Description:
The current protocol will examine the use of a plasmid DNA vaccine encoding AR, alone or with
nivolumab, to induce and/or augment therapeutic T-cells following androgen deprivation in
patients with newly diagnosed prostate cancer scheduled to undergo prostatectomy. Patients
without evidence of metastatic disease, with tissue remaining from a pre-treatment biopsy,
and who are being considered for standard treatment by prostatectomy, will be invited to
participate and will be on study for up to 15 months.
Title
- Brief Title: Androgen Deprivation, With or Without pTVG-AR, and With or Without Nivolumab, in Patients With Newly Diagnosed, High-Risk Prostate Cancer
- Official Title: Phase I/II Trial of Androgen Deprivation, With or Without pTVG-AR, and With or Without Nivolumab, in Patients With Newly Diagnosed, High-Risk Prostate Cancer
Clinical Trial IDs
- ORG STUDY ID:
UW21015
- SECONDARY ID:
Protocol Version 6/15/2021
- SECONDARY ID:
2021-0575
- SECONDARY ID:
W81XWH2110270
- SECONDARY ID:
A534260
- SECONDARY ID:
SMPH/MEDICINE/HEM-ONC
- NCT ID:
NCT04989946
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Degarelix | | Degarelix |
pTVG-AR | | Degarelix and pTVG-AR |
Nivolumab | Opdivo | Degarelix and pTVG-AR and Nivolumab |
Purpose
The current protocol will examine the use of a plasmid DNA vaccine encoding AR, alone or with
nivolumab, to induce and/or augment therapeutic T-cells following androgen deprivation in
patients with newly diagnosed prostate cancer scheduled to undergo prostatectomy. Patients
without evidence of metastatic disease, with tissue remaining from a pre-treatment biopsy,
and who are being considered for standard treatment by prostatectomy, will be invited to
participate and will be on study for up to 15 months.
Detailed Description
The current protocol will examine the use of a plasmid DNA vaccine encoding Androgen Receptor
(AR), alone or with nivolumab, to induce and/or augment therapeutic T-cells following
androgen deprivation in participants with newly diagnosed prostate cancer scheduled to
undergo prostatectomy. All participants will receive treatment with degarelix for 8 weeks
prior to prostatectomy. Participants will be also be randomized to receive either no
additional treatment, a DNA vaccine encoding AR, or a DNA vaccine encoding AR and nivolumab.
Participants receiving vaccination will begin that treatment prior to degarelix, based on
preclinical findings that this may be a preferred sequence of treatment. The overall goal is
to determine whether a DNA vaccine can augment the number of prostate tumor-specific
infiltrating CD8+ T cells elicited with androgen deprivation, and whether this might be
further augmented by combination with PD-1 blockade.
Because these cells should have cytolytic effector function, the primary clinical endpoint is
pathological response (pCR and secondarily MRD) at the time of prostatectomy. This endpoint
was chosen based on observations from previous clinical trials evaluating androgen
deprivation therapies alone in this setting.
Safety will also be a primary objective of the current study, as this vaccine and nivolumab
have not been previously used in this early stage population. An additional secondary
clinical endpoint will be 1-year PSA progression-free survival, after completion of all
therapy, and with evidence of testosterone recovery.
Laboratory and correlative endpoints will include whether vaccination, with or without
concurrent PD-1 blockade, elicits greater numbers of CD8+ tumor-infiltrating lymphocytes, and
whether AR-specific prostate tissue-infiltrating CD8+ T cells and persistent systemic
immunity are detectable after treatment with vaccination. Other correlative studies will
evaluate FLT PET/CT as an investigational means of specifically identifying tumor
infiltration by proliferating T cells as an early marker of treatment response, and whether
uptake in other normal tissues is associated with autoimmune toxicity. While this is a
relatively small trial, given a focus on correlative endpoints, a phase 2 expansion design
was chosen to further evaluate the safety and clinical efficacy if pathological responses are
observed in the initial part of the trial. If pathological responses exceeding 20% are
observed, this will be considered significantly different from what has been historically
observed, and would justify proceeding with future larger studies evaluating these
combination approaches in the neoadjuvant stage of prostate cancer.
