Open-Label, Multi-Center, Phase 1, Dose Escalation Study With Phase 2 Expansion Cohort to Determine the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Intravenous TKM-080301 in Subjects With Advanced Hepatocellular Carcinoma

This study is an open-label, multi-center, phase 1, dose escalation study with a phase 2 expansion cohort to determine the safety, pharmacokinetics and preliminary anti-tumor activity of intravenous TKM-080301 in subjects with advanced hepatocellular carcinoma (HCC).
This study is being done to:
Test the safety and tolerability of TKM-080301 in subjects with advanced hepatocellular carcinoma
Find the highest dose of TKM-080301 that can be given without causing side effects, called the maximum tolerated dose (MTD).
Provide a preliminary assessment of anti-tumor activity of TKM-080301

Start Date01 Jun 2014

Sponsor / Collaborator

Arbutus Biopharma Corp.

NCT01437007 / CompletedPhase 1IIT

A Phase 1 Dose Escalation Study of Hepatic Intra-Arterial Administration of TKM 080301 (Lipid Nanoparticles Containing siRNA Against the PLK1 Gene Product) in Patients With Colorectal, Pancreas, Gastric, Breast, Ovarian and Esophageal Cancers With Hepatic

Background:
Cancer in the liver can start in the liver (e.g., primary liver cancer or hepatocellular cancer) or spread to the liver from cancers in other parts of the body (e.g. colon, pancreas, gastric, breast, ovarian, esophageal cancers, cancer with metastases to the liver.) People who have tumors that can be removed by surgery live longer than those whose cancer cannot be removed. Chemotherapy can shrink some tumors in the liver, which also helps people to live longer, and sometimes chemotherapy can shrink tumors enough that they can be removed by surgery. However, most chemotherapy drugs do not work well on tumors in the liver. In this study we are testing a new drug, TKM-080301, given directly into the cancer blood supply in the liver circulation, to see if it will cause tumors to shrink.
Objectives:
- To test the safety and effectiveness of TKM-080301 for cancer in the liver that has not responded to standard treatments.
Eligibility:
- Individuals at least 18 years of age who have inoperable cancer that has started in or spread to the liver.
Design:
Participants will be screened with a medical history and physical exam. They will also have blood tests, and imaging studies.
Participants will have a liver angiogram (type of X-ray study) to look at the blood flow in the liver and to place a catheter for delivery of the TKM080301.
Participants will have a single dose of TKM-080301 given directly into the liver. After the drug has been given, the catheter will be removed. They will have frequent blood tests and keep a diary to record side effects.
Participants may have two more doses, each dose given 2 weeks apart. {Before each dose, participants will have another angiogram and catheter placement.}They may also have liver biopsies to study the tumors.
Two weeks after the third treatment (one full course), participants will have a physical exam, blood tests, and imaging studies. If the tumor is shrinking, they may have up to three more courses of the study drug.
Participants will have follow up visits every 3 months for 2 years after the last course and then every 6 months as required.

Start Date26 Aug 2011

Sponsor / Collaborator

National Cancer Institute

NCT01262235 / CompletedPhase 1/2

A Phase 1/2 Dose Escalation Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of Intravenous TKM-080301 in Patients With Advanced Solid Tumors

This study will be a Phase I/II, open-label, non-randomized, dose-finding trial conducted at multiple clinical centers. The study is designed to determine the safety, tolerability and PK of TKM-080301 in adult patients with solid tumors or lymphomas that are refractory to standard therapy or for whom there is no standard therapy. After the determination of the maximum tolerated dose this dose will be utilized in an expansion cohort or subjects with refractory neuroendocrine tumors (NET) or adrenocortical carcinoma (ACC) tumors.

Start Date01 Dec 2010

Sponsor / Collaborator

Arbutus Biopharma Corp.

100 Clinical Results associated with TKM-PLK1

100 Translational Medicine associated with TKM-PLK1

100 Patents (Medical) associated with TKM-PLK1

Literatures (Medical) associated with TKM-PLK1

01 Jun 2019·The oncologistQ2 · MEDICINE

An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma

Q2 · MEDICINE

Article

Author: Lin, Chia-Chi ; Kelley, Robin K. ; Abou-Alfa, Ghassan K. ; Chao, Tsu-Yi ; Choi, Hye Jin ; Modiano, Manuel ; El Dika, Imane ; Freilich, Bradley ; Lim, Ho Yeong ; Brown, Joanne ; Yoon, Jung-Hwan ; Yong, Wei Peng ; Yau, Thomas ; Ryoo, Baek-Yeol ; Knox, Jennifer

Abstract:

Lessons Learned:

TKM-080301 showed a favorable toxicity profile at the studied dose. TKM-080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early-phase study does not support further evaluation as a single agent.

