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

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.

Sex

Female

Minimum age

18 Years

Maximum age

99 Years

Inclusion Criteria:

1. Adult women over 18 years of age.
2. Patients with a diagnosis of histopathologically confirmed stage II-III invasive breast cancer who are candidates for treatment with standard neoadjuvant chemotherapy.
3. Documented results of the status of estrogen receptors (ER), progesterone (RP), KI 67, and epidermal growth factor receptor 2 (HER-2).
4. Patients eligible for neoadjuvant treatment with AC (Doxorubicin / cyclophosphamide) every 2 or 3 weeks followed by taxanes (paclitaxel for 12 weeks or docetaxel every 3 weeks for 4 cycles)
5. ECOG scale status from 0 to 1 with survival greater than 3 months.
6. Subject is able to swallow and retain oral medication and does not have uncontrolled emesis or persistent diarrhea.
7. Adequate renal, hematological, and hepatic function at the discretion of the investigator.
8. No uncontrolled or significant comorbidities determined by medical history, physical examination and screening laboratories at the discretion of the investigator. (Leukocytes greater than 2000 / mm3, neutrophils greater than 1500 / mm3, hemoglobin greater than 9 g / dl, creatinine less than 1.5 times the upper limit, transaminases less than 3 times the upper limit, bilirubin less than 1.5 times the upper limit).
9. Patients of childbearing age and without safe non-hormonal planning methods should have a negative pregnancy test before screening and each treatment cycle.
10. Fertile female subjects (those who are not postmenopausal for at least 12 months or are surgically sterile by bilateral tubal ligation, bilateral oophorectomy or hysterectomy) and their male partners, must use at least one of the contraceptive methods that are listed below during study entry, throughout the study, and for at least 6 months after use of the P2Et extract (the effects of the P2Et extract on the developing human fetus are unknown):

to. Complete abstinence from sexual intercourse, beginning at least one complete menstrual cycle before administration of study drug; (It should be noted: sexual abstinence as a contraceptive method should be limited to those cases in which it is already established as the choice of the patient's pre-existing lifestyle).

b. Vasectomy in the partner of a female subject c. Intrauterine device (IUD) d. Double barrier method (condom, contraceptive sponge, diaphragm or vaginal ring with jelly or spermicidal cream).

k) Desire to complete the study and follow-up interventions.

Exclusion Criteria:

1. Subjects treated in any other clinical therapeutic protocol in the 30 days prior to study entry or during study participation.
2. Patients who are receiving other agents under investigation.
3. History of allergic reactions attributed to polyphenol-type compounds similar to those found in green tea.
4. The subject is a pregnant or breastfeeding woman.
5. Patients who due to their clinical condition should receive anti-HER2 antibodies
6. Concomitant severe morbidity, active at the discretion of the investigator
7. Subjects with malabsorption syndrome or another condition that affects the enteral route of administration
8. Subjects with confirmed HIV diagnosis prior to enrollment or HIV positive diagnosis at the time of screening.
9. Solid organ transplant recipients or hematopoietic component.
10. The use of other phytomedicines, vitamins or herbal supplements must have been suspended at least one week before entering the study.
11. Previous malignant disease active within the previous 3 years, except for locally curable cancers that have apparently been cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or mother
12. Any condition that at the discretion of the principal investigator renders the subject ineligible to participate in this study

• BACKGROUNDAllemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Niksic M, Bonaventure A, Valkov M, Johnson CJ, Esteve J, Ogunbiyi OJ, Azevedo E Silva G, Chen WQ, Eser S, Engholm G, Stiller CA, Monnereau A, Woods RR, Visser O, Lim GH, Aitken J, Weir HK, Coleman MP; CONCORD Working Group. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018 Mar 17;391(10125):1023-1075. doi: 10.1016/S0140-6736(17)33326-3. Epub 2018 Jan 31. PMID 29395269
• BACKGROUNDBardia A, Baselga J. Neoadjuvant therapy as a platform for drug development and approval in breast cancer. Clin Cancer Res. 2013 Dec 1;19(23):6360-70. doi: 10.1158/1078-0432.CCR-13-0916. PMID 24298066
• BACKGROUNDBayet-Robert M, Kwiatkowski F, Leheurteur M, Gachon F, Planchat E, Abrial C, Mouret-Reynier MA, Durando X, Barthomeuf C, Chollet P. Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol Ther. 2010 Jan;9(1):8-14. doi: 10.4161/cbt.9.1.10392. Epub 2010 Jan 21. PMID 19901561
• BACKGROUNDBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. PMID 30207593
• BACKGROUNDBurnet FM. The concept of immunological surveillance. Prog Exp Tumor Res. 1970;13:1-27. doi: 10.1159/000386035. No abstract available. PMID 4921480
• RESULTAli HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, Earl HM, Poole CJ, Hiller L, Dunn JA, Bowden SJ, Twelves C, Bartlett JM, Mahmoud SM, Rakha E, Ellis IO, Liu S, Gao D, Nielsen TO, Pharoah PD, Caldas C. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014 Aug;25(8):1536-43. doi: 10.1093/annonc/mdu191. Epub 2014 Jun 9.