Dose Escalation Study of TriN2755 in Advanced Solid Tumors and Sarcomas

Trin Therapeutics

Status and phase

Unknown

Phase 1

Conditions

Neoplasms

Treatments

Drug: TRIN2755

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT01259518

TRIN2755-I-01

Details and patient eligibility

About

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.

Full description

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.

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.

Enrollment

48 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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