Background:

Polo-like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA-induced silencing complex and a reduction in cell proliferation.

Methods:

A 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child-Pugh score A received TKM-080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days.

Results:

The study enrolled 43 patients. The starting dose of TKM-080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression-free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months.

Conclusion:

TKM-080301 was generally well tolerated. In this early-phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted.

01 Jun 2015·Translational oncologyQ3 · MEDICINE

Targeting Polo-Like Kinases: A Promising Therapeutic Approach for Cancer Treatment

Q3 · MEDICINE

ReviewOA

Author: Liu, Xiaoqi

Polo-like kinases (Plks) are a family of serine-threonine kinases that regulate multiple intracellular processes including DNA replication, mitosis, and stress response. Plk1, the most well understood family member, regulates numerous stages of mitosis and is overexpressed in many cancers. Plk inhibitors are currently under clinical investigation, including phase III trials of volasertib, a Plk inhibitor, in acute myeloid leukemia and rigosertib, a dual inhibitor of Plk1/phosphoinositide 3-kinase signaling pathways, in myelodysplastic syndrome. Other Plk inhibitors, including the Plk1 inhibitors GSK461364A, TKM-080301, GW843682, purpurogallin, and poloxin and the Plk4 inhibitor CFI-400945 fumarate, are in earlier clinical development. This review discusses the biologic roles of Plks in cell cycle progression and cancer, and the mechanisms of action of Plk inhibitors currently in development as cancer therapies.

News (Medical) associated with TKM-PLK1

10 Sep 2021

·endpts.com

Canada's Bausch to pay $300M in antitrust settlement; Cardiff releases data on mCRC trial

Canadian pharma company Bausch Health has agreed to settle an antitrust class-action suit from a 2015 price increase. According to Reuters , the class-action lawsuit accused Bausch of maintaining an illegal monopoly on diabetes drug Glumetza, enabling a price hike of nearly 800% in 2015 from $5.72 to $51 per tablet. Lawyers for companies that bought Glumetza and filed the suit against Bausch revealed the deal in a court filing on Wednesday, asking US District Judge William Alsup in San Francisco to approve it. The case had been scheduled to go to trial next month. “Plaintiffs are pleased with the settlement, which recovers for the class a very substantial portion of the overcharges that they suffered,” Steve Shadowen, a lawyer for the purchasers, said in an email. California biotech Cardiff Oncology has new data from its lead clinical program evaluating their PLK1 inhibitor onvansertib in combination with standard-of-care chemotherapies Folfiri/bevacizumab for second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC). Highlights of the data as of July 2 in the multi-center and single arm study include: To be considered eligible for the trial, patients must have confirmed metastatic and unresectable colorectal carcinoma harboring a KRAS mutation. They must also have failed treatment with, or be intolerant to the Folfox regimen (fluoropyrimidine and oxaliplatin, with or without bevacizumab). “Our Phase Ib/II trial continues to generate data suggesting that the addition of onvansertib to SOC results in an objective response rate and median progression-free survival that substantially exceed those previously achieved with SOC alone,” said Cardiff CMO Katherine Ruffner in a statement. “I look forward to the trial’s continued advancement and future data readouts.” Endo International and subsidiaries have settled three cases brought by the state of New York and two major counties for $50 million in a still-ongoing saga regarding the opioid crisis. The Irish pharma had been accused alongside other companies of deceptive marketing practices and downplaying the risks of opioid addiction. A jury trial on liability has been ongoing since June. As a result of the settlement, the state and NY counties have ended their cases against Endo. Endo does not admit wrongdoing. Endo is now shifting its focus to obtaining a global settlement, according to a statement put out by the company yesterday. Endo is exploring other alternatives and said that they may try to implement one or more of those alternatives if a global settlement is not possible. Agenus announced the launch of its new subsidiary SaponiQx today. Its goal is to drive innovation in novel adjuvant discovery and vaccine design while building saponin molecules — and to that end, the company is partnering with Ginkgo Bioworks. According to a statement put out by Agenus, Ginkgo’s experience in metabolic engineering, enzymatic diversification, and process optimization can be applied to discover novel adjuvants and improve current manufacturing processes — which is where SaponiQx comes in and applies best practices toward developing better vaccines. “Agenus is pleased for SaponiQx to collaborate with Ginkgo Bioworks to develop its novel saponin products from sustainably sourced raw materials, with a goal to meet the current demands placed on the vaccine industry for pandemic vaccines,” said Garo Armen, CEO and Chairman of Agenus and Executive Chairman of SaponiQx The National Cancer Institute is considering granting an exclusive patent license to Seattle biotech Sana for an anti-CD22 CAR-T therapy. The document, signed on Tuesday by Richard Rodriguez with the National Cancer Institute, will be published on the federal register on Monday. The biotech unicorn went public earlier this year, when it raised a massive $587.5 million in its IPO in February. It has set big aims to remake cell therapy with new targets, off-the-shelf products and even in vivo administration. There is no update on when Sana’s therapy will be ready for the clinic. Other companies have gone after CD-22 before —most notably Juno, which worked in concert with the NCI. Bristol Myers Squibb, though, has offered few updates on the candidate since buying out the biotech in 2018.

