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Trial of SBRT With Concurrent Ipilimumab in Metastatic Melanoma

Primary Purpose

Melanoma, Effects of Immunotherapy, Adverse Effect of Radiation Therapy

Status

Completed

Phase

Phase 1

Locations

Belgium

Study Type

Interventional

Intervention

Stereotactic body radiotherapy (SBRT)

Ipilimumab

About this trial

This is an interventional treatment trial for Melanoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Signed informed consent and willingness to comply to the treatment and follow-up
Histological diagnosis of melanoma,
at least 3 extracranial measurable metastatic lesions per RECIST 1.1,
Karnofsky Performance score >60,
Age ≥18,
Life expectancy ≥ 16 weeks
Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment. Men and women should agree to use effective contraception, during the study and for 1 month following the last dose of investigational product.
≥ 28 days between last treatment with standard or experimental chemotherapy, surgery, radiotherapy, cytokine therapy or immunotherapy. Patient should be completely recuperated of any clinical toxicity developed during previous treatments.
Patients should have adequate organ function for ipilimumab treatment

Exclusion Criteria:

Central nervous system (CNS) metastases at baseline, with the exception of those subjects who have previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or enzyme-inducing anticonvulsants.
Prior malignancy: Subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible
Prior radiotherapy preventing treatment with SBRT.
Disorder precluding understanding of trial information.
Autoimmune disease: Patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus or autoimmune vasculitis [e.g., Wegener's Granulomatosis] are excluded from this study.
Known Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C.
Concomitant therapy with any of the following: IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses).
Pregnant women
Breast feeding
History of or current immunodeficiency disease or prior treatment compromising immune function, prior allogeneic stem cell transplantation.

Sites / Locations

Dept. of Radiotherapy, Ghent University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (SBRT, Ipilimumab)

Arm Description

Drug: Ipilimumab Dosage: Ipilimumab will be administered intravenously at 3 mg/kg every 3 weeks for 4 cycles, Radiation: Stereotactic Body Radiotherapy Radiation therapy 24 Grays in 8 Grays fractions, Radiation therapy 30 Grays in 10 Grays fractions, Radiation therapy 36 Grays in 12 Grays fractions

Outcomes

Primary Outcome Measures

Maximal tolerated dose (MDT) that is associated with dose-limiting toxicity (DLT) in 25% of patients.

Secondary Outcome Measures

Preliminary anti-tumor activity following escalating doses of radiation combined to ipilimumab using the immune related response criteria irRC

Overall survival

Progression-free survival

Immunomonitoring (absolute lymphocyte count)

absolute lymphocyte count

Immunomonitoring (frequencies of Foxp3+ Treg-cells)

frequencies of Foxp3+ Treg-cells

Immunomonitoring (functional analysis looking at shifts in Th1/Th2/Th17)

functional analysis looking at shifts in Th1/Th2/Th17

Immunomonitoring (plasmacytoid dendritic cells and myeloid derived suppressor cells and their IDO expression)

plasmacytoid dendritic cells and myeloid derived suppressor cells and their IDO expression,

Full Information

NCT ID

NCT02406183

First Posted

March 17, 2015

Last Updated

January 9, 2017

Sponsor

Radiotherapie

1. Study Identification

Unique Protocol Identification Number

NCT02406183

Brief Title

Trial of SBRT With Concurrent Ipilimumab in Metastatic Melanoma

Official Title

Phase I Trial of Stereotactic Body Radiotherapy With Concurrent Fixed Dose Immune Checkpoint Inhibitors in Metastatic Melanoma: Dose Limiting Toxicity and Abscopal Effect

Study Type

Interventional

2. Study Status

Record Verification Date

January 2017

Overall Recruitment Status

Completed

Study Start Date

March 2015 (undefined)

Primary Completion Date

August 2016 (Actual)

Study Completion Date

August 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Radiotherapie

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The prognosis of advanced metastatic melanoma remains poor although a breakthrough has been achieved with the novel anti-CTLA-4 treatment (ipilimumab) for a subset of patients. Unfortunately, due to immune resistance, the majority of patients do not obtain long-lasting clinical benefit. Radiotherapy is able to interfere with immune resistance by inducing immunogenic cell death. Preclinical evidence indicates that combining radiotherapy with anti-CTLA-4 treatment increases response rates compared to single agent treatment. These data are supported by several spectacular clinical cases and one retrospective study. The investigators hypothesize that combining ipilimumab with radiotherapy will result in a higher response rate compared to ipilimumab or radiotherapy in monotherapy. Given the complexity of the interaction in anti-tumor immunity, the first goal of this project is to assess the safety of the combined treatment.

