Oral STAT3 Inhibitor, TTI-101, in Patients with Advanced Cancers
Breast Cancer
Colon/Rectal Cancer
Liver Cancer / Hepatoblastoma
Lung Cancer
Melanoma
18 - 65 Years, Male and Female
SM_CP2016-0842 (primary)
NCI-2022-01107
Summary
Many patients have cancers that have increased activity of a protein called STAT3 that
contributes critically to the development and growth of their cancer. Despite our
knowledge of STAT3's importance to cancer, scientists and doctors have not developed a
drug that targets it and that patients can take to treat their cancer more effectively
than treatments that are now available. Tvardi Therapeutics, Incorporated has developed a
compound, TTI-101, which can be given by mouth and acts as a direct inhibitor of STAT3.
Administration of TTI-101 to mice demonstrated that it blocked growth of cancers of the
breast, head and neck, lung, and liver and it was safe when administered at high doses to
mice, rats, and dogs. In this application, Tvardi is proposing to further develop TTI-101
for treatment of solid tumors for which the prognosis is dismal. The investigators will
determine how safe it is when administered to patients with cancer, determine whether an
adequate dose can be administered to patients with cancer that will block STAT3 in their
cancer, and determine whether treatment with TTI-101 leads to reduced growth of their
cancer.
Objectives
Signal transducer and activator of transcription 3 (STAT3) is a member of a family of
seven closely related proteins responsible for transmission of peptide hormone signals
from the extracellular surface of cells to the nucleus. STAT3 is a master regulator of
most key hallmarks and enablers of cancer, including cell proliferation, resistance to
apoptosis, metastasis, immune evasion, tumor angiogenesis, epithelial mesenchymal
transition (EMT), response to DNA damage, and the Warburg effect. STAT3 also is a key
mediator of oncogene addiction and supports the self-renewal of tumor-initiating cancer
stem cells that contribute to cancer initiation, cancer maintenance, and relapse in
several types of tumors. STAT3 activity is increased in ~50% of all cancers, due either
to naturally occurring STAT3 mutations, as have been demonstrated in human inflammatory
hepatocellular adenomas and large granular lymphocytic leukemia, or, more commonly as a
result of activation of signaling molecules upstream of STAT3, including receptor
tyrosine kinases (RTK; e.g. epidermal growth factor receptor, EGFR), tyrosine
kinase-associated receptors (e.g. the family of IL-6 cytokine receptors or G-protein
coupled receptors, GPCR), and Src kinases (e.g. Src, Lck, Hck, Lyn, Fyn, or Fgr). Thus,
STAT3 is an attractive target for drug development to treat many types of cancer
including breast cancer, head and neck squamous cell carcinoma (HNSCC), non-small cell
lung cancer (NSCLC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), gastric
adenocarcinoma and melanoma.
Eligibility
- Inclusion Criteria
All of the following inclusion criteria must be fulfilled for eligibility:
1. Age =18 years;
2. For patients with solid tumors (not unresectable HCC): Patients with histologically
confirmed diagnosis of locally-advanced, inoperable, metastatic and/or treatment
refractory solid tumors for whom there are no available therapies that will confer
clinical benefit;
3. For patients with unresectable HCC: Patients with histologically confirmed diagnosis
of locally advanced, inoperable, unresectable HCC who have failed first and second
lines of therapy and Child-Pugh is A or beyond second line if the performance status
is preserved and Child-Pugh is A.
4. Eastern Cooperative Oncology Group Performance status 0-1;
5. Hemoglobin =9.0 g/dL, neutrophil count =1.0 x 109/l, platelets =75 x 109/L;
6. Adequate renal function capability, as calculated by creatinine clearance >40 ml/min
using the Cockroft-Gault formula;
7. Adequate liver function defined as total bilirubin <1.5 x ULN, and aspartate
aminotransferase (AST)/alanine aminotransferase (ALT) <3 x ULN. For subjects with
liver involvement, AST/ALT <5 x ULN; For subjects with liver involvement, AST/ALT <5
x ULN;
8. Measurable disease using clinically appropriate criteria for the type of malignancy,
RECIST v 1.1 for solid tumors;
9. Negative pregnancy test at the screening visit for women of childbearing potential,
defined as: female subjects after puberty unless they have been postmenopausal for
at least two years, are surgically sterile, or are sexually inactive and will remain
so for the course of the trial;
10. Willingness to avoid pregnancy and breast feeding beginning two weeks before the
first TTI-101 dose and ending three months after the last trial treatment. Male
subjects with female partners of childbearing potential and female subjects of
childbearing potential must use adequate contraception in the judgment of the
Investigator, such as a two-barrier method or a one-barrier method with spermicide
or intrauterine device during trial treatment dosing and for 3 months after the last
dose of the study; and
11. Ability to read and understand the informed consent form and willingness and ability
to give informed consent and demonstrate comprehension of the trial before
undergoing any trial activities.
Exclusion Criteria
Subjects are ineligible to enroll in this trial if they fulfill any of the following
exclusion criteria:
1. Previous therapy with:
1. Standard therapy including chemotherapy, immunotherapy, biologic therapy, or
any other anticancer therapy within 28 days (or five elimination half-lives for
non-cytotoxic drugs, whichever is shorter) of Day 1 of trial drug treatment (6
weeks for nitrosureas or mitomycin);
2. Any investigational agent within 28 days of Day 1 of trial drug treatment or 5
half-lives for a small molecule/targeted therapy;
2. Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone
marrow/stem cell transplantation within 5 years from enrollment; Ongoing toxicity
(except alopecia) due to a prior therapy, unless returned to baseline or Grade 1 or
less;
3. Major surgical intervention or participation in a therapeutic clinical trial within
28 days from Day 1 of the first dose of TTI-101;
4. Significantly impaired cardiac function such as unstable angina pectoris, congestive
heart failure with New York Heart Association (NYHA) class III or IV, myocardial
infarction within the last 12 months prior to trial entry; signs of pericardial
effusion, serious arrhythmia (including QTc prolongation of >470 ms and/or
pacemaker) or prior diagnosis of congenital long QT syndrome or left ventricular
ejection fraction <50% on screening echocardiogram;
5. History of cerebral vascular accident or stroke within the previous 2 years;
6. Uncontrolled hypertension (>160/100mm Hg);
7. History of Grade 3 or 4 allergic reactions attributed to compounds of similar
chemical or biologic composition as TTI-101 (hydroxyl-naphthalene sulfonamides);
8. Known active metastases in the central nervous system (unless stable by brain
imaging studies for at least 1 month without evidence of cerebral edema and no
requirements for corticosteroids or anticonvulsants);
9. History of difficulty swallowing, malabsorption, or other chronic gastrointestinal
disease or conditions that may hamper compliance and/or absorption of the
investigational product;
10. Known human immunodeficiency virus (HIV);
11. Subjects with chronic hepatitis B virus (HBV) infection, unless screening viral load
<100 IU/mL on stable doses of antiviral therapy. Note: Subjects with chronic HCV
infection are allowed to enroll in the study but do not have a defined maximum viral
load requirement for study entry;
12. Legal incapacity or limited legal capacity;
13. Pregnant or lactating women;
14. Any other condition, which in the opinion of the investigator, might impair the
subject's tolerance of trial treatment, the safety of the individual subject, or the
outcome of the trial;
15. Previous treatment of the current malignancy with a STAT inhibitor.
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts...
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