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

NCT02298946 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 15002115-C-0021
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Colorectal Cancer; Colorectal Neoplasms; Colorectal Carcinoma

Keywords

Anti-PD1 Therapy; Anti-Tumor Immunity; Liver Metastatic; B7-DC Fc Fusion Protein

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (10)

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

  12 months

• 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)

• 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.

• Count of Participants With Post-Treatment Biopsies

  Post treatment, day 29 +/- 7 days

• Median Progression-free Survival in Patients With Colorectal Cancer

  Baseline to disease progression, an average of 2.6 months.

Study Arms (2)

DL1 - CTX, SBRTx1 day, & AMP-224

EXPERIMENTAL

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

Drug: AMP-224; Radiation: Stereotactic Body Radiation Therapy(SBRT); Drug: Cyclophosphamide

DL2 - CTX, SBRTx3 days, and AMP-224

EXPERIMENTAL

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.

Drug: AMP-224; Radiation: Stereotactic Body Radiation Therapy(SBRT); Drug: Cyclophosphamide

Interventions

AMP-224 DRUG

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

DL1 - CTX, SBRTx1 day, & AMP-224; DL2 - CTX, SBRTx3 days, and AMP-224

Stereotactic Body Radiation Therapy(SBRT) RADIATION

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

DL1 - CTX, SBRTx1 day, & AMP-224; DL2 - CTX, SBRTx3 days, and AMP-224

Cyclophosphamide DRUG

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

Also known as: CTX

DL1 - CTX, SBRTx1 day, & AMP-224; DL2 - CTX, SBRTx3 days, and AMP-224

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histopathological confirmation of Colorectal Carcinoma (CRC) by the Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this study.
• Patients must have progressed on or been intolerant of prior oxaliplatin and irinotecan containing chemotherapeutic regimen and have disease that is not amenable to potentially curative resection. Patients who have a known KRAS wild type tumor must have progressed or been intolerant to cetuximab or panitumumab-based chemotherapy.
• Patients must have one focus of metastatic disease in the liver that is amenable to stereotactic body radiation therapy (SBRT) in the opinion of radiation oncology.
• All patients enrolled will be required to have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria outside the radiation field.
• Study patients must have disease that is amenable to pre and post treatment biopsy and be willing to undergo this.
• Age greater than or equal 18 years
• Life expectancy of greater than 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients must have acceptable organ and marrow function as defined below:
• leukocytes less than or equal to 3,000/mcL
• absolute neutrophil count less than or equal 1,500/mcL
• platelets less than or equal 100,000/mcL
• total bilirubin greater than or equal 1.5X institution upper limit of normal
• Patients are eligible with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) measuring up to 5 x ULN given the presence of liver metastasis.
• creatinine greater than 1.5X institution upper limit of normal

You may not qualify if:

• 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.
• 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.
• Patients with unhealed surgical wounds for more than 30 days.
• Patients with known sensitivity or allergy to any components of AMP-224.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 21364688 BACKGROUND

• 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.

  PMID: 17704786 BACKGROUND

• 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.

  PMID: 17187072 BACKGROUND

• 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.

  PMID: 31351862 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Radiosurgery; Cyclophosphamide

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Dr. Tim F. Greten
• Organization: National Cancer Institute

gretentf@mail.nih.gov

301-451-4723

Study Officials

• Tim F Greten, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 21, 2014
• First Posted: November 24, 2014
• Study Start: November 21, 2014
• Primary Completion: July 13, 2016
• Study Completion: March 7, 2017
• Last Updated: February 22, 2019
• Results First Posted: February 22, 2019

Record last verified: 2019-02

Locations

US (1)