A Prospective Study of Memantine Hydrochloride for the Treatment of Prostate Cancer Patients
Phase: PHASE2
Conditions: Metastatic Castration-resistant Prostate Cancer (mCRPC), Prostate Cancer, Neuroendocrine Prostate Cancer (NEPC)
Sponsor: Bin Xu

Version:02
july 22, 2025
Research Project Design Document
Project Name: A Prospective Study of Memantine Hydrochloride for the Treatment of
Prostate Cancer Patients
Department: Department of Urology
Institution Address/Postal Code: 87 Dingjiaqiao, Gulou District, Nanjing,
Jiangsu Province, 210009
Principal Investigator: Bin Xu
Telephone/Email: +86 18012949196
Supervising Department: Zhongda Hospital, Southeast University
Version:02
Version Date: July 22, 2025

Version:02
july 22, 2025
1. Rationale
Prostate cancer (PCa) has become a major threat to the health of the male urogenital
system. According to the global cancer statistics report from the WHO's International
Agency for Research on Cancer, there were 1,414,259 new cases of prostate cancer
worldwide in 2020, accounting for 7.3% of all malignant tumors and ranking third in
incidence after breast and lung cancer. The incidence of prostate cancer exhibits
significant geographical and ethnic disparities. Historically, data has shown a lower
incidence in Asia compared to regions like Europe, America, Australia, and New
Zealand. However, with an aging population, changes in lifestyle, and the
popularization of screening methods such as prostate-specific antigen (PSA) testing,
the incidence of prostate cancer in our country is also on a year-over-year rise.
Prostate cancer is often staged according to disease progression, with classifications
such as metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic
castration-resistant prostate cancer (nmCRPC), and metastatic castration-resistant
prostate cancer (mCRPC). Androgen deprivation therapy (ADT) is a cornerstone in
the treatment of prostate cancer, and many patients who experience recurrence after
local therapy or develop distant metastases are sensitive to ADT. Nevertheless, a
significant number of patients experience disease progression despite ADT, with
some developing castration-resistant prostate cancer (CRPC), which eventually
evolves into mCRPC. Therefore, there is an urgent need to develop novel and
effective therapeutic strategies to manage disease progression.
The tumor microenvironment (TME), comprising immune cells, the extracellular
matrix, and non-malignant cells within the tumor region, plays a crucial role in tumor
initiation and development and is a key focus for scientific research. The relationship
between the immune system and tumors is currently a major research focus in the
field of oncology. The TME plays a critical role in modulating the immune response
in cancer patients. Tumor cells and their microenvironment typically produce a large
number of immunoregulatory molecules that can have a negative (inhibitory) or
positive (stimulatory) impact on the function of immune cells. This has been
confirmed in prostate, breast, pancreatic, and gastric cancers.
It is now known that neuroendocrine differentiation (NED) and neuroendocrine
prostate cancer (NEPC) are significant contributors to castration resistance in prostate
cancer, often occurring after long-term castration therapy in CRPC patients. This is
characteristically marked by decreased expression of prostate-specific markers like
the androgen receptor (AR) and prostate-specific antigen (PSA), alongside increased
expression of neuro-associated markers such as chromogranin A, synaptophysin, and
neuron-specific enolase. Patients with prostate cancer featuring neuroendocrine (NE)
characteristics respond poorly to chemotherapy, have a poor prognosis, and most have
a survival period of less than one year. Given the significant role of neuroendocrine
differentiation in the progression of prostate cancer, our team aims to investigate the

