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). 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 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. In the expansion stage of the study, additional patients with melanoma, non-small cell lung cancer, epithelial ovarian carcinoma, or breast cancer 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) to provide further characterization of RGX-104 safety, efficacy, PK, and pharmacodynamics, including biomarkers of immunologic activity and LXR target activation.
- The patient must have histologic or cytologic evidence of a malignant solid tumor or lymphoma (any histology) and 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 likely to result in clinical benefit.
- The patient 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).
- The patient must have disease that is measurable by standard imaging techniques (excluding patients with prostate cancer with PSA > 2 and bone disease documented by bone scan or other imaging), per 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.
- The patient is ≥18 years old.
- The patient has an ECOG PS of ≤1.
The patient has adequate baseline organ function, as demonstrated by the following:
- Serum creatinine ≤1.5 times institutional upper limit of normal (ULN) or calculated creatinine clearance >30 mL/min;
- Serum albumin ≥2.5 g/dl;
- Bilirubin ≤1.5 times institutional ULN;
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times institutional ULN (patients with hepatic metastases must have AST/ALT ≤5 times ULN);
- For patients not taking warfarin: international normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 times ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤1.5 times ULN. For patients taking warfarin: INR <3.5.
The patient has adequate baseline hematologic function, as demonstrated by the following:
- Absolute neutrophil count (ANC) ≥1.5x10^9/L
- Hemoglobin ≥8 g/dL and no red blood cell (RBC) transfusions during the prior 14 days
- Platelet count ≥100x10^9/L and no platelet transfusions during the prior 14 days
- The patient has a normal left ventricular ejection fraction (LVEF) per institutional criteria as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scanning.
- 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.
- The patient (male and female) 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 treatment with RGX-104.
- The patient has signed informed consent prior to initiation of any study-specific procedures or treatment.
- The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.
- Tumor tissue (a minimum of 5 and up to 10 unstained slides, or paraffin block), ideally from the patient's most recent biopsy, must be delivered from the patient's local institution to the site prior to treatment with RGX-104.
- The patient has persistent clinically significant toxicities (Grade ≥2) from previous anticancer therapy (excluding Grade 2 chemotherapy-related neuropathy and alopecia which are permitted, and excluding Grade 2-3 laboratory abnormalities if they are not associated with symptoms, are not considered clinically significant by the Investigator, and can be managed with available medical therapies).
- The patient has received treatment with chemotherapy, external-beam radiation, or other systemic anticancer therapy within 14 days prior to RGX-104 administration (42 days for prior nitrosourea or mitomycin-C; patients with advanced prostate cancer who are receiving luteinizing hormone releasing hormone (LHRH) agonists are permitted onto the study and should continue use of these agents during study treatment).
- The patient has received treatment with an investigational systemic anticancer agent within 14 days prior to RGX-104 administration.
- The patient has previously received treatment with RGX-104 or another investigational agent that is a known LXR agonist.
- The patient has an additional active malignancy that may confound the assessment of the study endpoints. Patients with a past cancer history (active malignancy within 2 years prior to study entry) with substantial potential for recurrence must be discussed with the Sponsor 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 prostate cancer with no evidence of progressive disease.
- The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
- The patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.
- The patient has known active or suspected brain or leptomeningeal metastases (central nervous system [CNS] imaging is not required prior to study entry unless there is a clinical suspicion of CNS involvement). Patients with stable, treated brain metastases are eligible provided there is no evidence of CNS disease growth on imaging for at least 2 months following radiation therapy or other locoregional ablative therapy to the CNS.
- 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 RGX-104 administration. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
- The patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements.
- The patient is pregnant or breast feeding.
- The patient has known positive status for human immunodeficiency virus active or chronic Hepatitis B or Hepatitis C.
- The patient is oxygen-dependent.
- The patient has a history of pancreatitis.
- The patient has Grade ≥2 hypercholesterolemia (total cholesterol >300 mg/dL or >7.75 mmol/L) and/or hypertriglyceridemia (triglyceride >300 mg/dL or ≥3.42 mmol/L) in the fasting state.
- QTcF >450 msec (males) or >470 msec (females).
- The patient has a cataract of Grade ≥2 for posterior subcapsular cataract, cortical cataract, nuclear opalescence, or nuclear color based on the Lens Opacities Classification System III (LOCS III).
- The patient requires statin (e.g., rosuvastatin, atorvastatin, etc.) therapy.
- The patient requires treatment with a medication that is a strong inhibitor of CYP3A4 (boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole).
- The patient requires treatment with a pH elevating agent, including H2 blockers, proton pump inhibitors, and antacids. If the medication is considered to be medically necessary, the patient should be discussed with the Medical Monitor.
- The patient has any medical condition which in the opinion of the Investigator places the patient at an unacceptably high risk for toxicities.