Randomized, Multicenter, Double-blind, Phase 3 Trial of Tavocept Versus Placebo in Patients With Newly Diagnosed or Relapsed Advanced Primary Adenocarcinoma of the Lung Treated With Docetaxel or Paclitaxel Plus Cisplatin

Tavocept is an investigational drug that is being developed to see if it can increase the survival of patients who are being treated with chemotherapy as well as to see if it can prevent or reduce side effects of chemotherapy. This research study is aimed at trying to find out if people with advanced adenocarcinoma of the lung who are treated with a standard combination of chemotherapy drugs will live longer if they are also treated with an investigational drug called "Tavocept." Another objective of this research study is to find out whether or not Tavocept helps to prevent or reduce side-effects like kidney damage, anemia, and nausea and vomiting that can occur with these drug combinations. The drug combinations that will be used in this research study will include either paclitaxel and cisplatin, or docetaxel and cisplatin. These drug combinations are approved to be used to treat people with advanced NSCLC. Every patient on this research study will be treated with standard chemotherapy for primary NSCLC in the form of either docetaxel or paclitaxel (these will be recommended by your research study doctor), which will be given in combination with cisplatin.

Start Date01 Apr 2010

Sponsor / Collaborator

BioNumerik Pharmaceuticals, Inc.

[+1]

EUCTR2009-012983-14-HU / Not yet recruitingNot Applicable

Randomized, multicenter, double-blind, phase 3 trial of Tavocept versus Placebo in patients with newly diagnosed or relapsed advanced (stage IIIB/IV) primary adenocarcinoma of the lung treated with docetaxel or paclitaxel plus cisplatin

Start Date21 Oct 2009

Sponsor / Collaborator

BioNumerik Pharmaceuticals, Inc.

EUCTR2006-006950-81-PL / Not yet recruitingNot Applicable

A PHASE 3 STUDY OF SAFETY AND EFFICACY OF KARENITECIN VERSUS TOPOTECAN ADMINISTERED FOR 5 CONSECUTIVE DAYS EVERY 3 WEEKS IN PATIENTS WITH ADVANCED EPITHELIAL OVARIAN CANCER

Start Date20 Mar 2008

Sponsor / Collaborator

BioNumerik Pharmaceuticals, Inc.

100 Clinical Results associated with BioNumerik Pharmaceuticals, Inc.

0 Patents (Medical) associated with BioNumerik Pharmaceuticals, Inc.

Literatures (Medical) associated with BioNumerik Pharmaceuticals, Inc.

20 May 2020·Journal of Clinical Oncology

LP-300 as a potential first-in-class combination agent with tyrosine kinase inhibitors (TKIs) in non-smoker lung adenocarcinoma.

Author: Sharma, Panna ; Bhatia, Kishor ; Parker, Aulma ; Chen, Xinghai ; Kulkarni, Aditya ; Hausheer, Frederick H. ; Petluru, Pavankumar ; Barnhart, Kerry ; Kathad, Umesh ; Kochat, Harry ; Jair, Kamwing

e21660 Background: Lung cancer in non-smokers (LCINS) is the seventh leading cause of death among solid tumors. LCINS is more frequent in women, and the histological incidence of adenocarcinoma is higher among non-smokers. The mutation pattern by smoking status in non-small cell lung cancer (NSCLC) is distinct with genomic alterations in EGFR, MET and ROS1 being more frequent in non-smokers. Non-smoking status is the strongest clinical predictor of benefit from the EGFR TKIs. Lantern Pharma is developing LP-300/Dimesna, a non-toxic, well-tolerated, water-soluble disulfide as a combination therapy agent potentially indicated in female never-smokers with adenocarcinoma. Retrospective subgroup analyses of prior phase 3 trial data showed substantial overall survival benefit for LP-300 in combination with standard chemotherapy in patients with advanced NSCLC, especially in the female non-smoker adenocarcinoma subgroup (13.4 months in control arm to 27 months in treatment arm). Purpose of this work conducted at BioNumerik Pharmaceuticals was to determine if LP-300 modulates activity of selected receptor tyrosine kinases relevant to non-smoker NSCLC. Methods: In vitro luminescence-based kinase assays were used to evaluate the effect of LP-300 and LP-300-derived mesna-disulfide heteroconjugates, Erlotinib, and Crizotinib, in combination and as single agents, on EGFR, MET, and ROS1 kinase activity. Results: LP-300 inhibited WT EGFR kinase and MET kinase. LP-300 had a time-dependent inhibitory effect on ROS1 kinase activity. LP-300 and LP-300-derived mesna-disulfide heteroconjugates stimulated Erlotinib-mediated inhibition of WT and T790M EGFR. T790M EGFR is normally insensitive to Erlotinib but when LP-300 was used with Erlotinib, inhibition was more prominent. LP-300 also stimulated Crizotinib-mediated inhibition of MET kinase and displayed time-dependent stimulation of Crizotinib-mediated inhibition of ROS1 kinase. Conclusions: LP-300 is a multi-targeted modulator of enzymatic activities of EGFR, MET and ROS1, and potentiates the activity of Erlotinib and Crizotinib. EGFR family members contain conserved extracellular structures that are stabilized by disulfide bonds. Compounds that disrupt extracellular disulfide bonds could inactivate EGFR and potentially downregulate EGFR-dependent proliferative signaling in cancer cells. We propose LP-300 as a Disulfide Bond Disrupting Agent (DDA) that may complement existing EGFR-targeted agents functioning through alternate mechanisms.

01 Jan 2018·Journal of Veterinary Internal MedicineQ2 · AGRICULTURAL & FORESTRY SCIENCE

Clinical Evaluation of Tavocept to Decrease Diuresis Time and Volume in Dogs with Bladder Cancer Receiving Cisplatin

Q2 · AGRICULTURAL & FORESTRY SCIENCE

ArticleOA

Author: Tate, D.J. ; Selting, K.A. ; Bryan, M.E. ; Lattimer, J.C. ; Flesner, B.K. ; Bryan, J.N. ; Henry, C.J. ; Grubb, L. ; Hausheer, F. ; Bechtel, S.A.

BackgroundTransitional cell carcinoma is the most common bladder cancer of dogs. Cisplatin combined with piroxicam provides superior response rates, but unacceptable rates of nephrotoxicity. Tavocept is a chemoprotectant that has mitigated cisplatin toxicity and decreased the required infusion/diuresis volume in clinical trials in humans.Hypothesis/ObjectivesWe hypothesized that Tavocept would decrease diuresis volume and time and facilitate safe administration of a cisplatin/piroxicam protocol to dogs with bladder cancer. Secondary objectives were to compare response rate and survival times to an historical comparator group treated without Tavocept.AnimalsFourteen client‐owned dogs were prospectively enrolled.MethodsTumor volume was measured by computed tomography at days 0, 42, and 84. Dogs received combination Tavocept/cisplatin with a shortened diuresis protocol. A total of 4 doses was planned, with concurrent administration of piroxicam. Serial biochemical analyses were evaluated for azotemia.ResultsA 90‐minute infusion/diuresis time was used for all dogs. Three dogs (21%) had concurrent increases in serum creatinine (>2.0 mg/dL) and BUN (>42 mg/dL) concentrations; 2 of these dogs were isosthenuric. This frequency of nephrotoxicity is significantly less (P= 0.0406) than that of an historical control group treated without Tavocept. Overall response rate was 27%. Median survival time was comparable to historical controls (253 vs. 246 days).Conclusions and Clinical ImportanceTavocept decreased the required diuresis time with cisplatin from > 6 hours to 90 minutes, while also decreasing occurrence of azotemia. Survival time was comparable, but the response rate was inferior to an historical comparator group. Further evaluation in other tumors susceptible to platinum agents is warranted.

01 Apr 2015·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

Stabilization of the Karenitecin ® lactone by alpha-1 acid glycoprotein

Q4 · MEDICINE

Article

Author: Daoyuan Ding ; Shijie Yao ; Frederick Hausheer ; Pavankumar Petluru ; Xinghai Chen ; Qiuli Huang ; Aulma Parker ; Harry Kochat

PURPOSECamptothecins contain a lactone ring that is necessary for antitumor activity, and hydrolysis of the lactone ring yields an inactive carboxylate species. Human serum albumin (HSA) and alpha-1 acid glycoprotein (AGP) are clinically significant plasma proteins thought to have important roles in camptothecin lactone stability. Herein, we examined the effect(s) of HSA and AGP on the lactone stability of Karenitecin, a novel, highly lipophilic camptothecin analog, currently at the phase 3 clinical testing stage.METHODSAn AGP-immobilized protein column was used to develop HPLC methods to evaluate the effect(s) of physiologically relevant HSA and AGP concentrations on the lactone/carboxylate ratio and hydrolysis kinetics of Karenitecin, camptothecin (CPT), and topotecan (TPT).RESULTSPhysiologically relevant concentrations of HSA and AGP substantially slowed Karenitecin lactone hydrolysis. AGP was notably more effective at protecting the Karenitecin lactone from hydrolysis than HSA was in promoting hydrolysis. Additionally, AGP reversed the hydrolysis of partially hydrolyzed Karenitecin lactone. In contrast, HSA and AGP had minimal effects on hydrolysis of the TPT lactone, while the AGP/HSA solutions dramatically accelerated hydrolysis of the CPT lactone.CONCLUSIONAGP strongly enhances the lactone stability of Karenitecin. Since Karenitecin is highly protein-bound in human plasma and exhibits greater lactone stability, relative to other camptothecins, in patient plasma samples, this newly identified role of AGP in promoting lactone stability may have important implications for the design of more effective anticancer agents within the Karentecin™ and camptothecin classes.

100 Deals associated with BioNumerik Pharmaceuticals, Inc.

100 Translational Medicine associated with BioNumerik Pharmaceuticals, Inc.

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Drug(Targets)	Indications	Global Highest Phase

Cositecan ( TOP1 )	Malignant melanoma, metastatic More	Discontinued
Anti-Estrogens(BioNumerik) ( ER )	Breast Cancer More	Discontinued
MDAM ( Folate )	Neoplasms More	Pending
Dimesna ( GLRX x TXN )	Metastatic breast cancer More	Pending

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