ECI301 and Radiation for Advanced or Metastatic Cancer

Phase I Trial of ECI301 in Combination With Radiation in Patients With Advanced or Metastatic Cancer

Background:

- ECI301 is a drug that may help make cancer cells more visible to the immune system after radiation. The drug may also help the immune system destroy the cancer at sites that have not received radiation therapy. Researchers want to study ECI301 in people with advanced cancer or cancer that has spread in the body (metastatic).

Objectives:

- To test ECI301 with radiation therapy for advanced or metastatic cancer.

Eligibility:

- People at least 18 years of age with either metastatic or advanced cancer that may benefit from radiation therapy.

Design:

• Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, and imaging studies.
• All participants will have radiation therapy 5 days a week for 2 weeks.
• They will have different doses of ECI301 to test its safety and effectiveness. ECI301 will be given in a vein during the second week of radiation therapy. Frequent blood tests and imaging studies will monitor the treatment.
• After participants have ECI301, tumor samples may be taken from the site that had radiation and another site that did not have radiation.
• Follow-up visits will include blood tests and imaging studies.

Study Overview

• Status: Terminated
• Conditions: Cancer; Neoplasm Metastasis; Metastasis; Neoplasm; Radiation Oncology
• Intervention / Treatment: Procedure: Radiation Therapy; Drug: ECI301

Detailed Description

Background:

• Patients with metastatic or locally advanced cancer frequently require palliative radiotherapy to relieve symptoms; however, progression of disease is frequent in patients with extended survival
• Radiation results in tumor cell death which can result in increased dendritic cell activation and trafficking
• ECI301 is a derivative of Macrophage Inflammatory Protein-1 alpha, a 70 amino acid chemokine that is a ligand for C-C chemokine receptor type 1 (CCR1) and C-C chemokine receptor type 5 (CCR5), the chemokine receptors of immature dendritic cells.
• ECI301 has been shown to enhance the effect of radiotherapy in animal models.

Objectives:

• The primary objective is to determine the maximum tolerated dose (MTD) of ECI301 delivered in combination with 30 Gray (Gy) of external beam radiation to patients with metastatic or locally advanced cancer.

• The secondary objectives are:

  • To describe the safety and tolerability of ECI301 delivered in combination with 30 Gy of external beam radiation to patients with metastatic or locally advanced cancer

  • To evaluate the humoral and cellular immune responses by:

    • Measurement of circulating precursor dendritic cells before and after the completion of ECI301
    • Measurement of circulating MIP-alpha before and after the completion of ECI301
    • Assessment of T-lymphocyte quantitative and qualitative changes by flow cytometry and assays for interferon (IFN-gamma) production
  • To define pharmacologic parameters following the intravenous dose of ECI301
  • To determine if neutralizing anti-EC301 antibodies occur after treatment
  • To describe the response at the radiated site and distant sites after radiation in combination with ECI301

Eligibility:

• Age >18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status <2.
• Life expectancy of greater than 3 months
• Histologically confirmed metastatic or locally advanced cancer for which radiotherapeutic management would be appropriate
• No recent history of myocardial infarction or unstable angina

Design:

• This is a Phase I trial to determine the maximum tolerated dose of ECI301 in combination with external beam radiation therapy in patients with locally advanced or metastatic solid tumors.
• Patients will be treated with radiation therapy in a standard manner with ECI301 given daily during radiation. The dose of ECI301 will be escalated over the course of the trial to determine the maximum tolerated dose (MTD of daily ECI301 in combination with radiotherapy.
• We anticipate that accrual to this trial of 30 patients will take approximately 2 years.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

2.1.1.1 Age greater than or equal to18 years.

2.1.1.2 Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

2.1.1.3 Life expectancy of greater than 3 months

2.1.1.4 Histologically confirmed cancer

2.1.1.5 Extracranial metastatic cancer or locally advanced cancer for which palliative radiotherapeutic management would be appropriate (no more than two sites will be treated on this trial)

2.1.1.6 Patients must have measurable or evaluable disease at the site(s) requiring radiation

2.1.1.7 Adequate marrow and organ function defined as

• absolute neutrophil count (ANC) > 1.5 times 10(9)/L,
• platelet count > 100 times 10(9),
• hemoglobin >9 g/L.
• creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal
• serum bilirubin <1.5 times upper limit reference range (ULRR),
• alanine aminotransferase (ALT), aspartate aminotransferase (AST), or

alkaline phosphatase (ALP) <2.5 times the ULRR (<5 times the ULRR in the presence

of liver metastases)

2.1.1.8 Female patients of childbearing potential must either be surgically sterile to prevent pregnancy, be at least 1-year post-menopausal, or have had no menses for 12 months, or agree to use reliable methods of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, copper banded intrauterine device, tubal ligation or abstinence) from time of screening until 4 weeks after discontinuing study treatment. It is not known whether ECI301 has the capacity to induce hepatic enzymes so hormonal contraceptives should be combined with a barrier method of contraception.

2.1.1.9 Male patients must agree to use barrier contraception (i.e. condoms) and refrain from donating sperm from the start of dosing until 16 weeks after discontinuing study treatment. If male patients wish to father children, they should be advised to arrange for freezing of sperm prior to the start of study treatment.

