(Press-News.org) Bottom Line: The investigational therapeutic ficlatuzumab in combination with chemotherapy showed signs of clinical efficacy in patients with relapsed/refractory acute myeloid leukemia.
Journal in Which the Study was Published: Blood Cancer Discovery, a journal of the American Association for Cancer Research
Author: Senior author Charalambos Andreadis, MD, professor of clinical medicine at the University of California, San Francisco (UCSF), and first author Victoria Wang, MD, PhD, an assistant professor of hematology and oncology at UCSF
Background: "Only about half of patients with acute myeloid leukemia (AML) will achieve long-term disease control," said Andreadis. Patients whose AML relapses or does not respond to initial therapy have worse outcomes, Andreadis explained. These patients typically undergo subsequent multi-agent chemotherapy, a toxic treatment with limited success in this population, he added.
"Unfortunately, patients whose cancers relapse or don't respond to initial therapy face a poor outlook, as only 30 to 40 percent of these patients respond to subsequent multi-agent chemotherapy and even fewer develop long-term remissions. Most patients will eventually succumb to their disease," he said.
New therapies targeting AML-specific mutations have been developed in recent years; however, these target select patients, highlighting the need for new, widely applicable therapies, according to Andreadis.
How the Study was Conducted: In their study, Andreadis and colleagues evaluated the safety and efficacy of an investigational agent targeting a shared chemical pathway in combination with single-agent chemotherapy in patients with relapsed/refractory AML. The investigational therapy, ficlatuzumab, is a first-in-class monoclonal antibody that binds the extracellular hepatocyte growth factor (HGF) to prevent it from activating MET signaling and stimulating tumor growth. "Unlike most existing targeted cancer therapies, ficlatuzumab targets an extracellular factor instead of a cancer-specific mutation," Andreadis noted, adding that some patients with refractory AML have higher levels of circulating HGF.
The phase I clinical trial enrolled 17 adult patients with AML that was either refractory to prior treatment or that had relapsed within 12 months of prior treatment. Patients received four doses of ficlatuzumab, administered 14 days apart, along with the chemotherapeutic cytarabine.
Results: Nine of 17 patients (53 percent) had a complete response, and four of the responding patients had no signs of minimal residual disease. Among responding patients, the progression-free survival was 31.2 months, and the overall survival was not reached. Ten patients (eight responders and two non-responders) proceeded to allogeneic hematopoietic cell transplantation; six of these patients remained in remission at the most recent follow-up.
The most common adverse event was febrile neutropenia. Serious adverse events occurred in two patients, and there was one death unrelated to the investigational therapy.
To identify molecular changes associated with treatment response, Andreadis and colleagues analyzed peripheral blood mononuclear cells collected at baseline and at several timepoints after treatment initiation. They found that ficlatuzumab treatment led to attenuated phosphorylation of MET, the receptor for HGF, thereby confirming on-target inhibition of HGF. Clinical response to ficlatuzumab treatment was associated with reduced phosphorylation of the S6 protein and increased expression of genes involved in myeloid and leukocyte activation, whereas non-responding patients were more likely to have increased expression of HGF, increased phosphorylation of S6, and expression of genes involved in protein translation, cell adhesion, and type I interferon signaling.
Author's Comments: "The 53 percent response rate was quite striking to us since historical response rates for the standard-of-care treatment are in the 30 percent range," noted Andreadis. "While these results need to be validated in a larger study, they suggest that ficlatuzumab in combination with single-agent chemotherapy may lead to better responses with less toxicity in patients with relapsed/refractory AML."
"By comparing pre-treatment to post-treatment blood samples using state-of-the art single-cell mass cytometry and RNA sequencing, we observed that ficlatuzumab successfully suppressed HGF signaling, and we also identified biomarkers of treatment response and resistance," said Wang. "This approach provided novel insight into the molecular changes that occur upon treatment, which could have clinical implications for tracking treatment response or identifying patients likely to respond."
"Together, our findings suggest that targeting an extracellular factor in conjunction with existing cancer therapies could be an effective therapeutic strategy for AML treatment," said Andreadis.
Study Limitations: Limitations of the study include the small sample size and its single-arm design. Andreadis and Wang noted that since the study was designed to assess safety and dosing, rather than efficacy, additional studies to validate the efficacy findings will be needed. A phase II clinical trial to evaluate ficlatuzumab plus chemotherapy has been initiated. An additional limitation was the lack of bone marrow specimens for the gene expression analyses.
INFORMATION:
Funding & Disclosures: The study was supported by the National Cancer Institute, the Damon Runyon Postdoctoral Award, the American Society for Clinical Oncology Young Investigator Award, the Department of Defense, and a Gateway for Cancer Grant. Andreadis and Wang declare no conflicts of interest.
Byron Bay (16/7/2021) - A new study from WCS and WWF reveals that nearly 20 percent of tropical Intact Forest Landscapes (IFLs) overlap with concessions for extractive industries such as mining, oil and gas. The total area of overlap is 376,449 square miles (975,000 square kilometers), about the size of Egypt. Mining concessions overlap most with tropical IFLs, at 11.33 percent of the total area, while oil and gas concessions overlap with 7.85 percent of the total area.
