UCDCC#271: Phase I/II Trial of Epacadostat, Intralesional SD101, Radiotherapy in Patients With Lymphoma
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|ClinicalTrials.gov Identifier: NCT03322384|
Recruitment Status : Active, not recruiting
First Posted : October 26, 2017
Last Update Posted : October 8, 2020
|Condition or disease||Intervention/treatment||Phase|
|Advanced Solid Tumors Lymphoma||Drug: epacadostat Drug: SD-101 Radiation: Radiotherapy||Phase 1 Phase 2|
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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||20 participants|
|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)|
|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|
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 will be administered orally, in pill form, twice daily until disease progression.
Four milligrams of SD-101 will be delivered into the treatment lesion by intralesional injection on days 1, 8, 15, 22, and 29.
Radiotherapy will be delivered to the treatment lesion during the first week of ERS therapy.
- 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.
- 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.
- 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.
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
|United States, California|
|University of California Davis Comprehensive Cancer Center|
|Sacramento, California, United States, 95817|
|Principal Investigator:||Arta M Monjazeb, MD, PhD||University of California, Davis|