A Study of RGX-104 in Patients With Advanced Lung & Endometrial Cancer

Inclusion Criteria:

1. The patient must have histologic or cytologic evidence of a malignant solid tumor orlymphoma (any histology) and must have advanced disease, defined as cancer that iseither metastatic or locally advanced and unresectable (and for which additionalradiation therapy or other locoregional therapies are not considered feasible).

2. With the exception of dose escalation with pembrolizumab pluscarboplatin/pemetrexed, patients enrolled in the dose escalation stages must havedisease that is resistant to or relapsed following available standard systemictherapy, or for which there is no standard systemic therapy or reasonable therapy inthe physician's judgment likely to result in clinical benefit or if such therapy hasbeen refused by the patient. Documentation of the reason must be provided forpatients who have not received a standard therapy likely to result in clinicalbenefit.

3. Patients enrolled in the expansion stages: Optional tumor biopsy may be obtainedduring the screening period and toward the beginning of Cycle 2 or at the time ofPD, if earlier. If a biopsy is deemed by the investigator to not be in the patient'sbest interest, prior approval must be obtained from the Medical Monitor to waivethis requirement.

4. The patient must have disease that is measurable by standard imaging techniques perRECIST or immune-related response criteria (irRC; all tumor types except lymphoma)or International Working Group (IWG) revised response criteria for malignantlymphoma (lymphoma only). For patients with prior radiation therapy, measurablelesions must be outside of any prior radiation field(s), unless disease progressionhas been documented at that disease site subsequent to radiation.

5. The patient is ≥18 years old.

6. The patient has an ECOG PS of ≤1.

7. The patient has adequate baseline organ function, as demonstrated by the following:

• Serum creatinine ≤1.5 × institutional upper limit of normal (ULN) or calculatedcreatinine clearance >30 mL/min (>45 ml/min for patients receivingcarboplatin/pemetrexed).

• Serum albumin ≥2.5 g/dl;

• Bilirubin ≤1.5 × institutional ULN.

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ×institutional ULN. Patients enrolled in an expansion stage may have ALT and AST < 5 × institutional ULN if the patient has hepatic metastases;

• For patients not taking warfarin or other oral anticoagulants: internationalnormalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 × ULN; and eitherpartial thromboplastin time or activated partial thromboplastin time (PTT oraPTT) ≤1.5 × ULN. Patients taking warfarin should be on a stable dose thatresults in a stable INR <3.5. Among patients receiving other oral anticoagulanttherapy, PT or aPTT must be within the intended therapeutic range of theanticoagulant.

8. The patient has adequate baseline hematologic function, as demonstrated by thefollowing:

• Absolute neutrophil count (ANC) ≥1.5×109/L;

• Hemoglobin ≥8 g/dL and no red blood cell (RBC) transfusions during the prior 14days;

• Platelet count ≥100×109/L and no platelet transfusions during the prior 14days.

9. The patient has a normal left ventricular ejection fraction (LVEF) per institutionalcriteria as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scanning.

10. If the patient is a woman of child-bearing potential (WOCBP), she has had a negativeserum or urine pregnancy test within 2 weeks prior to treatment.

11. The patient (men and WOCBP) agrees to use acceptable contraceptive methods for theduration of time on the study, and continue to use acceptable contraceptive methodsfor 1 month after the last dose of study therapy. Patients receiving combinationtherapy must agree to use acceptable contraceptive methods for the duration of timeon the study and continue to use acceptable contraceptive methods for 6 months afterthe last dose of study therapy.

12. The patient has signed informed consent prior to initiation of any study-specificprocedures or treatment.

13. The patient is able to adhere to the study visit schedule and other protocolrequirements, including follow-up for survival assessment.

14. Tumor tissue (a minimum of 10 and up to 15 unstained slides, or paraffin block,ideally from the patient's most recent biopsy, must be made available prior to thefirst dose of study therapy.