Cell TherapyVaccineLicense out/inCollaborateIPO

07 Jul 2021

·www.globenewswire.com

Cyclacel Pharmaceuticals to Present at Ladenburg Thalmann's

BERKELEY HEIGHTS, N.J., July 07, 2021 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals, Inc. (NASDAQ: CYCC, NASDAQ: CYCCP; "Cyclacel" or the "Company"), a biopharmaceutical company developing innovative medicines based on cancer cell biology, today announced that it will participate in the Ladenburg Thalmann’s Virtual 2021 Healthcare Conference held July 13-14, 2021. Spiro Rombotis, President & Chief Executive Officer, will present an overview of Cyclacel’s business followed by an analyst-led fireside chat. Presentation Information: Investor registration: click here The webcast will be archived for 90 days and can be found on the Cyclacel website at . About Cyclacel Pharmaceuticals, Inc. Cyclacel is a clinical-stage, biopharmaceutical company developing innovative cancer medicines based on cell cycle, transcriptional regulation and mitosis biology. The transcriptional regulation program is evaluating fadraciclib, a CDK2/9 inhibitor, and the anti-mitotic program CYC140, a PLK1 inhibitor, in patients with both solid tumors and hematological malignancies. Cyclacel's strategy is to build a diversified biopharmaceutical business based on a pipeline of novel drug candidates addressing oncology and hematology indications. For additional information, please visit . Forward-looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and intended utilization of Cyclacel’s product candidates, the conduct and results of future clinical trials, plans regarding regulatory filings, future research and clinical trials and plans regarding partnering activities. Factors that may cause actual results to differ materially include the risk that product candidates that appeared promising in early research and clinical trials do not demonstrate safety and/or efficacy in larger-scale or later clinical trials, trials may have difficulty enrolling, Cyclacel may not obtain approval to market its product candidates, the risks associated with reliance on outside financing to meet capital requirements, the potential effects of the COVID-19 pandemic, and the risks associated with reliance on collaborative partners for further clinical trials, development and commercialization of product candidates. You are urged to consider statements that include the words "may," "will," "would," "could," "should," "believes," "estimates," "projects," "potential," "expects," "plans," "anticipates," "intends," "continues," "forecast," "designed," "goal," or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to our most recent Annual Report on Form 10-K and other periodic and other filings we file with the Securities and Exchange Commission and are available at . Such forward-looking statements are current only as of the date they are made, and we assume no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Contacts © Copyright 2021 Cyclacel. All Rights Reserved. The Cyclacel logo and Cyclacel® are trademarks of Cyclacel.

05 Feb 2021

·www.globenewswire.com

Tiziana Life Sciences plc ("Tiziana" or the "Company")

