AMP-224, a PD-1 Inhibitor, With Stereotactic Body Radiation Therapy in Metastatic Colorectal Cancer
- Conditions
- Colorectal CancerColorectal NeoplasmsColorectal Carcinoma
- Interventions
- Registration Number
- NCT02298946
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 17
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description DL1 - CTX, SBRTx1 day, & AMP-224 Cyclophosphamide Dose Level 1 (DL1) Cyclophosphamide (CTX) 200mg/m(2) intravenous (IV) on day 0. Stereotactic body radiation therapy (SBRT) 8 (gray)Gy x 1 day on day 0, AMP-224 10mg/kg on day 1 then every (q)14 days for a total of 6 doses DL2 - CTX, SBRTx3 days, and AMP-224 AMP-224 Dose Level 2 (DL2) CTX 200mg/m(2) IV on day 0, SBRT 8Gy x 3 day on days -2, -1, and 0. AMP-224 10mg/kg on day 1 then q14 days. DL2 - CTX, SBRTx3 days, and AMP-224 Stereotactic Body Radiation Therapy(SBRT) Dose Level 2 (DL2) CTX 200mg/m(2) IV on day 0, SBRT 8Gy x 3 day on days -2, -1, and 0. AMP-224 10mg/kg on day 1 then q14 days. DL1 - CTX, SBRTx1 day, & AMP-224 AMP-224 Dose Level 1 (DL1) Cyclophosphamide (CTX) 200mg/m(2) intravenous (IV) on day 0. Stereotactic body radiation therapy (SBRT) 8 (gray)Gy x 1 day on day 0, AMP-224 10mg/kg on day 1 then every (q)14 days for a total of 6 doses DL1 - CTX, SBRTx1 day, & AMP-224 Stereotactic Body Radiation Therapy(SBRT) Dose Level 1 (DL1) Cyclophosphamide (CTX) 200mg/m(2) intravenous (IV) on day 0. Stereotactic body radiation therapy (SBRT) 8 (gray)Gy x 1 day on day 0, AMP-224 10mg/kg on day 1 then every (q)14 days for a total of 6 doses DL2 - CTX, SBRTx3 days, and AMP-224 Cyclophosphamide Dose Level 2 (DL2) CTX 200mg/m(2) IV on day 0, SBRT 8Gy x 3 day on days -2, -1, and 0. AMP-224 10mg/kg on day 1 then q14 days.
- Primary Outcome Measures
Name Time Method Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) Date treatment consent signed to date off study, approximately 24 months and 8 days Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
- Secondary Outcome Measures
Name Time Method Duration of Response in Patients With Colorectal Cancer During and Following Treatment With AMP-224 in Combination With SBRT 12 months Duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is recorded first) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is complete disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Number of Participants in Which Specimens Were Collected for Pre and Post Pharmacokinetic (PK) AMP-224 Analyses Baseline and post infusion AMP-224 (e.g. 15 minutes after infusion ended) This outcome measure only represents the number of participants with metastatic colorectal cancer who had specimens collected for pre and post pharmacokinetic (PK) AMP-224 analyses.
Overall Survival in Patients With Colorectal Cancer Following Treatment With AMP-224 in Combination With SBRT Baseline to end of study, which is date of death. Average time participants were followed was 10.6 months. Overall survival is defined as the time from treatment start date until date of death or date last known alive.
Count of Participants With Post-Treatment Biopsies Post treatment, day 29 +/- 7 days Mandatory post treatment biopsies of the tumor were attempted on all patients.
Median Progression-free Survival in Patients With Colorectal Cancer Baseline to disease progression, an average of 2.6 months. Progression free survival is defined as the time interval from start of treatment to documented evidence of disease progression. Disease progression was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions).
Immunogenicity of AMP-224 as Measured by Human Anti-Murine Antibodies (HAMA) and Human Anti-Chimeric Antibodies (HACA) Concentrations Baseline, D1, D29, and D57 (pre-infusion), D79, D85 and 90 days post last dose (D169) Blood samples were collected to measure HAMA and HACA concentrations using the ELISA method in all patients.
Area of the Curve (AUC) of AMP-224 Pre and post-infusion with all the AMP infusion and Day 1 at 8, 15, 29, 43, 57, and 71 hours. The AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. The lower limit of quantification (LLOQ) is the smallest concentration of the drug that can be reliably measured.
Objective Response Rate Restaging was done every 8 weeks for an average of 2.6 months. Objective response will be evaluated according to the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and is defined as Complete Response + Partial Response. Briefly, complete response (CR) is defined as the disappearance of all target lesions, and Partial Response is defined as "at least" 30% decrease in the sum of the diameters of the target lesions from baseline measurement.
Terminal Elimination Half-Life of AMP-224 10 days Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Time to Maximum Observed Plasma Concentration (Tmax) of AMP-224 12.7 hours following intravenous (IV) infusion. Time maximum drug absorption is reached in the blood following administration of AMP-224.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States