Dekk-Tec, Inc.

NEW ORLEANS, LA, United States

Dekk-Tec, Inc.

NEW ORLEANS, LA, United States
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Strong M.J.,Tulane University | Strong M.J.,Tulane Cancer Center | Rosenlof T.,Tulane University | Padmanabha S.,East Jefferson General Hospital | And 4 more authors.
Journal of Neurosurgery: Spine | Year: 2015

The authors describe the case of a patient who initially presented with uterine leiomyosarcoma (LMS) that later metastasized to the spine. The patient was treated at another institution for her primary uterine LMS, undergoing resection followed by adjuvant chemotherapy. After several years of disease remission, the patient presented in January 2011 to the authors' institution with recurrent uterine LMS metastatic to the spine, which has been treated with multiple therapeutic modalities in a combination of surgery, radiosurgery, and chemotherapy. As a result of this approach, the patient has been progression free for 35 months since her presentation (April 2011 to March 2014). We herein describe our experience treating this patient with recurrent uterine LMS of the spine and suggest that patients with recurrent uterine LMSs should be considered for treatment using a multimodality approach with emphasis on enrollment into clinical trials. ©AANS, 2015.


Adams D.J.,Duke University | Waud W.R.,Southern Research Institute | Wani M.C.,Research Triangle Institute International | Manikumar G.,Research Triangle Institute International | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2011

Hypoxia is a common feature of solid tumors. Up-regulation of hypoxia-inducing factor-1 (HIF-1) occurs in the majority of primary malignant tumors and in two-thirds of metastases, while most normal tissues are negative. HIF-1 induces the glycolytic phenotype, which creates an acidic extracellular microenvironment and associated pH gradient such that drugs that are weak acids are selectively taken up and retained in acidic tumors. 7-Butyl-10-amino- camptothecin (BACPT) is a prime example of an agent that can exploit the tumor pH gradient for enhanced selectivity. Purpose: This study profiles the antitumor activity of BACPT in vitro and its water-soluble dipeptide ester, BACPTDP, in vivo. Methods: Antitumor activity was evaluated by proliferation assays in cancer cell lines and in murine xenograft models for human neuroblastoma (IMR-32), colon (HT29), ovarian (SK-OV-3), pancreatic (Panc-1), glioma (SF-295) and non-small-cell lung (NCI-H460) cancers. Results: BACPT had superior antiproliferative activity compared to established drugs in monolayer cultures of human neuroblastoma and pancreatic tumor cell lines and in 3-dimensional histocultures of colon and primary ovarian cancer. Antitumor activity of BACPTDP was comparable to irinotecan in IMR-32, HT29, SF-295 and NCI-H460 xenografts, significantly greater in SK-OV-3 and in Panc-1 where complete regressions were observed. Combination of BACPT with gemcitabine produced additive to synergistic interactions in Panc-1 cells that were independent of drug ratio and optimal when gemcitabine was administered 24 h prior to BACPT. Conclusions: BACPTDP is a water-soluble camptothecin pro-drug that spontaneously generates the lipid-soluble active agent, BACPT. This topoisomerase inhibitor exploits solid tumor physiology for improved selectivity and activity against multiple tumor types with particular promise for use in treating pediatric neuroblastoma and pancreatic carcinoma. © 2010 Springer-Verlag.


PubMed | Dekk-Tec, Inc., Ochsner Medical Center, Tulane University and East Jefferson General Hospital
Type: | Journal: Journal of neurosurgery. Spine | Year: 2015

The authors describe the case of a patient who initially presented with uterine leiomyosarcoma (LMS) that later metastasized to the spine. The patient was treated at another institution for her primary uterine LMS, undergoing resection followed by adjuvant chemotherapy. After several years of disease remission, the patient presented in January 2011 to the authors institution with recurrent uterine LMS metastatic to the spine, which has been treated with multiple therapeutic modalities in a combination of surgery, radiosurgery, and chemotherapy. As a result of this approach, the patient has been progression free for 35 months since her presentation (April 2011 to March 2014). We herein describe our experience treating this patient with recurrent uterine LMS of the spine and suggest that patients with recurrent uterine LMSs should be considered for treatment using a multimodality approach with emphasis on enrollment into clinical trials.


