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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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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
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

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