Showing posts sorted by relevance for query Carboplatin. Sort by date Show all posts
Showing posts sorted by relevance for query Carboplatin. Sort by date Show all posts

Friday, July 29, 2016

Added benefit of crizotinib drug for first-line treatment of advanced bronchial carcinoma not proven


Crizotinib.svg

In continuation of my update on crizotinib

The drug crizotinib (trade name: Xalkori) has been available since 2012 for patients with advanced non-small cell lung cancer (bronchial carcinoma) who have a high activity of the enzyme anaplastic lymphoma kinase (ALK) and have already received another treatment. In November 2015, the approval was extended to first-line treatment.

After its assessment in 2013, the German Institute for Quality and Efficiency in Health Care (IQWiG) therefore now reassessed the added benefit of the drug in comparison with the appropriate comparator therapy - and found out: An added benefit of crizotinib for the first-line treatment of advanced bronchial carcinoma is not proven.

Carboplatin only in advanced risk of cisplatin side effects

Advanced bronchial carcinoma can only be treated palliatively. The Federal Joint Committee (G-BA) specified several appropriate comparator therapies for this. Either cisplatin in combination with a third-generation cytostatic agent was to be used in the control arm, or - in case of an increased risk of cisplatin side effects - carboplatin with a third-generation cytostatic agent. Monotherapy with gemcitabine or vinorelbine was an alternative option for patients with already severe limitations.

Use of carboplatin attached to condition

The drug manufacturer did not use the latter option and only submitted data from a randomized study in which crizotinib was directly compared with cisplatin or carboplatin, each in combination with the cytostatic agent pemetrexed. Carboplatin is not approved for the treatment of advanced non-small cell lung cancer, but can be prescribed in so-called off-label use. This is only the case for patients with an advanced risk of cisplatin side effects, e.g. in neuropathy, hearing impairment or susceptibility to nausea, renal insufficiency or cardiac failure.

The only submitted study did not fulfil the condition

Almost half of the participants received carboplatin in the control arm of the PROFILE 1014 study; the criteria for this individual medical decision were not comprehensible. A large proportion of the patients in the control arm did not correspond to the criteria of the Pharmaceutical Directive for the off-label use of carboplatin. Patients with neuropathy, renal insufficiency or cardiac failure were excluded from participation in the study and only about two and six per cent of the participants had notable hearing impairment or nausea as accompanying disease.

Hence the control group of the study did not adequately represent the appropriate comparator therapy. The data submitted were therefore unsuitable for the derivation of an added benefit of crizotinib in comparison with this comparator therapy.


Added benefit of crizotinib drug for first-line treatment of advanced bronchial carcinoma not proven: The drug crizotinib (trade name: Xalkori) has been available since 2012 for patients with advanced non-small cell lung cancer (bronchial carcinoma) who have a high activity of the enzyme anaplastic lymphoma kinase (ALK) and have already received another treatment. In November 2015, the approval was extended to first-line treatment.

Wednesday, June 16, 2010

Two-drug phase I trial shows promise in treating late-stage ovarian cancer

In continuation of my update on carboplatin .....

Researchers from Indiana University School of Medicine, have come up  with interesting finding from a two-Drug Phase I Trial Show, i.e.,  the combination of decitabine (see structure) and carboplatin appears to improve the outcome of women who have late-stage ovarian cancer. Researchers report four of 10 patients who participated in a phase I clinical trial had no disease progression after six months of treatment. One patient experienced complete resolution of tumor tissue for a period of time.

"Carboplatin is the most efficient drug therapy for ovarian cancer,"  unfortunately, patients with recurrent disease become resistant to the drug after one or two rounds claims the lead researcher.."
Decitabine was first used to treat the study patients intravenously daily for five days followed on the eighth day with carboplatin. After a month, the regimen begins again.

