Concurrent Ipilimumab and Stereotactic Ablative Radiation Therapy (SART) for Oligometastatic But Unresectable Melanoma (SART)

Study Description

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Brief Summary:

The purpose of this study is to evaluate if precisely-targeted radiation therapy, known as stereotactic ablative radiotherapy (SART), given during treatment with the drug ipilimumab (Yervoy) will improve survival for patients with melanoma that has spread to five or fewer sites (oligometastatic).

Blood samples will be collected for research purposes. Planned studies include exploration of certain gene mutations and serum markers as predictors of response to ipilimumab treatment. Research lab studies will also evaluate if circulating tumor cells (CTC) can be accurately detected and isolated from the blood using novel laboratory techniques and if they are a prognostic/predictive marker for treatment response. Test results will not be given to participants or their physicians. In some cases, CTC may be grown for long-term cell lines for further research.

Condition or disease	Intervention/treatment	Phase
Melanoma	Drug: Ipilimumab; Radiation: Stereotactic Ablative Radiosurgery (SART)	Phase 2

Detailed Description:

Primary Objectives:

1. To evaluate the effectiveness of concurrent ipilimumab therapy and SART of melanoma based on 1-year and 2-year overall survival.
2. To evaluate the safety and tolerability of concurrent ipilimumab therapy and SART of melanoma based on CTCAE grading of toxicities, and to identify any novel or unexpected Grade 3 or 4 toxicities thought specifically related to ipilimumab and concurrent SART during first 3 cycles of ipilimumab therapy (prior to week 9) in a Phase II study.

Secondary Objectives:

1. To evaluate the 1-year and 2-year disease control rates (CR+PR+SD)
2. Assess treatment response based on Immune Related Response Criteria (irRC) and mWHO criteria.
3. Characterize overall survival by Kaplan-Meier analysis.

Exploratory Objectives:

1. Evaluate individual lesion control (<25% progression) following body SART at 6, 12, 24 months.
2. Describe number of patients requiring retreatment of any local lesion with surgery or other treatments.
3. Describe the incidence of new brain metastases following ipilimumab therapy.
4. Describe the incidence of treatment related toxicity and/or symptomatic bleeding, perforation, or necrosis at SART treated tumor sites.
5. Explore the use of circulating melanoma cells and serum metastasis gene expression levels as prognostic and predictive (intermediate) markers to identify responding patients.
6. Assess the effect of therapy on quality of life, using ECOG score as a surrogate.

Study Rationale:

Ipilimumab may markedly enhance the immunologic responses to tumor antigen released from necrotic tumor cells by radiotherapy by promoting cytotoxic T cell activation, while preventing induction of antigen tolerance. In addition, further beneficial immunologic effects may be achieved by the reduction in the amount of viable tumor cell mass. The net effect may be to promote a significantly enhanced antitumor T cell response. This will result in improved 1-year and 2-year survival, especially if a minimal or microscopic disease state can be achieved within a patient following SART.

Biologic Correlation Studies:

There are currently no standard prognostic or predictive markers to evaluate or predict outcome of ipilimumab therapy. This study provides the opportunity for exploratory analysis of several candidate hypotheses that may predict outcome.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	50 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II Evaluation of Concurrent Ipilimumab Therapy and Stereotactic Ablative Radiation Therapy (SART) for Oligometastatic But Unresectable Malignant Melanoma
Study Start Date :	August 2012
Estimated Primary Completion Date :	November 2016
Estimated Study Completion Date :	November 2017

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Ipilimumab + SART; Patients with oligometastatic but unresectable malignant melanoma will receive induction ipilimumab plus concurrent SART followed by maintenance ipilimumab.

Drug: Ipilimumab; Ipilimumab 10mg/kg administered intravenously over 90-minute period every 3 weeks for a total of four doses as tolerated. Maintenance ipilimumab (10 mg/kg intravenously every 3 months) will be administered beginning Week 24, as long as there is clinical benefit in the opinion of the investigator using immune related response criteria, and there are no novel or unexpected Grade 3 or 4 toxicities.; Other Names: Yervoy; MDX-010 Radiation: Stereotactic Ablative Radiosurgery (SART); Definitive radiotherapy will be administered to up to 1-5 lesions using SART techniques after initial dose of ipilimumab. Radiotherapy will be timed before start of 3rd cycle of ipilimumab treatment to maximize synergy (week 6).

