Clinical Trials /

UCDCC#271: Phase I/II Trial of Epacadostat, Intralesional SD101, Radiotherapy in Patients With Lymphoma

NCT03322384

Description:

Checkpoint blockade immunotherapy has revolutionized the management of a variety of advanced malignancies. Monoclonal antibodies targeting the PD-1 / PD-L1 interaction have received FDA approvals for non-small cell lung cancer, melanoma, Merkel cell carcinoma, renal cell carcinoma, hepatocellular, squamous cell carcinoma of the head and neck, microsatellite instability high colorectal carcinoma, urothelial carcinoma, and classical Hodgkin's lymphoma. Despite the promising evidence for deep and durable responses with these agents, the majority of patients either fail to respond or develop resistance to treatment. Thus, there is interested in developing alternative immunotherapeutic strategies. The investigators hypothesize that a novel immunotherapeutic combination of radiotherapy (RT) with intralesional CpG and indolamine-2,3-dioxygenase blockade may offer significant clinical benefit to patients and proposing a microtrial testing this combination for advanced/refractory solid tumors and lymphoma.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: UCDCC#271: Phase I/II Trial of Epacadostat, Intralesional SD101, Radiotherapy in Patients With Lymphoma
  • Official Title: UCDCC#271: A Phase I/II Trial of Epacadostat (Indolamine 2,3 Dioxygenase Inhibitor), Intralesional SD101 (Toll-receptor 9 Agonist), and Radiotherapy in Patients With Advanced Solid Tumors and Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 1057229
  • SECONDARY ID: UCDCC#271
  • NCT ID: NCT03322384

Conditions

  • Advanced Solid Tumors
  • Lymphoma

Interventions

DrugSynonymsArms
epacadostatExperimental
SD-101Experimental

Purpose

Checkpoint blockade immunotherapy has revolutionized the management of a variety of advanced malignancies. Monoclonal antibodies targeting the PD-1 / PD-L1 interaction have received FDA approvals for non-small cell lung cancer, melanoma, Merkel cell carcinoma, renal cell carcinoma, hepatocellular, squamous cell carcinoma of the head and neck, microsatellite instability high colorectal carcinoma, urothelial carcinoma, and classical Hodgkin's lymphoma. Despite the promising evidence for deep and durable responses with these agents, the majority of patients either fail to respond or develop resistance to treatment. Thus, there is interested in developing alternative immunotherapeutic strategies. The investigators hypothesize that a novel immunotherapeutic combination of radiotherapy (RT) with intralesional CpG and indolamine-2,3-dioxygenase blockade may offer significant clinical benefit to patients and proposing a microtrial testing this combination for advanced/refractory solid tumors and lymphoma.

Detailed Description

      Checkpoint blockade immunotherapy has revolutionized the management of a variety of advanced
      malignancies. Monoclonal antibodies targeting the PD-1 / PD-L1 interaction have received FDA
      approvals for non-small cell lung cancer, melanoma, Merkel cell carcinoma, renal cell
      carcinoma, hepatocellular, squamous cell carcinoma of the head and neck, microsatellite
      instability high colorectal carcinoma, urothelial carcinoma, and classical Hodgkin's
      lymphoma. Despite the promising evidence for deep and durable responses with these agents,
      the majority of patients either fail to respond or develop resistance to treatment. Thus,
      there is interested in developing alternative immunotherapeutic strategies. The investigators
      hypothesize that a novel immunotherapeutic combination of radiotherapy (RT)with intralesional
      CpG and indolamine-2,3-dioxygenase (IDO) blockade may offer significant clinical benefit to
      patients and proposing a microtrial testing this combination for advanced/refractory solid
      tumors and lymphoma.

      Unmethylated CpG DNA is a component bacterial genomes and is the agonist of Toll Like
      Receptor-9, an endosomal pattern recognition receptor of antigen presenting cells. TLR9
      activation results in downstream production of IFN-α, interleukin-6 interleukin-12. These
      cytokines induce naive T cells to differentiate to helper T cells. CpG has demonstrated
      significant synergy with radiotherapy to induce regression of refractory systemic and
      cutaneous lymphomas both within radiation treatment field and un-irradiated metastases.
      SD-101 is a synthetic oligodeoxynucleotide enriched with CpG motifs.

