Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Behaviors and Mental Disorders

Breast Neoplasms

Breast Diseases

Skin Diseases

Quality of Life

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Taxane

Patients in the placebo group will receive the stable daily dose divided into 2 doses with meals of the optimal biological dose determined in stage I every 12 hours for the duration of standard therapy. The patient will self-administer the phytomedicine until completing the established treatment days. The taking of the phytomedicine will only be suspended 3 days before each cycle of standard therapy and will restart 3 days after having passed the cycle. That is, in the anthracycline and cyclophosphamide (AC) phase, the patient will start taking the phytomedicine 3 days after having received their standard chemotherapy cycle and will suspend it 3 days before the next cycle begins. For the taxane phase, the patient will take the P2Et without suspension during the treatment cycles.

Patients in the P2Et group will receive the stable daily dose divided into 2 doses with meals of the optimal biological dose determined in stage I every 12 hours for the duration of standard therapy. The patient will self-administer the phytomedicine until completing the established treatment days. The taking of the phytomedicine will only be suspended 3 days before each cycle of standard therapy and will restart 3 days after having passed the cycle. That is, in the anthracycline and cyclophosphamide (AC) phase, the patient will start taking the phytomedicine 3 days after having received their standard chemotherapy cycle and will suspend it 3 days before the next cycle begins. For the taxane phase, the patient will take the P2Et without suspension during the treatment cycles.

Patients who meet inclusion criteria will begin taking 4000mg daily, distributed in 2 doses with meals of 2000mg of P2Et extract during neoadjuvant treatment. In case of presenting toxicity, it will be lowered to the next dose level, that is, 2000 mg under the same dosage schedule and 1000 mg following the same principle. The taking of the phytomedicine will only be suspended 3 days before each cycle of standard neoadjuvant therapy and will restart 3 days after having passed the cycle. That is, in the anthracyclines and cyclophosphamide (AC) phase, the patient will start taking the phytomedicine 3 days after having received their standard chemotherapy cycle and will suspend it 3 days after the next cycle begins. For the taxane phase, the patient will take the P2Et without suspension during the treatment cycles.

P2Et (Caesalpinia spinosa extract)

After determining the optimal biological dose (OBD), the patients will be divided into the placebo arm or the treatment arm. In the anthracyclines and cyclophosphamide (AC) phase, the patient will start taking according to the asignation as stated in the drug intervention.

Placebo

Susana Fiorentino, PhD

Marìa M Manrique, MSC

Lilian Torregrosa, Dr

Currently, the study of many extracts in different types of cancer has allowed the validation of scientific knowledge either as a therapy that reduces the size of the tumor or that helps to improve the quality of life of the patient by reducing the associated effects of the treatment.

In the Immunobiology and Cell Biology group of the Pontificia Universidad Javeriana, a standardized extract of Caesalpinia spinosa (Dividivi) called P2Et has been obtained. This extract has been shown to have cytotoxic activity in different human and murine tumor cell lines, favoring the induction of immunogenic cell death with the release of danger signals such as calreticulin, HMGB1 and ATP. Additionally, treating mice with murine melanoma and sinus tumors significantly reduces tumor size and metastases. On the other hand, induction of complete autophagic flux and synergistic effects with anthracycline-type chemotherapeutics have been shown in human cell lines and in animal models of breast cancer.

With this background, and the results of the Phase I clinical study carried out in healthy volunteers that showed that the extract is safe, the investigators propose that treatment with the P2Et extract in patients with breast cancer could improve their general condition, impacting their quality of life. , and induce antitumor immune response, improving the immune infiltrate and acting as a transforming agent from a cold tumor to a warm tumor. This would lead to an improvement in the long-term survival of patients treated with the phytomedicine in conjunction with the chemotherapeutic treatment selected by the treating oncologist.

In order to advance on this path, and responding to the adjustments suggested in the phase I study in healthy individuals, it is proposed to carry out a clinical study that allows determining the optimal biological dose of the P2Et extract in a design based on randomized simulations of adaptive form and considering the safety of the extract as an objective in patients with breast cancer. Additionally, those parameters that allow defining the best indicators of effectiveness of P2Et in this group of patients will be evaluated, such as modulation of the immune response, quality of life, reduction of adverse effects and progression-free survival.

Natural products and traditional herbal medicine are an important source of alternative bioactive compounds, but very few herbal preparations have been scientifically evaluated and validated for their potential as treatments in medical practice. Phytotherapy is a promising field in current therapies based on plant-derived compounds given its immunomodulation properties and its ability to act against tumors, favoring the activation of the immune response and the reversal of the tumor phenotype through its action on the tumor microenvironment.

Over the last 8 years, the investigators have shown that a standardized extract of Caesalpinia spinosa, which the investigators call P2Et and which is the study drug of this protocol, presents an antioxidant activity both intracellular and in solution, which is much higher than that of of the positive controls used as the TROLOX. P2Et can also modulate drug resistance pumps, increasing sensitivity to anthracyclines in vitro and in vivo. It induces apoptosis through the depolarization of the mitochondria in various tumor cells and specifically in murine breast cancer cells, decreases clonogenicity, which seems to be related to the reduction of the primary tumor and metastases in animal models of breast cancer. It can also decrease the production of serum IL-6 in these animals, possibly related to a reduction in the protumorigenic activity of tumor-associated fibroblasts (results not yet published). The P2Et-induced tumor death process is accompanied by the expression of immunogenic death markers such as the expression of calreticulin, secretion of HMGB1 and ATP, which participate in the activation of dendritic cells. Vaccination of the animals with tumor cells treated with P2Et allows the generation of long-lived memory LTs, producers of IFN-gamma, TNF-alpha and IL-2, 4 and 5, which can be detected ex vivo. In vivo in animals, treatment with a vaccine prepared with tumor cells treated with P2Et favors the recruitment and differentiation of LT to the draining lymph nodes, which produce cytokines in response to tumor antigens, showing their ability to recognize the tumor. The investigators were also able to show that P2Et induces a tumor-specific immune response that is superior to that induced by Doxorubicin, since the LTs generated present greater multifunctionality in terms of cytokine production. Doxorubicin is known to also induce an immune response through immunogenic cell death, however, it has also been observed that treatment with anthracyclines can favor the selection of CMT within the tumor, which suggests that although they induce antitumor immune response, it is necessary to improve the recognition of MTCs by the immune system. Vaccination of animals with wild type 4T1 tumor cells treated with P2Et can induce cytotoxic LTs capable of recognizing murine 4T1 tumor MTCs called H17. This strongly suggests that there are cross-reactive antigens in both tumor lines and that in vivo, treatment with P2Et could induce a cross-presentation of antigens that allows the activation of CMT-specific LTs, which would be reflected in a greater disease-free survival. in animals, and that the same could be observed in patients.

The ability of P2Et to carry out its antitumor activity has also been observed in a murine model of melanoma, in which the investigators show that treatment with P2Et induces LT CD8 specific for the melanoma-specific tumor antigen Trp-2, through a effective cross-presentation and antigenic presentation by dendritic cells. In fact, the antitumor activity of P2Et was reduced in RAGg KO immunodeficient animals, which do not present LT or LB, confirming that the effect of this phytomedicine is partially mediated by the immune response and that the immune response is required to be activated, to exercise its function.

The antitumor activity of P2Et may be due to the particular form of immunogenic cell death induction that is different from that induced by anthracyclines, which allows tumor antigens to not easily degrade when the cell is dying, due to its high capacity. antioxidant, which is concomitant with the expression by the tumor cell of immunogenic cell death markers. These two elements, together, allow dendritic cells to carry out better antigen processing with complete antigens and therefore the diversity of the LT response, measured at the clonotypic level, is greater.

The investigators are currently evaluating the local intratumoral and peripheral immune response induced by anthracycline treatment in patients with breast cancer at Hospital San Ignacio, in conjunction with a clonotypic analysis of the LTs generated in both compartments (unpublished data). These results will serve as a basis for later comparing whether the quality of the response in patients treated with P2Et in conjunction with conventional chemotherapy is different and whether this may be related to its antitumor activity in vivo.

On the other hand, in previous studies it has been observed that P2Et can modulate the expression of PD-L1 in tumor cells, improving the therapeutic effect of the anti PD-L1 antibody in vivo in a murine melanoma model. Although the same additive response to co-treatment (P2Et + anti-PD-L1) was not observed in the breast cancer model, protection of the affected hematopoietic cells was evidenced with anti-PD-L1 therapy with an improvement in the number of platelets, lymphocytes, monocytes and granulocytes in animals that received P2Et in conjunction with anti-PD-L1 compared to those that only received anti-PD-L1. The differences in melanoma and breast could be due to the increase in the expression of PD-L1 mainly in the murine melanoma line and not in the 4T1 line in response to P2Et, so it is important to measure the effect of the P2Et extract on the PD-L1 expression in human tumor cells and study the relationship with tumor type and other biological variables.

With this background, and the results of the Phase I clinical study carried out in healthy volunteers that showed that the extract is safe, the investigators propose that treatment with the P2Et extract in patients with breast cancer could improve their general condition, impacting their quality of life. , and induce an antitumor immune response, improving the immune infiltrate and acting as a transforming agent from a cold tumor to a warm tumor. This would lead to an improvement in the long-term survival of patients treated with phytomedicine in conjunction with the chemotherapeutic treatment selected by the treating oncologist.

In order to advance on this path, and responding to the adjustments suggested in the phase I study in healthy individuals, it is proposed to carry out a clinical study that allows determining the optimal biological dose of the P2Et extract in a design based on randomized simulations of adaptive form and considering the safety of the extract as an objective in patients with breast cancer. Additionally, those parameters that allow defining the best indicators of the effectiveness of P2Et in this group of patients will be evaluated, such as modulation of the immune response, quality of life, reduction of adverse effects and progression-free survival.

This study is a design based on adaptive randomized simulations (BOIN12) (Zhou, Lee, \& Yuan, 2019). Each of the patients included in the different groups will undergo the analysis of the immune response parameters described in Annex 1.

With the optimal biological dose calculated in stage 1, it will go to stage 2 where 40 randomized breast cancer patients will be enrolled in treatment with the P2Et extract or placebo. In these patients, parameters related to the immune response, progression-free survival, quality of life and tumor reduction will be evaluated.

Safety and Efficacy Evaluation of the P2Et Extract in Patients With Breast Cancer

Determination of the Optimal Biological Dose and Safety Evaluation of the P2Et Extract in Patients With Breast Cancer (Phase I / II)

Determination of the optimal Biological Dose according to the toxicological profile

To determine the effect of treatment with P2Et extract and neoadjuvant chemotherapy on the clinical and pathological response in the cohort.

To assess the disease-free survival of breast cancer patients treated with the P2Et extract in the expanded cohort of patients.

To evaluate the effect of treatment with P2Et extract and neoadjuvant chemotherapy on the quality of life of patients with breast cancer by applying the QLQ C-30 version 3 questionnaire and QLQ B23 in the expanded cohort of

Evaluate the adverse events of the P2Et extract in combination with neoadjuvant chemotherapy in breast cancer patients

Pontificia Universidad Javeriana

Hospital Universitario San Ignacio

Nervous System Diseases

Skin Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Yi-Hua YH Liao, PhD

Yao-Chen YC Tseng, Master

Yi-Hua Liao

The goal of this clinical trial is to develop an imaging platform for intraoperative tumor margin delineation in 250 cases of tumor-suffered patients. The main questions it aims to answer are:

• to develop the protocol of rapid assessment of surgical specimens without need for fixation, embedding, and cryosectioning required for conventional histopathology.

Participants will provide a small piece of their surgical specimens from tumor removal surgery .

If there is a comparison group: Researchers will compare normal specimens to see if we can observe the difference.

Microscopy Imaging of Whole-mount Stained Human Tissues

Microscopy Imaging of Whole-mount Stained Human Tissues: Development of an Imaging Platform for Intraoperative Tumor Margin Delineation

Do comparison with images acquired by our microscopy (with the whole-mount staining method) and bright field microscopy (with standard FFPE method) and do assessment to interpret tumor characteristics

National Taiwan University Hospital

Symptoms and General Pathology

Recurrence

There will be one treatment cohort. Radiation therapy will be delivered daily for 15 daily fractions, 2.67Gy per fraction, delivered using a 3-D or IMRT(Intensity Modulate Radiation Therapy) plan. For participants with high-risk features deemed by the radiation oncologist who would otherwise be a candidate for a boost (age \<50, high grade, poor biology, close margins), 48 Gy delivered in fifteen fractions of 3.2 Gy is allowed.

Weeks 1, 2 and 3

* Weeks 1, 2 and 3 will include 5 days of treatment.
* One radiation treatment to breast on each of the 5 days. Each radiation treatment session will last a 30 minutes.

Radiation Therapy

Janice Lyons, MD

Chirag Shah, MD

The standard treatment for participants whose cancer has returned after breast conserving surgery is radiation given twice daily (separated by at least 6 hours) for a total of 30 treatments. The purpose of this study is to find out if giving radiation once a day for 15 treatments after repeat breast conserving surgery works as well as giving it the standard way.

Breast cancer survival rates have greatly improved with advances in both screening and treatment. The standard of care for both early stage and selected locally advanced breast cancers is breast conserving therapy (BCT), consisting of a partial mastectomy followed by radiation treatment. Traditionally, a salvage mastectomy was the standard treatment for women who initially underwent BCT and experienced an ipsilateral breast tumor recurrence (IBTR). Many participants have become increasingly motivated to avoid mastectomy, and there has been rising interest in repeat BCS (Breast Conserving Surgery) with focal radiation for certain participants motivated to keep their breast. The current standard of care for breast re-irradiation after an in-breast tumor recurrence is partial breast irradiation consisting of a dose of 45 Gy delivered BID for 30 fractions. While this regimen demonstrated excellent local control and low AEs, the regimen itself is difficult for participants. Receiving RT twice daily at smaller doses per fraction (1.5 Gy) for 30 treatments can be burdensome, especially for those without reliable transportation or difficulty getting time away from work. Given the excellent local control rates and low rate of AEs, in this study, we hypothesize that daily hypofractionated EBRT(External Beam Radiation Therapy) for re-irradiation after repeat BCS would be at least as well tolerated with good local control and provide a more convenient option for participants than the current standard of care established by RTOG 1014. Some participants will present with high-risk features (e.g. age \<50, high grade, ER negative tumors, close margins) making dose escalation an attractive option to improve local control. Options for dose escalation include sequential and concurrent administration of a boost.

Participants will receive once daily radiation for 15 fractions to 40.05 Gy total dose. Participants with high risk features (high grade disease, young age, close margins (\<2mm), triple negative subtype, HER2 positive tumors not receiving HER2 targeted systemic therapy) may receive a simultaneous boost to 48 Gy in 15 fractions.

Repeat Breast Conserving Surgery Followed by Daily Partial Breast Irradiation in Ipsilateral Breast

Repeat Breast Conserving Surgery Followed by Daily Partial Breast Irradiation for Participants With Ipsilateral Breast Tumor Recurrence Treated Initially With Breast Conserving Surgery and Whole Breast Radiation Therapy

Data will be used for study purposes only and not otherwise shared

Rate of grade 3+ treatment-related skin, fibrosis, and breast pain adverse events occurring within 1 year from the completion of re-irradiation as graded by CTCAE criteria.

The overall in-breast tumor recurrence rate will be estimated using the cumulative incidence function.

The overall in-breast tumor recurrence rate is estimated using the cumulative incidence function.

The freedom from mastectomy rate will be estimated using the cumulative incidence function.

