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An attractive area of research regards immune manipulations to recover some of the patient's immune response to his/her tumor, a strategy that has the advantages of being both natural and potentially long-lasting.[1] We propose to combine immunotherapy with radiotherapy directed to a metastatic site, to create a "hub" for in vivo immunization to the tumor, to enable "tumor rejection" at the other metastatic sites. This "in vivo immunization" is explored as a viable alternative to an individualized vaccine approach. Preclinical data generated by us and others support a "proof of principle" clinical trial that may open the field to an alternative use of radiotherapy in a novel partnership with cancer immunotherapy.[2]
Full description
In addition, we propose to perform immune-monitoring of the patients accrued to the trial to generate important information for hypothesis-driven research about the mechanisms behind the clinical findings, to be tested in the laboratory.
An attractive area of research regards immune manipulations to recover some of the patient's immune response to his/her tumor, a strategy that has the advantages of being both natural and potentially long-lasting.[1] We propose to combine immunotherapy with radiotherapy directed to a metastatic site, to create a "hub" for in vivo immunization to the tumor, to enable "tumor rejection" at the other metastatic sites. This "in vivo immunization" is explored as a viable alternative to an individualized vaccine approach. Preclinical data generated by us and others support a "proof of principle" clinical trial that may open the field to an alternative use of radiotherapy in a novel partnership with cancer immunotherapy.[2]
In addition, we propose to perform immune-monitoring of the patients accrued to the trial to generate important information for hypothesis-driven research about the mechanisms behind the clinical findings, to be tested in the laboratory.
The specific aims of the study are:
All patients with metastatic melanoma with at least 2 measurable sites of disease are eligible. Extent of metastatic disease is recorded by CT scanning or MRI before therapy. Patients will then be randomized to Ipilimumab 3 mg/kg IV over 90 minutes alone versus Ipilimumab 3 mg/kg IV over 90 minutes plus radiotherapy to one of their measurable lesions, 6 Gy delivered daily x 5 days (Monday through Friday) (conformally or by IMRT/IGRT, to maximally spare normal tissue), for a total of 30 Gy. For patients assigned to the Ipilimumab/RT arm, Ipilimumab treatment starts after radiotherapy, with a dose given on day 4 from the first radiotherapy fraction. All patients will then have ipilimumab infusions repeated on Days 25, 46 and 67. Patients will be re-imaged (CT imaging or MRI) on Week 12 and evaluated for response (defined as an objective response of another metastatic site outside the radiation field).
The main immunological end-point will be the induction or boosting of treatment induced T cells (CD4+ and CD8+) and B cells for defined antigen approaches. In addition, the magnitude and duration of T- and B-cell responses will be examined. Treatment-induced responses will be calculated as the difference between the pre-treatment measurement and the measurement at the different time points at which blood will be collected (time of evaluation) in the same patient. The percentage of patients with the induction of treatment-induced T- and B-cell responses will be reported.
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Inclusion criteria
Ability to understand and the willingness to sign a written informed consent document;
Histologic diagnosis of locally unresectable, metastatic melanoma.
Any BRAF status is permitted
Any prior therapy is permitted except prior therapy with ipilimumab.
Patients must have at least 2 distinct measurable metastatic sites, with one of at least 1 cm or larger in its largest diameter and may have additional non-measurable but established metastatic lesions (i.e. bone metastases).
Patients must have adequate organ and marrow function as defined by initial laboratory tests:
Performance status ECOG 0-1 or Karnofsky > 50%;
Men and women, ages > 18 year old of age;
Life expectancy > 3 months
Stable brain metastases for at least 4 weeks and not steroid dependent;
Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study.
Exclusion criteria
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Allocation
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10 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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