Primary Objectives:
1. To evaluate the safety of androgen deprivation and pTVG-AR DNA vaccine, alone or in
combination with nivolumab, in patients with newly diagnosed prostate cancer
2. To determine if pathological complete responses or minimal residual disease (MRD) can
occur in patients with prostate cancer treated with androgen deprivation and pTVG-AR,
alone or in combination with nivolumab, prior to definitive surgery
Secondary Clinical Objective:
1. To determine 1-year PSA progression-free survival (post-prostatectomy)
2. To determine whether treatment with androgen deprivation and pTVG-AR DNA vaccine, alone
or in combination with nivolumab, leads to residual cancer burden (RCB) <0.25 cm3 at the
time of prostatectomy
Laboratory / Correlative Objectives:
1. To determine whether treatment with pTVG-AR elicits persistent systemic AR-specific
Th1-biased T-cell responses
2. To determine whether treatment with androgen deprivation and pTVG-AR elicits greater
numbers of prostate tissue-infiltrating CD8+ T cells compared with androgen deprivation
alone, and whether this is augmented with nivolumab
3. To determine if vaccination with pTVG-AR elicits AR-specific tumor-infiltrating CD8+ T
cells
4. To determine whether PD-1 blockade treatment with androgen deprivation and vaccine
increases the frequency of CD8+ T cells with memory and effector function, relative to
exhausted phenotype, compared with androgen deprivation and vaccine alone
5. To determine whether treatment elicits changes detectable by FLT PET imaging
Trial Arms
Name | Type | Description | Interventions |
---|
Degarelix | Active Comparator | Degarelix 240 mg s.c. day 29, 80 mg s.c. day 57 | |
Degarelix and pTVG-AR | Experimental | Degarelix 240 mg s.c. day 29, 80 mg s.c. day 57 pTVG-AR (100 µg) administered intradermally (i.d.) at days 1, 8, 15, 22, 29, 43, 57 and 71 | |
Degarelix and pTVG-AR and Nivolumab | Experimental | Degarelix 240 mg s.c. day 29, 80 mg s.c. day 57 pTVG-AR (100 µg) administered intradermally (i.d.) at days 1, 8, 15, 22, 29, 43, 57 and 71 Nivolumab 240 mg IV administered at days 29, 43, 57 and 71 | - Degarelix
- pTVG-AR
- Nivolumab
|
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed adenocarcinoma of the prostate
- Patients must be considered candidates for prostatectomy as per standard of care
- High-risk patients for recurrent disease, with high risk defined based on one of the
following criteria:
- Gleason score 7 and baseline serum prostate specific antigen (PSA) > 20 ng/mL
- Gleason score > 7
- Life expectancy of at least 12 months at screening
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Adequate hematologic, renal and liver function as evidenced by the following within 4
weeks of day 1:
- Absolute neutrophil count (ANC) > 1000 / mm3
- HgB > 9.0 gm/dL independent of transfusion
- Platelets > 100,000 / mm3
- Creatinine < 2.0 mg/dL
- Aspartate aminotransferase (AST), Alanine transaminase (ALT) < 2.5 x
institutional upper limit of normal (ULN)
- Total bilirubin < 2x institutional ULN (NOTE: in subjects with Gilbert's
syndrome, if total bilirubin is >2x ULN, measure direct and indirect bilirubin
and if direct bilirubin is within normal range, subject may be eligible)
- No known history of HIV 1 and 2, HTLV-1, or active Hepatitis B or Hepatitis C
- Must have adequate tissue (ten 5µm unstained formalin-fixed paraffin-embedded (FFPE)
sections containing prostate cancer) remaining from pre-treatment diagnostic prostate
biopsy for research purposes
- Patients must be willing to undergo large-volume blood draws (up to 200mL per time
point) for the investigational component of this trial
- For those patients who are sexually active, they must be willing to use barrier
contraceptive methods during the period of treatment on this trial
- Patients must be informed of the experimental nature of the study and its potential
risks, and must sign an IRB-approved written informed consent form indicating such an
- Ability to comply with all study procedures and willingness to remain supine for 120
minutes during imaging
Exclusion Criteria:
- Small cell or other variant (non-adenocarcinoma) prostate cancer histology
- Prior treatment for prostate cancer, including androgen deprivation therapy (ADT),
orchiectomy, antiandrogens, ketoconazole, abiraterone acetate or enzalutamide
- Prior radiation to the prostate
- Patients may not be receiving other investigational agents or be receiving concurrent