NEW YORK and LONDON, Feb. 05, 2021 (GLOBE NEWSWIRE) -- Tiziana Life Sciences plc (NASDAQ: TLSA / LSE: TILS) ("Tiziana" or the "Company"), a biotechnology company focused on innovative therapeutics for oncology, inflammation, and infectious diseases, today announces the appointment of Dr. Thomas Adams, Ph.D. as an executive director. Dr. Adams will assume the position of Head of Drug Development with immediate effect and his executive role will be to manage and oversee all matters relating to the Company's pre-clinical and clinical drug development programs and associated intellectual property. Dr. Thomas H. Adams (age: 78) Dr. Adams holds a Ph.D. in Biochemistry from the University of California, Riverside. The Board believes that Dr. Adams’ executive leadership and the extensive healthcare expertise he has developed makes Dr. Adams ideally qualified to serve as an additional director of the Company. Dr. Adams, has been a director of Cardiff Oncology, Inc (NASDAQ: CRDF) ("Cardiff") since June 2018, serving in the roles of Chief Executive Officer from June 2018 to May 2020, as chairman of the board from April 2009 to December 2020 and as Executive Chairman from May through December 2020. At Cardiff, Dr. Adams led the development and repurposing of onvansertib, a first-in-class, third-generation Polo-like Kinase 1 (PLK1) inhibitor, in combination with standard-of-care chemotherapy and targeted therapeutics, for the potential treatment of KRAS-mutated metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer and relapsed or refractory acute myeloid leukemia. He is currently a Director at Hepion Pharmaceuticals, Inc. (NASDAQ: HEPA), where he has served since 2014. Previously, Dr. Adams served as Chairman of Clearbridge BioPhotonics, Inc., an imaging solutions company, from 2013 to 2019, and as Director of Synergy Pharmaceuticals, Inc. from 2009 to 2019. He served in several leadership roles at IRIS International, including Director, Head of Personalized Medicine and Chief Technology Officer, from 2005 until the company’s acquisition by Danaher Corporation in 2012. From 1998 to 2006, Dr. Adams was Chairman and Chief Executive Officer of Leucadia Technologies, a privately held biotechnology company which was acquired by IRIS International, Inc. in 2006. Dr. Adams founded Genta, Inc. in 1989 and served as its Chief Executive Officer until 1997. He also founded Gen-Probe, Inc. in 1984 and served as Chairman and Chief Executive Officer until its acquisition by Chugai Biopharmaceuticals, Inc. in 1989. Dr. Adams stated, “I am excited to join the team at Tiziana to focus on developing Foralumab and Milciclib. These new targeted therapies promise to deliver relief to patients suffering from cancer, inflammatory and infectious disease. My experience in precision medicine utilizing targeted therapies with precision diagnostics should accelerate the delivery of these important therapeutics.” Gabriele Cerrone, Chairman of Tiziana, said, "We are delighted to welcome Dr. Adams to the Board and consider that his proven track record in the field of cancer could add significant value to the development of the Company's Milciclib and Foralumab oncology programs." This announcement contains inside information. Pursuant to Listing Rule 9.6.13, in connection with Dr. Adams' appointment, Dr. Adams was Executive Chairman of Synergy Pharmaceuticals Inc. until October 2018. In December 2018 Synergy Pharmaceuticals Inc. (then listed on NASDAQ), filed for Chapter 11 bankruptcy in the USA. The company currently remains in the administration process. There are no other disclosures to make pursuant to Listing Rule 9.6.13, in respect of Dr. Adams' appointment. About Tiziana Life Sciences Tiziana Life Sciences plc is a UK biotechnology company that focuses on the discovery and development of novel molecules to treat human disease in oncology and immunology. In addition to Milciclib, the Company is also developing Foralumab for liver diseases. Foralumab is the only fully human anti-CD3 monoclonal antibody in clinical development in the world. This Phase 2 compound has potential application in a wide range of autoimmune and inflammatory diseases, such as nonalcoholic steatohepatitis (NASH), ulcerative colitis, multiple sclerosis, type-1 diabetes (T1D), Crohn's disease, psoriasis and rheumatoid arthritis, where modulation of a T-cell response is desirable. The company is accelerating development of anti-Interleukin 6 receptor (IL6R) mAb, a fully human monoclonal antibody for treatment of IL6-induced inflammation, especially for treatment of COVID-19 patients. For further enquiries:United Kingdom Investors: U.S. Investor Contact:RedChip Companies, Inc.Dave Gentry407-491-4498dave@redchip.com

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Hepatocellular Carcinoma	Phase 2	US	Arbutus Biopharma Corp.	01 Jun 2014
Advanced Hepatocellular Carcinoma	Phase 2	CN	Arbutus Biopharma Corp.	01 Jun 2014
Advanced Hepatocellular Carcinoma	Phase 2	CA	Arbutus Biopharma Corp.	01 Jun 2014
Advanced Hepatocellular Carcinoma	Phase 2	SG	Arbutus Biopharma Corp.	01 Jun 2014
Advanced Hepatocellular Carcinoma	Phase 2	KR	Arbutus Biopharma Corp.	01 Jun 2014
Advanced Hepatocellular Carcinoma	Phase 2	TW	Arbutus Biopharma Corp.	01 Jun 2014
Hepatocellular Carcinoma	Phase 2	US	Arbutus Biopharma Corp.	01 Jun 2014
Hepatocellular Carcinoma	Phase 2	CN	Arbutus Biopharma Corp.	01 Jun 2014
Hepatocellular Carcinoma	Phase 2	CA	Arbutus Biopharma Corp.	01 Jun 2014
Hepatocellular Carcinoma	Phase 2	SG	Arbutus Biopharma Corp.	01 Jun 2014

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02191878 (Pubmed \| Oncologist)	Phase 1	Advanced Hepatocellular Carcinoma	43	TKM-080301	gtllchqmge(fuejhlwhbe) = xkivcocoph fxuwxsnotu (lzcvwfcxib ) View more	Negative	01 Jun 2019

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