Summary

Study RGX-104-001 is a Phase 1, first-in-human, dose escalation and expansion study of
RGX-104, an oral small molecule targeting the liver X receptor (LXR), as a single agent
and in combination with nivolumab, ipilimumab, docetaxel, or pembrolizumab plus
carboplatin/pemetrexed.

Objectives

RGX-104 activates LXR, resulting in depletion of both myeloid-derived suppressor cells
(MDSCs) as well as tumor blood vessels. MDSCs block the ability of T-cells and other
cells of the immune system from attacking tumors.

During the dose escalation stage, multiple doses and schedules of orally administered
RGX-104 with or without nivolumab, ipilimumab, docetaxel, or pembrolizumab plus
carboplatin/pemetrexed (single agent or combination therapy) will be evaluated in
patients with advanced solid tumors and lymphoma (i.e., locally advanced and
unresectable, or metastatic) who have had progressive disease (PD) on available standard
systemic therapies or for which there are no standard systemic therapies of relevant
impact. Dose escalation in combination with pembrolizumab plus carboplatin/pemetrexed
will be restricted to patients with non-small cell lung cancer (NSCLC).

In the expansion stage of the study, additional patients with endometrial cancer,
epithelial ovarian carcinoma (EOC), NSCLC, or small cell lung cancer (SCLC)/high-grade
neuroendocrine tumors (HG-NET) will be treated at the MTD (or maximum tested dose if no
MTD is identified, or dose below the MTD if there is evidence suggesting a more favorable
risk/benefit profile). This stage will provide further characterization of the safety,
efficacy, PK, and pharmacodynamics, including biomarkers of immunologic activity and LXR
target activation, of RGX-104 as a single agent (EOC), in combination with docetaxel
(SCLC/HG-NET), and and in combination with pembrolizumab plus carboplatin/pemetrexed
(NSCLC).

Eligibility

1. The patient must have histologic or cytologic evidence of a malignant solid tumor or lymphoma (any histology) and must have advanced disease, defined as cancer that is either metastatic or locally advanced and unresectable (and for which additional radiation therapy or other locoregional therapies are not considered feasible).
2. With the exception of dose escalation with pembrolizumab plus carboplatin/pemetrexed, patients enrolled in the dose escalation stages must have disease that is resistant to or relapsed following available standard systemic therapy, or for which there is no standard systemic therapy or reasonable therapy in the physician's judgment likely to result in clinical benefit or if such therapy has been refused by the patient. Documentation of the reason must be provided for patients who have not received a standard therapy likely to result in clinical benefit.
3. Patients enrolled in the expansion stages: Optional tumor biopsy may be obtained during the screening period and toward the beginning of Cycle 2 or at the time of PD, if earlier. If a biopsy is deemed by the investigator to not be in the patient's best interest, prior approval must be obtained from the Medical Monitor to waive this requirement.
4. The patient must have disease that is measurable by standard imaging techniques per RECIST or immune-related response criteria (irRC; all tumor types except lymphoma) or International Working Group (IWG) revised response criteria for malignant lymphoma (lymphoma only). For patients with prior radiation therapy, measurable lesions must be outside of any prior radiation field(s), unless disease progression has 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:
8. Serum creatinine =1.5 × institutional upper limit of normal (ULN) or calculated creatinine clearance >30 mL/min (>45 ml/min for patients receiving carboplatin/pemetrexed).
9. Serum albumin =2.5 g/dl;
10. Bilirubin =1.5 × institutional ULN.
11. 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;
12. For patients not taking warfarin or other oral anticoagulants: international normalized ratio (INR) =1.5 or prothrombin time (PT) =1.5 × ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) =1.5 × ULN. Patients taking warfarin should be on a stable dose that results in a stable INR <3.5. Among patients receiving other oral anticoagulant therapy, PT or aPTT must be within the intended therapeutic range of the anticoagulant.
13. The patient has adequate baseline hematologic function, as demonstrated by the following:
14. Absolute neutrophil count (ANC) =1.5×109/L;
15. Hemoglobin =8 g/dL and no red blood cell (RBC) transfusions during the prior 14 days;
16. Platelet count =100×109/L and no platelet transfusions during the prior 14 days.
17. The patient has a normal left ventricular ejection fraction (LVEF) per institutional criteria as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scanning.
18. If the patient is a woman of child-bearing potential (WOCBP), she has had a negative serum or urine pregnancy test within 2 weeks prior to treatment.
19. The patient (men and WOCBP) agrees to use acceptable contraceptive methods for the duration of time on the study, and continue to use acceptable contraceptive methods for 1 month after the last dose of study therapy. Patients receiving combination therapy must agree to use acceptable contraceptive methods for the duration of time on the study and continue to use acceptable contraceptive methods for 6 months after the last dose of study therapy.
20. The patient has signed informed consent prior to initiation of any study-specific procedures or treatment.
21. The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.
22. 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 the first dose of study therapy.
23. For patients with endometrial cancer enrolled in the ipilimumab combination expansion stage:
24. The patient has Stage III, Stage IV, or recurrent, histologically-confirmed endometrial carcinoma with disease that is measurable per RECIST 1.1.
25. The patient may have received up to THREE lines of prior therapy: Prior systemic platinum-based adjuvant and/or neoadjuvant chemotherapy counts as one prior line of therapy. A prior systemic therapy for advanced or recurrent disease counts as one prior line of therapy (if not given in the adjuvant or neoadjuvant setting). A prior checkpoint inhibitor therapy (anti PD-1/PD-L1) with or without an angiogenesis inhibitor counts as one prior line of therapy. Prior hormone and radiation therapy is not counted as prior therapies. The patient has either archival tumor tissue sample available (preferable) or in the absence has documented determination of mismatch repair (MMR) status.
26. The patient may not have received treatment with immune checkpoint inhibitors (e.g., products that target PD-L1, PD-1, or CTLA-4).
27. The patient must not have required a paracentesis within the preceding 4 weeks nor be projected to require a paracentesis within the next 8 weeks.
28. For patients with NSCLC enrolled in the pembrolizumab plus carboplatin/pemetrexed combination dose escalation or expansion stages:
29. The patient must have histologic or cytologic evidence of newly-diagnosed non-squamous, NSCLC that is advanced disease, defined as cancer that is either metastatic (Stage 4) or locally advanced (Stage 3B) and unresectable.
30. The patient has confirmation that epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-directed therapy is not indicated.
31. The patient has not received prior systemic treatment for their advanced/metastatic disease.
32. For patients in the expansion stage only: the patient's tumor block must demonstrate PD-L1 expression TPS <1% as determined with a validated assay.
33. The patient must have adequate organ function and performance status eligible for treatment with a platinum-based regimen and checkpoint inhibitor.

Treatment Sites in Georgia