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Trial of SBRT With Concurrent Ipilimumab in Metastatic Melanoma

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ClinicalTrials.gov Identifier: NCT02406183
Recruitment Status : Completed
First Posted : April 2, 2015
Last Update Posted : January 10, 2017
Information provided by (Responsible Party):
Radiotherapie, University Hospital, Ghent

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.

Condition or disease Intervention/treatment Phase
Melanoma Effects of Immunotherapy Adverse Effect of Radiation Therapy Radiation: Stereotactic body radiotherapy (SBRT) Drug: Ipilimumab Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : March 2015
Actual Primary Completion Date : August 2016
Actual Study Completion Date : August 2016

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma
Drug Information available for: Ipilimumab

Arm Intervention/treatment
Experimental: Treatment (SBRT, Ipilimumab)

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

Radiation: Stereotactic body radiotherapy (SBRT)
The SBRT dose will be escalated in 3 steps as described above and will be given on d39, d41 and d43
Other Name: SABR

Drug: Ipilimumab
Ipilimumab 3mg/kg will be given IV on d1, d22, d43 and d64
Other Name: Yervoy

Primary Outcome Measures :
  1. Maximal tolerated dose (MDT) that is associated with dose-limiting toxicity (DLT) in 25% of patients. [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Preliminary anti-tumor activity following escalating doses of radiation combined to ipilimumab using the immune related response criteria irRC [ Time Frame: 2 years ]
  2. Overall survival [ Time Frame: 2 years ]
  3. Progression-free survival [ Time Frame: 2 years ]
  4. Immunomonitoring (absolute lymphocyte count) [ Time Frame: 2 years ]
    absolute lymphocyte count

  5. Immunomonitoring (frequencies of Foxp3+ Treg-cells) [ Time Frame: 2 years ]
    frequencies of Foxp3+ Treg-cells

  6. Immunomonitoring (functional analysis looking at shifts in Th1/Th2/Th17) [ Time Frame: 2 years ]
    functional analysis looking at shifts in Th1/Th2/Th17

  7. Immunomonitoring (plasmacytoid dendritic cells and myeloid derived suppressor cells and their IDO expression) [ Time Frame: 2 years ]
    plasmacytoid dendritic cells and myeloid derived suppressor cells and their IDO expression,

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02406183

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Dept. of Radiotherapy, Ghent University Hospital
Ghent, Oost-Vlaanderen, Belgium, 9000
Sponsors and Collaborators
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Principal Investigator: Piet Ost, MD, PhD University Hospital, Ghent
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Responsible Party: Radiotherapie, MD, PhD, University Hospital, Ghent
ClinicalTrials.gov Identifier: NCT02406183    
Other Study ID Numbers: EC 2015/0025
First Posted: April 2, 2015    Key Record Dates
Last Update Posted: January 10, 2017
Last Verified: January 2017
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action