anticancer therapy other than the treatment-prescribed androgen deprivation therapy
- Treatment with any of the following medications while on study is prohibited, washout
period not required except as indicated:
- Systemic corticosteroids (at doses over the equivalent of 10 mg prednisone daily)
- not permitted within 3 months of registration; inhaled, intranasal or topical
corticosteroids are acceptable
- PC-SPES
- Herbal supplements that have been shown to modulate testosterone or androgen
signaling (e.g. Saw Palmetto) are not allowed while on study
- Megestrol
- Ketoconazole
- 5-α-reductase inhibitors - patients already taking 5-α-reductase inhibitors prior
to 28 days prior to registration may stay on these agents throughout the course
of therapy, but these should not be started while patients are on study
- Diethylstilbesterol
- Any other non-study hormonal agent or supplement being used with the intent of
cancer treatment
- Major surgery within 4 weeks of registration is prohibited
- Active cardiac disease defined as active angina, symptomatic congestive heart failure,
or myocardial infarction within 6 months of registration
- Patients with known psychological or sociological conditions, addictive disorders or
family problems, which would preclude compliance with the protocol
- Patients with a history of life-threatening autoimmune disease
- Patients who have undergone splenectomy
- Patients must not have other active malignancies other than non-melanoma skin cancers
or carcinoma in situ of the bladder. Subjects with a history of other cancers who have
been adequately treated and have been recurrence-free for > 3 years are eligible.
- Any other medical intervention or condition, which, in the opinion of the principle
investigator (PI) or treating physician, could compromise patient safety or adherence
with the study requirements (including leukapheresis or biopsy procedures) over the
primary 3-6 month treatment period.
- Patients cannot have concurrent enrollment on other phase I, II, or III
investigational treatment studies
- Patients who have received a live vaccine within 14 days prior to the first dose of
study treatment. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever,
rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza
vaccines for injection are generally killed virus vaccines and are allowed; however,
intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not
allowed
- Patients with active autoimmune disease that has required systemic treatment in the
past 2 years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment
- Patients with a history of non-infectious pneumonitis that required corticosteroid
treatment, or has current pneumonitis
- Patients with a history of allergic reactions to the tetanus vaccine
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | Male |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Pathological Complete Response Rate (pCR) |
Time Frame: | at prostatectomy (up to 3 months) |
Safety Issue: | |
Description: | The pathological complete response will be estimated for each arm and reported along with the corresponding 95% confidence interval which will be constructed using the Wilson score method. Formal comparisons between arms will be conducted using Fisher's exact test. Participants in this study with unknown pathological response will be treated as non-responders in the primary analysis. |
Secondary Outcome Measures
Measure: | Progression-Free Survival (PSA) at 1-year |
Time Frame: | up to 15 months on study (1 year after prostatectomy) |
Safety Issue: | |
Description: | Defined as a serum PSA <0.2 ng/mL at 1 year after prostatectomy, in patients with non-castrate (>25 ng/dL) testosterone levels. |
Measure: | Residual Cancer Burden (RCB) |
Time Frame: | at prostatectomy (up to 3 months) |
Safety Issue: | |
Description: | RCB will be determined using three-dimensional volume estimation based on the largest cross-sectional tumor dimension and number of cross-sections involved by tumor, corrected for tumor cellularity. The amount of RCB will be summarized for each arm in terms of medians and ranges. Comparisons between arms will be conducted using a nonparametric Wilcoxon rank sum test. Linear regression analysis will be conducted to evaluate whether AR-specific immune response is associated with RCB. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | University of Wisconsin, Madison |
Last Updated
August 17, 2021