15. For patients with endometrial cancer enrolled in the ipilimumab combinationexpansion stage:

• The patient has Stage III, Stage IV, or recurrent, histologically-confirmedendometrial carcinoma with disease that is measurable per RECIST 1.1.

• The patient may have received up to THREE lines of prior therapy: Prior systemic platinum-based adjuvant and/or neoadjuvant chemotherapy counts as oneprior line of therapy. A prior systemic therapy for advanced or recurrent disease counts as one prior lineof therapy (if not given in the adjuvant or neoadjuvant setting). A prior checkpoint inhibitor therapy (anti PD-1/PD-L1) with or without anangiogenesis inhibitor counts as one prior line of therapy. Prior hormone and radiation therapy is not counted as prior therapies. The patienthas either archival tumor tissue sample available (preferable) or in the absence hasdocumented determination of mismatch repair (MMR) status.

• The patient may not have received treatment with immune checkpoint inhibitors (e.g., products that target PD-L1, PD-1, or CTLA-4).

• The patient must not have required a paracentesis within the preceding 4 weeksnor be projected to require a paracentesis within the next 8 weeks.

16. For patients with NSCLC enrolled in the pembrolizumab plus carboplatin/pemetrexedcombination dose escalation or expansion stages:

• The patient must have histologic or cytologic evidence of newly-diagnosednon-squamous, NSCLC that is advanced disease, defined as cancer that is eithermetastatic (Stage 4) or locally advanced (Stage 3B) and unresectable.

• The patient has confirmation that epidermal growth factor receptor (EGFR) oranaplastic lymphoma kinase (ALK)-directed therapy is not indicated.

• The patient has not received prior systemic treatment for theiradvanced/metastatic disease.

• For patients in the expansion stage only: the patient's tumor block mustdemonstrate PD-L1 expression TPS <1% as determined with a validated assay.

• The patient must have adequate organ function and performance status eligiblefor treatment with a platinum-based regimen and checkpoint inhibitor.

Exclusion Criteria:

1. The patient has persistent clinically significant toxicities (Grade ≥2) fromprevious anticancer therapy (excluding Grade 2 chemotherapy-related neuropathy andalopecia which are permitted). Prior toxicities that resulted in laboratoryabnormalities should have resolved to Grade ≤1, unless a higher-grade abnormality isallowed by the inclusion criteria. If medical therapy is required for the treatmentof a laboratory abnormality, the dose and laboratory value(s) should be stable.

2. If considered for combination therapy with nivolumab or ipilimumab, the patient has:

• Uncontrolled clinically significant pulmonary disease.

• A history of any grade immune-related ocular event.

• A history of Grade ≥3 immune-related adverse event regardless of offendingagent.

• Active autoimmune disease that required systemic treatment in the past.Patients who have not required systemic treatment for at least two years may beenrolled if permission is provided after discussion with the Medical Monitor (replacement therapy, e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, is not considered aform of systemic treatment, and is allowed).

• Evidence of active noninfectious pneumonitis or history of interstitial lungdisease.

• A risk of reactivation of hepatitis B or C.

• Previously received an immune therapy that was discontinued due toimmune-related AEs, regardless of grade.

• Uncontrolled endocrine disorder. Patients who are on endocrine replacementtherapy must be on a stable dose.

3. The patient has received treatment with chemotherapy, external-beam radiation, orother systemic anticancer therapy within 14 days prior to study therapyadministration (42 days for prior nitrosourea or mitomycin-C; patients with advancedprostate cancer who are receiving luteinizing hormone releasing hormone (LHRH)agonists are permitted onto the study and should continue use of these agents duringstudy treatment).

4. The patient has received treatment with an investigational systemic anticancer agentwithin 14 days prior to study therapy administration.

5. The patient has previously received treatment with RGX-104 or anotherinvestigational agent that is a known LXR agonist.

