved therapeutic efficacy has been demonstrated with
various chemotherapeutic agents including alkylating agents, such as
TMZ. Initial results and correlative studies of the first in humans
administration of MX have been presented (AACR Annual Meeting
2009, abstract#5433).
Initial PK analyses on patient samples receiving MX as a five-day
continuous infusion revealed a distinct PK profile, 10-fold greater than
previously estimated in dogs, where half-life of MX was estimated to
be 4.5 hours. As a result, the protocol has been amended with MX
administration adjusted from a five-day continuous infusion to a onehour intravenous infusion. PK results of the one-hour intravenous
infusion regimen are now presented.
Schema
Tail length (arbitrary units)
Abstract
TMZ
3
TMZ+MX
2
1
TMZ
3
TMZ+MX
2
1
0
0
0
2
4
Time (hr)
24
0
2
4
24
Time (hr)
DNA strand breaks detected by Comet assay in PBMCs in patients
treated with TMZ and MX. (A) DNA double strand breaks detected by
neutral comet assay. (B) DNA single strand breaks detected by alkaline
comet assay. The cells were mixed with low-melting agarose, lysed and
the DNA was electrophoresed in both alkaline and neutral conditions to
detect DNA single and double strand breaks, respectively.
Conclusion
● TRC102 has a distinct PK profile in humans, corresponding to a 10-fold increase in estimated
half-life when compared to dogs
● Prolonged half-life has allowed a convenient one-hour infusion regimen for further development
● TRC102 biologic activity has been demonstrated even at the lowest dose level
Supported in part by: NIH grant R21 CA126149
ClinicalTrials.gov Identifier: NCT00892385
0h