Patient case: 64-year-old male with cholangiocarcinoma; genetic feature: BRAF (V600E)

Clinical trial: A Study of RGX-104 With or Without Nivolumab in Patients With Advanced Solid Malignancies and Lymphoma

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. 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 (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.
  In the expansion stage of the study, additional patients with epithelial ovarian carcinoma (EOC), melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), renal cell cancer (RCC), bladder cancer (BLC), or triple negative breast cancer (TNBC) 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) and in combination with nivolumab (melanoma, NSCLC, SCLC, RCC, BLC, and TNBC).


Eligibility: Inclusion Criteria:
  1. 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. 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 must agree to a tumor biopsy to be obtained during the screening period and during 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. Patients enrolled in the single agent expansion stage must have a diagnosis of EOC, while patients enrolled in the combination dose escalation or expansion stage must have a diagnosis of melanoma, NSCLC, SCLC, RCC, BLC, or TNBC.
  5. For patients with EOC enrolled in the single agent expansion stage:
  -  The patient must have a pathologically confirmed (by histology or cytology) diagnosis of epithelial ovarian, fallopian tube or primary peritoneal carcinoma, which is currently recurrent or persistent Stage 3 or Stage 4 disease. A histologic diagnosis of borderline, low malignant potential epithelial carcinoma is not permitted.
  -  The patient must have received an appropriate platinum-based chemotherapy in the first line setting.
  -  If the patient has platinum-sensitive relapsed disease (first relapse > 6 months from end of initial platinum disease), the patient should have been re-treated with platinum for relapsed disease (or be intolerant or have refused such treatment).
  -  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 weeks nor be projected to require a paracentesis within the next 8 weeks.
  6. For patients with melanoma enrolled in the combination dose escalation or expansion stage:
  -  The patient must have a pathologically confirmed (by histology or cytology) diagnosis of melanoma, which is currently Stage 3 (unresectable) or Stage 4 disease.
  -  The patient must have received treatment with an immune checkpoint inhibitor or combination (e.g., products that target PD-1, PD-L1, or CTLA-4) or be intolerant to, or refuse such treatment.
  -  If the patient has disease with a BRAF mutation, s/he must have received treatment with appropriate BRAF/MEK inhibitor as single agent therapy or in combination, or be intolerant to, or refuse such treatment.
  7. For patients with NSCLC enrolled in the combination dose escalation or expansion stage:
  -  The patient must have a pathologically confirmed (by histology or cytology) diagnosis of NSCLC, which is currently Stage 3B or Stage 4 disease.
  -  A patient with non-squamous NSCLC must have been tested for relevant EGFR mutations, ALK translocation or other genomic aberrations (e.g. ROS rearrangement, BRAF V600E mutation) for which FDA-approved targeted therapy is available and, if positive, the patient should have received such therapy prior to study entry.
  -  In the absence of relevant EGFR mutation, ALK translocation, ROS rearrangement or BRAF V600E mutation, the patient must have received first-line therapy with a platinum-based regimen, be intolerant to, or refused such treatment.
  -  The patient must have received no more than 3 prior lines of therapy for metastatic disease.
  -  A patient with a tumor with an EGFR mutation, ALK translocation, ROS rearrangement, or BRAF V600E mutation may have received appropriate inhibitors of EGFR, ALK, ROS or BRAF in addition to 3 prior lines of therapy for metastatic disease.
  -  The patient may have received treatment with an immune checkpoint inhibitor (e.g., products that target PD-L1, PD-1, or CTLA-4).
  8. For patients with SCLC enrolled in the combination dose escalation or expansion stage:
  -  The patient must have a pathologically confirmed (by histology or cytology) diagnosis of SCLC, which is currently extensive disease.
  -  The patient must have demonstrated disease progression following platinum-based chemotherapy.
  -  The patient must have received no more than 1 prior line of therapy for extensive disease.
  -  The patient may not have received treatment with an immune checkpoint inhibitor (e.g., products that target PD-L1, PD-1, or CTLA-4).
  9. For patients with RCC enrolled in the combination dose escalation or expansion stage:
  -  The patient must have a pathologically confirmed diagnosis of clear cell (renal cell) carcinoma, which is currently Stage 4 disease.
  -  The patient must have received no more than 2 prior regimens with VEGF inhibitors and 1 prior regimen with checkpoint inhibitors for metastatic disease.
  -  The patient may have been treated with an immune checkpoint inhibitor (e.g., products that target PD-L1, PD-1, or CTLA-4).
  10. For patients with BLC enrolled in the combination dose escalation or expansion stage:
  -  The patient must have a pathologically confirmed diagnosis of urothelial BLC, which is currently Stage 4 disease.
  -  The patient may have been treated with an immune checkpoint inhibitor (e.g., products that target PD-L1, PD-1, or CTLA-4).
  -  The patient must have received no more than 2 prior lines of therapy for metastatic disease.
  -  A patient with urothelial carcinoma with variant histologic differentiation (e.g. squamous cell differentiation, glandular differentiation, neuroendocrine differentiation) will be eligible provided that the predominant histology is urothelial carcinoma.
