This is a first-in-human, phase I clinical research study with TT-00420, an investigational,
oral, multi-target, dual mechanism kinase inhibitor targeting both mitosis and tumor
micro-environment, for the treatment of triple negative breast cancer (TNBC) and other
advanced solid tumors. The study consists of a dose escalation part followed by a MTD
expansion part.
Dose Escalation Cohorts: Eligible adult patients with advanced solid tumors will be enrolled
into Dose Escalation cohorts. Starting dose of TT-00420 mono-therapy will be 1 mg p.o., q.d.
TT-00420 capsule will be administered once daily on a continuous schedule. A treatment cycle
consists of 28 days. An ABLRM guided by the EWOC principle will evaluate the risk of
under-dose or over-dose for the dose tested in each cohort and provide the recommendation
dose for next cohort. Dose limiting toxicity (DLT) will be evaluated per the pre-defined DLT
criteria and managed by the pre-defined rules detailed in the protocol. Maximum Tolerated
Dose (MTD) and/or Dose Recommend for Dose Expansion (DRDE) will be determined in Dose
Escalation cohorts.
Dose Expansion Cohorts:
TNBC Cohort:
TNBC Dose-Expansion cohort will be opened to enroll the patients with advanced TNBC and
evaluate the safety, PK and preliminary efficacy of TT-00420 to identify the optimal
biological dose (OBD), when feasible, in patients with advanced TNBC.
SAT Cohort:
A parallel basket SAT Dose Expansion Cohort will be open to enroll patients with selected
advanced tumors (SAT) to evaluate the safety, PK and preliminary efficacy of TT-00420 to
identify the optimal biological dose (OBD), when feasible, in patients with SATs.
Recruitment in dose expansion cohorts may be put on hold if any significant safety finding(s)
that was not observed in dose escalation cohorts is identified. Bayesian modeling will be
updated with the new findings to evaluate if the previously determined MTD or DRDE still
suitable for further enrollment.
Inclusion Criteria:
1. Aged 18 years to 75 years at the time of provision of informed consent
2. Dose Escalation Cohorts: Histopathological or cytologically documented locally
advanced or metastatic solid tumors who have no available standard therapeutic
treatment options Dose Expansion Cohorts: Histopathological or cytologically
documented locally advanced or metastatic TNBC or SATs
3. TNBC Dose Expansion Cohort:
1. Histologically proven invasive breast carcinoma with triple negative receptor
status per institutional standard and with confirmed negative for ER and PR by
IHC (<10% positive tumor nuclei)
2. relapsed/refractory to at least one line of systemic chemotherapy
4. At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors
5. ECOG performance status of 0 or 1
6. Adequate organ function confirmed at Screening and within 10 days of initiating
treatment, as evidenced by:
- Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L
- Hemoglobin (Hgb) ≥ 9 g/dl
- Platelets (plt) ≥ 100 x 10^9/L
- AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver
metastases are present
- Total bilirubin ≤ 1.5 x ULN, or direct bilirubin < ULN for patients with total
bilirubin levels >1.5 ULN
- Serum creatinine ≤ 1.5 x ULN or calculated 24-hour clearance ≥ 50 mL/min
- Negative pregnancy test within 72 hours before starting study treatment in all
pre-menopausal women and women < 12 months after the onset of menopause
7. Must agree to take sufficient contraceptive methods to avoid pregnancy during the
study and until at least 6 months after ceasing study treatment
8. Able to sign informed consent and to comply with the protocol
Exclusion Criteria:
1. Women who are pregnant or lactating
2. Women of child-bearing potential (WOCBP) who does not use adequate birth control
3. Patients with any hematologic malignancy. This includes leukemia (any form), lymphoma,
and multiple myeloma.
4. Patients with
1. a history of primary central nervous system tumors or
2. carcinomatous meningitis Note: Patients with treated brain metastases that are
off corticosteroid and have been clinically stable 28 days are eligible for
enrollment
5. Patients with the following mood disorders as judged by the Investigator or a
psychiatrist, or as result of patient's mood assessment questionnaire:
- Medically documented history of or active major depressive episode, bipolar
disorder (I or II), obsessive-compulsive disorder, schizophrenia; a history of
suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm
to others)
- ≥ CTCAE grade 3 anxiety
- The psychiatric judgment, if available, overrules the mood assessment
questionnaire result/investigator judgment
6. Impaired cardiac function or clinically significant cardiac diseases, including but
not limited to any of the following:
1. LVEF < 45% as determined by MUGA scan or ECHO
2. Congenital long QT syndrome
3. QTc ≥ 450 msec on screening ECG
4. Unstable angina pectoris ≤ 3 months prior to starting study drug
5. Acute myocardial infarction ≤ 3 months prior to starting study drug
7. Patients with
1. unresolved diarrhea ≥ CTCAE grade 2, or
2. impairment of gastrointestinal (GI) function, or
3. GI disease that may significantly alter the absorption of TT-00420 (e.g.,
ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption
syndrome, or small bowel resection).
8. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
uncontrolled hypertriglyceridemia [triglycerides > 500 mg/dL], active or uncontrolled
infection) that could cause unacceptable safety risks or compromise compliance with
the protocol
9. Patients who have received chemotherapy, targeted therapy or immunotherapy ≤ 4 weeks
(6 weeks for nitrosourea or mitomycin-C) prior to starting study drug or who have not
recovered from side effects of such therapy
10. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field
radiation for palliation ≤ 2 weeks prior to starting study drug or who have not
recovered from side effects of such therapy
11. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
who have not recovered from side effects of such therapy
12. Patients who have been treated with any hematopoietic colony-stimulating growth
factors (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin
or darbepoetin therapy, if initiated before enrollment, may be continued
13. Patients who are currently receiving treatment with therapeutic doses of warfarin
sodium (Coumadin®) or any other coumarin-derivative anticoagulants
14. Patients who have received corticosteroids ≤ 2 weeks prior to starting study drug or
who have not recovered from the side effects of such treatment
15. Patients who are currently receiving treatment with medication that has known risk to
prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot
either be discontinued or switched to a different medication prior to starting study
drug
16. Patients who are receiving high to moderate CYP3A inhibitors and inducers as listed in
Appendix F
17. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
mandatory)
18. Known history of active infection with Hepatitis B (e.g., HBsAg reactive), or
Hepatitis C (e.g., HCV RNA (qualitative) is detected)
19. Has received a live-virus vaccination within 30 days of planned first dose Note:
Seasonal flu vaccines are permitted.
20. Inability to swallow or tolerate oral medication
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that, in the opinion of the investigator, might confound the results of the trial,
interfere with the patient's participation and compliance in the trial
