NCT02298946

AMP-224, a PD-1 Inhibitor, With Stereotactic Body Radiation Therapy in Metastatic Colorectal Cancer

A Pilot Study of AMP-224, a PD-1 Inhibitor, in Combination With Stereotactic Body Radiation Therapy (SBRT) in Patients With Metastatic Colorectal Cancer

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 17 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 99 Years
• Healthy volunteers: Not accepted

Summary

Background: \- T-cells are white blood cells that can find and kill germs and tumors. Cancer can keep T-cells from working. Researchers think a new drug called AMP-224 might help the T-cells in people with cancer. They think the drug might work even better when combined with a certain type of radiation therapy. Objective: \- To study the safety and effectiveness of AMP-224 together with 1 or 3 days of stereotactic body radiation therapy (SBRT) directed to the liver. Eligibility: \- People age 18 and older with metastatic colorectal cancer. Their cancer must have spread to the liver and not be responding to treatment. Design: * Participants will be screened with a medical history, physical exam, and blood and urine tests. Their tumors will be measured with computerized tomography (CT) scans or magnetic resonance imaging (MRI) of the chest, stomach, and pelvis. They will have an electrocardiogram (ECG) heart test. * Participants will have a small part of their tumor removed by needle (biopsy). * Participants will have 8 study visits over about 10 weeks. * At 1 visit, they will have another tumor biopsy. * At 1 visit, they will get a chemotherapy drug through a vein (intravenous (IV)). * At 6 visits, they will receive AMP-224 through an IV. * At 1 or 3 visits, they will have SBRT. Computed tomography (CT) scans will map the position of their tumor. Radiation beams of different intensities at different angles will be directed to the tumor. * At all visits, some screening procedures may be repeated. * After treatment ends, participants will have 7 follow-up visits over about 5 months. Blood will be drawn. Some screening procedures may be repeated.

Detailed description

Background: * Colorectal cancer remains the second leading cause of cancer death in western countries with a median survival of approximately 24 months despite recent advances in systemic treatment. * Several preclinical studies have documented an increase in peripheral antitumor immunity following radiation, a phenomenon known as the abscopal effect. Tumor PDL1 expression has also been shown to be induced by radiation, which can suppress the anti-tumor immune response. Inhibition of programmed cell death-1 (PD-1)/programmed death ligand-1(PDL-1) axis has been shown to improve anti-tumor immunity by blocking the tumor-mediated suppression of cytotoxic T cells. * AMP-224, a B7-DC Fc fusion protein, binds to PD-1, an inhibitory receptor that is present on the cell surface of exhausted, activated, effector, and memory T cells. AMP- 224 has a unique mechanism of action in that it binds specifically to PD-1HI T cells (chronically stimulated / exhausted T cells) but not to PD-1LO cells which represent the normal activated T cells population * The aim of the study is to evaluate whether the anti-tumor immunity of anti-PD1 therapy (with AMP-224) can be enhanced by radiation therapy. Objectives: \- To assess safety, tolerability and feasibility of AMP-224 in combination with stereotactic body radiation therapy (SBRT) in patients with metastatic colorectal cancer. Eligibility: * Histologically confirmed metastatic colorectal cancer. * Patient must have progressed on or been intolerant of prior oxaliplatin- and irinotecan containing regimen and have metastatic lesions that are not amenable to curative resection. * Patient must have one focus of metastatic disease in the liver that is amenable to SBRT. * Patient must have at least one measurable metastatic lesion by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria outside the radiation field. * Patients must be willing to undergo mandatory pre and post treatment tumor biopsy. Design: * This is a pilot study whereby all patients will receive SBRT to one liver lesion and concomitant AMP-224. A single treatment of low dose/cyclophosphamide will be administered in conjunction with the SBRT therapy prior to the first AMP-224 treatment. * Hypofractionated radiation will be administered to a metastatic disease site at a dose and schedule of 8Gy for 1 or 3 days in dose levels (DL)1 or 2 respectively. The day of first administration of AMP-224 will be designated as Day 1. In DL1 the SBRT will be administered on Day 0. In DL2 the SBRT will be administered from D-2 to D0. The study will begin with DL1 and escalate to DL2 once all subjects enrolled at DL1 have remained on study for 4 weeks, which is the DLT period. * AMP-224 therapy will be given as an intravenous infusion beginning on Day 1 and then every 14 days for a total of 6 treatments only. Optional continuation of treatment q2- weekly until progressive disease (PD) will be considered in responding patients. * Cyclophosphamide 200 mg/m(2) intravenous will be given on Day 0, prior to the first dose of AMP-224. * Correlative studies: Peripheral blood will be collected (pre-dose) on days 1, 29, 57 and 93 for immune studies (including immunogenicity, circulating PD plasma samples, immune monitoring for phenotyping and peripheral blood mononuclear cells (PBMC) for T-cell activation). Tumor biopsies (formalin-fixed paraffin-embedded (FFPE) + Frozen) of an irradiated and non-irradiated liver lesion will be collected on day 1 and day 29, which will be analyzed by immunohistochemistry for tumor-infiltrating lymphocytes in addition to ribonucleic acid (RNA) analysis. * Pharmacokinetic (PK) samples will be collected on Days 1, 15, 29, 43, 57, 71 in addition to up to 5 post treatment dates (if feasible).

Conditions

• Colorectal Cancer
• Colorectal Neoplasms
• Colorectal Carcinoma

Interventions

Type	Name	Description
DRUG	AMP-224	10mg/kg on day 1 then every 14 days for a total of 6 doses.
RADIATION	Stereotactic Body Radiation Therapy(SBRT)	Dose Level 1: 8Gy x 1 day. Dose Level 2: 8Gy x 3 days
DRUG	Cyclophosphamide	200mg/m(2) IV on day 0.

Timeline

• Start date: 2014-11-21
• Primary completion: 2016-07-13
• Completion: 2017-03-07
• First posted: 2014-11-24
• Last updated: 2019-02-22
• Results posted: 2019-02-22

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study