Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05806385 |
| Other study ID # |
L21-076 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
January 2024 |
| Est. completion date |
June 2027 |
Study information
| Verified date |
October 2023 |
| Source |
Texas Tech University Health Sciences Center |
| Contact |
Rakhshanda Layeequr Rahman, MD |
| Phone |
806-743-2289 |
| Email |
rakhshanda.rahman[@]ttuhsc.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Summary Points:
1. High Risk Breast Cancers: Triple negative cancer is considered high risk due to high
rate of local and systemic failure. Newer innovative treatment strategies are needed to
improve systemic control of disease and survival.
2. Immune system modulation: is an emerging modality in cancer treatment. Tumor antigens
can stimulate T cells to identify and destroy cancer cells. Cancers express "altered
self" antigens that tend to induce weaker responses than the "foreign" antigens
expressed by infectious agents. Thus, immune stimulants and adjuvant approaches have
been explored widely. Opportunities to develop effective cancer vaccines may benefit
from seminal recent advances in understanding how immunosuppressive barricades are
erected by tumors to mediate immune escape. This concept is precisely applicable to
triple negative breast cancer due to their antigenicity. Checkpoint inhibitors are an
attractive method for treatment of high-risk breast cancers. However, to leverage the
efficacy of checkpoint inhibition, approaches are needed to enhance delivery of cancer
antigens to the T cells.
3. Cryoablation: offers an efficacious and safe method to enhance tumor antigen
presentation to the immune cells while destroying the primary tumor. This ablation
method is superior by virtue of antigen preservation in situ despite toxicity to the
tumor cell. Impact of cryoablation in enhancing immunological responses in tumor
microenvironment are well established; however, cryoablation can also cause tumor
antigen tolerance via non-specific stimulation of T cells.
4. Rationale for combining cryoablation and checkpoint inhibitors: Since checkpoint
inhibitors curtail the tolerance developed by tumor antigens, and cryoablation enhances
antigen presentation and T cell recruitment, it is intuitive that combination of these
two approaches presents an ideal opportunity to leverage the benefits of both approaches
while curtailing the limitations of either. Therefore, the investigators hypothesize in
this study that their combination will improve the response rate and the degree of
response.
Description:
AIMS:
The main goal of proposed study is to assess synergy of tumor cryoablation and immune
checkpoint inhibitor in high-risk breast cancer in humans. This will be achieved by comparing
cryoablation alone and cryoablation in combination with pembrolizumab - a [checkpoint
inhibitor (anti PD-1/PD-L1 antibody) currently FDA approved as cancer therapy] with the
current standard of care including surgical resection. The current standard of neoadjuvant/
adjuvant therapies will remain unchanged for ethical reasons of providing best-known standard
of care to all patients.
OBJECTIVES:
The investigators propose a prospective randomized exploratory trial where patients with
clinical stage I/II, triple negative invasive breast cancer will be randomized to one of the
three arms of the study:
1. Standard of care - neoadjuvant therapy followed by surgical resection followed by
appropriate adjuvant therapy as needed.
2. Cryoablation arm - cryoablation followed by appropriate neoadjuvant therapy followed by
surgical resection followed by appropriate adjuvant therapy as needed.
3. Cryoablation with Pembrolizumab - Single dose of Pembrolizumab of 200 mg before (within
24-48 hours) of cryoablation followed by appropriate neoadjuvant therapy followed by
surgical resection followed by appropriate adjuvant therapy as needed.
Outcome measures will include blood and tumor analysis of immune response with flow
cytometry and cytokine analysis at baseline, after intervention, and before surgery.
Tissue from core biopsy at baseline, repeat biopsy before chemotherapy and tumor
resection will also be analyzed for tumor microenvironment.
INTRODUCTION / BACKGROUND / SIGNIFICANCE:
High Risk Breast Cancer and Need for Newer Treatment Approaches: Triple- negative breast
cancer, which represent 15-20% of all breast cancer diagnoses are considered high-risk.
While surgical resection remains the mainstay of treatment, therapeutic backbone
includes neoadjuvant and adjuvant chemotherapy. For patients who continue to have
significant residual disease even after surgical resection and completion of
chemotherapy, further aggressive systemic therapies such as capecitabine are performed.
