Minnelide and Osimertinib for the Treatment of Advanced EGFR Mutated Non-Small Cell Lung Cancer

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• Assent, when appropriate, will be obtained per institutional guidelines

• Agreement to two research biopsies

• If tumor is unbiopsiable or not safely biopsied, exceptions may be granted withstudy principal investigator (PI) approval

• Age: >= 18 years

• Karnofsky performance >= 70%

• Histologically confirmed advanced non-small cell lung cancer (NSCLC). Patients withlocally advanced NSCLC must not be candidates for surgical resection, radiation, orchemoradiation with curative intent

• The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR)mutations known to be associated with epidermal growth factor receptor tyrosinekinase inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or incombination with other epidermal growth factor receptor (EGFR) mutations, which mayinclude T790M

• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

• Tumor progression after receiving standard/approved osimertinib

• Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 toprior anti-cancer therapy. Grade 2 neuropathy is allowed

• Absolute neutrophil count (ANC) >= 1,500/mm^3 (within 14 days prior to day 1 ofprotocol therapy)

• NOTE: Growth factor is not permitted within 14 days of ANC assessment

• Platelets >= 100,000/mm^3 (within 14 days prior to day 1 of protocol therapy)

• NOTE: Platelet transfusions are not permitted within 14 days of plateletassessment

• Hemoglobin >= 9 g/dL (within 14 days prior to day 1 of protocol therapy)

• Total bilirubin =< 1.5 X ULN (unless has Gilbert's disease). Total bilirubin < 3 xULN in the presence of documented Gilbert's disease (within 14 days prior to day 1of protocol therapy)

• Aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) (if livermetastases are present, then =< 5 x ULN is allowed) (within 14 days prior to day 1of protocol therapy)

• Alanine aminotransferase (ALT) =< 2.5 x ULN if liver metastases are present, then =< 5 x ULN is allowed) (within 14 days prior to day 1 of protocol therapy)

• Alkaline phosphatase =< 2.5 x ULN if liver metastases are present, then =< 5 x ULNis allowed) (within 14 days prior to day 1 of protocol therapy)

• Serum creatinine within normal limits, OR creatinine clearance of >= 60 mL/min per 24 hour urine test for patients with creatinine levels above ULN (within 14 daysprior to day 1 of protocol therapy)

• Creatinine clearance (CrCl, by Cockcroft-Gault) is utilized for all patients toallow for evaluation of the effect of CrCl on the minnelide/triptolideexposures

• If not receiving anticoagulants: International normalized ratio (INR) OR prothrombintime (PT) =< 1.5 x ULN (within 14 days prior to day 1 of protocol therapy)

• If on anticoagulant therapy: PT must be within therapeutic range of intendeduse of anticoagulants

• If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) =< 1.5x ULN (within 14 days prior to day 1 of protocol therapy)

• If on anticoagulant therapy: aPTT must be within therapeutic range of intendeduse of anticoagulants

• Albumin >= 3.0 /dL (within 14 days prior to day 1 of protocol therapy)

• Urinalysis - no clinically significant abnormalities (within 14 days prior to day 1of protocol therapy)

• QT corrected (QTc) =< 470 ms (using the Bazett's formula)

• Note: To be performed within 28 days prior to Day 1 of protocol therapy.

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 14 days prior to day 1 of protocol therapy)

• If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required

• Agreement by females and males of childbearing potential to use an effective methodof birth control or abstain from heterosexual activity for the course of the studythrough at least 6 weeks after the last dose of protocol therapy. Contraception mustbe continued following discontinuation of the study drugs for at least fivehalf-lives of both study drugs

• Childbearing potential defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only)

• Female patients of childbearing potential must:

• Agree to practice 1 highly effective method of non-hormonal contraceptionand one additional effective (barrier) method at the same time, from thetime of signing the informed consent through 180 days after the last doseof study drug, or

• Agree to practice true abstinence, when is in line with the preferred andusual lifestyle of the subject. (Periodic abstinence [e.g. calendar,ovulation, symptothermal, postovulation methods], withdrawal, spermicidesonly, and lactational amenorrhea are not acceptable methods ofcontraception. Female and male condoms should not be used together.)

• Agree not to donate eggs (ova) during the course of this study or 180 daysafter receiving their last dose of study drug. Agree not to breast-feedfor the duration of treatment through 6 months post treatment.

• Male patients of childbearing potential must:

• Agree to practice effective barrier contraception during the entire studytreatment period and through 180 days after the last dose of study drug,or

• Agree to practice true abstinence, when this is in line with the preferredand usual lifestyle of the subject. (Periodic abstinence [e.g. calendar,ovulation, symptothermal, postovulation methods for the female partner]and withdrawal are not acceptable methods of contraception. Female andmale condoms should not be used together.)

• Agree not to donate sperm during the course of this study or within 180days after receiving their last dose of study drug.

• Patients must be able to swallow and retain oral medications

• Previously tolerant of osimertinib at 80 mg QD

Exclusion Criteria:

• Treatment with radiation therapy, surgery, chemotherapy, or investigational therapywithin 21 days prior to day 1 of protocol therapy (6 weeks for nitrosoureas orMitomycin C). Exceptions to this exclusion are brain radiation and osimertinib

• Biological therapy, immunotherapy within 21 days prior to day 1 of protocol therapy

• Strong CYP3A4 inducers/ inhibitors within 14 days prior to day 1 of protocol therapy

• Patients receiving class 1A or class III antiarrhythmic agents within 14 days priorto Day 1 of protocol therapy

• Herbal and alternative (eg. turmeric, cannabidiol, ginseng) medications within 7days prior to Day 1 of protocol therapy

• Clarithromycin, loperamide, ondansetron within 7 days prior to day 1 of protocoltherapy

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to study agent

• Active diarrhea

• Clinically significant uncontrolled illness

• Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis Cinfection

• Prior malignancy other than carcinoma in situ of the cervix, or nonmelanoma skincancer, unless that prior malignancy was diagnosed and definitively treated 5 ormore years prior to study entry with no subsequent evidence of recurrence. Patientswith a history of low grade (Gleason score =< 6 = Gleason Group 1) localizedprostate cancer will be eligible even if diagnosed less than 5 years prior to studyentry

• Females only: Pregnant or breastfeeding

• Any malabsorption condition

• Any other condition that would, in the Investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures.

• New York Heart Association Class III or IV, cardiac disease, myocardial infarctionwithin the past 6 months, unstable arrhythmia, or evidence of ischemia onelectrocardiogram (ECG)

• Clinical evidence of central nervous system (CNS) metastases or leptomeningealcarcinomatosis, except for individuals who have previously-treated CNS metastases,are asymptomatic, and have had no requirement for steroid medication for 1 weekprior to the first dose of study drug and have completed radiation 2 weeks prior tothe first dose of study drug

• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemictherapy

• Diagnosis of congenital long QT syndrome

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)