First in human phase 1 clinical trial of the base-excision repair inhibitor
Methoxyamine-HCl (TRC102; MX) given as an one-hour intravenous infusion
in combination with Temozolomide (TMZ) in patients with solid tumors.
Panos S. Savvides, Yan Xu, Lili Liu, Lisa Rogers, Joseph Bokar, Paula Silverman, Afshin Dowlati, Stanton L. Gerson
Seidman Cancer Center and CASE Comprehensive Cancer Center, Cleveland, OH.
Patient Characteristics
TMZ
↓
MX
↔
Cycle 2 and subsequent (q 4 weeks)
Week1 Day1 Day2 Day3 Day4 Day5
TMZ
↓
MX
↔
↓
↓
↓
-1
1
2
3
4
5
Dose level 1
Dose level 2
Primary tumors
N= 13
N= 4
Lung, breast, pancreatic,
colon, esophageal, ovarian,
oropharyngeal, salivary gland,
skin adnexal tumor
Dose level -1
Dose level 1
Primary tumors
15
15
30
60
100
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
2.5
1DLT (grade 3 psychosis)
Note: Expansion to 10 evaluable
patients b/o 1 idiosyncratic event
(gr 3 allergic reaction) with no DLTs
Dose level 2
No DLTs
Cohort B (CNS disease)
Dose level -1
Dose level 1
No DLTs
No DLTs
1.5
2
1.0
1.5
1
0.5
0.5
2.0
2h
0h
4h
24h
0h
2h
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.
Treatment Toxicities
Dose level 1
MX-bound AP site
TMZ+MX
0
N=3
N=3
Brain, pancreatic, head and
neck
Cohort A ( No CNS disease)
2.0
TMZ
Typical PK profile:
TRC102 15mg/m2,
(Pt #13, cycle#1)
Comet Assay, Neutral conditions
(Detect DNA double strand breaks)
A
100
150
150
150
150
150
3
TRC102 half-life:55.04 h
(range:12.2-100.3h, n=20)
Cohort B (CNS disease)
↓
DOSE-ESCALATION SCHEDULE (cohort A)
Dose
TMZ
MX
Dose Level
(mg/m2/day) x5days
(mg/m2)
Level
Level
Level
Level
Level
Level
Cohort A ( No CNS disease)
Comet Assay, Alkaline conditions
(Detect DNA single strand breaks)
B
4
4
Tail length (arbitrary units)
Cycle 1 (duration: 2 weeks)
Week1 Day1 Day2 Day3 Day4 Day5
Correlative studies
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. The final results of the phase I clinical trial of the
combination of pemetrexed and oral MX have been published
(GJ Weiss et al).
Initial results and correlative studies of the alkylating agent
TMZ and MX were previously presented (AACR Annual
Meeting 2009, abstract#5433). As initial PK analyses on
patient samples revealed a distinct PK profile in humans,
with a 10-fold increase in estimated half-life when compared
to the half-life observed in dogs, the protocol has been
amended with MX administration adjusted from a 5-day
intravenous continuous infusion to a 1-hour intravenous
infusion.
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 during the 5-day treatment, are included.
Results: 23 patients have enrolled, at dose-levels (DL) 1
and 2 (TMZ 150 mg/m2/day, days 1-5 and MX 15 mg/m2
and 30 mg/m2 respectively) in two cohorts. In cohort A
(patients with no-CNS disease, n =13 at DL1 and n=4 at
DL2) primary tumors include lung, breast, pancreatic, colon,
esophageal, ovarian, oropharyngeal, salivary gland, skin
adnexal tumors. In cohort B (patients with CNS disease, n
=3 at each DL1 and 2) primary tumors include brain,
pancreatic, head and neck tumors.The combination of MX
and TMZ has been well-tolerated. For the non-CNS
involvement cohort, one DLT was observed at DL1; grade 3
psychosis in a patient with progressive disease on increasing
doses of opioids. A grade 3 allergic reaction classified as an
idiosyncratic event resulted in further expansion of the
cohort to 10 evaluable patients with no additional DLTs
observed. No DLTs have been observed at DL2. For the CNSinvolved cohort no DLTs have been observed to date. Three
patients had stable disease (lung, ovarian, head and neck
primaries)
Conclusions: MX has a distinct PK profile in humans, which
has allowed us to move to a convenient one-hour infusion
regimen for further development. Ongoing data from the 1hour infusion MX regimen in the first in humans MX phase I
clinical trial demonstrate that MX in combination with TMZ is
well tolerated. No significant anemia (the DLT observed in the MX
and pemetrexed trial) has been observed at DL1 and 2 to date;
possibly because of lower MX dose administered at DLs 1 and 2
compared to MX DLT dose in the pemetrexed trial. Trial remains
open to accrual.
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
Best Response
● Stable disease ( n = 3)
● Treatment duration 7, 10, 11 months
● Primary tumors (lung, ovarian, head & neck)
● TRC102 can be safely administered as a one-hour
infusion
● The combination of TRC102 with TMZ is well tolerated
● Correlative studies demonstrate that TRC102
interrupts base excision repair in all treated patients,
even at the lowest level
Supported in part by NIH grant: R21 CA126149
ClinicalTrials.gov Identifier: NCT00892385