Triple-negative subtype is associated with the highest number of mutations across the
genome and non-metastatic disease is associated with 17-20% local failure and 35- 40%
distant failure at 5-10 years of follow up. These data suggest that micrometastatic
hematogenous spread happens in a substantial number of patients with operable high-risk
breast cancer and newer approaches are required that potentiate local control while
simultaneously controlling the systemic spread of disease.
Scope of Immune-modulation: Cancer immunotherapy has experienced extraordinary success
in recent decades. Antigens that can evoke anti-tumor immune responses form a suitable
immunotherapeutic target. The approach of T cell checkpoint blockade therapies has shown
remarkable clinical responses in several types of solid cancers such as, melanoma,
non-small cell lung cancer, bladder cancer and mismatch repair- deficient cancers. An
effective anti-tumor immune response is thought to be initiated by the taking up of
tumor antigens by antigen- presenting cells (APCs), which is turn present them, and
provide co-stimulatory signals to both CD4+ and CD8+ T cells. APCs, particularly
dendritic cells, process antigens through an exogenous antigen processing pathway where
tumor cell material is phagocytosed and converted into HLA class I and class II binding
peptides that are presented to CD8+ (cross-presentation) and CD4+ T cells, respectively.
Utilizing this knowledge, recent phase 1 trials have reported enhanced response to
immune checkpoint inhibitor therapy in combination with conventional chemotherapy in
triple-negative breast cancers. Certainly, percentage of tumor infiltrating lymphocytes
(TILs) has been identified as an important immunologic parameter, particularly for
high-risk breast cancers, that correlates with response to systemic therapy, suggesting
a strong role of host immune response in cancer control irrespective of therapeutic
intervention.
Limitation of Immune-modulation - T cells are key players in anti-tumor immunity and
therefore form the major target for immunotherapeutic research. The current breakthrough
in cancer immunotherapy results from the identification and targeting of checkpoint
mechanism involving CTLA-4, PD-1, and PD-L1. CTLA-4 and PD-1 are co-inhibitory receptors
found on the surface of T cells. Upon binding to their corresponding ligands (CD 80/86
and PD-L1/L2, respectively), T cells become anergic - a physiologic mechanism of
tolerance. In the context of tumor microenvironment, the aberrant expression along with
chronic exposure to tumor antigens can lead to undesirable suppression of T cell
immunity.
Recently developed checkpoint blockers, such as PD-1/ PD-L1 inhibitor, pembrolizumab,
has provide a new weapon against cancer with durable clinical responses and long-term
remissions. However, checkpoint blockade has been shown to be most effective in tumors
with high mutation burden, in line with the notion that T cell recognition of
neo-antigens plays a major role in checkpoint blockade. Many studies show that when the
tumor-reactive T cell infiltrate is absent or low (low percentage of TILs), the
substrate for checkpoint blockade is lacking. Additionally, majority of patients with so
called hyper-mutated tumors do not respond to checkpoint blockade due to immune-editing,
which compromises the T cells' ability to fulfill their cytotoxic activity of adequate
tumor infiltration and recognition of tumor-antigen-loaded HLA class I molecules.
Therefore enhancing antigen presentation within the tumor is essential for checkpoint
blockade to be effective.
Role of Ablative Therapies - Particularly Cryoablation: Thermal ablation with
cryotherapy, laser, radiofrequency, microwave, and focused ultrasound present a unique
opportunity to address both, the primary tumor and the micrometastatic disease. The
effects of tumor ablation are multifold: (1) the destruction of tumor mass, lowering
tumor burden and (2) the release of tumor antigens, making them available for uptake by
antigen presenting cells (APCs) and the treatment itself leads to (3) the release of
damage associated molecular patterns (DAMPs) and (4) the induction of a physiological
wound healing response. Ablation leads to creation of an in situ antigen depot
containing all types of tumor protein, which leads to initiation of systemic anti-tumor
immune response that can potentially eliminate occult metastatic disease. Ablation of
tumors at temperatures above 65 °C leads to denaturation of proteins. This can affect
immune responses in opposing ways as high temperatures denature immune activating
signals, such as danger signals like heat shock proteins (HSPs). Therefore cryoablation
is the most promising ablative technique, as it offers minimal invasiveness, less damage
to surrounding tissues, and better preservation of tumor antigens, and most robust data
on immune stimulation.
