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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03322384
Recruitment Status : Active, not recruiting
First Posted : October 26, 2017
Last Update Posted : October 8, 2020
Sponsor:
Information provided by (Responsible Party):
Megan Daly, MD, University of California, Davis

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Lymphoma Drug: epacadostat Drug: SD-101 Radiation: Radiotherapy Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: All 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.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 17, 2018
Actual Primary Completion Date : February 24, 2020
Estimated Study Completion Date : March 20, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Experimental
All 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.
Drug: epacadostat
Epacadostat will be administered orally, in pill form, twice daily until disease progression.

Drug: SD-101
Four milligrams of SD-101 will be delivered into the treatment lesion by intralesional injection on days 1, 8, 15, 22, and 29.

Radiation: Radiotherapy
Radiotherapy will be delivered to the treatment lesion during the first week of ERS therapy.




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: Up to 30 days of treatment ]
    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.

  2. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Through study completion, an average of one year ]
    To characterize the safety profile of this regimen using CTCAE v4.03 (Common Toxicity Criteria for Adverse Events version 4.03) in the phase II expansion . The expansion phase (phase II) will be conducted using the MTD defined as the highest dose at which no more than one of six patients develops a DLT or Dose Level 1 if the MTD is not reached. Patients will be monitored every week during the first 30 days of study and then monthly thereafter up to a period of 1 year.


Secondary Outcome Measures :
  1. Abscopal Response Rate [ Time Frame: Through study completion, an average of one year ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03322384


Locations
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United States, California
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States, 95817
Sponsors and Collaborators
University of California, Davis
Investigators
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Principal Investigator: Arta M Monjazeb, MD, PhD University of California, Davis
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Responsible Party: Megan Daly, MD, Assistant Professor, University of California, Davis
ClinicalTrials.gov Identifier: NCT03322384    
Other Study ID Numbers: 1057229
UCDCC#271 ( Other Identifier: UC Davis IRB )
First Posted: October 26, 2017    Key Record Dates
Last Update Posted: October 8, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases