Ipilimumab and Local Radiation for Selected Solid Tumors

January 4, 2024 updated by: George Albert Fisher, Stanford University

A Phase I/II Study of Intratumoral Injection of Ipilimumab in Combination With Local Radiation in Melanoma, Non-Hodkgkin Lymphoma and Colorectal Carcinoma

This pilot phase 1-2 trial studies the side effects and best of dose ipilimumab when given together with local radiation therapy and to see how well it works in treating patients with recurrent melanoma, non-Hodgkin lymphoma, colon, or rectal cancer. Monoclonal antibodies, such as ipilimumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiation therapy uses high energy x rays to kill cancer cells. Giving monoclonal antibody therapy together with radiation therapy may be an effective treatment for melanoma, non-Hodgkin lymphoma, colon, or rectal cancer.

  • The phase 1 component ("safety") of this study is ipilimumab 25 mg monotherapy.
  • The phase 2 component ("treatment-escalation") of this study is ipilimumab 25 mg plus radiation combination therapy.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the safety of combining intratumoral anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) immunotherapy with local radiation therapy in patients with melanoma, non-Hodgkin lymphoma, and colorectal carcinoma with a monotherapy ipilimumab safety lead-in.

SECONDARY OBJECTIVES:

  1. To assess the induction of an anti-tumor immune responses using laboratory correlative studies.
  2. To determine tumor response rates and duration of response at unirradiated tumor sites in patients with advanced malignancies.
  3. To identify putative immunologic biomarkers of tumor response.

OUTLINE: This is a phase I safety study of ipilimumab monotherapy, followed by a phase 2 study. Only a few subjects participated in the phase 1 portion of this study. The phase 2 treatment-escalation portion of this study (ipilimumab plus radiation combination therapy) was not conducted.

Patients receive ipilimumab intratumorally on day 1 and undergo local radiation therapy within 48 hours for at least 3 fractions.

After completion of study treatment, patients are followed up at 4 and 8 weeks, and then every 24 weeks for 5 years.

Study Type

Interventional

Enrollment (Actual)

3

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Stanford, California, United States, 94305
        • Stanford University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Willing and able to give written informed consent

    • Before any study procedures are performed, subjects (or their legally acceptable representatives) will have the details of the study described to them, and they will be given a written informed consent document to read; then, if subjects consent to participate in the study, they will indicate that consent by signing and dating the informed consent document in the presence of study personnel

  • Histologically confirmed malignancy

    • In Phase 1, histologically confirmed melanoma.
    • In Phase 2, histologically confirmed melanoma, non-Hodgkin lymphoma, or colorectal carcinoma
  • Must have failed at least 1 systemic therapy or be intolerant to at least one prior systemic treatment
  • Must have at least 2 lesions of evaluable size by modified World Health Organization (mWHO)/Cheson criteria; 1 of 2 lesions must be amenable to biopsy (core or fine needle aspirate) and intratumoral injection of up to 5 mL (diameter ≥ 10mm)
  • Subjects with asymptomatic brain metastases are eligible; (systemic steroids should be avoided if possible, or the subject should be stable on the lowest clinically effective dose, as steroids as they may interfere with the activity of ipilimumab if administered at the time of the first ipilimumab dose)
  • Must be at least 28 days since treatment with standard or investigational chemotherapy, biochemotherapy, surgery, radiation, cytokine therapy, or immunotherapy, and recovered from any clinically significant toxicity experienced during treatment
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Life expectancy of ≥ 16 weeks
  • Subjects must have baseline (screening/baseline) radiographic images, (e.g. brain, chest, abdomen, pelvis, and bone scans with specific imaging tests to be determined by the attending physician) within 6 weeks of initiation of ipilimumab
  • White blood cell (WBC) ≥ 2000/uL (~2 x 10^9/L)
  • Absolute neutrophil count (ANC) ≥ 1000/uL (~0.5 x 10^9/L)
  • Platelets ≥ 75 x 10^3/uL (~75 x 10^9/L)
  • Hemoglobin ≥ 9 g/dL (may be transfused)
  • Creatinine ≤ 2.0 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN for subjects without liver metastasis ≤ 5 times for liver metastases
  • Bilirubin ≤ 2.0 x ULN (except for subjects with Gilbert's syndrome, who must have a total bilirubin of less than 3.0 mg/dL)
  • No active or chronic infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C

  • Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized; WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal; post-menopause is defined as:

    • Amenorrhea ≥ 12 consecutive months without another cause, or
    • For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35 mIU/mL
  • Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential; WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours before the start of ipilimumab
  • Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study (and for up to 26 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized

Exclusion Criteria:

  • Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix
  • Autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis)
  • Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea
  • Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology consult
  • Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab)
  • A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4 inhibitor or agonist

  • Concomitant therapy with any of the following: interleukin-2 (IL 2), interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids

    • A history of AEs with prior IL-2 or Interferon will not preclude subjects from entering the current study
  • Any investigational agents
  • Immunosuppressive agents (unless required for treating potential AEs)
  • Chronic systemic corticosteroids (unless required for treating treatment emergent AEs or required for management of signs or symptoms due to brain metastases, upon discussion with Bristol-Myers Squibb [BMS] medical monitor)
  • Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness

  • Women of childbearing potential (WOCBP) who:

    • Are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 8 weeks after cessation of study drug, or
    • Have a positive pregnancy test at baseline, or
    • Are pregnant or breastfeeding
  • Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 8 weeks after ipilimumab is stopped; sexually active WOCBP must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized; before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during study participation and the potential risk factors for an unintentional pregnancy; all WOCBP MUST have a negative pregnancy test before first receiving ipilimumab; if the pregnancy test is positive, the patient must not receive ipilimumab and must not be enrolled in the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ipilimumab 25 mg (Phase 1)
Participants receive ipilimumab intratumorally on Day 1
Biological: Ipilimumab
Given intratumorally
Other Names:
  • MDX-010
  • MDX-CTLA-4
  • Anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody
  • Monoclonal antibody CTLA-4
Experimental: Ipilimumab 25 mg and radiation therapy (Phase 2)
Participants receive ipilimumab intratumorally on Day 1 and undergo local radiation therapy (10 Gy/fraction) within 48 hours for at least 3 fractions
Biological: Ipilimumab
Given intratumorally
Other Names:
  • MDX-010
  • MDX-CTLA-4
  • Anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody
  • Monoclonal antibody CTLA-4
Radiation: Radiation therapy
Undergo local radiation therapy, 10 Gy x 3 fractions
Other Names:
  • Irradiation
  • Radiotherapy
  • Therapy, radiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose-limiting Toxicity
Time Frame: 4 weeks
Safety as the percentage of patients in Phase 1 (ipilimumab monotherapy) of the study, who experienced dose-limiting toxicities (DLTs) or serious adverse events (SAEs), using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
4 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Immune Response (Phase 2 Only)
Time Frame: 4 weeks
Data will be summarized using proportions with exact 95% confidence intervals, means, standard deviations, and ranges.
4 weeks
Immune Response (Phase 2 Only)
Time Frame: 8 weeks
Data will be summarized using proportions with exact 95% confidence intervals, means, standard deviations, and ranges.
8 weeks
Response Rate (Phase 2 Only)
Time Frame: 8 weeks
Response rates calculated based on the Response Evaluation Criteria in Solid Tumors (RECIST)/RECIST Immunotherapy and Cheson criteria (Phase 2 only). Response rate data will be summarized using proportions with exact 95% confidence intervals, means, standard deviations, and ranges.
8 weeks
Overall Survival (Phase 2 Only)
Time Frame: Up to 5 years
Data will be summarized using Kaplan-Meier estimates for time to event data.
Up to 5 years
Duration of Response (Phase 2 Only)
Time Frame: Up to 5 years
Data will be summarized using Kaplan-Meier estimates for time to event data.
Up to 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Stanford University

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: George A. Fisher, MD, PhD, Stanford University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2013

Primary Completion (Actual)

November 1, 2014

Study Completion (Actual)

June 1, 2015

Study Registration Dates

First Submitted

January 14, 2013

First Submitted That Met QC Criteria

January 14, 2013

First Posted (Estimated)

January 16, 2013

Study Record Updates

Last Update Posted (Estimated)

January 24, 2024

Last Update Submitted That Met QC Criteria

January 4, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB-25597
  • NCI-2012-02988 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • VAR0090 (Other Identifier: OnCore)
  • 5136 (Stanford IRB alternate)

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

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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