Immune Stimulation Effected by Cryoablation - Deep freezing and thawing during
cryoablation induces necrosis and the up-regulation of DAMP molecules that render tumor
cells more susceptible to APCs and tumor specific T-cell-mediated killing. Cryoablation
upregulates DAMPs, such as HMG1, calreticulin, S100A8/A9 and HSP70, which stimulate the
immune system through Receptor for Advanced Glycosylation End-products (RAGE) and
toll-like receptors and enhance antigen presentation. Additionally, the central zone
cytokine milieu resulting from cryoablation is typically a Th1 cytokine profile of IL-2,
INF-γ, TNF-α, and IL-12. These cytokines and DAMPs presumably drive the cytotoxic CD8+
T-cell response. Preclinical evidence supporting immune response of cryoablation:
Several preclinical studies on cryoimmunology explored whether freezing the tumor and
leaving it in situ would render the animal resistant to a re-challenge. Animal models
utilizing carcinoma and sarcoma cell lines in rabbits and mice demonstrated tumor-
specific resistance to re-challenge. Re-challenge with same tumor cell lines showed
resistance to growth in animals after cryoablation compared to surgical resection.
Similar experience was reported by Blackwood and Cooper with models involving rats
inoculated with myosarcoma and carcinosarcoma cell lines. Rats with cryoablated tumors
were more likely to resist re-challenge, and demonstrated regression of secondary tumors
compared to surgically treated rats. Bagley compared cryoablation with surgery in using
MCA-10 fibrosarcoma in C57BL/6 mice, harvesting splenic lymphocytes at weekly intervals
after treatment for cytotoxicity assays. Mice undergoing cryoablation had significantly
higher cytotoxicity than surgically treated or untreated mice. Sabel studied MT-901
mammary adenocarcinoma tumors in BALB/c mice treated with cryoablation or surgical
resection. After re-challenge, 86% of mice treated with surgery developed second tumors
compared with 16% of mice treated with cryoablation. This was tumor- specific, as the
cryoablation offered no protection against challenge with other cell lines. More
recently, Kim utilizing renal cell carcinoma cell lines in BALB/c mice reported similar
results. More recently, abscopal effect of tumor regression in untreated tumors in
animal models where only one of the implanted tumors was cryoablated, has been reported
as a result of systemic immune response.
Clinical evidence supporting immune response of cryoablation: Although clinical use of
cryoablation for cancer has recently expanded, there are relatively few studies
examining the immunological impact in humans. Ravindranath measured the level of serum
tumor gangliosides and their antibody titers in patients receiving cryoablation,
radiofrequency ablation or resection of liver metastasis from colorectal cancer. Serum
ganglioside levels were significantly higher in cryoablated patients compared to
radiofrequency or surgery. Cryoablated patients also demonstrated higher titers of IgM
against tumor gangliosides. Si studied 20 patients with prostate cancer undergoing
cryoablation of primary tumor and reported an increase in in cytolytic activity against
LNCaP, and an increase in number of IFN-ɣ producing T cells. Thakur conducted a pilot
study of cryoablation and GM-SCF for patients with renal cell carcinoma metastatic to
lung. GM-CSF was infiltrated near a lung metastatic lesion selected for cryoablation.
Additional GM-CSF therapy was used post-procedure. The combination of GM-CSF and
cryoablation produced an enhanced immune response in terms of cytotoxicity and serum
antibodies.
Limitation of Cryoablation: Despite the data reviewed above, immune response to
cryoablation has not been uniform. Some preclinical studies on osteogenic sarcoma, and
prostate cancer models, failed to show any increase in immune function after
cryoablation. More importantly, several studies have reported immune suppression with
cryosurgery. The majority of these studies involved fibrosarcoma cell lines in rats and
showed decreased resistance to re-challenge after cryoablation, as well increased growth
of metastatic tumors and secondary tumors. From a breast cancer perspective, Sabel
reported that a high freeze rate resulted in increased tumor-specific T-cells in the
tumor draining lymph nodes, reduction in lung metastasis and improved survival compared
to low freeze rates which also had more Tregs (CD3,CD4,CD127-,CD25+). Therefore, the
magnitude of systemic effect induced by cryotherapy alone has proven to be either
insufficient or counter-productive. Current understanding is that close to the ablative
source, direct injury and cell death with necrosis releases tumor antigens and (DAMPs)
which recruit and activate dendritic cells that in turn stimulate proliferation of T
cells and immune components. Transition zone away from the ablative source causes
indirect cellular injury and apoptotic cell death without release of DAMPs, which causes
release of suppressive cytokines and T-cell clonal deletion and anergy. Intuitively,
cryoablation stimulates an immune response but the ultimate clinical impact is dictated
by the ratio of CD4+ T-effector cells to T-regulatory cells. Higher T-effector to
T-regulatory cell ratio promotes the more favorable CD8 cytotoxic T cell response. While
CD8+ cytotoxic cells eliminate the primary tumor and systemic micrometastasis, it is
important that anergy is kept in check and both effector (CD45RO+, CCR7-) and central
(CCR7+, CD45RO+) memory T-cells are established for long-term protective anti- tumor
immunity.
HYPOTHESIS:
"Combination of cryoablation with Pembrolizumab for local control in high-risk triple
negative breast cancer is superior to surgical resection alone or cryoablation alone in
generating antitumor immune response".
METHODS:
Site of Study:
Proposed exploratory work is a randomized trial that will be conducted at Texas Tech
University Health Sciences Center-Breast Center of Excellence, UMC Cancer Center.
Type of study:
Prospective Randomized Trial - hypothesis driven
Experimental Design:
The investigators propose a single blinded prospective randomized trial, where women
with Stage I/II triple negative breast cancer will be enrolled in one of the three arms
in 1:1:1 randomized fashion: (I) Control arm with neoadjuvant chemotherapy followed by
lumpectomy/mastectomy with sentinel node biopsy +/- axillary dissection; (II)
Intervention with cryoablation alone followed by neoadjuvant chemotherapy followed by
lumpectomy/mastectomy with sentinel node biopsy +/- axillary dissection; (III)
Intervention with cryoablation + Pembrolizumab followed by neoadjuvant chemotherapy
followed by lumpectomy/mastectomy with sentinel node biopsy +/- axillary dissection. The
treatment schedule is designed to optimize antigen exposure time. The trial will be
registered at the National Clinical Trials Network once IRB approval is obtained.
Subjects:
All patients 18 and older with clinical stage I/II triple negative disease will be
offered to participate. These patients will be screened during an oncology/surgery
appointment by the study team. A computerized randomization list will be used for
treatment arm assignment using the website:
https://www.sealedenvelope.com/simple-randomiser/v1/lists
Inclusion Criteria:
- Females
- Stage I/II Cancer
- Age range 18 - 90 years
- Diagnoses: Invasive carcinoma, ER -, PR-, HER2- (triple negative)
- Radiology findings: Unifocal disease visible on ultrasound
Exclusion Criteria:
- Additional primary cancer
- Inflammatory breast cancer
- History of autoimmune disease
- History of chronic immunosuppression
- Prior immunotherapy
- Recent vaccination (within 4 wks.)
- Prior radiation therapy
- Prior investigational agent therapy within last 1 year
- Pregnancy at the time of diagnosis and/ or treatment
- Breast feeding
Study visits:
Informed consent will be obtained then the patient will be randomized. All visit will
coincide with standard of care visits. Next, the following will occur:
Visit 1: Day 1:
Baseline Blood draw; up to 20ml will be collected in EDTA tubes; the blood will be
centrifuged at TTUHSC. Plasma will be used for cytokine analysis and phenotyping at TTU
lab. One EDTA tube will be sent to University of Houston (throughout the study
time-points). Following outcomes will be measured:
Cytokine analysis
- RNA seq PBMC analysis Baseline core biopsy tissue (already available from
diagnostic workup) will be evaluated for: (2 unstained slides will be prepared for
RNA seq from fixed tissue)
- TIL %
- RNA Seq tumor tissue
Visit 2 (Group II & III Only) After Cryoablation: Day 3 (+/- 7 days):
Post-ablation blood draw (Group II & III)- up to 10ml of blood in EDTA tube(s):
• Cytokine analysis
Visit 3 (All groups) Pre Neoadjuvant Chemotherapy: Day 21 (+/- 14 days):
Blood draw at the time of port insertion for chemotherapy- up to 20ml of blood in EDTA
tubes:
- Immune phenotyping by flow cytometry
- Cytokine analysis
- RNA seq PBMC analysis
- Tumor biopsy will be repeated for TIL and RNA seq analysis
Visit 4 (All groups): Post Chemotherapy Resection (approximately 6 months after original
biopsy):
Preoperative blood draw- up to 20ml blood in EDTA tubes (similar to baseline):
- Immune phenotyping by flow cytometry
- Cytokine analysis
- RNA seq PBMC analysis Surgical specimen tissue analysis (2 unstained slides from
fixed tissues will be prepared for RNA seq)
- TIL%
- RNA seq tumor tissue
Sample Size:
Tumor-infiltrating lymphocytes (TILs), particularly in the stroma of triple negative
breast cancer are prognostic and predictive of response to therapy. Therefore,
recommendations by the International TILs Working Group were used to calculate the
sample size for this project. The percentage change of TILs is assumed to be 10% for the
control arm and 50% for the treatment arm. A sample of 10 patients per group can achieve
80% power to detect a mean difference of 0.4 (0.5 vs. 0.1) with a standard deviation of
0.3, using a two-sided two-sample equal variance t-test (alpha=0.05). Assuming 30% drop
out rate, a total of 12 patients in each arm would suffice for a total of 36 patients;
this would achieve a 90% power. This means that a minimum of 10 patients per arm and a
maximum of 12 patients per arm will lead to a statistically meaningful study.
Statistical Plan:
Descriptive statistics will be used to compute the ranges, means, and variances for the
independent variables standard care, cryo, cryo+pembro. This will suggest that the
concentration of the observations around the mean, and variation of the observations
from the means. The normality test will be considered to check whether or not data
follow normal distribution. Normal quantile-quantile plots (also called q-q plots) will
be utilized to determine if data sets come from a normal population. To detect the
outliers (if there is any) several statistical measures will be taken into
consideration. To check the homogeneity of variances for the independent variables
standard care, cryo, cryo+pembro, Levene's test will be performed by setting up null and
alternative hypotheses. To compare the significance difference among the means of the
variables, a one-way analysis of variance (ANOVA) will be performed. The null and
alternative hypotheses for the means will be introduced. In ANOVA, statistical
significance of the means will be tested (α = 0.05) by using the F-test statistic. If
the means are found statistical significant difference then the post-hoc multiple
comparisons tests will be performed. Post-hoc multiple comparisons tests (LSD,
Bonferroni, Scheffe, Tukey, etc.) will be utilized to detect the appropriate significant
group means. If the samples do not meet the normality assumptions then several
non-parametric tests will be considered for the statistical analyses.
Tumor Cryoablation:
All registered patients will be randomized to one of the three arms of the study.
Patients in arm II and III will receive cryoablation according to the following protocol
(similar to the protocol used in ACOSOG Z1072 trial).
Cryoablation Device: Cryoablation will be performed using the commercially available
ProSense Cryosurgical System (IceCure Medical Ltd, Caesarea, Israel) consisting of a
console, cryoprobe and associated liquid nitrogen (cryogen) Case Dewars. The console is
a self-contained unit that features an interface for controlling and monitoring the
cryoablation procedure. It operates with standard 120 VAC (60Hz) power.
