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

• Sponsor: University of California, Davis (Other)
• Overall Status: Completed
• CT.gov ID: NCT03322384
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arm: 1
• Actual Duration (Months): 26.7
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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.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: Jan 17, 2018
• Actual Primary Completion Date: Feb 24, 2020
• Actual Study Completion Date: Apr 8, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) [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 Related Adverse Events [Safety and Tolerability] [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 [Through study completion, an average of one year]

   Abscopal Response Rate (ARR) is 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

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

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

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

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

5. INR and aPTT < 1.5 x ULN.

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

7. 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.

8. No other active malignancy.

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

10. 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.

11. Signed informed consent.

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

13. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817

Sponsors and Collaborators

• University of California, Davis

Investigators

• Principal Investigator: Megan Daly, MD, University of California, Davis

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 19, 2020

More Information

Publications

None provided.

• Responsible Party: Megan Daly, MD, Associate Professor, University of California, Davis
• ClinicalTrials.gov Identifier: NCT03322384
• Other Study ID Numbers: 1057229; UCDCC#271
• First Posted: Oct 26, 2017
• Last Update Posted: Feb 1, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lymphoma

Study Results

Participant Flow

Arm/Group Title	Experimental
Arm/Group 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. epacadostat: Epacadostat will be administered orally, in pill form, twice daily until disease progression. 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. Radiotherapy: Radiotherapy will be delivered to the treatment lesion during the first week of ERS therapy.
Period Title: Overall Study
STARTED	20
COMPLETED	14
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Experimental
Arm/Group 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. epacadostat: Epacadostat will be administered orally, in pill form, twice daily until disease progression. 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. Radiotherapy: Radiotherapy will be delivered to the treatment lesion during the first week of ERS therapy.
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 50%
>=65 years	10 50%
Sex: Female, Male (Count of Participants)
Female	11 55%
Male	9 45%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 5%
Asian	2 10%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 10%
White	15 75%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD)
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.
Time Frame	Up to 30 days of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group 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. epacadostat: Epacadostat will be administered orally, in pill form, twice daily until disease progression. 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. Radiotherapy: Radiotherapy will be delivered to the treatment lesion during the first week of ERS therapy.
Measure Participants	6
Number [mg]	300

2. Primary Outcome

Title	Incidence of Related Adverse Events [Safety and Tolerability]
Description	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.
Time Frame	Through study completion, an average of one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group 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. epacadostat: Epacadostat will be administered orally, in pill form, twice daily until disease progression. 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. Radiotherapy: Radiotherapy will be delivered to the treatment lesion during the first week of ERS therapy.
Measure Participants	20
Count of Participants [Participants]	17 85%

3. Secondary Outcome

Title	Abscopal Response Rate
Description	Abscopal Response Rate (ARR) is 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.
Time Frame	Through study completion, an average of one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group 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. epacadostat: Epacadostat will be administered orally, in pill form, twice daily until disease progression. 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. Radiotherapy: Radiotherapy will be delivered to the treatment lesion during the first week of ERS therapy.
Measure Participants	14
Count of Participants [Participants]	4 20%

Adverse Events

Time Frame	Up to 1 year.
Adverse Event Reporting Description	Incidence of Treatment-Emergent Adverse Events according CTCAE v4.03
Arm/Group Title	Experimental
Arm/Group 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. epacadostat: Epacadostat will be administered orally, in pill form, twice daily until disease progression. 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. Radiotherapy: Radiotherapy will be delivered to the treatment lesion during the first week of ERS therapy.
All Cause Mortality
	Experimental
	Affected / at Risk (%)	# Events
Total	10/20 (50%)
Serious Adverse Events
	Experimental
	Affected / at Risk (%)	# Events
Total	9/20 (45%)
Gastrointestinal disorders
Gastrointestinal disorders - Other, specify: lower GI bleed	1/20 (5%)
Infections and infestations
Sepsis	1/20 (5%)
Upper respiratory infection	1/20 (5%)
Investigations
Investigations - Other, specify: transanimitis	1/20 (5%)
Metabolism and nutrition disorders
Hyponatremia	1/20 (5%)
Metabolism and nutrition disorders - Other, specify: electrolyte and fluid disorder	1/20 (5%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/20 (5%)
Muscle weakness lower limb	1/20 (5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify:disease progres	1/20 (5%)
Renal and urinary disorders
Acute kidney injury	1/20 (5%)
Urinary retention	1/20 (5%)
Other (Not Including Serious) Adverse Events
	Experimental
	Affected / at Risk (%)	# Events
Total	18/20 (90%)
Blood and lymphatic system disorders
Anemia	5/20 (25%)
Cardiac disorders
Sinus tachycardia	2/20 (10%)
Gastrointestinal disorders
Constipation	5/20 (25%)
Diarrhea	3/20 (15%)
Dysphagia	2/20 (10%)
Nausea	13/20 (65%)
Vomiting	9/20 (45%)
General disorders
Chills	2/20 (10%)
Edema limbs	6/20 (30%)
Fatigue	11/20 (55%)
Injection site reaction	5/20 (25%)
Investigations
Alkaline phosphatase increased	3/20 (15%)
Aspartate aminotransferase increased	4/20 (20%)
Creatinine increased	4/20 (20%)
Lymphocyte count decreased	10/20 (50%)
Neutrophil count decreased	7/20 (35%)
Weight loss	2/20 (10%)
White blood cell decreased	6/20 (30%)
Metabolism and nutrition disorders
Anorexia	9/20 (45%)
Dehydration	3/20 (15%)
Hyperglycemia	2/20 (10%)
Hypoalbuminemia	3/20 (15%)
Hyponatremia	2/20 (10%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	2/20 (10%)
Pain in extremity	2/20 (10%)
Nervous system disorders
Dizziness	2/20 (10%)
Dysgeusia	2/20 (10%)
Headache	5/20 (25%)
Paresthesia	2/20 (10%)
Psychiatric disorders
Confusion	2/20 (10%)
Depression	2/20 (10%)
Skin and subcutaneous tissue disorders
Skin hyperpigmentation	2/20 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.