Patients with stable disease or partial/complete remissions will continue therapy.
The endpoints are response rate-RR, disease control rate-DCR, PFS-progression-free survival,
CTCAEv5.0 toxicities, plasma lipid levels, collection of sebaceous secretion via Sebutape,
and 11C-acetate PET tumor imaging.
In the first stage, 13 patients will be enrolled. If fewer than 2 patients achieve response,
the study will be stopped. If 2 or more patients have a radiographic response, an additional
21 patients will be enrolled , for a total accrual of 34 patients.
1. Histologically or cytologically confirmed metastatic or advanced-stage NSCLC and
molecular identification of KRAS mutation. KRAS mutant NSCLC must be refractory,
relapsed, and/or intolerant of combination platinum-doublet chemotherapy and
subsequent immune checkpoint inhibitor therapy
· Molecular characterization (tissue- or blood-based [ie, cell-free/circulating tumor
DNA]) must have been performed and must have demonstrated a KRAS mutation (exon 12,
13, or 61 mutation detected by sequencing) by a CLIA-certified assay (source
2. Subjects' EGFR mutation and ALK gene rearrangement status must be known prior to study
entry. Subjects with EGFR mutation or ALK gene rearrangement must have progressed
after appropriate FDA-approved targeted therapy options prior to eligibility.
3. Patient has evidence of disease progression on most recent line of therapy.
4. Patient has measurable disease by RECIST v1.1 (Eisenhauer, 2009).
5. Age ≥ 18 years.
6. ECOG performance status of 0 or 1.
7. Predicted life expectancy of >3 months.
8. Adequate organ and marrow function as defined below:
- absolute neutrophil count ≥ 1,500/mcL
- platelets ≥ 75,000/mcL
- total bilirubin <2X institutional upper limit of normal
- AST and ALT ≤5X institutional upper limit of normal
- serum creatinine <1.5X institutional upper limit of normal
- LVEF >50%
- QTcF <470msec
9. Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 90 days following completion of therapy.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.
- A female of child-bearing potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy; or
- Has not been naturally postmenopausal for at least 12 consecutive months
(i.e., has had menses at any time in the preceding 12 consecutive months).
10. No significant ischemic heart disease or myocardial infarction within 6 months of
first dose of TVB-2640 and with current adequate cardiac function as in 3.1.8.
11. Ability to understand and the willingness to sign a written informed consent.
1. Patient is unable to swallow oral medications or has impairment of GI function or GI
disease that may significantly alter drug absorption such as active inflammatory bowel
disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome.
2. Patient has a history of risk factors for torsade de pointes such as uncontrolled
heart failure, severe hypokalemia with potassium less than 3mM/L, history of long QT
syndrome or require use during study participation of concomitant medications known to
prolong QT/QTc interval.
3. Patients who require use of strong CYP3A4/5 agonists or inhibitors during study
4. Patient has uncontrolled or severe intercurrent medical condition including
uncontrolled brain metastases. Patients with stable brain metastases either treated or
untreated, on a stable dose of steroids/anticonvulsants, with no dose increase within
4 weeks before the first dose of TVB-2640, and no anticipated dose change, are
5. Patient underwent major surgery within 4 weeks before the first dose of TVB-2640 or
received cancer-directed therapy either chemotherapy, radiotherapy, hormonal therapy,
biologic or immunotherapy, etc. or an investigational drug or device within 2 weeks (6
weeks for mitomycin C and nitrosoureas) or 5 half-lives of that agent, whichever is
shorter before the first dose of TVB-2640. In addition, any drug- related toxicity,
with the exception of alopecia, an endocrinopathy controlled with replacement therapy,
or a clinically stable toxicity not expected to increase from study therapy (eg,
cisplatin-associated ototoxicity) should have recovered to <Grade 1.
6. If female, patient is pregnant or breast-feeding.
7. Patient has evidence of a serious active infection-infection requiring treatment with
8. Patient has known immunodeficiency virus-HIV or hepatitis B or C infection, as such
patients may be at increased risk for toxicity due to concomitant treatment and
disease-related symptoms may preclude accurate assessment of the safety of TVB-2640.
9. Patient has an important medical illness or abnormal laboratory finding that, in the
Investigator's opinion, would increase the risk of participating in this study.
10. Patients with prior or concurrent malignancy whose natural history or treatment has
the potential to interfere with the safety or efficacy assessment of the
11. History of clinically significant dry eye (xerophthalmia) or other corneal abnormality
or, if a contact lens wearer, does not agree to abstain from contact lens use from
baseline through the last study drug dose.
12. Patient has a known allergy or hypersensitivity to components of TVB-2640.
13. Patient has a prior history of hypersensitivity, drug/radiation-induced, or other