6. The patient has an additional active malignancy that may confound the assessment ofthe study endpoints. Patients with a past cancer history with substantial potentialfor recurrence must be discussed with the Medical Monitor before study entry.Patients with the following concomitant neoplastic diagnoses are eligible:non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma,cervical intraepithelial neoplasia, and melanoma in situ), organ-confined prostatecancer with no evidence of progressive disease.

7. The patient has clinically significant cardiovascular disease (e.g., uncontrolled orany New York Heart Association Class 3 or 4 heart failure (see Appendix 1),uncontrolled angina, history of myocardial infarction, unstable angina or strokewithin 6 months prior to study entry, uncontrolled hypertension or clinicallysignificant arrhythmias not controlled by medication).

8. The patient has uncontrolled, clinically significant pulmonary disease (e.g.,chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinionof the Investigator would put the patient at significant risk for pulmonarycomplications during the study.

9. The patient has known active or suspected brain or leptomeningeal metastases.Central Nervous System (CNS) imaging is not required prior to study entry unlessthere is a clinical suspicion of CNS involvement. Patients with stable, treatedbrain metastases are eligible provided there is no evidence of CNS disease growth onimaging for at least 8 weeks following radiation therapy or other locoregionalablative therapy to the CNS.

10. The patient has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to study therapy administration. Inhaled or topical steroids arepermitted in the absence of active autoimmune disease.

11. The patient has uncontrolled intercurrent illness including, but not limited to,uncontrolled infection requiring therapy, disseminated intravascular coagulation, orpsychiatric illness/social situations that would limit compliance with studyrequirements.

12. The patient is pregnant or breast feeding.

13. The patient has known positive status for human immunodeficiency virus or active orchronic Hepatitis B or Hepatitis C.

14. The patient is oxygen-dependent.

15. The patient has a history of pancreatitis.

16. The patient has Grade ≥2 hypercholesterolemia (total cholesterol >300 mg/dL or >7.75mmol/L) and/or hypertriglyceridemia (triglyceride >300 mg/dL or >3.42 mmol/L) in thefasting state.

17. QTcF >450 msec (males) or >470 msec (females).

18. The patient has a physical abnormality or medical condition that limits swallowingmultiple pills, or has a history of non-adherence to oral therapies.

19. The patient requires statin (e.g., rosuvastatin, atorvastatin, etc.) therapy. If thepatient is taking a statin but discontinuation is considered appropriate, the statinmust be discontinued at least 5 days prior to starting study therapy.

20. The patient requires treatment with a medication that is a strong inhibitor ofCYP3A4 (boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir,itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole).

21. For the docetaxel escalation stage, patients with NSCLC with alkaline phosphatase > 2.5 × institutional ULN and AST or ALT > 1.5 × institutional ULN.

22. For patients with NSCLC enrolled in the pembrolizumab plus carboplatin/pemetrexedcombination dose escalation or expansion stages:

• The patient received radiation therapy to the lung that is >30 Gray (Gy) within 6 months of the first dose of study medication

• The patient completed palliative radiotherapy ≤7 days of the first dose ofstudy medication

• The patient has received live-virus vaccination ≤30 days of planned start ofstudy medication

• The patient has clinically active diverticulitis, intra-abdominal abscess,gastrointestinal obstruction, peritoneal carcinomatosis

• The patient is expected to require any other form of antineoplastic therapywhile on study.

• The patient has known hypersensitivity to another monoclonal antibody (mAb)

• The patient has known sensitivity to any component of carboplatin or pemetrexed

• The patient is unable to interrupt aspirin or other nonsteroidalanti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day,for a 5-day period (8-day period for long-acting agents, such as piroxicam)

• The patient is unable or unwilling to take folic acid or vitamin B12supplementation

23. The patient has clinical or laboratory evidence of a paraneoplastic syndrome.

24. The patient has experienced weight loss of >10% of their body weight over thepreceding 3 months.

25. The patient has any medical condition which, in the opinion of the Investigator,places the patient at an unacceptably high risk for toxicities.