      IDO is an enzyme that converts the essential amino acid tryptophan to kynurenine. The
      availability of tryptophan is essential to sustaining both helper T cell and effector T cell
      activation. Overexpression of IDO by tumor cells or antigen presenting cells serves to arrest
      T cell activation thus acting as an immunosuppressive enzyme. Epacadostat (INCB024360) is an
      inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) that has shown promise in the
      treatment of solid tumors and lymphomas in ongoing Phase I/II studies.

      The investigators have shown in animal studies that IDO upregulation limits tumor response to
      RT + CpG and that addition of IDO blockade improves therapeutic efficacy. On the basis of
      these data, the investigators hypothesize that IDO inhibition will improve upon the known
      historical efficacy of RT + CpG therapy, and will be highly effective and well tolerated in
      the management of advanced solid tumors and lymphomas.

      This is a phase I/II study. For the phase I portion the primary endpoint is to determine the
      maximum tolerated dose of epacadostat in combination with radiotherapy and SD-101. For the
      phase II portion the primary endpoint is safety and toxicity per CTCAE v4.03 criteriae. The
      secondary endpoint is the abscopal response rate defined as the objective response rate at
      un-irradiated lesions per irRECIST criteria.

      Up to three dose levels of epacadostat will be evaluated: 100 mg bid, 200 mg bid and 300 mg
      bid each day of the study. Radiotherapy will be delivered to the treatment lesion during the
      first week using standard-of-care palliative fractionation regimens of 8 Gy x 3 fractions, 4
      Gy x 5 fractions, or 2 Gy x 2 fractions. Four milligrams of SD-101 will be delivered into the
      treatment lesion by intralesional injection on days 1, 8, 15, with optional additional
      injections on days 22, and 29. On Day 1, biopsy will precede intralesional injection, RT, or
      epacadostat. Intralesional injections will be performed by palpation of the lesion or under
      ultrasound or CT guidance as indicated. CT response assessments and labs will be performed
      every 60 days. Patients will continue on epacadostat until progression.
    

Trial Arms

NameTypeDescriptionInterventions
ExperimentalExperimentalAll patients will begin epacadostat on day 1 of radiotherapy, which will consist of three threatments over one week. Epacadostat will continue until disease progression or intolerance occurs. On days 1, 8, 15, 22, 29, intralesional injectinons of SD101 will be given to patients.
  • epacadostat
  • SD-101

Eligibility Criteria

        Inclusion Criteria:

          1. Adults >18 years of age with histologically proven solid malignancy, high-grade
             lymphoma or low-grade lymphoma.

          2. Patients with incurable, advanced or metastatic disease refractory to at least one
             previous line of standard of care therapy.

          3. ECOG (Eastern Cooperative Oncology Group) performance status score of 0 - 2 (Appendix
             1).

          4. Presence of a candidate treatment lesion (subcutaneous, nodal, or visceral) accessible
             and safe for radiotherapy and serial intralesional injections as specified by the
             protocol.

          5. Presence of at least one target lesion (distinct from treatment lesion and outside of
             treatment lesion radiation field) evaluable for response by irRECIST.

          6. 14 day wash-out period from any previous chemotherapy, targeted therapy or
             radiotherapy, 21 day washout period from previous immunotherapy.

          7. Life expectancy ≥ 6 months.

          8. Adequate hematologic and end organ function, defined by the following laboratory
             results obtained within 14 days of the first study treatment:

             o ANC > 1500 cells/ul; WBC count > 2500/uL; Lymphocyte count >500/uL; Platelet count >
             100,000/uL; Hemoglobin > 9 g/dL

          9. Liver function tests meeting one of the following criteria:

               1. AST and ALT < 2.5 x ULN with alkaline phosphatase < 2.5 x ULN OR

               2. AST and ALT < 1.5 x ULN, with alkaline phosphatase > 2.5 x ULN

               3. Serum bilirubin < 1.0 x ULN. Direct bili < 40% if total bili > ULN in patients
                  with Gilbert's syndrome.