Encouraged by the results of the phase I trial, which determined the safety of two different dosing regimens, a phase II trial is now under way with 17 patients already enrolled. Phase II trials are primarily focused on assessing the effectiveness of a drug or treatment protocol.

As per the claim by the researcher, decitabine  (a known methylation inhibitor) can help return tumor suppression genes to an active state, and also improve cells' susceptibility to anti-cancer drugs like carboplatin. Researchers adds that decitabine isn't just targeting active ovarian cancer cells, but also cancer stem cells that seem to survive the first treatments. 

Researchers conclude that, by keeping tumor suppression genes from being methylated, carboplatin and other platinum-based treatments for ovarian cancer have a better chance of success in the late stages.

Ref : http://www3.interscience.wiley.com/journal/123500856/abstract?CRETRY=1&SRETRY=0

Tuesday, August 18, 2015

Combination therapy provides promising results in patients with advanced non-small cell lung cancer

An early phase study testing an anti-PDL1 agent in combination with standard chemotherapy in the treatment of advanced non-small cell lung cancer has provided promising early results, prompting multiple phase III studies in lung cancer. The findings are being presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

In this phase 1b study, patients with untreated non-small cell lung cancer received one of three standard platinum-based chemotherapy regimens (paclitaxel/carboplatin, pemetrexed/carboplatin or nab-paclitaxel/carboplatin) with MPDL3280A, an antibody targeting PD-L1. Early results from the 

Taxol.svgPaclitaxel Carboplatin-skeletal.svgCarboplatin Pemetrexed.svgPemetrexed

first 37 patients showed impressive response rates between 60-75 percent, comparing favorably to historical outcomes with chemotherapy alone, where historical response rates from randomized trials are around 30 - 35 percent. In addition, two complete responses already have been documented, with no evidence of lung cancer on CT scans.

"A complete response is not typically seen in patients with stage IV lung cancer," says the abstract's lead author, Stephen V. Liu, MD, assistant professor of medicine at Georgetown Lombardi Comprehensive Cancer Center. "And the response rates seen with MPDL3280A and chemotherapy were higher than one would expect with chemotherapy alone."

Tuesday, January 15, 2013

Results from Morphotek’s farletuzumab Phase III combination study on ovarian cancer

In continuation of my update on carboplatin and a taxane


Morphotek® Inc., a wholly-owned subsidiary of Eisai Inc., announced top-line results from a Phase III study of its investigational agent farletuzumab (MORAb-003) in combination with carboplatin and a taxane in patients with platinum-sensitive epithelial ovarian cancer in first relapse. 

The study found that farletuzumab in combination with carboplatin and a taxane did not meet the study's primary endpoint of progression-free survival (PFS). The post hoc exploratory analysis showed, however, a trend toward improved PFS in some patient subsets and further analysis is ongoing.

The preliminary safety analysis indicated that the most commonly reported adverse events were those known to be associated with the study chemotherapy agents. Additionally, some immune-mediated events were observed with farletuzumab.

After further analysis of these clinical results, the company will determine a new development strategy based on discussion with external experts and relevant health authorities. In the double-blind, placebo-controlled study, 1,100 patients were enrolled to receive standard-of-care (carboplatin and a taxane [paclitaxel or docetaxel]) chemotherapy and were randomized to three parallel groups to receive one of two different dose levels of farletuzumab or placebo.

"While we are disappointed with these results, we know that ovarian cancer is a difficult disease to treat successfully," says Dr. Nicholas Nicolaides , President and CEO of Morphotek. "Morphotek remains committed to research to understand the potential role of farletuzumab in ovarian and other types of cancer."......