Device Operation: The ProSense Cryosurgical System uses a closed system to circulate
liquid nitrogen within the cryoprobe tip creating sub-freezing temperatures that result
in ablation of target tissue. The lesion is identified with ultrasound and the cryoprobe
is placed in the center of the lesion under ultrasound guidance after adequate local
anesthesia, and ablation is carried out according to predetermined freeze-thaw-freeze
algorithm. The probe is then warmed by an internal electrical resistance heater and
removed from the patient. Cryoablation Procedure: Tumor is identified using
high-resolution linear array ultrasound probe in two orthogonal views. Longest dimension
of the tumor is identified for parallel insertion of the probe. This dimension is
entered into the console; the console provides the length of cryoprobe tip to be past
the lesion upon insertion. After insertion, the probe position is confirmed in two
orthogonal views. Cryoablation is done using the freeze-thaw-freeze cycle according to
the tumor size. Entire procedure is monitored under vision and saline is infiltrated to
avoid skin frostbite by hydro- dissecting the skin away from the ice-ball. Size of
ice-ball is recorded in orthogonal dimensions. In our protocol, if a patient has more
than one lesions, only one lesion will be ablated; however biopsies from other lesions
will be studied for abscopal affect.
Infusion of Pembrolizumab and Dosing:
As an initial step, the investigators confirmed the safety and tolerability of immune
checkpoint inhibitors with tumor cryoablation in women with newly diagnosed breast
cancer. One important consideration was selection of an immune modulating antibody.
Pembrolizumab, an FDA-approved antibody against PD-1/PD-L1, has a well-established
safety profile, and induces long-term remissions lasting >10 years in 10-20% of advanced
melanoma patients. Furthermore, because T cells acutely upregulate expression of
PD-1/PD-L1 after being exposed to antigens, which in turn may blunt the cytotoxic
response, pembrolizumab is ideally suited for immune modulation in combination with
cryoablation. Memorial Sloan Kettering Cancer Center (MSKCC) published a pilot study on
this combination; no serious side effects attributable to ipilimumab were reported; no
surgery was delayed. MSKCC used 10 mg/Kg as a single dose; however, since the studies
report higher adverse events at that dose, the investigator propose the recommended 200
mg for IV over 90 minutes dose before cryoablation, which is the currently utilized dose
in clinical setting for triple negative cancers.
Methodology for Outcome Measures:
The investigators will observe and monitor the immune response(s) following the
cryoablation procedures with and without the pembrolizumab. Blood samples will be
collected in EDTA-blood collection tubes and then aliquoted for T-cell phenotypic
analysis, and plasma collection for cytokine/chemokine, and for RNA seq analysis, at the
indicated time points. Pathology slides will be made for research from core biopsy
samples at baseline and from lumpectomy and sentinel nodes at the time of surgery. Five
slides will be made per specimen (after completion of routine pathology) for H&E and
immunohistochemistry for immune cell infiltrates to calculate TILs percentage. All
collaborators/Key personnel involved in performing the outcome measure analysis will be
blinded to the randomization groups.
Following are the details for outcome analysis:
TIL Calculation: All tissue specimens that undergo routine pathology reporting will be
evaluated for TIL reporting according to guidelines put forth by the International TILs
Working Group. Change in TIL score between original core biopsy tissue and surgical
tissue will be the focus of analysis to assess the impact of proposed interventions.
Measurement of T-cell Changes in Blood: T-cell subtypes can be defined by differential
expression of cell surface markers. The investigators will monitor T-cells for
activation, increased CD8+ effector T-cells and development of effector and central
memory. For T-cell phenotyping, whole blood staining (100 µl/stain) will be performed
with antibodies to CD3, CD4, CD8, CD25, CD27, CD45RO, CD127, CD137, ICOS, CCR7 and Ki67
with appropriate isotype controls. Following RBC lysis, the stained mononuclear cells
will be run on an Attune NxT 14-color flow cytometer (Thermofisher, Waltham, MA) and
analyzed using FlowJo software (Becton, Dickinson and Company). T-cells (CD3+, CD4+ or
CD8+) will be analyzed for changes in naïve (CD27+, CCR7+, CD45RO-), effector (CCR7-,
CD45RO-), effector memory (CD27-, CCR7-,CD45RO+) and central memory (CD27+, CCR7+,
CD45RO+) phenotypic markers as well as for activation (ICOS and CD137) and proliferation
(Ki67). The investigators will further analyze for percentages of T-regulatory cells
(CD25+, CD127-). The investigators will use this data to determine a T-cell immune
signature to correlate the effectiveness of the cryoabalation+/- Pembrolizumab to
predict the long-term anti-tumor immunity.
