SUPPORT HOTLINE (888) 901-2226
Donate Now

BRIEF TITLE: RGX-104, a Small Molecule LXR Agonist, With or Without Nivolumab in Patients With Advanced Solid Malignancies and Lymphoma With an Expansion in Select Malignancies

A Phase 1 Study of RGX-104, a Small Molecule LXR Agonist, With or Without Nivolumab in Patients With Advanced Solid Malignancies and Lymphoma With an Expansion in Select Malignancies


  • Org Study ID: RGX-104-001
  • Secondary ID:
  • NCT ID: NCT02922764
  • NCT Alias:
  • Sponsor: Rgenix, Inc. - Industry
  • Source: Rgenix, Inc.

Brief 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).

Overal Status Start Date Phase Study Type
Recruiting Start Date: November 2016 Phase 1 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Maximum tolerated dose (MTD), or the maximum tested dose at which multiple dose-limiting toxicities (DLTs) are not observed, of RGX-104 as a single agent, and separately, in combination with nivolumab.

Primary Outcome 1 - Time Frame: 6 months

Primary Outcome 2 - Measure: Overall response rate associated with RGX-104 treatment as a single agent, and separately, in combination with nivolumab.

Primary Outcome 2 - Time Frame: 24 months

Primary Outcome 3 - Measure: Progression-free survival associated with RGX-104 treatment as a single agent, and separately, in combination with nivolumab.

Primary Outcome 3 - Time Frame: 24 months

Primary Outcome 4 - Measure: Number of participants with treatment-emergent adverse events with severity as determined by CTCAE v4.03 associated with RGX-104 treatment as a single agent, and separately, in combination with nivolumab.

Primary Outcome 4 - Time Frame: 24 months

Condition:

  • Malignant Neoplasms

Eligibility

Criteria:
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.
Show More

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Contact

Name: Michael Szarek, PhD

Phone: 646-856-9261

Email: trials@rgenix.com

Locations

Facility Status Contact
Cedars-Sinai Medical Center
Los Angeles, California 90048
United States
Recruiting Monica Mita, MD
310-248-6729
Monica.Mita@cshs.org
University of California, Los Angeles
Los Angeles, California 90095
United States
Recruiting Bartosz Chmielowski, MD, PhD
310-586-2650
BChmielowski@mednet.ucla.edu
Sarah Cannon Research Institute
Denver, Colorado 80218
United States
Recruiting Gerald Falchook, MD
281-221-0693
gerald.falchook@scresearch.net
University of New Mexico Comprehensive Cancer Center
Albuquerque, New Mexico 87106
United States
Recruiting Olivier Rixe, MD
505-272-4946
Columbia University Medical Center
New York, New York 10032
United States
Recruiting Emerson Lim, MD
202-305-5874
el2342@cumc.columbia.edu
Memorial Sloan Kettering Cancer Center
New York, New York 10065
United States
Recruiting Michael Postow, MD
646-888-4589
postowm@mskcc.org
The Sarah Cannon Research Institute
Nashville, Tennessee 37203
United States
Recruiting Erika Hamilton, MD
615-329-7274
ehamilton@tnonc.com
Mary Crowley Cancer Research - Medical City
Dallas, Texas 75230
United States
Recruiting James F Strauss, MD
214-739-4175
The University of Texas MD Anderson Cancer Center
Houston, Texas 77030
United States
Recruiting Shubham Pant, MD
713-563-0181
SPant@mdanderson.org