Version:02
july 22, 2025
long-term concurrent use of memantine hydrochloride in some prostate cancer
patients. The goal is to reduce neuroendocrine differentiation in prostate cancer,
thereby overcoming castration resistance and drug resistance in advanced stages.
NMDA receptor antagonists, such as the representative drug memantine, are used to
treat Alzheimer's disease by regulating glutamate activity, primarily in moderate to
severe cases. Memantine has minimal side effects when administered at low doses
over the long term, making it an excellent candidate for combination therapy.
Therefore, exploring the use of memantine hydrochloride in prostate cancer patients
to reduce neuroendocrine differentiation and overcome castration resistance and drug
resistance in advanced disease holds significant guiding value for the clinical
treatment of neuroendocrine CRPC.
1.1Research Status
Tumors are one of the greatest threats to human health today. Based on whether a
tangible mass can be detected through imaging, tumors can be broadly classified into
two types: solid tumors and non-solid tumors. Among these, solid tumors such as lung,
liver, pancreatic, gastric, and colorectal cancer are the more common type. Traditional
treatment methods for solid tumors, whether surgical resection, radiotherapy, or
chemotherapy, have focused solely on the tumor itself, lacking intervention in the
tumor microenvironment. Recent research indicates that the development and
progression of solid tumors are not only influenced by the accumulation of genetic
mutations within tumor cells; the tumor microenvironment also plays a crucial role in
the progression of solid tumors.
The tumor microenvironment is closely related to tumor development and progression.
For instance, in the context of tumor immunity, NMDA receptor antagonists promote
T-cell and NK-cell-mediated anti-tumor immunity. The combination of NMDA
receptor antagonists with anti-PD-1 therapy can eliminate the majority of established
preclinical liver tumors. These studies highlight the significant research value and
immense potential of NMDA receptor antagonists (memantine hydrochloride) for
anti-tumor applications.
1.2The Rationale and Significance of This Study
In 2013, an article published in
Cell on the treatment of pancreatic neuroendocrine tumors with NMDA receptor
antagonists reported that treating tumor-derived cell lines with these antagonists
inhibited tumor cell proliferation and invasion. This revealed that, beyond their
traditional role in neurons, NMDA receptors induce a glutamatergic signaling
autocrine loop in human tumors, stimulating malignancy. In 2023, an article in
Cell Biology on the effective inhibition of tumor-associated macrophage (TAM)
immune activity by NMDA receptor antagonists discovered the important role of

Version:02
july 22, 2025
these antagonists in anti-tumor immunity in hepatocellular carcinoma. Our team plans
to conduct a single-arm, prospective study in collaboration between Zhongda Hospital,
Southeast University, and Lianyungang First People's Hospital. Information on
patients receiving prostate cancer treatment will be obtained from the electronic
medical record systems of both hospitals. Patients who meet the inclusion and
exclusion criteria will be selected and administered memantine hydrochloride in a
clinical drug trial. Through long-term follow-up, we will compare their outcomes with
a historical external control group of prostate cancer patients who received traditional
therapy to study the impact on patient prognosis.
2. Research Content
2.1 Research Objectives
To conduct a prospective study evaluating the effect of long-term combination
therapy with memantine hydrochloride on the prognosis of patients with prostate
cancer.
2.2 Research Scope
(1) Selection of Study Sites: This study will be conducted at the Department of
Urology, Zhongda Hospital, Southeast University, and the Department of Urology,
Lianyungang First People's Hospital.
(2) Selection of Study Subjects: Information of patients receiving treatment for
prostate cancer will be retrieved from the multi-center electronic medical record
systems. Patients who meet the inclusion and exclusion criteria will be screened and
enrolled in this clinical trial with memantine hydrochloride.
Sample Size: It is planned to enroll a total of 15 patients from the multi-center sites
who are receiving treatment for prostate cancer and will be on long-term combination
therapy with memantine hydrochloride.
（3）Sample Size Calculation Method: According to previous literature,
the median time from randomization to objective tumor progression or
all-cause death (PFS) is approximately 6 months. Assuming the PFS for the
investigational combination therapy is approximately 8 months, with a
one-sided alpha of 0.05, a sample size of N=88 would be required based
on a single-sample log-rank test. However, due to the small number of such
patients and the difficulty in recruitment, we will first conduct an
exploratory evaluation of PFS in 15 patients. If the efficacy meets
expectations, the sample size will be expanded.