Outcome Measures

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Primary Outcome Measures :

1. Safety and tolerability of concurrent ipilimumab and SART - Acute Toxicity [ Time Frame: Week 9 ]
2. Safety and tolerability of concurrent ipilimumab and SART - Subacute Toxicity [ Time Frame: Week 15 ]

Secondary Outcome Measures :

1. 1-year disease control rates (CR+PR+SD) based on irRC and mWHO criteria [ Time Frame: 2 year minimum follow up on study participants ]
2. 2-year disease control rates (CR+PR+SD) based on irRC and mWHO criteria [ Time Frame: 2 year minimum follow up on study participants ]
3. 1-year overall survival [ Time Frame: 2 year minimum follow up on study participants ]
4. 2-year overall survival [ Time Frame: 2 year minimum follow up on study participants ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Stage III or IV melanoma (AJCC 6th edition) with 5 or less metastatic sites that are not amenable to curative surgical resection, but can be adequately delineated for SART
• All sites of metastatic disease acceptable except brain-only and eye metastases, provided SART can be safely delivered to the site.
• Up to 2 prior systemic treatments for metastatic disease.
• Mucosal or ocular melanoma is allowed.
• Radiotherapy consultation and insurance preapproval for SART prior to enrollment.
• CT or MRI within 28 days of enrollment showing no evidence of brain metastases. Brain metastases allowed if stable by scans for ≥ 28 days following treatment.
• CT, PET/CT or MRI scan of chest, abdomen, pelvis (and soft tissue as indicated); bone scan (as indicated); and photographs of skin lesions (if applicable) within 28 days of enrollment.
• Hematology, liver function and renal function lab tests within required parameters.
• Recovered from all prior surgery and/or adjuvant treatment.
• No active or chronic infection with HIV, Hepatitis B or Hepatitis C.
• ECOG Performance Status 0 or 1.
• Men and women ≥ 18 years old.
• Men/Women of childbearing potential must use adequate contraception.

Exclusion Criteria:

• Untreated or uncontrolled brain metastases.
• Prior treatment with CTLA-4 agent, PD-1 or PD-1 ligand mAb or inhibitor for metastatic disease or as adjuvant therapy (or participation in blinded study).
• History of melanoma-associated retinopathy.
• History of other active malignancy within last 2 years, except adequately treated basal cell carcinoma or squamous cell skin cancer or carcinoma in situ of cervix, unless disease-free for 2 years.
• Autoimmune disease (vitiligo is not a basis for exclusion).
• History of clinically active diverticulitis (diverticulosis is not exclusion criterion per se).
• Serious uncontrolled medical disorder or active infection that would impede treatment.
• Underlying medical or psychiatric condition that would cause administration of ipilimumab to be hazardous, or would obscure interpretation of AEs.
• Any non-oncology vaccine therapy up to 1 month before or after any dose of ipilimumab.
• Concomitant therapy with IL-2, interferon, other non-study immunotherapy, or cytotoxic chemotherapy; immune-suppressive agents within 30 days of registration; other investigational therapies; chronic use of systemic corticosteroids (however, a low stable dose steroid for mild brain edema or adrenal insufficiency is allowed; topical and inhaled standard dose corticosteroids are allowed).
• Dementia or significantly altered mental status that would prohibit understanding or rendering of informed consent and compliance with protocol requirements.
• Pregnant or breastfeeding women.
• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g. infectious) illness.

Contacts and Locations

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Contacts

Contact: Wolfram Samlowski, MD	702-952-1251	wolf.samlowski@usoncology.com
Contact: Khin Win	702-419-5550	khin.win@usoncology.com

Locations

United States, Nevada
Comprehensive Cancer Centers of Nevada	Recruiting
Las Vegas, Nevada, United States, 89148
Contact: Khin Win 702-419-5550 khin.win@usoncology.com

Sponsors and Collaborators

Wolfram Samlowski

Comprehensive Cancer Centers of Nevada

Investigators

Principal Investigator:	Wolfram Samlowski, MD	Comprehensive Cancer Centers of Nevada

More Information

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Responsible Party:	Wolfram Samlowski, Physician, Comprehensive Cancer Centers of Nevada; Member, Developmental Therapeutics and Genitourinary Committee, US Oncology Research; Clinical Professor, University of Nevada, Reno, Comprehensive Cancer Centers of Nevada
ClinicalTrials.gov Identifier:	NCT01565837 History of Changes
Other Study ID Numbers:	BMS CA184-168
First Posted:	March 29, 2012
Last Update Posted:	February 1, 2016
Last Verified:	January 2016

Keywords provided by Wolfram Samlowski, Comprehensive Cancer Centers of Nevada:

Melanoma; Malignant Melanoma; Metastatic; Oligometastatic; Radiosurgery; Radiosurgery, Stereotactic	Stereotactic Radiosurgery; Ipilimumab; Yervoy; MDX-010; Circulating Tumor Cells

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms	Neoplasms, Nerve Tissue; Nevi and Melanomas; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs