AMP-224, a PD-1 Inhibitor, With Stereotactic Body Radiation Therapy in Metastatic Colorectal Cancer
Condition: Colorectal Cancer; Colorectal Neoplasms; Colorectal Carcinoma
MeSH terms: Colorectal Neoplasms
Study type: Interventional
Phase: Phase 1

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).
    

Intervention name(s): AMP-224; Stereotactic Body Radiation Therapy(SBRT); Cyclophosphamide
Intervention type(s): Drug; Radiation; Drug
Intervention description(s): 10mg/kg on day 1 then every 14 days for a total of 6 doses.; Dose Level 1: 8Gy x 1 day. Dose Level 2: 8Gy x 3 days; 200mg/m(2) IV on day 0.
Other intervention name(s): CTX
Intervention MeSH terms: Cyclophosphamide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Anti-PD1 Therapy; Anti-Tumor Immunity; Liver Metastatic; B7-DC Fc Fusion Protein