Adams D.J.,Dekk-Tec, Inc. | Adams D.J.,Duke University | Morgan L.R.,Dekk-Tec, Inc.
Current Medicinal Chemistry | Year: 2011

Charge is an important characteristic of drug molecules, since ionization sites determine the pKa at a particular pH. The pKa in turn can affect many parameters, including solubility, dissolution rate, reaction kinetics, formulation, cell permeability, tissue distribution, renal elimination, metabolism, protein binding and receptor interactions. The impact of charge dynamics is amplified in human solid tumors that exhibit the glycolytic phenotype and associated acidic extracellular microenvironment. This phenotype is driven by hypoxia and creates a pH gradient in tumors that favors uptake of weak acids and exclusion of weak bases. Established anticancer drugs exhibit a range of pKa's and thus variable ability to exploit the tumor pH gradient. The camptothecins are a prime example as they represent a diverse class of approved anticancer drugs and drug candidates whose charge distribution varies with pH. An in silico method was used to predict charge distribution of camptothecins at physiological versus acidic pH in both the lactone and carboxylate forms. A significant amount of uncharged carboxylate was predicted at acidic pH that could enter tumor cells and accumulate in mitochondria to inhibit mitochondrial topoisomerase I. A model is presented to describe the charge dynamics of a new camptothecin analog and the impact on nuclear and mitochondrial mechanism(s) of action. This example illustrates the importance of integrating tumor physiology and charge dynamics into anticancer drug development. © 2011 Bentham Science Publishers Ltd.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 90.36K | Year: 2016

DESCRIPTION provided by applicant The primary goal of this Phase I pediatric oncology clinical trial will be to evaluate the safety and use of demethyl cholesteryloxycarbonylpenclomedine DM CHOC PEN as anticancer therapy for children with advanced cancer involving the central nervous system CNS DM CHOC PEN is a polychlorinated pyridine cholesteryloxycarbonate that crosses the blood brain barrier BBB accumulates in CNS tumor tissue in humans and has produced objective responses with acceptable reversible hepatic toxicities in patients with prior liver disease and no evidence of hematological renal neuro toxicities with improved quality of life and overall survival in adult Phase I II clinical trials IND The FDA supports the proposed Phase I clinical trial designed to identify safety toxicities and an acceptable MTD in children with CNS cancers now that the adult Phase I trial has been completed with acceptable toxicity and MTDs identified Primary malignant cancers of the central nervous system CNS account for less than of all malignancies yet brain tumors are the nd most common cause of death in children Some childhood malignancies e g intrinsic diffuse pontine gliomas are located such that surgery is not attempted A critical component in designing an agent that will cross the protective blood brain barrier BBB is that the agent must be readily transported intracerebrally does not produce local irritation neurotoxicity and is not recycled back into the general circulation After IV administration DM CHOC PEN readily penetrates the BBB is not a substrate for the transporter protein P glycoprotein P gp and has shown anticancer activity in CNS tumors The effective transport of DM CHOC PEN into CNS tumors in adults without neurotoxic behavioral alterations and associated events supports the drugandapos s use in children with CNS tumors at an age in which brain development and maturation is still very active with cognitive ability The observed responses noted in adults with metastatic cancers involving the CNS and cerebellum treated with DM CHOC PEN Table may also occur in medulloblastoma a primitive cerebellar tumor of neuroectodermal origin that is the nd most common brain tumor in children Thus the drugandapos s unique properties and lack of toxicities noted in the adult studies merits the Phase I trial proposed here in children The specific objectives of this Phase I study will be to Conduct a Phase I clinical trial with DM CHOC PEN in children that have advanced cancers involving the central nervous system to document toxicities define an acceptable maximum tolerated dose MTD and identify anticancer activity for the drug All data will be communicated through an e RAP program This will be accomplished through IND Studying the pharmacokinetic dynamic profiles of DM CHOC PEN and metabolites in children with advanced cancers involving the central nervous system Analyze data and prepare a Phase II clinical trial in children for FDA review Dr Johannes Wolff Chief Department of Pediatric Oncology Cleveland Clinic Cleveland OH will be the trial site director Dr Wolff is an established pediatric neurooncologist and qualified to direct the clinical trial Consultants are identified in the Design Section PUBLIC HEALTH RELEVANCE Primary malignant cancers of the central nervous system CNS account for less than of all malignancies yet brain tumors are the nd most common cause of death in children Surgery is the primary treatment with radiation always a concern and often not offered secondary to long term changes in development and cognitive functions in brain function Some childhood malignancies e g intrinsic diffuse pontine gliomas are located such that surgery is not attempted effective chemotherapy is not available DM CHOC PEN is a polychlorinated pyridine cholesteryloxycarbonate that crosses the blood brain barrier BBB accumulates in CNS tumor tissue in humans and has produced objective responses with acceptable reversible hepatic toxicities in patients with prior liver disease and no evidence of hematological renal or neuro toxicities with improved quality of life and overall survival in adul Phase I II clinical trials IND The FDA supports a Phase I clinical trial with DM CHOC PEN designed to identify safety toxicities and an acceptable MTD in children with CNS cancers now that the adult Phase I trial has been completed with safety acceptable reversible toxicity and MTDs identified A critical component in designing an agent that will cross the protective blood brain barrier BBB is that the agent must be readily transported intracerebrally does not produce local irritation neurotoxicity and is not recycled back into the general circulation DM CHOC PEN readily penetrates the BBB is not a substrate for the transporter protein P glycoprotein P gp and has shown anticancer activity in CNS tumors The effective transport of DM CHOC PEN into CNS tumors in adults without neurotoxic behavioral alterations and associated events supports the drugandapos s use in children with CNS tumors at an age in which brain development and maturation is in progress with cognitive ability The drugandapos s unique properties and lack of toxicities noted in the adult studies merits the Phase I trial proposed here in childre The specific objectives of this Phase I study will be to Conduct a clinical Phase I trial with DM CHOC PEN in children that have advanced cancers involving the central nervous system to document toxicities define an acceptable maximum tolerated dose MTD and identify anticancer activity for the drug This will be accomplished through IND Studying the pharmacokinetic dynamic profiles of DM CHOC PEN and metabolites in children with advanced cancers involving the central nervous system Prepare a Phase II clinical trial in children for FDA review Dr Johannes Wolff MD Chief Department of Pediatric Oncology Cleveland Clinic Cleveland OH will be the trial site director Established and qualified consultants are included in the Relevant Experience Section