IFLs are globally important for conserving biodiversity and fighting climate change. ...
Oncotarget published "Occurence of RAS reversion in metastatic colorectal cancer patients treated with bevacizumab" which reported that a disappearance of RAS mutations in the plasma of about 50% of mCRCs treated with bevacizumab-based chemotherapy has been reported.
Using next-generation sequencing and real-time PCR approaches, these authors characterized the primary tumor and paired liver metastases in 28 RAS mutant mCRCs.
RAS mutant alleles are at the same percentage in PT and liver metastases in the control group, while a significant reduction of the level ...
Hiroshi Tanimoto, Director of the Earth System Division at the National Institute for Environmental Studies (NIES), Japan, and Astrid Müller together with their international research team, have developed a new method to evaluate satellite observations of XCO2 over open ocean areas, which are currently inaccessible through established validation network sites. In the new approach, a reference CO2 dataset is formulated by combining cargo ship and passenger aircraft observations which were conducted in cooperation with operators of the private sector.
(Background)
After the Paris Agreement entered into force, commitment to reduce greenhouse gas emissions are being expedited. CO2 is the most important anthropogenically produced greenhouse ...
Researchers from National University of Singapore and Stanford University published a new paper in the Journal of Marketing that investigates how rural consumers in India shift their expenditures towards branded consumption when they migrate to urban areas.
The study, forthcoming in the Journal of Marketing, is titled "The Economic and Social Impacts of Migration on Brand Expenditure: Evidence from Rural India" and is authored by Vishal Narayan and Shreya Kankanhalli.
With Covid-19 disrupting work patterns and increased investment in rural employment, many of India's 450 million internal migrants are returning to their villages. Consumer goods companies view this as an opportunity to grow their presence in rural markets, with migrants serving as unofficial brand ambassadors ...
A team of researchers from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), the University of Liège and the Helmholtz Institute Erlangen-Nürnberg for Renewable Energy have developed a microswimmer that appears to defy the laws of fluid dynamics: their model, consisting of two beads that are connected by a linear spring, is propelled by completely symmetrical oscillations. The Scallop theorem states that this cannot be achieved in fluid microsystems. The findings have now been published in the academic journal Physical Review Letters.
Scallops can swim in water by quickly clapping their shells together. They are large enough to still be able to move forwards through the moment of inertia while the scallop ...
The UK government's latest pandemic plan involves recklessly exposing millions of people to the acute and long-term effects of mass infection, warn experts in The BMJ today.
A strategy that chooses mass infection in the young now over vaccination in order to achieve greater population immunity to protect the vulnerable in winter, is "unethical and unscientific" say Dr Deepti Gurdasani and colleagues.
Instead of allowing infections to rise, they urge the government to take urgent actions to inform and protect the public and prepare for autumn.
These include outlining a long-term strategy for pandemic control, keeping basic measures ...
A team of researchers from Stanford University and the University of Leuven in Belgium has further elucidated an intriguing process that could be an important step toward a methanol fuel economy with abundant methane as the feedstock, an advance that could fundamentally change how the world uses natural gas.
Methanol - the simplest alcohol - is used to make various products, like paints and plastics, and as an additive to gasoline. Rich in hydrogen, methanol can drive new-age fuel cells that could yield significant environmental benefits.
If natural gas, of which methane ...
In a new study from University of California San Diego School of Medicine, researchers have confirmed that patients taking statin medications had a 41 percent lower risk of in-hospital death from COVID-19. The findings were published July 15, 2021 in PLOS ONE and expand upon prior research conducted at UC San Diego Health in 2020.
Statins are commonly used to reduce blood cholesterol levels by blocking liver enzymes responsible for making cholesterol. They are widely prescribed: The Centers for Disease Control estimates that 93 percent of patients who use a cholesterol-lowering drug use a statin.
"When faced with this virus at the beginning of the pandemic, there was a lot of speculation ...
Undeniably the shark movie to end all shark movies, the 1975 blockbuster, Jaws, not only smashed box office expectations, but forever changed the way we felt about going into the water - and how we think about sharks.
Now, more than 40 years (and 100+ shark movies) on, people's fear of sharks persists, with researchers at the University of South Australia concerned about the negative impact that shark movies are having on conservation efforts of this often-endangered animal.
In a world-first study, conservation psychology researchers, UniSA's Dr Briana Le Busque and Associate Professor Carla Litchfield have evaluated how sharks are portrayed in movies, finding that ...
CHAMPAIGN, Ill. -- A new study shows that it is possible to use mechanical force to deliberately alter chemical reactions and increase chemical selectivity - a grand challenge of the field.
The study led by University of Illinois Urbana-Champaign researcher Jeffrey Moore and Stanford University chemist Todd Martinezz demonstrates how external mechanical forces alter atomic motions to manipulate reaction outcomes. The study findings are published in the journal Science.
"We think of chemical reactions as molecules moving on a surface of potential energy in the way hikers follow the contour map of mountains and valleys along a trail," said lead author Yun ...