Detailed Description

The safety profiles of ipilimumab and SBRT are well studied separately 22-24, but prospective data on the combination of ipilimumab and high-dose SBRT are lacking. Consequently, the first goal of the proposed prospective phase I trial is to assess the safety (dose limiting toxicity, DLT) of the combination of high-dose SBRT and ipilimumab in patients with advanced melanoma.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma, Effects of Immunotherapy, Adverse Effect of Radiation Therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

13 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (SBRT, Ipilimumab)

Arm Type

Experimental

Arm Description

Intervention Type

Radiation

Intervention Name(s)

Stereotactic body radiotherapy (SBRT)

Other Intervention Name(s)

SABR

Intervention Description

The SBRT dose will be escalated in 3 steps as described above and will be given on d39, d41 and d43

Intervention Type

Drug

Intervention Name(s)

Ipilimumab

Other Intervention Name(s)

Yervoy

Intervention Description

Ipilimumab 3mg/kg will be given IV on d1, d22, d43 and d64

Primary Outcome Measure Information:

Title

Maximal tolerated dose (MDT) that is associated with dose-limiting toxicity (DLT) in 25% of patients.

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Preliminary anti-tumor activity following escalating doses of radiation combined to ipilimumab using the immune related response criteria irRC

Time Frame

2 years

Title

Overall survival

Time Frame

2 years

Title

Progression-free survival

Time Frame

2 years

Title

Immunomonitoring (absolute lymphocyte count)

Description

absolute lymphocyte count

Time Frame

2 years

Title

Immunomonitoring (frequencies of Foxp3+ Treg-cells)

Description

frequencies of Foxp3+ Treg-cells

Time Frame

2 years

Title

Immunomonitoring (functional analysis looking at shifts in Th1/Th2/Th17)

Description

functional analysis looking at shifts in Th1/Th2/Th17

Time Frame

2 years

Title

Immunomonitoring (plasmacytoid dendritic cells and myeloid derived suppressor cells and their IDO expression)

Description

plasmacytoid dendritic cells and myeloid derived suppressor cells and their IDO expression,

Time Frame

2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Signed informed consent and willingness to comply to the treatment and follow-up Histological diagnosis of melanoma, at least 3 extracranial measurable metastatic lesions per RECIST 1.1, Karnofsky Performance score >60, Age ≥18, Life expectancy ≥ 16 weeks Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment. Men and women should agree to use effective contraception, during the study and for 1 month following the last dose of investigational product. ≥ 28 days between last treatment with standard or experimental chemotherapy, surgery, radiotherapy, cytokine therapy or immunotherapy. Patient should be completely recuperated of any clinical toxicity developed during previous treatments. Patients should have adequate organ function for ipilimumab treatment Exclusion Criteria: Central nervous system (CNS) metastases at baseline, with the exception of those subjects who have previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or enzyme-inducing anticonvulsants. Prior malignancy: Subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible Prior radiotherapy preventing treatment with SBRT. Disorder precluding understanding of trial information. Autoimmune disease: Patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus or autoimmune vasculitis [e.g., Wegener's Granulomatosis] are excluded from this study. Known Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C. Concomitant therapy with any of the following: IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses). Pregnant women Breast feeding History of or current immunodeficiency disease or prior treatment compromising immune function, prior allogeneic stem cell transplantation.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Piet Ost, MD, PhD

Organizational Affiliation

University Hospital, Ghent

Official's Role

Principal Investigator

Facility Information:

Facility Name

Dept. of Radiotherapy, Ghent University Hospital

City

Ghent

State/Province

Oost-Vlaanderen

ZIP/Postal Code

9000

Country

Belgium

12. IPD Sharing Statement

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Trial of SBRT With Concurrent Ipilimumab in Metastatic Melanoma

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