  11. For patients with TNBC enrolled in the combination dose escalation or expansion stage:
  -  The patient must have a pathologically confirmed (by histology, cytology, or immunohistology) diagnosis of TNBC (a cancer that does not meaningfully express the estrogen or progesterone hormone receptors or overexpress the human epidermal growth factor receptor 2 tyrosine kinase), which is currently advanced/metastatic disease.
  -  The patient must have received at least 1 and no more than 2 prior lines of treatment in the metastatic setting.
  -  The patient may not have received treatment with immune checkpoint inhibitors (e.g., products that target PD-L1, PD-1, or CTLA-4).
  12. Disease that is measurable by standard imaging techniques per RECIST and 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.
  13. ≥18 years old.
  14. ECOG PS of ≤1.
  15. Adequate baseline organ function, as demonstrated by the following:
  -  Serum creatinine ≤1.5 times institutional ULN or calculated creatinine clearance >30 mL/min;
  -  Serum albumin ≥2.5 g/dl;
  -  Bilirubin ≤1.5 × institutional ULN;
  -  AST and 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: INR ≤1.5 or PT ≤1.5 × ULN; and either PTT or aPTT ≤1.5 × ULN. Patients taking warfarin should be on a stable dose that results in a stable INR <3.5.
  16. Adequate baseline hematologic function, as demonstrated by the following:
  -  Absolute neutrophil count (ANC) ≥1.5×109/L
  -  Hemoglobin ≥8 g/dL and no red blood cell (RBC) transfusions during the prior 14 days
  -  Platelet count ≥100×109/L and no platelet transfusions during the prior 14 days
  17. Normal LVEF per institutional criteria as determined by either ECHO or MUGA scanning.
  18. If 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 available at the patient's local institution prior to the first dose of study therapy.
  Exclusion Criteria:
  1. Persistent clinically significant toxicities (Grade ≥2) from previous anticancer therapy (excluding Grade 2 chemotherapy-related neuropathy and alopecia which are permitted). Prior toxicities that resulted in laboratory abnormalities should have resolved to Grade ≤1. If medical therapy is required for the treatment of a laboratory abnormality, the dose and laboratory value(s) should be stable.
  2. If considered for combination therapy:
  -  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 offending agent.
  -  Active autoimmune disease that required systemic treatment in the past. Patients who have not required systemic treatment for at least two years may be enrolled if permission is provided after discussion with the Medical Monitor.
  -  Evidence of active noninfectious pneumonitis or history of interstitial lung disease.
  -  A risk of reactivation of hepatitis B or C.
  -  Previously received an immune therapy that was discontinued due to immune-related AEs, regardless of grade.
  -  Uncontrolled endocrine disorder. Patients who are on endocrine replacement therapy must be on a stable dose.
  3. The patient has received treatment with chemotherapy, external-beam radiation, or other systemic anticancer therapy within 14 days prior to study therapy administration (42 days for prior nitrosourea or mitomycin-C; patients with advanced prostate cancer who are receiving LHRH agonists are permitted onto the study and should continue use of these agents during study treatment).
  4. The patient has received treatment with an investigational systemic anticancer agent within 14 days prior to study therapy administration.
  5. Previously received treatment with RGX-104 or another investigational agent that is a known LXR agonist.
  6. Additional active malignancy that may confound the assessment of the study endpoints. Patients with a past cancer history with substantial potential for 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 prostate cancer with no evidence of progressive disease.
  7. Clinically significant cardiovascular disease (e.g., uncontrolled or any NYHA Class 3 or 4 CHF, uncontrolled angina, history of MI, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
  8. 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.
  9. Known active or suspected brain or leptomeningeal metastases. 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 8 weeks following radiation therapy or other locoregional ablative therapy to the CNS.
  10. 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 are permitted in the absence of active autoimmune disease.
  11. 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.
  12. The patient is pregnant or breast feeding.
  13. Known positive status for human immunodeficiency virus or active or chronic Hepatitis B or Hepatitis C.
  14. The patient is oxygen-dependent.
  15. The patient has a history of pancreatitis.
  16. Grade ≥2 hypercholesterolemia (TC >300 mg/dL or >7.75 mmol/L) and/or hypertriglyceridemia (TG >300 mg/dL or >3.42 mmol/L) in the fasting state.
  17. QTcF >450 msec (males) or >470 msec (females).
  18. Physical abnormality or medical condition that limits swallowing multiple pills, or has a history of non-adherence to oral therapies.
  19. Cataract of Grade ≥2 for posterior subcapsular cataract, cortical cataract, nuclear opalescence, or nuclear color based on the LOCS III.
  20. The patient requires statin therapy. Patients who are taking a statin and are considered appropriate to discontinue treatment, must discontinue the statin at least 5 days prior to starting study therapy.
  21. 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).
  22. 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.
  23. The patient has any medical condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities.
  24. The patient has uveal melanoma.

Relevance to patient case: possibly relevant