Kevetrin™

Kevetrin™ 

Kevetrin is a small molecule compound with a structure that is distinct from other anti-cancer agents currently on the market. One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. Kevetrin has been studied extensively (in vitro and in vivo) demonstrating potent anti-cancer activity against various cancer cell lines. It has consistently shown activity as good as or better than standard chemotherapeutic therapies, given at approximately equitoxic doses. Kevetrin has demonstrated potent anti-tumor efficacy against various carcinoma xenograft models: lung, breast, colon, prostate and squamous cell carcinoma, and in a leukemia tumor model. In drug-resistant cell lines, Kevetrin has shown excellent activity, galvanizing the Company to focus on Kevetrin’s development potential in this area.

Kevetrin’s primary mechanism of action has been shown to induce activation of p53, often referred to as the “Guardian Angel Gene” due to its crucial role in controlling cell mutations.  p53 is a tumor suppressor protein that is encoded by the TP53 gene in humans and has been widely regarded as possibly holding a key to the future of cancer therapies. p53 has been shown to play critical roles in the homeostatic health of the human body by activating proteins required to repair DNA and plays a major role in the life cycle of cells by inducing cell cycle arrest and apoptosis to maintain cellular and genetic stability. Please click here for more detailed information about Kevetrin.

Kevetrin is water-soluble and easily synthesized from commercially available starting materials. Cellceutix holds a patent covering pharmaceutical compositions comprising Kevetrin.

Clinical Development

Harvard’s  Dana-Farber Cancer Institute and partner Beth Israel Deaconess Medical Center

Cellceutix is currently conducting a Phase 1 clinical trial at Harvard Cancer Center’s Dana-Farber Cancer Institute and partner Beth Israel Deaconess Medical Center. The open-label, dose-escalation clinical trial is evaluating Kevetrin, administered intravenously in patients with advanced solid tumors. The objective of the trial is to determine PK/PD, tolerance, safety, and maximum tolerated dose (MTD) in patients with the diagnosis of refractory solid tumors. The study is designed to enroll approximately 40 patients in the dose-escalation portion of study. Once the MTD has been established, up to 12 additional patients may be enrolled at the MTD dose level to further evaluate this dosage safety and pharmacodynamics. The primary objectives of the study are to determine the MTD and dose limited toxicity (DLT) of Kevetrin and to establish a safe dose level of Kevetrin that can be used for future studies. More information about the trial can be found at http://www.clinicaltrials.gov/ct2/results?term=Kevetrin&Search=Search.

Cellceutix Reports Spleen Lesion ‘Disappears’ in Patient With Metastatic Stage 4 Ovarian Cancer in Clinical Trial of Anti-Cancer Drug Kevetrin

BEVERLY, MA–(Marketwired – Jan 20, 2015) – Cellceutix Corporation (OTC: CTIX) (the “Company”), a clinical stage biopharmaceutical company developing innovative therapies with oncology, dermatology and antimicrobial applications, is pleased to report the near complete disappearance of a metastatic lesion in the spleen of a Stage 4 ovarian cancer patient who was enrolled in the Company’s Phase 1 clinical trial of anti-cancer drug candidate Kevetrin™ being conducted at Harvard Cancer Center’s Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center. According to information supplied by the hospital, the patient, who successfully completed three Kevetrin 3-dose cycles before discontinuing the trial, experienced increased energy, while scans showed a reduction in the amount of peritoneal fluid (ascites) during treatment with Kevetrin. Subsequent to the second and third Kevetrin cycles, scans showed the spleen lesion to be essentially undetectable and the patient’s disease to be clinically stable.

With the completion of the ninth cohort, and commencement of tenth cohort at 450 mg/m2, the hospital has continued research to determine the effect of Kevetrin on p21, the key biomarker tightly controlled by the tumor suppressor protein p53. p53 is often referred to as the “Guardian Angel Gene” because of its crucial role in controlling cell mutations. In nearly all cancers, p53 is deficient or mutated, thus failing to perform its role as a master cell regulator, which exacerbates tumor progression and metastasis. As such, a drug to reactivate p53 to its normal state is a prime target for a next generation cancer therapy. Because p21 is a recognized downstream target of activated p53, increased levels of p21 in peripheral blood cells suggest that Kevetrin is having an impact on returning p53 to its effectiveness as a tumor suppressor.

Research conducted by the hospital evaluating p21 expression in earlier cohorts, for which the level of exposure to Kevetrin was substantially lower, showed that about 50 percent of the patients demonstrated at least a 10% increase in p21. The data supported the hypothesis that enhanced p21 is dose related, meaning that as the amount of Kevetrin increased, so did the p21 expression. Hospital scientists are now running samples examining the effect of Kevetrin on p21 at higher dosing levels in more recent cohorts and Cellceutix hopes to disclose the results shortly.

Additionally, the Principal Investigators for the Kevetrin trial have requested that the Company start preparing a presentation to be used for an article on the safety and pharmacological effect of Kevetrin on multiple cancer lines as demonstrated in the clinical trial. Cellceutix interprets this recommendation as a very optimistic sign regarding anticipated outcomes for the trial and clinical advancement of Kevetrin.

 The University of Bologna

The University of Bologna in Italy plans on testing Kevetrin for efficacy against Acute Myelogenous Leukemia (AML).  The planned Phase 1B is a multi-center, open-label, dose optimization trial with Kevetrin, administered intravenously with Cytarabine administered either subcutaneously or intravenously.  The University of Bologna will source the funding for this trial and plans to initiate the trial once a higher MTD is achieved in the Phase 1 trial conducted at Dana-Farber.

 

Select Highlights from Pre-Clinical Studies:

  • In a human head and neck cancer xenograft model in combination with local radiation, the delay in tumor growth was significantly increased by 36 days when Kevetrin was administered in conjunction with radiation, more than two-fold compared to controls.
  • In GLP toxicology and safety pharmacology tests, Kevetrin was well tolerated.  A GLP repeated dose toxicity study in rats with 5 weekly doses of Kevetrin, in the range of 60 to 120 mg/kg given intravenously showed a NOAEL of Kevetrin of 90 mg/kg.  A GLP repeated dose toxicity study in dogs with 5 weekly doses of Kevetrin, in the range of 5 to 60 mg/kg given intravenously showed a NOAEL of 5 mg/kg.
  • Kevetrin showed a biphasic time vs. drug concentration curve with an elimination half-life of about 0.7 to 2.2 hours in mice and rats, respectively, and 1 hour in dogs and a dose dependent pattern in terms of the plasma concentration, C max, and exposure.
  • Kevetrin was shown to be non-genotoxic. Most currently available chemotherapeutic are genotoxic in nature and damage DNA. Our results showed that Kevetrin, in a non-genotoxic way, induces p53 leading to apoptosis. DNA damaging drugs result in rapid phosphorylation of H2A.X at Ser 139 by PI3K-like kinases. Kevetrin did not induce phosphorylation of H2A.X protein.

Kevetrin Efficacy Studies in Drug-Resistant and other Cancer Cell Lines

» Lung Cancer

» Kevetrin was studied in two cell lines of multi-drug resistant lung cancer. In two studies with the multi-drug resistant non-small cell lung carcinoma human cell line, A549, Kevetrin showed average tumor growth delay of 72% and average tumor volume reduction of 81% compared to controls. Both tumor growth delay and tumor volume reduction were also significantly greater with Kevetrin than with paclitaxel. (p<0.001).
Please click here to see a more detailed summary of these studies.

» In two studies with the NCI-H1975 non-small cell lung carcinoma multi-drug resistant lung cancer, Kevetrin showed average tumor growth delay of 149% and tumor volume reduction of 94% compared to controls. Both tumor growth delay and tumor volume reduction were greater with Kevetrin than with paclitaxel (p<0.001).
Please click here to see a more detailed summary of these studies.

» Breast Cancer

» In animal model testing on a taxane-resistant, estrogen receptor-negative breast cancer human cell line, MDA-MB-435s, tumor volume was reduced by 72% and tumor growth was delayed by more than 52% with Kevetrin when compared with paclitaxel.  Please click here to see a more detailed summary of these studies.

» In a study with the MDA-MB-231 breast cancer cell line, Kevetrin demonstrated tumor growth delay of 90% compared to controls.

» Colon Cancer

» Kevetrin showed tumor growth delay of 43% compared to controls and paclitaxel when tested on animals with HCT-15 P-glycoprotein drug resistant colon cancer. Please click here to see a more detailed summary of these studies.

» Kevetrin was studied in two experiments alone and in combination with 5-FU against the HT-29 cell line of colon cancer. Kevetrin alone demonstrated average tumor growth delay of 43% compared to controls. 5-FU alone showed an average tumor growth delay of 20%. The combination of Kevetrin and 5-FU resulted in an average tumor growth delay of 97%.

» Head and Neck Cancer

» Kevetrin was studied in multiple experiments alone and in conjunction with radiation against the SCC-15 cell line of head and neck cancer. Kevetrin alone showed an average tumor growth delay of 45% compared to controls, similar to radiation alone. When administered in conjunction with radiation, Kevetrin showed an average tumor growth delay of 116%.
Please click here to see a more detailed summary of these studies.

» Prostate Cancer

» Kevetrin was studied against the PC-3 cell line of prostate cancer. In two studies, Kevetrin demonstrated an average tumor growth delay of 54% compared to controls, while cisplatin showed an average tumor growth delay of 49%.

» Retinoblastoma

» The Company conducted pre-clinical studies using human retinoblastoma cells (WERI-Rb-1) in nude mice that were implanted either subcutaneously or directly into the eye, intravitreally. Treatment with Kevetrin significantly reduced the tumor volume by more than half in the subcutaneous tumor model and showed a significant improvement in the clarity of the eye in mice treated with Kevetrin.

 





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