Wednesday, September 16, 2015

Possible New Combination Chemotherapy for Patients with Advanced Prostate Cancer

For more than a decade, oncologists using cytotoxic chemotherapy to treat patients with advanced metastatic castration-resistant prostate cancer (mCRPC) have relied on the sequential use of single agent taxanes such as docetaxel and cabazitaxel. For example, docetaxel is commonly used as the "first-line" therapy, while cabazitaxel is used as the "second-line" therapy. A role for combination therapy using two or more chemotherapy agents at the same time has not been well studied. This week, however, results of a clinical trial presented at the American Society of Clinical Oncology meeting by researchers at The University of Texas MD Anderson Cancer Center may change the perspective on a role for combination chemotherapy in advanced disease.
Carboplatin-skeletal.svg Carboplatin Cabazitaxel.png Cabazitaxel  Docetaxel.svg Docetaxel

The study compared the effectiveness of cabazitaxel alone versus cabazitaxel combined with carboplatin -- a type of platinum chemotherapy -- in patients with metastatic castrate-resistant prostate cancer (mCRPC). To date, 160 men have been randomized to treatment with either the single or dual chemotherapy drug regimen. Each patient received up to 10 cycles of chemotherapy.
To monitor the effects of treatment, MD Anderson researchers tracked several variables including Progression Free Survival, as well as changes in blood levels of prostate-specific antigen (PSA) and bone-specific alkaline phosphatase (BAP, a marker of prostate cancer in bone cells). In addition, safety and toxicity were monitored for both patient groups.

Analysis and comparison of the data demonstrated that median PFS was significantly longer for patients receiving combination versus single agent chemotherapy (6.7 months vs 4.4 months, respectively, p = 0.01). Furthermore, reductions in both PSA and BAP were greater for the combination therapy group. PSA reductions greater than 50 percent occurred 60 percent of the time with combined chemotherapy vs. 44 percent with the single drug. PSA reductions greater than 90 percent occurred 28 percent of the time with two chemotherapy drugs vs. 20 percent with one. In addition, BAP reductions greater than 50 percent for combination vs. single drug were 63 percent and 25 percent respectively.

Side effects, such as fatigue, anemia and neutropenia were comparable for both the single-drug regimen and two-drug regimen. In addition, there were no significant toxicity events.

"We believe cabazitaxel-carboplatin combination chemotherapy may become the clinical standard for advanced prostate cancer once additional safety, efficacy and overall survival data is generated," explained Paul Corn, M.D., Ph.D., an associate professor of genitourinary medical oncology at MD Anderson. "Dr. Ana Aparicio's lab is currently developing tumor-specific biomarkers to identity patients with an aggressive variant of prostate cancer most likely to benefit from this approach."

Tuesday, January 27, 2015

Carboplatin and paclitaxel show promise for advanced thymic carcinoma

In continuation of carboplatin and paclitaxel

A multicentre, phase II study of carboplatin and paclitaxel (CbP) in chemotherapy-naïve patients with advanced thymic carcinoma has shown that the treatment has promising efficacy compared with standard anthracycline-based chemotherapy.

Thymic carcinoma is very rare, and consequently it is hard to investigate it separately from thymoma. Previous studies evaluating chemotherapy regimens have included patients with both types of tumour, explain Takashi Seto (National Kyushu Cancer Center, Fukuoka, Japan) and colleagues.

Forty patients from 21 centres across Japan were enrolled in the current study from May 2008 until November 2010. One patient subsequently dropped out. The sample size was decided on the basis that it was large enough to reject the primary endpoint of an objective response rate (ORR) of 20%.

Thursday, August 11, 2011

Positive results from combination drug trial for late-stage ovarian cancer

In continuation of my update on  carboplatin

Researchers from IU Medical Sciences Program-Bloomington  and Indiana University Melvin, have found that, an experimental two-drug combination (decitabine & carboplatin) for treating late-stage ovarian cancer continues to produce strong results, leading its Indiana University researchers to actively pursue the next step, conducting a larger clinical trial to test the therapy and to see how it compares with existing treatments for ovarian cancer.

The researchers have been investigating the addition of decitabine, which is marketed as Dacogen in the United States, because they suspect it reactivates tumor suppression genes that are turned off in ovarian cancer cells and improves cells' susceptibility to anti-cancer drugs like carboplatin.

