Phase II Randomized Trial of Ipilimumab Versus Ipilimumab and Radiotherapy in Metastatic Melanoma
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. 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. 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:
1. To explore the induction of immunity-mediated tumor response outside the radiation
field (abscopal effect) after radiation/Ipilimumab in metastatic melanoma, by
estimating and comparing response rates in patients treated with Ipilimumab alone (Arm
A) versus ipilimumab and radiation (Arm B).
2. To compare the induction of a T-cell response in patients with metastatic melanoma
treated with either ipilimumab alone or in combination with radiation.
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.
Allocation: Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To estimate response rates of ipilimumab alone and of ipilimumab with radiation therapy and to estimate the difference between response rates with ipilimumab alone and ipilimumab with radiation therapy
Eligible patients have metastatic melanoma with at least 2 measurable sites of disease. All patients with metastatic melanoma are eligible to be randomly assigned to Ipilimumab 3mg/kg IV over 90 minutes versus Ipilimumab 3 mg/kg IV over 90 minutes and radiotherapy to one of their measurable lesions, 6 Gy X5 (conformally or by IMRT/IGRT, to maximally spare normal tissue). For patients assigned to the Ipi/RT arm, Ipilimumab treatment starts after radiotherapy, with a dose given on day 4 from the first radiotherapy fraction and repeated on Days 25, 46 and 67. Patients will be re-imaged on Week 12 and evaluated for response (defined as an objective response of another metastatic site outside the radiation field). This response will be evaluated assessing clinical and CT responses in the non-irradiated measurable metastatic sites.
Silvia C. Formenti, M.D.
NYULMC Department Radiation Oncology
United States: Institutional Review Board
|NYU Clinical Cancer Center||New York, New York 10016|