         10. INR and aPTT < 1.5 x ULN.

         11. Serum Cr < 1.5 X ULN or CrCl > 50 ml/min.

         12. No active auto-immune disease and not on therapy for auto-immune disease. Patients
             with a history of autoimmune-related hypothyroidism on a stable dose of thyroid
             replacement hormone are eligible. Patients who have adrenal insufficiency and
             hypophysitis from prior immunotherapy if they are on stable medical replacement doses
             are eligible.

         13. No other active malignancy.

         14. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are
             eligible.

         15. For female patients of childbearing potential and male patients with partners of
             childbearing potential agreement (by patient and/or partner) to use highly effective
             form(s) of contraception (i.e., one that results in a low failure rate [<1% per year]
             when used consistently and correctly) and to continue its use for 6 months after trial
             completion.

         16. Signed informed consent.

         17. At least 9 months from stem cell transplant with no active graft versus host disease.

         18. Ability to comply with the protocol.

        Exclusion Criteria:

          1. Uncontrolled concomitant disease that in the opinion of the investigator would
             interfere with the patient's safety or compliance on trial.

          2. Significant cardiovascular disease (NYHA Class II or greater); myocardial infarction
             within 3 month prior to randomization, unstable arrhythmias, unstable angina or a
             patient with a known LVEF (Left Ventricular Ejection Fraction) < 40%

          3. Severe infection that in the opinion of the investigator would interfere with the
             patients safety or compliance on trial within 2 weeks prior to enrollment. Oral or IV
             antibiotics within 2 weeks or 5 half-lives prior to enrollment.

          4. Active tuberculosis

          5. History of severe autoimmune disease that in the opinion of the investigator would
             interfere with patient safety or compliance on trial.

          6. Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface
             Antigen [HBsAg] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid
             [HCV RNA] (qualitative) is detected)

          7. Previous treatment with epacadostat, SD-101, or any other IDO inhibitor or CpG
             molecule.

          8. Treatment with systemic corticosteroids or other systemic immunosuppressive
             medications within past 4 weeks or 5 half-lives whichever is shorter. Use of inhaled
             or topical steroids or systemic corticosteroids < 10 mg/ day of prednisone (or
             equivalent) is permitted.

          9. Pregnant and/or lactating women.

         10. Evidence of active interstitial lung disease or active non-infectious pneumonitis

         11. Receipt of live attenuated vaccine within 30 days before the first dose of study
             treatment.

         12. Use of any UGT1A9 inhibitor while on active study treatment, including the following:
             diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid.

         13. Known allergy or reaction to any component of either study drug formulation.

         14. Subjects receiving Monoamine Oxidase Inhibitors (MAOIs) or drug which has significant
             MAOI activity (meperidine, linezolid, methylene blue) from 21 days prior to Day 1
             through 2 weeks after the final dose of epacadostat has been administered.

         15. Any history of Serotonin Syndrome (SS) after receiving serotonergic drugs.

         16. Known contraindications to radiotherapy including but not limited to radiation
             sensitivity syndromes such as xeroderma pigmentosum and ataxia telangiectasia mutated.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:Up to 30 days of treatment
Safety Issue:
Description:To determine the maximum tolerated dose (MTD) of epacadostat that can be given with radiotherapy and intralesional SD-101 immunotherapy for the phase I portion of the study. The MTD will be determined using a standard 3+3 design. Patients will be monitored weekly during a 30-day dose-limiting toxicity (DLT) period. MTD can be defined as The maximum dose at which <2 of 6 patients experienced a DLT.

Secondary Outcome Measures

Measure:Abscopal Response Rate
Time Frame:Through study completion, an average of one year
Safety Issue:
Description:To determine the ARR defined as objective response rate (the percentage of patient that achieve a partial or complete response) at unirradiated sites using irRECIST criteria using imaging obtained every 60 days during the 1 year study period.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, Davis

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