"The science associated with the trial is novel and exciting and could have impact in the future," she said.....
More...

Friday, October 7, 2022

Specific sequence of drugs reduces cost of treating metastatic breast cancer while preserving quality of life

The researchers developed three different computer models to predict how a hypothetical set of 10,000 patients with specific types of metastatic breast cancer would respond to different sequences and types of chemotherapy. For this study, the patient's cancer was either no longer responding to hormone therapies (endocrine resistant) or was a type of the disease called triple-negative breast cancer.

Currently, there are many chemotherapy choices to treat metastatic breast cancer. Oncologists have some preferences of which drugs to use early in treatment, but there is little clear evidence on the best order in which to give the drugs. The researchers consulted oncologists and experts in the field to choose which chemotherapy drugs were preferred choices to include in the study.

Mimicking clinical practice, and based upon existing data, the researchers then assumed that if a person started treatment with one drug, they would change to a second-choice treatment after their cancer stopped responding to the first drug, or if the side effects weren't tolerable. The purpose of the study was to test whether putting the drugs in one sequence compared to another could keep the patient on treatment for similar times while decreasing their side effect and/or cost burden.

"The cost of cancer drugs in the U.S. has rapidly increased, even for generics. As a society, we urgently need more strategies to reduce cancer drug costs without compromising outcomes, and our analysis provides quantifiable evidence to help providers choose lower priced, but equally effective sequences of drugs," said Stephanie B. Wheeler, PhD, MPH, professor of health policy & management at UNC Gillings and associate director of community outreach and engagement at UNC Lineberger and corresponding author of the article. "More spending on cancer care does not necessarily confer greater health benefits."

The costs calculated in this study were inclusive of medical and nonmedical costs borne by patients, including lost productivity. In this simulation, after two years, nearly all women would have completed the first three sets of treatment, but the cancer would cause the death of about one-third of the women. Productivity days lost due to sickness were similar across chemotherapy sequences, so most of the cost difference was due to drug savings. In the simulation, patients were placed in three groups, depending on what treatments they had already received for earlier episodes of breast cancer.

Outcomes in the three groups were:

  • For people who had not previously received the common chemotherapy drug categories, including a taxane (e.g., paclitaxel) or an anthracycline (e.g., capecitabine), treatment with paclitaxel then capecitabine followed by doxorubicin corresponded to the highest expected gains in quality of life and lowest costs.
  • For people who had previously received a taxane and an anthracycline drug, treatment with carboplatin, followed by capecitabine, followed by eribulin, corresponded to the highest expected gains in quality of life and lowest costs.
  • For people who had previously received a taxane but not an anthracycline, treatment sequences beginning with capecitabine or doxorubicin, followed by eribulin, were most cost-effective.

"The drugs we studied are already recommended and reimbursed for the treatment of metastatic breast cancer, but the optimal sequencing of them has been unclear, which has led to considerable variation in physician preference and practice. Our study suggests that treatment sequencing approaches that minimize costs early may improve the value of care," Wheeler said. "The implications of this study are fairly straightforward for medical oncologists and those developing value-based clinical pathways to implement in practice now."

UNC Lineberger's Katherine E. Reeder-Hayes, MD, MBA, MSc, section chief of breast oncology and associate professor of medicine at UNC School of Medicine and one of the study's authors, said the treatment choices for metastatic breast cancer are constantly changing, and new options for targeted therapy have emerged even since this study was conducted. "Many oncologists and patients find that there aren't any more targeted therapies that fit the cancer's molecular profiles, so they are left with the choice of a number of chemotherapy drugs that may feel pretty similar or have an unclear balance of pros and cons.

"In that scenario, I hope our study will help expand the framework that we use to make these decisions from one where we just think about the biologic action of the drug to one where we also consider the bigger picture of what the treatment experience is like for the patient, including their financial burden, investment of time, and side effects," Reeder-Hayes added. "The most potent drug isn't always the next best choice depending on what the patient values and wants to accomplish with their treatment."

