Randomized phase II study comparing 4 monthly doses of ipilimumab (MDX-010) as a single agent or in combination with a single dose of docetaxel in patients with hormone-refractory prostate cancer

Abstract

4609 Background: Ipilimumab is a fully human anti-CTLA-4 IgG1 monoclonal antibody that blocks CTLA-4 and augments immune responses. The current study evaluated the safety and activity of ipilimumab alone or with a single dose of docetaxel in hormone-refractory prostate cancer (HRPC). Methods: 43 chemotherapy naïve patients (pts) with HRPC, were treated; 23 were in arm A (ipilimumab at 3 mg/kg q 4 weeks × 4 doses) and 20 in arm B (ipilimumab as in Arm A and one dose of 75 mg/m2 of docetaxel on day 1). Results: Six pts, 3 in each arm, demonstrated a decrease in PSA of > 50%. Three pts, 2 in arm A, and 1 in arm B had confirmed PSA responses with durations of 79+ days, 169+ days, and 280 days, respectively. There were no radiologic responses with these PSA responses. Thirty-six (84%) of the 43 pts experienced 1 or more adverse events considered to be related to treatment with ipilimumab. The most common adverse events included fatigue (44%), pruritus (26%), nausea (19%), rash (12%), constipation (12%), and weight loss (12%). Serious adverse events (SAEs) occurred in 18 patients (42%), who experienced 52 SAEs. The majority (42 out of 52, 81%) were judged by the Investigator to be unrelated or unlikely to be related to treatment with ipilimumab. Five of the 52 SAEs reported in 3 pts were considered to be possible immune breakthrough events (IBEs), associated with drug exposure and consistent with an immune-based mechanism of action. These were adrenal insufficiency (1), diarrhea, colitis, and melena (all in one patient) and colitis (1). One of these pts had a confirmed PSA response. Conclusions: Ipilimumab was well tolerated in this group of pts with HRPC. Three pts overall (6%) experienced an IBE, a phenomenon that has been correlated in other studies with efficacy. There were several confirmed responses as assessed by PSA, one of which was correlated with an IBE. There was no apparent enhancement of activity by coadministration of a single dose of docetaxel. Further studies exploring ipilimumab in prostate cancer are warranted, either as monotherapy at higher doses, or in combination with immune modulators or vaccines. [Table: see text]

Immune checkpoint inhibitors and prostate cancer: a new frontier?

“… 45-48 Conversely, data from a small trial ipilimumab assessing in combination with a single dose of docetaxel versus ipilimumab alone failed to demonstrate a benefit from the addition of chemotherapy. 49 …”

Is there a role for immune checkpoint blockade with ipilimumab in prostate cancer?

“…Results have since been reported for six other clinical studies of ipilimumab in CRPC. Together, these seven trials encompassed 240 patients across multiple settings of advanced CRPC, roughly 20% of whom had progressed on or relapsed after docetaxel (Table 1) [25][26][27][28][29][30][31][32][33][34][35].…”

“…Reflecting the dose-finding nature of many of these trials, the studies utilized multiple doses (ranging from 0.5 to 10 mg/kg as either monotherapy or in combination studies) and schedules (ranging from a single dose of ipilimumab to recurring doses every 3 weeks for four cycles). In the phase 1 and 2 trials in CRPC, ipilimumab was active whether used as monotherapy [25,28] or with other interventions such as radiotherapy [26], docetaxel [27], or other immunotherapeutics with different mechanisms of action [29][30][31][32][33][34][35]. Notably, one study in 43 chemotherapy-eligible patients compared ipilimumab monotherapy (3 mg/kg, every 4 weeks, for four doses) with ipilimumab plus a single 75 mg/m 2 dose of docetaxel on day 1; this small study did not reveal a clear difference in safety or PSA response (around 15%) between the two groups [27].…”

“…Some immediate responses (within 1 month of initiating treatment) were noted, and some late responses (after 6 months of treatment) were also observed [26,27]. In some cases, responses to ipilimumab lasted for 1 year or more [26,27]. Although these phase 2 data require further verification in phase 3 trials, these observed patterns do suggest that an individual's immune response to cancerous cells may be dynamic and, in a select number of patients, durable over the course of disease.…”

Immunotherapeutics in Development for Prostate Cancer

“…Chemotherapy has also been added to CTLA-4 blockade with the theory that it results in the release of dying prostate cancer cells, which release antigen to stimulate an immune response, although there is no confirmation of this presumed mechanism. In a study of 43 chemotherapy-naïve patients with CRPC, all patients received ipilimumab at a dosage of 3 mg/kg every 4 weeks for four doses [37]. Patients on one arm also received a single infusion of docetaxel at a dosage of 75 mg/m 2 on day 1 of therapy.…”