EXCLUSION CRITERIA:

2.1.2.1 Pregnant or lactating females

2.1.2.2 Contraindications to radiotherapy (i.e. prior radiotherapy to the intended treatment site)

2.1.2.3 Untreated or previously treated but progressive intracranial metastases (Patients with previously treated intracranial metastases should have no clinical evidence of progression and be at least 4 weeks from therapy for intracranial metastases)

2.1.2.4 Need for emergent radiotherapy (defined as need for radiotherapy within 24 hours of consultation at the judgment of the treating radiation oncologist)

2.1.2.5 Active treatment with immunosuppressive therapy and subjects taking systemic corticosteroid therapy for any reason including replacement therapy for hypoadrenalism

2.1.2.6 Chemotherapy, radiation therapy, Tamoxifen or investigational therapy during the 4 weeks prior to initiation of protocol therapy

2.1.2.7 History of rheumatoid arthritis, systemic lupus erythematosus, Sjogren's disease, sarcoidosis, vasculitis, polymyositis, temporal arteritis or any other autoimmune disease

2.1.2.8 History of organ transplant

2.1.2.9 Human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C positivity

2.1.2.10 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

2.1.2.11 Use of excluded immune modulating medications within 4 weeks prior to protocol therapy, or requirement for concurrent use.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ECI301 Dose level 1 - 25 ug/kg and Radiation for Advanced or Metastatic Cancer	Procedure: Radiation Therapy; Drug: ECI301

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) of ECI301 Delivered in Combination With 30 Gray (Gy) External Beam Radiation to Participants With Metastatic or Locally Advanced Cancer	MTD is defined as the highest dose level at which no more than 1 of 6 participants experience dose-limiting toxicity (DLT) during treatment or the first three weeks after treatment, and the dose below that at which at least 2 (of ≤6) participants have DLT as a result of the drug. Examples of DLT is any grade 3 or greater non-hematologic toxicity, ang grade 3 neutropenia or thrombocytopenia, any grade 4 anemia, and toxicity requiring a cumulative radiation treatment delay of 4 or more days.	During treatment or the first three weeks after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events Unrelated, Unlikely, and Possibly Related to ECI301 Delivered in Combination With 30 Gray (Gy) of External Beam Radiation to Participants With Metastatic or Locally Advanced Cancer	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) and the Radiation Therapy Oncology Group (RTOG) criteria.	Date treatment consent signed to date off study, and up to 30 days following the last dose of study drug, approximately 5 months and 25 days.
Humoral and Cellular Immune Responses	Measurement of circulating precursor dendritic cells, circulating macrophage inflammatory protein-1 alpha (MIP-α), and assessment of T-lymphocytes will be measured by flow cytometry and assays for type II interferon (IFNγ) production.	Before and after completion of ECI301
Pharmacologic Parameters Following the Intravenous Dose of ECI301	Pharmacologic parameters will be derived using non-compartmental analysis.	Following the intravenous dose of ECI301
Number of Participants With Response at the Radiated Site and Distant Site After Radiation in Combination With ECI301	Response will be measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progression. Stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Here is the Number of Participants With Non-Serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the number of participants with non-serious adverse events assessed by the Common Terminology Criteria for 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, and up to 30 days following the last dose of study drug, approximately 5 months and 25 days.
Number of Participants With a Dose-Limiting Toxicity (DLT)	Examples of DLT is any grade 3 or greater non-hematologic toxicity, any grade 3 neutropenia or thrombocytopenia, any grade 4 anemia; nausea, vomiting, diarrhea, tumor pain, or pre-existing hyponatremia, dyselectrolytemia, or orthostatic hypotension that has been optimally treated with anti-emetics, anti-diarrheal, analgesics, or hydration and which persists for over 48 hours despite maximal medical therapy, and toxicity requiring a cumulative radiation treatment delay of 4 or more days.	During treatment or the first three weeks after treatment

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Friedman EJ. Immune modulation by ionizing radiation and its implications for cancer immunotherapy. Curr Pharm Des. 2002;8(19):1765-80. doi: 10.2174/1381612023394089.
• Sharp HJ, Wansley EK, Garnett CT, Chakraborty M, Camphausen K, Schlom J, Hodge JW. Synergistic antitumor activity of immune strategies combined with radiation. Front Biosci. 2007 Sep 1;12:4900-10. doi: 10.2741/2436.
• Maurer M, von Stebut E. Macrophage inflammatory protein-1. Int J Biochem Cell Biol. 2004 Oct;36(10):1882-6. doi: 10.1016/j.biocel.2003.10.019.

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2011
• Primary Completion (Actual): April 24, 2013
• Study Completion (Actual): April 24, 2013

Study Registration Dates

• First Submitted: September 24, 2011
• First Submitted That Met QC Criteria: September 24, 2011
• First Posted (Estimate): September 27, 2011

Study Record Updates

• Last Update Posted (Actual): December 28, 2021
• Last Update Submitted That Met QC Criteria: November 30, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Cancer; Locally Advanced; Metastatic Cancer; Radiation Therapy; Metastasis; Palliation
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplastic Processes; Neoplasms; Neoplasm Metastasis; Neoplasms, Second Primary
• Other Study ID Numbers: 110248; 11-C-0248

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No