Version:02
july 22, 2025
Table 1: Number of events and sample size given different median survival
time (in months). The result for initial user input is highlighted in
yellow.
Study Period August 2025 – June 2028.
(4)Subject Recruitment and Allocation Method Information of patients who have
undergone radical prostatectomy will be obtained from the electronic medical
record systems of Zhongda Hospital and Lianyungang First People's Hospital. Patients
meeting the inclusion and exclusion criteria will be selected, administered
memantine hydrochloride for the clinical drug trial, and followed long-term. Their
prognosis will be compared with an external historical control group of prostate
cancer patients who received traditional treatment.
(5) Informed Consent of Study Subjects Informed consent will be obtained from the
subjects, and they will sign an informed consent form. Subjects without a
comorbidity of Alzheimer's disease will also receive and sign an informed consent
form for off-label use of the drug.
(6) Evaluation Endpoints Post-operative patients will undergo regular follow-up
checks of blood PSA levels and imaging studies to determine the presence of
biochemical or imaging recurrence. Disease-free survival will be used as a key
indicator to measure prognosis.
(7) Intervention Methods No intervention methods.
3. Research Methods
(1) Study Design
This study will adopt a single-arm, prospective research design.
(2) Inclusion and Exclusion Criteria
Inclusion criteria for subjects are as follows:
·Age ≥18 years.

Version:02
july 22, 2025
·Patients with mCRPC who have previously failed first- and second-line treatments.
Patients with comorbid Alzheimer's disease will be prioritized for enrollment.
·Patients with complete baseline clinical data who agree to long-term follow-up.
·ECOG performance status of 0-1.
Exclusion criteria for subjects are as follows:
·Patients with metastatic prostate cancer at initial diagnosis who have not
progressed to mCRPC.
·Patients currently with other primary tumors.
(3) Enrollment and Treatment Plan
Information of patients who have undergone radical prostatectomy will be obtained
from the electronic medical record systems of Zhongda Hospital and Lianyungang
First People's Hospital. Patients who meet the inclusion and exclusion criteria will be
selected, and after signing the informed consent form, will be administered
memantine hydrochloride. The baseline treatment regimen will be determined by
the attending physician based on a comprehensive assessment of the patient's prior
first- and second-line treatments, disease progression, and individual physical
condition. This ensures that each subject can participate in this study while
continuing to receive clinically recognized, effective standard-of-care treatment.
The baseline treatment will follow the principle of conventional androgen
deprivation therapy (ADT) combined with a novel endocrine therapy. The specific
plan is as follows:
Androgen Deprivation Therapy (ADT): All enrolled subjects will continue to
receive treatment with a gonadotropin-releasing hormone (GnRH) agonist or
antagonist to maintain serum testosterone at castration levels (< 50 ng/dL).
Novel Endocrine Therapy: On top of continuous ADT, the attending physician
will select a novel endocrine drug that the patient has not previously used,
primarily abiraterone acetate (in combination with prednisone) or
enzalutamide.
The study drug,
memantine hydrochloride, will be used in combination with this baseline
therapy.
The study medication regimen is as follows: For the first 3 weeks of treatment, the
dose will be gradually increased by 5 mg each week to reach the maintenance dose.
The dose for the first week is 5 mg once daily, 10 mg once daily for the second week,
and 15 mg once daily for the third week. Starting from the fourth week, the
recommended maintenance dose of 20 mg once daily will be administered. One
month after starting the study drug, patients will return to our hospital for follow-up
checks of blood PSA levels and imaging studies (including pelvic CT, prostate MRI,