All treatment-related adverse events for the defined time periods

Determined by an established Global Cosmesis Score grading from 1 through 4, with 1 being excellent and 4 being rated as poor

Overall survival will be estimated using Kaplan-Meier Method

Mastectomy-free survival will be estimated using Kaplan-Meier Method

Case Comprehensive Cancer Center

Mammary Neoplasms, Animal

Two dose levels will be evaluated in Arm A (without lymphodepletion)

Two dose levels will be evaluated in Arm B (with lymphodepletion)

Arm A -- Two dose levels will be evaluated:

Dose level One: 1.00E+06

Dose level Two: 1.00E+07

HTR2 T Cells

Arm B -- Two dose levels will be evaluated:

Dose level Two: 1.00E+07

Dose Level Three: 1.00E+08

Valentina Hoyos, MD

Wendy Callejas

Wendy Callejas, MD

The purpose of this study is to find the biggest dose of HTR2 T cells that is safe, to see how long these cells last in the body, to learn the side effects, and to see if these cells are able to fight and kill HER2 expressing breast cancer.

Patients eligible for this study have metastatic breast cancer that has HER2 expression and has progressed on at least one line of therapy. This is a gene transfer research study using special immune cells called T cells. T cells are a type of white blood cell that helps the body recognize and fight cancer cells.

The body has different ways of fighting diseases and no single way seems perfect for fighting cancer. This research combines two different ways of fighting cancer: antibodies and T cells. Antibodies are proteins that protect the body from infectious disease and possibly cancer. T cells, or T lymphocytes, are special blood cells that can kill other cells, including tumor cells. Both antibodies and T cells have shown promise treating cancer but have not been strong enough to cure most patients.

Previous research has found that investigators can put genes into T cells that helps them recognize cancer cells and kill them. Investigators now want to see if by putting a new gene in those T cells to help recognize breast cancer cells expressing HER2 can kill the cancer cells. In clinical trials for various cancer types that express HER2, our center engineered a CAR that recognizes HER2 and put this CAR into patients own T cells and gave them back. Investigators saw that the cells did grow and patients did tolerate and respond to the treatment.

Investigators will add a gene to the HER2 recognizing CAR T cells that will improve the T cells function. Investigators know that some immune cells in the body can lower T cells ability to kill cancer cells. Investigators have identified an antibody that will inactivate those immune suppressive cells thereby allowing T cells to survive better to recognize and kill cancer cells. This antibody targets the Trail-R2 receptor and is referred to as TR2.

Also, investigators know that T cells need the support of cytokines to perform their immune functions. There is evidence showing that the addition of interleukin 15 (IL15) enhances CAR T cells ability to kill cancer cells. As a result, investigators also added IL15 to the HER2 and TR2 targeting CAR T cells (HTR2 T cells).

The HTR2 T cells are an investigational product not approved by the Food and Drug Administration.

To make the T cells, the investigators will take the patient's blood and stimulate it with growth factors to make T cells grow. Investigators use a retrovirus to insert HER CAR, TR2 antibody and IL 15 genes into the T cells.

HTR2 cells are generated from the patient's T cells and are frozen. At the time the patient is scheduled to be treated, the cells will then be thawed and injected into the patient over 5 to 10 minutes. Patients will only get one dose of HTR2 T cells during the infusion. If the patient has a good response and tolerance, we may be able to repeat infusion in the future. The patent may be pretreated with Tylenol and Benadryl to prevent possible allergic reaction to the T cell administration.

If investigators need to stop the HTR2 T cells due to bad side effects, investigators have inserted a gene called iCasp9 into the T cells. This allows investigators to eliminate the HTR2 T cells in the blood when the gene comes into contact with a medication called Rimiducid. The drug Rimiducid is not yet FDA approved and is an experimental drug, but it has been tested in humans without bad side-effects. Investigators will only use this drug to kill the T cells if necessary due to side effects. Since investigators do not know exactly what dose will effectively stop HTR2 T cells in individual patients, investigators will start at a low dose with the ability to increase the dose two more times based on how patients are doing. Blood work will be done to ensure that the HTR2 T cells have been successfully eliminated.

The treatment will be given by the Center for Cell and Gene Therapy at Houston Methodist Hospital.

MEDICAL TESTS BEFORE TREATMENT

Before being treated, patients will receive a series of standard medical tests:

* Physical exam and history
* Blood tests to measure blood cells and organ function
* Measurements of the tumor by scans at baseline prior to treatment
* Ultrasound of the heart to make sure the patient has good baseline cardiac function

Additionally, patients will need a biopsy of their tumor tissue to both confirm HER2 expression and to be used for research purposes.