Plasma Cytokine/Chemokine Analysis: Our initial analysis will be to determine which
cytokines/chemokines and what concentrations are detected in the blood following
cryoablation +/- pembrolizumab and how their profiles are altered. The investigators
will focus on the inflammatory and helper T-cell cytokine profiles and how these
cytokines influence and direct the T-cell response. Additionally, the investigators will
look at changes in chemokines. Their altered expression in malignancies have been shown
to dictate leukocyte recruitment and activation, angiogenesis, cancer cell
proliferation, and metastasis in all the stages of the disease. At baseline, 24-48 hours
post ablation, between pre chemotherapy, blood will be collected and plasma isolated by
centrifuging 1-2 mls of blood at 1-2000 x g for 10 minutes and then aliquoting 120 µl
into 0.65 mL microcentrifuge tubes. Standard of care group will only have 3 blood sample
time points. Plasma samples will be analyzed with a Bio-Plex 200 at Eve Technologies
Corporation (Calgary, AB Canada) using the Human High Sensitivity T-Cell Discovery Array
14-plex (HDHSTC14): GM-CSF, IFNy, IL-1B, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70,
IL-13, IL-17A, IL-23, TNF-a.
DATA SHEET:
See Excel spreadsheet. The RNA seq will be collected as heat maps for differentially
expressed genes.
RISKS:
Blood draw risks:
The risks of a blood draw include: pain, discomfort, bleeding, bruising, redness,
infection where the needle enters the skin; feeling lightheaded, fainting.
Cryoablation related risks:
Cryoablation has been a very safe procedure; PI has been routinely offering this
procedure to benign and cancer disease in the breast; so far, 18 cancer patients and 36
benign lesions have been subjected to the procedure. The following mild complications
have been reported thus far:
- Bruising at the site of ablation - self-limited.
- Pain - managed with OTC analgesics.
- Skin necrosis is a theoretical possibility however, following the procedure
protocol; the investigators have never had this complication.
Pembrolizumab related risks:
There have been extensive studies on toxicities of immune checkpoint inhibitors.
Standard recommended dose for Pemrolizumab is 200 mg IV per dose (approved by the FDA).
Anticipated adverse effects include:
- Rash
- Diarrhea
- Constipation
- Nausea
- Weight loss
- Dry eyes
- Fatigue
- Headache
- Fever
- Joint pain
- Thyroid dysfunction
Loss of Confidentiality:
All data will be maintained in password-protected files within the CRI and PI's office.
All data will be de-identified for compilation and analysis. All protocols for HIPAA
compliance will be followed. However, minimal risk of breach in confidentiality is
possible due to human error.
BENEFITS:
The patients in arm II and III may benefit by participation in the trial. If our
intuition of immune modulation via combination of cryotherapy and checkpoint inhibitor
drug actually affects the control of tumor, these two groups will directly benefit form
participation. However, the control arm I is not going to benefit from the trial beyond
providing a comparison arm for the study. The main goal of the proposed study is to
identify a novel low-risk treatment approach to these high-risk cancers, which will
ultimately benefit the future cancer patients.
MONITORING:
To ensure compliance with the study protocol, GCP guidelines, and TTUHSC Human Research
Protection Program research policies and procedures during the conduct of the study, as
well as quality data, a monitor in the Clinical Research Institute will conduct the
monitoring of the study. The first monitoring visit will be conducted within two weeks
after the first subject has been enrolled into the study. The succeeding monitoring
visits will be scheduled periodically, but no less than every 2 months when there is an
active study participant, at a mutually agreed timeframe by the PI and study monitor.
All data collected will be 100% source document verified. The study monitor may inspect
and audit all study documents, i.e. data collection forms, questionnaires, drug
accountability, and medical records within the applicable confidentiality regulations.
FUNDING:
Applied for NIH grant R21
