VS-6063-201 is a non-randomized, open-label, multi-center, multi-cohort phase ii study of VS-6063 in patients with KRaS mutant non-small cell lung cancer (nSCLC). eligible patients will be those who have received a minimum of one course of treatment that included at least one platinum-based chemotherapy doublet for metastatic or locally recurrent disease. at least one disease site must be measurable per Response evaluation Criteria in Solid Tumors (ReCiST) v1.1.
* FFPe tumor or Dna samples will be tested prior to enrollment in VS-6063-201 to demonstrate the KRaS mutation status and to perform additional characterization in tumors with identified KRaS mutation needed for assignment of patients to the appropriate cohort. Patients will be enrolled into one of 4 cohorts:
* Cohort a: nSCLC with KRaS mutation, wild type inK4a/arf, and wild type p53
* Cohort B: nSCLC with KRaS mutation, inK4a/arf mutation/inactivation and wild type p53
* Cohort C: nSCLC with KRaS mutation, wild type inK4a/arf, and p53 mutation
* Cohort D: nSCLC with KRaS mutation, inK4a/arf mutation/ inactivation and p53 mutation
each cohort will enroll 11 patients at the first stage and will be terminated if [LessThanorequalTo] 3 patients are progression free at 12 weeks. otherwise the cohort will be expanded to 34 patients.
* Patients will take VS-6063 400 mg Po twice daily (approximately every 12 hours); treatment will be continuous in each 3-week cycle with no scheduled interruptions. efficacy will be assessed locally per ReCiST Version 1.1. Response assessments will be performed every 6 weeks. Patients will remain on therapy until disease progression or unacceptable toxicities occur.
* Dose level adjustment for recurrent Grade 3 and Grade 4 non-hematological adverse events (except alopecia and nausea, vomiting, or diarrhea not managed by optimal medical interventions) includes a dose reduction from 400 mg BiD to 200 mg BiD. (Dose level adjustment will also be required following the first episode of Grade 3 or 4 hyperbilirubinemia with an increase in aST and/or aLT above the baseline grade.)
FFPe tumor or Dna samples will be used to demonstrate the KRaS status, provide additional characterization needed for assignment of patients to the appropriate cohort, and to perform other VS-6063-201 correlative studies. archival tissue is acceptable.
Patients must meet all of the following criteria to be considered for participation in this study:
1. >= 18 years of age.
2. ECOG Performance Score of 0 or 1
3. Ability and willingness to swallow oral medication.
4. Histologic or cytologic confirmation of non-small cell lung cancer (NSCLC).
5. Molecular characterization of the tumor must have been performed and must have demonstrated a KRAS mutation (exon 12, 13, or 61 mutations detected by sequencing) by a CLIA-certified assay (source documentation required). Adequate archival tissue, tissue core biopsy specimen, or DNA must be available for central testing of INK4a/Arf and p53 if not performed previously by CLIA-certified assay. For patients with inadequate archival tissue, a study-specific biopsy may be performed.
6. Documented evidence of distant metastasis or locoregional recurrence per required assessments within 28 days prior to starting study therapy. CT scans with contrast should be performed as listed below..
x CT scan of chest, abdomen, and pelvis
x MRI of the brain with contrast (CT scan may be substituted) only in patients with a known history of treated brain metastases
Note: Histologic confirmation of metastatic disease is not required.
7. For patients with brain metastases, the following criteria must be met:
x Previously untreated brain metastases that are asymptomatic and not requiring steroids are permitted.
x Previously treated (surgery and/or radiation therapy) brain metastases are permitted as long as most recent CNS radiographic imaging demonstrates stability or improvement.
x For patients with previously untreated brain metastases enrolled on study, CNS imaging must be included at the time of other disease imaging throughout treatment. .
8. At least one measurable disease site that meets the target lesion requirements per RECIST v1.1 criteria.
9. Patients must have received a minimum of one course of treatment that included at least one platinum-based chemotherapy doublet for metastatic or locally recurrent disease.
10. Most recent blood counts performed within 14 days prior to the first dose of study therapy indicate adequate hematologic function per the following criteria:
x ANC must be >= 1200/mm3;
x Hemoglobin >= 9 g/dL (transfusion is permitted to meet this criterion)
x Platelet count >= 100,000/mm3.
11. Most recent liver function tests performed within 14 days prior to the first dose of study therapy indicate adequate hepatic function per the following criteria:
<= 2.5 x ULN for the lab, if liver metastasis is NOT present or
<= 5 x ULN for the lab if liver metastasis is present
x Total bilirubin <= 1.5 x ULN for the lab.
12. Most recent serum creatinine performed within 14 days prior to the first dose of study therapy must be <= 1.5 x ULN for the lab OR a calculated creatinine clearance (using the Cockcroft-Gault formula must be >= 45 mL/minute.
13. Most recent ECG performed within 28 days prior to the first dose of study therapy must demonstrate a QTc interval < 480 msec.
14. Acute toxicity from previous therapy (excluding alopecia) must have resolved to <= Grade 1 per CTCAE v4.0 criteria unless otherwise specified in the inclusion/exclusion criteria.
15. Negative serum pregnancy test within 14 days prior to the first dose of study therapy for women of child-bearing potential (WCBP), defined as a woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses any time in the preceding 24 consecutive months).
16. Sexually active WCBP and male patients must agree to use acceptable methods of contraception to avoid pregnancy (for example, oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) during study therapy and for 3 months after the last dose of study therapy.