MEDICAL TESTS DURING AND AFTER TREATMENT

Within four weeks after infusion, patients will be monitored on a weekly basis for dose limiting side effects of the HTR2 T cells:

* Physical exam and history
* Blood tests to measure blood cells and organ function

After the initial six weeks, patients will be monitored at a minimum every 3 months for the 1st year and every 6 months between 1 to year 5 or as frequently as deemed necessary:

* Physical exam and history
* Blood tests to measure blood cells and organ function
* Measurements of patient's tumor by scans to assess treatment response

To learn more about the way T cells work in the patient's body, investigators will obtain up to 50 ml of blood from patient before chemotherapy, before the T-cell infusion, 1 to 4 hours, 1, 2, 3, 4 weeks and 8 weeks after infusion, every 3 months for a year followed by every 6 months for 4 years and then every year for the the next 10 years. Total participation on this study will be 15 years. During the time points listed above, if the T cells are found in the blood at a certain amount, an extra half a tablespoon of blood may be needed for additional testing.

Investigators will obtain one tissue biopsy within 4 weeks after infusion and as clinically indicated thereafter. If additional clinically indicated tumor biopsies are obtained, investigators will ask for a portion of the sample for research.

TRAIL-R2 and HER2 Bi-Specific Chimeric Antigen Receptor (CAR) T Cells for the Treatment of Metastatic Breast Cancer

(TRAILBLASER) TRAIL-R2 and HER2 Bi-Specific Chimeric Antigen Receptor T Cells for the Treatment of Metastatic Breast Cancer

Rate of incidents of dose limiting toxicity by dose levels.

Proportion of subjects with best overall response of complete response (CR) or partial response (PR) according to RECIST criteria

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy Evaluation of the P2Et Extract in Patients With Breast Cancer	NCT05007444	Breast Cancer Quality of Life Tumor, Breast	P2Et (Caesalpin... Placebo	18 Years - 99 Years	Hospital Universitario San Ignacio
Microscopy Imaging of Whole-mount Stained Human Tissues	NCT05689112	Tumor, Brain Tumor, Breast Tumor Skin		20 Years -	National Taiwan University Hospital
Safety and Efficacy Evaluation of the P2Et Extract in Patients With Breast Cancer	NCT05007444	Breast Cancer Quality of Life Tumor, Breast	P2Et (Caesalpin... Placebo	18 Years - 99 Years	Hospital Universitario San Ignacio
Repeat Breast Conserving Surgery Followed by Daily Partial Breast Irradiation in Ipsilateral Breast	NCT06129747	Breast Cancer Tumor, Breast	Radiation Thera...	19 Years -	Case Comprehensive Cancer Center
Microscopy Imaging of Whole-mount Stained Human Tissues	NCT05689112	Tumor, Brain Tumor, Breast Tumor Skin		20 Years -	National Taiwan University Hospital
Microscopy Imaging of Whole-mount Stained Human Tissues	NCT05689112	Tumor, Brain Tumor, Breast Tumor Skin		20 Years -	National Taiwan University Hospital
TRAIL-R2 and HER2 Bi-Specific Chimeric Antigen Receptor (CAR) T Cells for the Treatment of Metastatic Breast Cancer	NCT06251544	Breast Cancer Tumor, Breast Breast Tumor Malignant Neopl... Mammary Cancer Mammary Neoplas... Mammary Neoplas... Neoplasm, Breas...	HTR2 T Cells HTR2 T Cells	18 Years - 80 Years	Baylor College of Medicine
TRAIL-R2 and HER2 Bi-Specific Chimeric Antigen Receptor (CAR) T Cells for the Treatment of Metastatic Breast Cancer	NCT06251544	Breast Cancer Tumor, Breast Breast Tumor Malignant Neopl... Mammary Cancer Mammary Neoplas... Mammary Neoplas... Neoplasm, Breas...	HTR2 T Cells HTR2 T Cells	18 Years - 80 Years	Baylor College of Medicine

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