A Phase I Dose Escalation Study on the Tolerability and Activity of TriN 2755 in Patients With Advanced Solid Tumors and Sarcomas Using Two Different Dosage Regimens
18 Years
N/A
Both
Neoplasms
Trial Information
A Phase I Dose Escalation Study on the Tolerability and Activity of TriN 2755 in Patients With Advanced Solid Tumors and Sarcomas Using Two Different Dosage Regimens
Classical chemotherapeutic agents include the class of alkylating agents with covalent
modification of biopolymers and in particular, bases of DNA, as proposed mechanism of
cytotoxic action. Bifunctional alkylating agents, which yield inter- or intrastrand
cross-links include nitrogen mustards, mitomycin C and platinum complexes. In contrast,
monofunctional alkylating agents act by reacting with single electron-rich sites in bases of
DNA strands. The most prominent class of the latter group is the triazene, which is based on
nitrogen-rich chemistry. It is generally accepted that triazenes, upon metabolic activation
via N demethylation, yield highly reactive carbocations, which covalently bind to
biopolymers. The novel triazene TriN 2755 differs from other triazenes through its
physicochemical properties such as high hydrophilicity and photostability, and in particular
by its potent, dose dependent antitumor activity in a spectrum of cancers including
dacarbazine-resistant tumors, where treatment options for metastatic disease are still not
satisfactory and medical needs exist.
This is an open-label, parallel-group, two-center, safety, activity and pharmacokinetic
study of TriN 2755 given at increasing dose levels as intravenous infusions administered
over 4 hours. The study is divided into two parts: Part I a dose escalation phase and Part
II an extension phase.
Part I of the Study (Dose Escalation Phase):
In the first part of the study, two treatment schedules will be investigated in parallel:
Treatment schedule A: The study medication will be infused once every 28 days in a 4-week
cycle (Group A) Treatment schedule B: The study medication will be infused once every 7 days
in a 4-week cycle (Group B)
In treatment schedule A (Group A), the planned starting dose to be investigated is 25 mg
TriN 2755 given once followed by a recovery period of 4 weeks. Subsequent patients can only
be included on a new dose level when the safety review from all patients included at the
preceding dose level(s) at Day 28 after infusion (end of Cycle 1) does not indicate relevant
toxicity.
In treatment schedule B (Group B), the planned starting dose to be investigated is 800mg,
given once every 7 days in a 4 week cycle. Subsequent patients can only be included on a new
dose level when the safety review from all patients included at the preceding dose level(s)
at Day 28 after the start of the first infusion (end of Cycle 1) does not indicate relevant
toxicity.
Plasma samples to evaluate the pharmacokinetics of TriN 2755 are collected at predefined
schedules after the first administration at each dose level and at pre-dose and at expected
peak times during the subsequent administrations within the first treatment cycle only
(Group B). Urine samples are collected over 24 hours after the first administration at each
dose level within the first treatment cycle only.
Once the MTD is reached, two expanded cohorts of patients are treated with the Maximum
Recommended Dose (MRD) which is one dose level below the MTD or at lower dose levels, if
indicated. This second part of the study (expansion) allows for enrolment of approximately
additional 9 patients per treatment schedule, at the chosen dose, in order to better assess
the safety and possible antitumor activity of TriN 2755. The exact number of patients to be
enrolled in this expanded phase is decided by a Monitoring Board. The patients are treated
at or near the planned phase II dose, without expanding or prolonging the study excessively.
Inclusion Criteria:
- Male or female patients of age > 18 years
- Patients with a histologically / cytologically confirmed diagnosis of advanced solid
tumor or sarcoma for which a treatment of proven efficacy does not exist or an
established treatment(s) had failed
- Measurable or non-measurable disease according to RECIST v1.0 criteria. Patients
should have at least one measurable lesion or disease which is non-measurable but can
clearly be evaluated for response
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
- Life expectancy of at least 3 months
- Ability to understand the nature of the study and willingness to sign a written
informed consent document
- Willingness and ability to comply with the study protocol for the duration of the
study
Exclusion Criteria:
- Any lymphoma or other hematological tumors
- Known brain metastases
- Earlier history of other tumors, except non melanoma-skin cancer or in situ cervical
carcinoma curatively excised
- Major surgery within 4 weeks prior to treatment start
- Extensive radiotherapy, within 2 weeks of treatment start, or cytotoxic chemotherapy
or limited radiotherapy within 2 weeks of treatment start
- Unresolved toxicity from prior chemotherapy (including approved and experimental
drugs)
- Any of the following abnormal baseline hematological values:
- Hb < 10g/dl,
- WBC < 3.0 x 109/l Neutrophils < 1.5 x 109/l
- Platelets < 100 x 109/l
- Any of the following abnormal baseline liver function tests:
- Serum bilirubin > 1.5 x upper normal limit, > 3 x if due to tumor
- ALAT and/or ASAT > 2.5 x upper normal limit, > 5 x if due to tumor
- The following abnormal baseline renal function test:
- Serum creatinine > 1.5 mg/dl
- Creatinine clearance < 50 ml/min
- All clinically relevant cardiovascular abnormalities (i.e. myocardial infarction
within the prior 6 months, cardiac arrhythmia requiring medication, uncontrolled
hypertension, abnormal cardiac function (* class II of NYHA classification), cardiac
failure or non compensated active heart disease (* class II of NYHA classification)
- Neurologic: symptomatic motor or sensory neurotoxicity grade 2 NCI CTC
- Primary tumor associated with central nervous system-related symptoms interfering
with the informed consent or with the study
- History of psychiatric disabilities, seizures or central nervous system disorders,
which is considered to be clinically significant by the investigator and could
interfere with informed consent or adequate follow-up
- Major fluid effusions (e.g. ascites, pleural effusion), or clinically relevant blood
loss
- Interstitial pneumonia or lung fibrosis
- History or presence of thromboses or clotting disorders
- Concomitant medication for non-vital indications with known hepatotoxic or
nephrotoxic potential (e.g, aminoglycoside antibiotics)
- Serious (Grade 3-4) uncontrolled intercurrent infections
- Any history of alcohol abuse or drug addiction
- Positive results of virus serology tests (i.e. detection of HBsAg and antibodies to
HCV, HIV1, HIV2, CMV and EBV)
- Clinical conditions equal to protocol definitions of DLT
- Participation in any investigational drug study within 30 days preceding treatment
start
- Male or pre-menopause female patients unable to practice a medically approved method
of contraception during the study and the 3-month period thereafter (all patients
potentially fertile)
- Pregnancy or breast feeding women
- Any condition which in the judgment of the investigator would place the subject at
undue risk or interfere with the results of the study (e.g. increased medical risks
due to non malignant organ or systemic disease or secondary effects of cancer)
- History of allergic reactions attributed to compounds of the same chemical class
(dacarbazine, temozolomide) as TriN 2755 or any excipients of IMP
- Mental handicap or legal incapacity
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Outcome Time Frame:
at baseline and beginning of every cycle
Safety Issue:
Yes
Principal Investigator
Max E Scheulen, PHD MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Department of Internal Medicine West German Cancer Centre University Hospital Essen Essen, Germany
Authority:
Germany: Federal Institute for Drugs and Medical Devices
Study ID:
TRIN2755-I-01
NCT ID:
NCT01259518
Start Date:
November 2009
Completion Date:
January 2012
Related Keywords:
- Neoplasms
- Neoplasms
- Sarcoma
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