Patient case: 57-year-old male with lung adenocarcinoma; genetic feature: KRAS (G12V), high tumor mutational burden

Clinical trial: Phase 2 Study of TVB-2640 in KRAS Non-Small Cell Lung Carcinomas

Summary: This is a prospective one arm, single center phase 2 trial of TVB-2640 in KRaS mutant nSCLC patients. 12 patients will be treated with a minimum of 1 cycle of TVB-2640 therapy over 8 weeks.

Detailed description: This is a prospective one arm, single center phase 2 trial of TVB-2640 in KRaS mutant nSCLC patients. 12 patients will be treated with a minimum of 1 cycle of TVB-2640 therapy over 8 weeks. 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, CTCaev4.03 toxicities, plasma lipid levels and 11C-acetate PeT tumor imaging.
  Primary endpoints are ReCiST v1.1 best response and response duration and nCi CTCaev4.1 toxicity profile over eight weeks. Secondary endpoints are 11C-acetate tumor uptake pretreatment and at four weeks of treatment and plasma lipidomics pretreatment and at four weeks of treatment.

Eligibility: Inclusion Criteria:
  1. Histologically or cytologically confirmed metastatic or advanced-stage KRAS mutant NSCLC that is refractory, relapsed, and intolerant of combination chemotherapy and subsequential immune checkpoint therapy.
  2. Patient has progressive disease.
  3. Patient has measurable disease by RECIST v1.1 (Eisenhauer, 2009).
  4. Age ≥ 18 years.
  5. ECOG performance status of 0 or 1.
  6. Predicted life expectancy of >3 months.
  7. Adequate organ and marrow function as defined below:
  1. - absolute neutrophil count ≥ 1,500/mcL 2. - platelets ≥ 100,000/mcL 3. - total bilirubin <2X institutional upper limit of normal 4. - AST and ALT ≤5X institutional upper limit of normal 5. - creatinine <1.5X institutional upper limit of normal 6. -LVEF >50% 7. -QTcF <470msec
  8. 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.
  1. 3.1.6.1 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:
  9. Has not undergone a hysterectomy or bilateral oophorectomy; or 10. 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).
  11. 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 3.1.7.
  12. Ability to understand and the willingness to sign a written informed consent.
  Exclusion Criteria
  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 heart failure, severe hypokalemia with potassium less than 3mM/L, family history of long QT syndrome or require use during study participation of concomitant medications known to prolong QT/QTc interval—see http://crediblemeds.org/everyone/ composite-list-all-qtdrugs/?rf=US.
  3. Patients who require use of strong CYP3A4/5 agonists or inhibitors during study participation.
  4. Patient has uncontrolled or severe intercurrent medical condition including uncontrolled brain metastases. Patients with stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants, with no dose change within 4 weeks before the first dose of TVB-2640, and no anticipated dose change, are allowed.
  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 4 weeks and 6 weeks for mitomycin C and nitrosoureas or 5 half-lives of that agent whichever is shorter before the first dose of TVB-2640. A minimum of 10 days between termination of the investigational drug and administration of TVB-26740 is required. In addition, any drug-related toxicity, with the exception of alopecia, 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 intravenous antibiotics.
  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. Patient has a history of other malignancy treated with curative intent within the previous 5 years with the exception of adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix.or breast. Subjects with previous invasive cancers are eligible if the treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease.
  11. Patient has a history of clinically significant abnormality on slit-lamp examination or other clinically significant ophthalmologic finding, as determined by an ophthalmologist.
  12. Patient has a known allergy or hypersensitivity to components of TVB-2640.

Relevance to patient case: possibly relevant