Version:02
july 22, 2025
etc.). If the patient experiences no significant drug-related discomfort and no
biochemical or imaging recurrence, subsequent follow-ups will be scheduled every 3
months. The medication dosage will be adjusted by the physician based on the
follow-up results.
Efficacy Evaluation:
Post-operative patients will undergo regular follow-up checks of blood PSA levels
and imaging studies to determine the presence of biochemical or imaging recurrence.
Progression-free survival (PFS) and disease control rate (DCR) will be used as
important indicators to measure short- and long-term efficacy.
(4) Statistical Analysis:
Categorical data will be described using counts and percentages. For comparisons of
continuous data between groups, independent t-tests or Mann-Whitney U tests will
be used; for within-group comparisons, paired t-tests or Wilcoxon signed-rank tests
will be used. Categorical data will be analyzed using the χ² test or Fisher's exact test.
All statistical tests will be two-sided, and a p-value of less than or equal to 0.05 will
be considered statistically significant.
4. Technical Roadmap

Version:02
july 22, 2025
5. Feasibility Analysis
(1) Theoretical Feasibility: Regarding research on NMDA receptor antagonists, an
article in Cell on treating pancreatic neuroendocrine tumors showed that using
NMDA receptor antagonists on tumor-derived cell lines inhibited tumor cell
proliferation and invasion. This revealed that, in addition to their traditional role in
neurons, NMDA receptors induce a glutamatergic signaling autocrine loop in human
tumors that stimulates malignancy. Furthermore, an article in
Cell Biology on the effective inhibition of tumor-associated macrophage (TAM)
immune activity by NMDA receptor antagonists discovered the important role of
these antagonists in anti-tumor immunity in hepatocellular carcinoma.
(2) Clinical Operational Feasibility: This is a single-arm, prospective study.
Information on patients receiving prostate cancer treatment will be obtained
through multi-center electronic medical record systems. The drug experiment will be
conducted using memantine hydrochloride, with regular follow-ups and phone calls
to collect data on patient outcomes.
6. Innovation of the Project
In the tumor immunity context, memantine hydrochloride promotes T-cell and
NK-cell-mediated tumor immunity; combining NMDA receptor antagonists with
anti-PD-1 therapy can eliminate most established preclinical liver tumors. It has
minimal side effects during long-term low-dose administration, making it an
excellent choice for combination therapy. Therefore, exploring the use of
memantine hydrochloride in prostate cancer patients to reduce neuroendocrine
differentiation and overcome castration resistance and drug resistance in advanced
stages offers significant guidance for the clinical treatment of neuroendocrine CRPC.
7.Research plan and predicted progress
Work Progress
Main Content
AUG 2025 to Dec 2027
Enroll relevant clinical research
patients
and
conduct
clinical
experiments.
Jan 2028 to Jun 2028
Complete clinical data collection
and analysis.
8. Expected Research Outcomes

Version:02
july 22, 2025
The application of memantine hydrochloride in prostate cancer patients is expected
to reduce neuroendocrine differentiation, overcome castration resistance and drug
resistance in advanced prostate cancer, and demonstrate a degree of safety and
efficacy in the clinical treatment of neuroendocrine CRPC.
Work Basis and Conditions
Research Experience Related to This Project: The Department of Urology at
Zhongda Hospital, Southeast University has established a relatively comprehensive
clinical database for malignant tumors of the urinary system. The department
frequently performs radical prostatectomies and communicates well with patients
regarding informed consent. Our team has completed the relevant literature search
and has already constructed a knowledge framework regarding neuroendocrine
differentiation in prostate cancer and memantine hydrochloride.
Budget
The main expense for this project is the cost of the study medication. According to
the research plan, the 15 patients are expected to require a total of 91 boxes of
memantine hydrochloride (Memantine) during the study period, with a total drug
cost of 2,075 RMB. This cost will be covered by the project team.
Apart from the aforementioned drug costs, this study will not incur other additional
expenses. All research data (such as blood PSA levels, imaging results) will be
obtained from the patients' routine clinical follow-ups, requiring no payment for
extra examinations.