AzTrials
AzTrials

Colorectal CancerPhase 1NCT02298946

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

A Phase 1 study testing AMP-224, Stereotactic Body Radiation Therapy(SBRT) and Cyclophosphamide in people with Colorectal Cancer and Colorectal Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 99 years
What is being tested?
AMP-224, Stereotactic Body Radiation Therapy(SBRT) and Cyclophosphamide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
17 participants
Where
1 siteUnited States
Study dates
21 Nov 2014to 7 Mar 2017
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 99 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

None listed.

Who cannot join

  • Prior immune checkpoint inhibition with anti-programmed cell death-1 (PD1)/programmed death ligand-1(PD-L1) or anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) therapy or other specific T cell targeting agents.
  • Patients who have had chemotherapy (or so-called targeted systemic therapy), large field radiotherapy, or major surgery must wait 4 weeks after completing treatment prior to entering the study.
  • Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic blood pressure (BP) greater than 160, diastolic BP greater than 100), ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes or psychiatric illness/social situations that would limit compliance with study requirements.
  • Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and the investigational agent.
  • History of chronic autoimmune disease (e.g., systemic lupus erythematosus or Wegener's granulomatosis, Addison's disease, multiple sclerosis, Graves disease, Hashimoto's thyroiditis, hypophysitis, etc.) with symptomatic disease within the 3 years before randomization. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion. In addition, a past history of certain autoimmunity eg rheumatoid arthritis or thyroiditis may be allowed per principal investigator (PI) discretion provided it has been quiescent for a minimum of three years.
Show all 14Show fewer
  • Active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea.
  • Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requirements of the protocol.
  • Currently receiving immunosuppressive doses of steroids or other immunosuppressive medications (inhaled and topical steroids are permitted)
  • History of sarcoidosis syndrome
  • History of hypersensitivity reaction to human or mouse antibody products.
  • Pregnancy and breast feeding are exclusion factors. The effects of AMP-224 on the developing human fetus are unknown. Enrolled patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 3 months after the end of the treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Patients with unhealed surgical wounds for more than 30 days.
  • Patients with known sensitivity or allergy to any components of AMP-224.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

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

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.
Read more

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.
Read the 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).
Being tested
AMP-224, Stereotactic Body Radiation Therapy(SBRT), Cyclophosphamide
Keywords
Anti-PD1 Therapy, Anti-Tumor Immunity, Liver Metastatic, B7-DC Fc Fusion Protein
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AMP-224Drug

    10mg/kg on day 1 then every 14 days for a total of 6 doses.

  • Stereotactic Body Radiation Therapy(SBRT)Radiation

    Dose Level 1: 8Gy x 1 day. Dose Level 2: 8Gy x 3 days

  • CyclophosphamideDrug

    Also called CTX

    200mg/m(2) IV on day 0.

Study groups in NCT02298946
Study groupRoleWhat they receive
DL1 - CTX, SBRTx1 day, & AMP-224ExperimentalDose 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
Receives: Drug: AMP-224; Radiation: Stereotactic Body Radiation Therapy(SBRT); Drug: Cyclophosphamide
DL2 - CTX, SBRTx3 days, and AMP-224ExperimentalDose 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.
Receives: Drug: AMP-224; Radiation: Stereotactic Body Radiation Therapy(SBRT); Drug: Cyclophosphamide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

    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.

    Measured: Date treatment consent signed to date off study, approximately 24 months and 8 days

Secondary outcomes (10)

  1. Duration of Response in Patients With Colorectal Cancer During and Following Treatment With AMP-224 in Combination With SBRT

    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.

    Measured: 12 months

  2. Number of Participants in Which Specimens Were Collected for Pre and Post Pharmacokinetic (PK) AMP-224 Analyses

    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.

    Measured: Baseline and post infusion AMP-224 (e.g. 15 minutes after infusion ended)

  3. Overall Survival in Patients With Colorectal Cancer Following Treatment With AMP-224 in Combination With SBRT

    Overall survival is defined as the time from treatment start date until date of death or date last known alive.

    Measured: Baseline to end of study, which is date of death. Average time participants were followed was 10.6 months.

  4. Count of Participants With Post-Treatment Biopsies

    Mandatory post treatment biopsies of the tumor were attempted on all patients.

    Measured: Post treatment, day 29 +/- 7 days

  5. Median Progression-free Survival in Patients With Colorectal Cancer

    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).

    Measured: Baseline to disease progression, an average of 2.6 months.

  6. Objective Response Rate

    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.

    Measured: Restaging was done every 8 weeks for an average of 2.6 months.

  7. Immunogenicity of AMP-224 as Measured by Human Anti-Murine Antibodies (HAMA) and Human Anti-Chimeric Antibodies (HACA) Concentrations

    Blood samples were collected to measure HAMA and HACA concentrations using the ELISA method in all patients.

    Measured: Baseline, D1, D29, and D57 (pre-infusion), D79, D85 and 90 days post last dose (D169)

  8. Terminal Elimination Half-Life of AMP-224

    Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.

    Measured: 10 days

  9. Area of the Curve (AUC) of AMP-224

    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.

    Measured: Pre and post-infusion with all the AMP infusion and Day 1 at 8, 15, 29, 43, 57, and 71 hours.

  10. Time to Maximum Observed Plasma Concentration (Tmax) of AMP-224

    Time maximum drug absorption is reached in the blood following administration of AMP-224.

    Measured: 12.7 hours following intravenous (IV) infusion.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Nov 2014 (estimated)
  2. Study start21 Nov 2014
  3. Primary completion13 Jul 2016
  4. Study completion7 Mar 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
17 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02298946
Sponsor's protocol ID
150021
Other IDs
15-C-0021
Status last verified
Feb 2019
First submitted
21 Nov 2014
Last updated
22 Feb 2019
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol. 2011 Mar;8(3):151-60. doi: 10.1038/nrclinonc.2010.223.

    PubMed 21364688

  • Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, Andre F, Delaloge S, Tursz T, Kroemer G, Zitvogel L. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007 Sep;13(9):1050-9. doi: 10.1038/nm1622. Epub 2007 Aug 19.

    PubMed 17704786

  • Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007 Jan;13(1):54-61. doi: 10.1038/nm1523. Epub 2006 Dec 24.

    PubMed 17187072

  • Floudas CS, Brar G, Mabry-Hrones D, Duffy AG, Wood B, Levy E, Krishnasamy V, Fioravanti S, Bonilla CM, Walker M, Morelli MP, Kleiner DE, Steinberg SM, Figg WD, Greten TF, Xie C. A Pilot Study of the PD-1 Targeting Agent AMP-224 Used With Low-Dose Cyclophosphamide and Stereotactic Body Radiation Therapy in Patients With Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2019 Dec;18(4):e349-e360. doi: 10.1016/j.clcc.2019.06.004. Epub 2019 Jul 2.

    PubMed 31351862

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing AMP-224, Stereotactic Body Radiation Therapy(SBRT) and Cyclophosphamide in people with Colorectal Cancer and Colorectal Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 0 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) (time frame: Date treatment consent signed to date off study, approximately 24 months and 8 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02298946, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Feb 2019.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in