The present disclosure relates to salts and compositions of isophosphoramide mustard and isophosphoramide mustard analogs. In one embodiment the salts can be represented by the formula I: (I) wherein A^(+) represents an ammonium species selected from the protonated (conjugate acid) or quaternary forms of aliphatic amines and aromatic amines, including basic amino acids, heterocyclic amines, substituted and unsubstituted pyridines, guanidines and amidines; and X and Y independently represent leaving groups. Also disclosed herein are methods for making such compounds and formulating pharmaceutical compositions thereof. Methods for administering the disclosed compounds to subjects, particularly to treat hyperproliferative disorders, also are disclosed.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 837.22K | Year: 2010

DESCRIPTION (provided by applicant): 7-Butyl-10-aminocamptothecin (BACPT), as a water-soluble dipeptide pro-drug - BACPTDP, is a novel camptothecin analog that has increased activity in hypoxic/acidic tumor tissues, characteristic of fast growing cancers that characteristically have deficient vasculature and outgrow their blood supply. Both in vitro and in vivo studies support the potential usefulness of BACPTDP in the treatment of pancreatic cancer. The significant responses seen with BACPTDP in the human PANC-1 xenograft model vs. other CPT controls are reviewed in support for the pre-clinical studies proposed in this application. The specific objectives of this Phase II study will be to: 1. Synthesize 7-butyl-10-aminocamptothecin dipeptide (BACPTDP) in 10-20 g quantities - sufficient for preclinical studies and formulation studies. 2. Conduct mouse and dog toxicity and pharmacokinetic studies. 3. Formulate the drug as a lyophilized powder. Document stability and potential clinical usefulness. 4. Develop and assay tissue/blood biomarkers as indicators for BACPTDP absorption and efficacy (pharmacodynamics). 5. Prepare the IND for future Phase I studies. Upon completion of these studies an FDA IND submission will be made. PUBLIC HEALTH RELEVANCE: BACPTDP is a novel camptothecins that was originally designed at Duke University to be used in the treatment of hypoxic, poorly vascularized tumors that possessed acidic environments. Studies conducted in the Phase I grant in pancreas, colon, ovarian and lung cancer xenograft models and reviewed herein, support our decision to move the product forward and ready it for clinical trials. Subsequently, DEKK-TEC has partnered with Duke and Research Triangle Institute (RTI) to complete the pre-clinical development, prepare the IND and ready the products for a Phase 1 clinical trial. Prior to the latter, DEKK-TEC proposes conducting the necessary pre- clinical toxicity, pharmacokinetic, formulation and stability studies. The studies as described will fulfill the requirements for a Phase I study to be designed.


Patent
Dekk-Tec, Inc. | Date: 2016-08-16

This disclosure concerns novel demethylpenclomedine analogs. Also disclosed are pharmaceutical compositions and methods for using such compositions to treat hyperproliferative disorders. In one embodiment the analogs are represented by the formula


The present disclosure relates to salts and compositions of isophosphoramide mustard and isophosphoramide mustard analogs. In one embodiment the salts can be represented by the formula I: (I) wherein A^(+) represents an ammonium species selected from the protonated (conjugate acid) or quaternary forms of aliphatic amines and aromatic amines, including basic amino acids, heterocyclic amines, substituted and unsubstituted pyridines, guanidines and amidines; and X and Y independently represent leaving groups. Also disclosed herein are methods for making such compounds and formulating pharmaceutical compositions thereof. Methods for administering the disclosed compounds to subjects, particularly to treat hyperproliferative disorders, also are disclosed.

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