Clinical Trials

Date: 2018-02-08

Type of information: Completion of the trial

phase: 2a

Announcement: completion of the trial

Company: Cellceutix (USA - MA) now Innovation Pharmaceuticals (USA - MA)

Product: Kevetrin® (thioureidobutyronitrile)

Action mechanism:

  •  In the majority of cancers, and regardless of origin, type, and location, the p53 pathway is mutated, preventing the body from performing its natural anti-tumor functions.
  • In the laboratory, Kevetrin® activates p53, a tumor suppressor protein that has an important role in protecting the body. p53 functions by activating proteins that repair DNA and kill cells that have genetic mutations such as in cancers. Research experiments showed that when cancer cells were treated with Kevetrin, it activated p53 which induced p21, a protein that inhibits cancer cell growth. p53 also induced PUMA (p53 up-regulated modulator of apoptosis), a protein that causes tumor cell death. Because of these activities, slowing cancer cell growth and causing cancer cell death, Kevetrin may help to treat tumors.
  • The FDA has awarded Kevetrin® orphan drug status for ovarian cancer, pancreatic cancer, and retinoblastoma, qualifying it for developmental incentives and a potential extra 7 years of market exclusivity upon drug approval. The FDA also has granted Kevetrin® rare pediatric disease designation for childhood retinoblastoma.

Disease: ovarian cancer

Therapeutic area: Cancer - Oncology

Country: USA

Trial details:

  • Cellceutix, now  Innovation Pharmaceuticals, has developed Kevetrin® (thioureidobutyronitrile), belonging to an anti-proliferative p53 activator pharmacological class, for the treatment of cancer. Nonclinical studies have demonstrated that Kevetrin induces apoptosis by activation of wild type p53 and induces apoptosis in mutant p53 cells by degradation of oncogenic mutant p53.
  • In this Phase 2 study, two different short-term treatment regimens of Kevetrin® will be evaluated for safety, tolerability, changes in biomarkers/objective tumor response, and to evaluate the pharmacokinetics of Kevetrin® when administered to subjects with platinum-resistant/refractory ovarian cancer. (NCT03042702)

Latest news:

  • • On February 8, 2018, Innovation Pharmaceuticals announced the closure of its Phase 2a clinical trial of Kevetrin® for the treatment of late-stage ovarian cancer. The company initiated the trial for the purpose of demonstrating modulation of the key tumor-suppressor protein p53, which was achieved in analysis of the first patients at the lowest dose of Kevetrin® (see below). Throughout pre-clinical testing and two successful clinical trials, Kevetrin® has demonstrated promising signs of efficacy as an anti-cancer agent and a favorable pharmacokinetic profile that includes a very short half-life and good bioavailability. It is believed that these characteristics make Kevetrin® an ideal candidate for oral delivery (capsule or tablet), which will facilitate convenient and frequent dosing, perhaps even multiple times daily, to maximize the therapeutic benefit of the compound. With the positive observation of intra-tumor p53 modulation, the company will now allocate resources to focus its efforts on completing development of an oral formulation, including performing bridging toxicology work.
  • • On December 27, 2017, Innovation Pharmaceuticals announced preliminary data from the first patients treated in the Company’s Phase 2a clinical trial  of Kevetrin® for ovarian cancer. Modulation of the p53 protein was observed in response to administration of Kevetrin®. Pathways analyses also point to concomitant cell cycle modulation at the level of gene expression. Importantly, these data are the first to directly support in ovarian cancer patient tumors, Kevetrin®’s ability to affect p53 and associated molecular pathways—a central gene signaling network involved in regulating cell growth and the cell cycle, helping to prevent cancer.
  • In more detail, preliminary analyses used Western Blots to assess relative levels of key proteins extracted from tumor biopsies before and after a series of nine Kevetrin® infusions administered over three weeks. The level of phospho-p53, the activated form of the protein, in addition to the noted p53 modulation, was also seen to change in response to Kevetrin® administration. These findings confirm in patient tumors Kevetrin®-induced anti-cancer effects similar to those demonstrated (pdf) preclinically in ovarian cancer cell-lines. These new data reinforce prior clinical data, from the earlier concluded Phase 1 study of Kevetrin® in advanced solid tumors (NCT01664000), in which observations of p21 expression in peripheral blood monocytes supported p53 involvement in Kevetrin’s mechanism of action. Data from RNAseq analyses of expressed mRNAs and sRNAs in tumors, before and after treatment with Kevetrin®, are being further analyzed to assess the nature and scope of molecular pathways modulations. The strongest signal so far detected concerns the cell cycle and a variety of transcription factors. Running in parallel, the company is making plans to develop Kevetrin® as an oral agent (tablet or capsule) that could be dosed multiple times per day, leveraging its short half-life and pharmacokinetic profile. Bioavailability and other lab studies have been encouraging.
  • • On September 14, 2017, Innovation Pharmaceuticals announced that a new clinical site has been added in the Company’s Phase 2 clinical trial of Kevetrin® for ovarian cancer.  The site, a renowned academic medical center, is now actively enrolling patients.
  • In the interventional study, Kevetrin® is being evaluated in patients with platinum-resistant/refractory ovarian cancer.  The primary outcomes for the study are incidence of treatment-emergent adverse events and evaluation of changes in cancer pathway biomarkers and molecular signatures, as measured in tissue/tumor samples pre-treatment and after three weeks of treatment.

Is general: Yes