PROSTVAC® abstracts
A randomized phase II study of flutamide with or without
PSA-TRICOM in nonmetastatic castration-resistant prostate cancer
(CRPC).
Background: PSA-TRICOM is a vector-based, therapeutic cancer
vaccine regimen consisting of recombinant poxviruses containing the
transgenes for prostate-specific antigen (PSA) and 3 T-cell
co-stimulatory molecules (TRICOM). A previous randomized,
placebo-controlled phase II study demonstrated an 8.5-month
improvement in median survival (25.1 months for PSA-TRICOM group
vs. 16.6 months for control group) in men with metastatic CRPC.
Methods: This study is currently enrolling patients with
non-metastatic CRPC on testosterone suppression therapy who have a
rising PSA. Patients are stratified by PSA doubling time and
randomized to androgen receptor antagonist alone (flutamide) or
flutamide plus PSA-TRICOM. Flutamide is given at the standard dose
of 400 mg TID while PSA-TRICOM is given by monthly subcutaneous
injections. The primary endpoint of the study is time to treatment
failure (TTF) which is defined as biochemical recurrence (PSA rise)
or development of metastatic lesions on scans. Results: The first
26 patients enrolled are evaluated in this analysis. For flutamide
alone (n = 13), the median age at enrollment was 64.7 years and
median Gleason Score was 8. For flutamide + PSA-TRICOM (n = 13),
the median age at enrollment was 67.1 years and median Gleason
score was 8. Median time to progression is 223 days for Fluatmide +
PSA- TRICOM (range 70-638) vs. 85 days for Flutamide alone
(56-372). Progression for 11/12 flutamide alone patients and 9/10
fluatmide + PSA-TRICOM patients has been by PSA rise only.
Conclusions: Preliminary evidence suggests improvement in time to
treatment failure using combination of hormonal therapy with
flutamide + PSA-TRICOM vaccine compared to fluatmide alone in
patients with non-metastatic CRPC. This trial will continue to
accrue a total of 62 patients and also will evaluate immunological
responses.
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Overall survival (OS) analysis of a phase l trial of a
vector-based vaccine (PSA-TRICOM) and ipilimumab (Ipi) in the
treatment of metastatic castration-resistant prostate cancer
(mCRPC).
Background: Therapeutic cancer vaccines have demonstrated great
promise in the treatment of mCRPC. PSA-TRICOM is a vector-based
vaccine that targets PSA and includes the transgenes for 3 human
costimulatory molecules (ICAM-I, LFA-3, and B7.1) to enhance T-cell
activation. A multicenter, randomized phase II trial demonstrated a
significant OS advantage versus placebo in mCRPC. A smaller NCI
phase II study demonstrated an association of OS with PSA-specific
immune response (IR). CTLA-4 is a molecule expressed by activated
T-cells and signaling through this turns off the IR. Preclinical
models demonstrate that a blockade of CTLA-4 can enhance T-cell
mediated IR to vaccine. Ipi is a monoclonal antibody that blocks
the moderating effects CTLA-4. Methods: Patients (pts) with mCRPC
were treated in this phase I, dose- escalation study. All pts
received PSA-TRICOM on days 1, 15, 29 and then monthly. Ipi was
administered at 1, 3, 5, or 10 mg/kg in sequential dose levels (DL)
monthly. After 6 months (mos), pts could receive maintenance Ipi
every 3 mos. Predicted OS was determined for each pt. Although the
first 6 pts enrolled received prior chemotherapy, the remainder of
pts enrolled were chemotherapy naive (CN). Results: The study has
fully accrued 30 pts. Median on-study age was 69 years (range:
49-81); median PSA was 49 mcg/L (3-729), median Gleason score was 8
(4-10), and median PSA doubling time was 2.3 mos. The median time
to radiographic progression for CN pts was 5.9 mos. The median
Halabi predicted OS for all pts was 18.5 mos. The median OS for all
pts was 31.8 mos with a 74% survival probability at 24 mos. The
median OS for CN pts is 30.9 months. There was no significant
difference in OS based on DL. 4 of 6 evaluable pts at the higher
DLs had a greater than 2-fold increase in antigen-specific T-cell
responses. Conclusions: Two phase II trials in CN mCRPC treated 114
pts with this same vaccine demonstrating an OS of ~26 mos. These
data suggest that the addition of immune checkpoint inhibition may
augment the clinical benefit of vaccines. Additional, randomized
trials are required to further investigate immune checkpoint
inhibition and vaccine in mCRPC
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A retrospective analysis of intramural NCI prostate
cancer trials: Progress made and insights gleaned.
Background: In solid tumors such as prostate cancer, novel
paradigms are needed to assess therapeutic efficacy. We describe a
method for estimating PSA growth and regression rate constants from
serial PSA measurements. We assessed the method's potential in
patients with metastatic castration resistant prostate cancer
(CRPC). Methods: Patients with CRPC enrolled in five phase II
studies conducted over more than a decade were evaluated. The
studies represent the evolution of CRPC therapy, and include a
vaccine trial. PSA measurements obtained prior to, and during,
therapy were used. Data analysis using a two-phase mathematical
equation yielded concomitant PSA growth and regression rate
constants Results: Incremental reductions in growth rate constants
were recorded in successive chemotherapy trials enrolling similar
patients. Growth rate constants correlated with survival, except in
patients receiving a vaccine-based therapy where the evidence
demonstrates prolonged survival presumably due to immunity
developing subsequent to vaccine administration. In combination
chemotherapy trials the analysis suggests prolonging drug exposure
could have increased survival Conclusions: Incremental reductions
in tumor growth rate constants suggest increased efficacy in
successive trials. Because the derived growth rate constant
correlates with survival, it may be useful in clinical trials to
assess differences in efficacy. The PSA-TRICOM vaccine appears to
have provided marked benefit not apparent during vaccination, but
consistent with development of a growth-retarding immune response.
If validated as a surrogate for survival the growth rate constant
would offer an important new efficacy endpoint for clinical trials.
Finally, pursuit of what appear to be very promising results with a
PSA-TRICOM vaccine is warranted.
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