Study of Oral Mifepristone as Salvage Therapy in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer

This is a non-randomized, multicenter, single-stage phase II study of mifepristone in patients with advanced or metastatic NSCLC who have failed two or more previous chemotherapy regimens.

The Investigator plans to enroll 18 evaluable patients in Stage 1, and additionally up to 22 evaluable patients in Stage 2 for a total of 40 evaluable patients. Participants will be followed for overall survival. Current salvage therapy in advanced NSCLC achieves a median progression free survival time of 10 weeks and overall survival of 10 months. The Investigator would like to provide evidence that mifepristone will increase the median progression-free survival time to 15 weeks and overall survival time of 16 months.

This is a non-randomized, multicenter, single-stage phase II study of mifepristone in patients with Stage IIIB or Stage IV NSCLC who have failed two or more previous chemotherapy regimens.

The primary objective of this trial is to evaluate the utility of mifepristone as a salvage therapy in patients with Stage IIIB or Stage IV non-small cell lung carcinoma who have failed at least two previous chemotherapy regimens. Efficacy will be measured by improvement in progression-free survival and life span; and overall response as compared to historical controls.

Plan to enroll 18 evaluable patients in Stage 1 and up to 22 evaluable patients in Stage 2 for a total of 40 evaluable patients. Anticipated duration of the study is approximately up to 36 months.

Patients who tolerate treatment in the first cycle are eligible to continue to receive treatment until they experience unacceptable toxicity, until they meet any of the withdrawal criteria, or until the study is terminated by the Sponsor.

Patient may continue treatment despite evidence of tumor progression if they feel better, i.e. improved quality of life.We will follow all patients for overall survival.

Current salvage therapy in advanced NSCLC achieves a median progression free survival time of 10 weeks and overall survival of 10 months. We would like to provide evidence that mifepristone will increase the median progression-free survival time to 15 weeks and overall survival time of 16 months.

Eligibility Criteria:
Inclusion Criteria:

Each patient must meet the following criteria to be enrolled in the study

1. Must understand and voluntarily sign an informed consent
2. Age ≥ 18 years at the time of signing the informed consent
3. Histological or cytological documented diagnosis of locally advanced, recurrent or metastatic (Stage IIIB or Stage IV) NSCLC
4. Patients must have evidence of disease, measurable or evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
5. Patients shall provide results of tumor testing for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement, and if positive for EGFR mutation or ALK rearrangement shall have received appropriate targeted therapy prior to enrollment. If not previously tested, EGFR and ALK testing must be performed prior to study entry.
6. Patients shall have progressed after two or more previous chemotherapy regimens for metastatic or locally advanced disease
7. Patients must have recovered from any toxic effects and at least 3-4 weeks must have elapsed from the last dose of previous therapy, prior to registration
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 3
9. Life expectancy of at least 12 weeks
10. Patients must have adequate bone marrow and renal/hepatic function at the screening visit, defined as:

    * Absolute neutrophil count ≥ 1,500/mm3 without granulocyte colony-stimulating factor (G-CSF) support within 7 days preceding the lab assessment
    * Platelet count ≥ 100,000/mm3, without transfusion within 7 days preceding the lab assessment
    * Hemoglobin ≥ 9 g/dL, without transfusion support within 7 days preceding the lab assessment
    * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
    * Total serum bilirubin ≤ 1.5 times ULN
    * Serum creatinine ≤ ULN
    * Potassium and magnesium levels within normal limits. Patients with potassium or magnesium below the lower limit of normal must have levels corrected to normal by supplementation prior to starting study drug
11. Disease-free period of \> 3 years from any other previous malignancies, excluding curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix
12. Female patient of childbearing potential must have a negative serum pregnancy test. Sexually active female patient f childbearing potential must be willing to use non-hormonal contraception, including condom use by male partner, and barrier method by the female partner (diaphragm or cervical cap both with spermicide) during the treatment period and for at least 3 months after the last dose of the study drug. Females considered not of childbearing potential include those who have been in menopause at least 2 years, or are surgically sterile (status post tubal ligation or hysterectomy).
13. Patients must be able and willing to comply with the study visit schedule and study procedures
14. Able to take oral medications.

Exclusion Criteria:

Patients who meet any of the following criteria will not be permitted entry to the study:

1. Pregnant or breast-feeding
2. Women with a history of unexplained vaginal bleeding.
3. Women with uterine hyperplasia - in pre-menopausal women hyperplasia \>18mm and in post-menopausal women hyperplasia of \>10mm Prior therapy with mifepristone
4. Prior therapy with mifepristone
5. Patients who have had recent systemic cytotoxic therapies or radiotherapy within 14 days prior to day 1 of cycle 1
6. Use of cytotoxic chemotherapeutic agents, erythropoiesis-stimulating agents (ESA), or experimental agents (agents that are not commercially available) within 30 days of the first day of study drug treatment.
7. Patients who have had any major surgery within 4 weeks prior to day 1 of cycle 1, or minor surgery within 2 weeks prior to day 1 of cycle 1
8. For two weeks prior to first day of study drug treatment, administration of any of the following cytochrome P450 3A (CYP3A) inducers: phenytoin, phenobarbital, carbamazepine, rifampin, rifabutin, St. John's Wort; or CYP3A inhibitors: ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole
9. Patients who are taking simvastatin or lovastatin. Patients should be switched to alternative therapies a minimum of 2 weeks before starting study drug
10. Patients who have been treated with an investigational agent within 21 days prior to day 1 of cycle 1.
11. Concomitant use of biological agents including growth factors
12. Patients who require treatment with systemic corticosteroids for serious medical conditions or illnesses (e.g. immunosuppression after organ transplantation)
13. Chronic liver disease as indicated by Child-Pugh score A (6) or greater
14. History of significant cardiac disease. Significant cardiac diseases includes second/third degree heart block; significant ischemic heart disease; mean QTc interval \> 480 msec on at least two separate electrocardiograms (ECGs) prior to study start; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea)
15. Any other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation
16. Concomitant use of progestational agents
17. Known history of human immunodeficiency virus (HIV) positivity
18. In the opinion of the Investigator, any serious medical condition or psychiatric illness that will prevent the patient from signing the informed consent or will place the patient at unacceptable risk if he/she participates in the study.