Looking ahead, the researchers have developed a financial navigation program to further support patients in managing the out-of-pocket costs of their cancer care. This program has been effective and well received by patients, caregivers and providers. The team is currently scaling up the intervention in nine rural and non-rural oncology practices across North Carolina to understand how well it works in different care settings. Cancer patients who need financial support managing the cost of their cancer care are being recruited for this undertaking.

Ref : https://ascopubs.org/doi/10.1200/JCO.21.02473

Saturday, November 21, 2009

Picoplatin a better drug than oxaliplatin for colorectal cancer !


In one of my earlier blog, I did mention about the Cisplatin (Cisplatin doubles lung cancer survival time in mice !).

About Cis-platin & other drivatives:

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) is a platinum-based chemotherapy drug used to treat various types of cancers, (sarcomas, some carcinomas (small cell lung cancer, and ovarian cancer), lymphomas, and germ cell tumors. It was the first member of a class of anti-cancer drugs which now also includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing crosslinking of DNA which ultimately triggers apoptosis (programmed cell death).

Now its the turn of Picoplatin [see structure , Amminedichloro(2-methylpyridine)platinium)], Poniard Pharmaceuticals, Inc. has come up with some interesting results from its Phase 2 trial of picoplatin in patients with metastatic colorectal cancer (CRC). Picoplatin, given once every four weeks in combination with 5-fluorouracil and leucovorin in the FOLPI regimen, has comparable efficacy to oxaliplatin, given in combination with 5-fluorouracil and leucovorin in the modified FOLFOX-6 regimen, as a first-line therapy for CRC, as assessed by one-year survival rate, progression-free survival (PFS) and disease control. The company claims that, (from the updated proof-of-concept Phase 2 safety and efficacy results) picoplatin could be superior to oxaliplatin as a neuropathy-sparing alternative when used in combination as a first-line treatment for metastatic colorectal cancer.

Source : http://investor.poniard.com/ReleaseDetail.cfm?ReleaseID=424813.

Wednesday, January 6, 2016

Lilly, Merck expand oncology clinical trial collaboration


Pemetrexed.svg


Eli Lilly and Company (NYSE: LLY) and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the extension of an existing collaboration to evaluate the safety and efficacy of the combination of Lilly's ALIMTA® (pemetrexed for injection) and Merck's KEYTRUDA® (pembrolizumab) in a pivotal Phase III study in first-line nonsquamous non-small cell lung cancer (NSCLC). The study will be sponsored by Merck and will be open to patients with NSCLC in the first-line setting, regardless of PD-L1 status. Financial details of the collaboration were not disclosed.

The expansion of this oncology clinical trial collaboration comes following the release of encouraging data from a Phase I study, presented earlier this year at the 16th World Congress on Lung Cancer, which evaluated pemetrexed, carboplatin and pembrolizumab in first-line nonsquamous NSCLC.

Pemetrexed is a leading therapeutic option used in combination with platinum-based therapies in this setting, making it an ideal candidate for combination studies with immunotherapy treatments. Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body's immune system to help detect and fight tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells – and is currently approved as a single-agent therapy for certain types of NSCLC.

Wednesday, January 8, 2014

2 Pre-Surgery Drug Treatments Show Promise Against Aggressive Breast Cancer - Drugs.com MedNews

This pre-surgical drug therapy boosts the likelihood that no cancer cells will be found in breast tissue removed during either mastectomy or lumpectomy, according to two new studies.
The approach, called "neoadjuvant" chemotherapy, is being given to an increasing number of women with what's known as triple-negative breast cancer. Currently, the approach results in no identifiable cancer cells at mastectomy or lumpectomy in about-one third of patients, experts estimate. In such cases, the risk of a tumor recurrence becomes lower.
"Chemotherapy [before surgery] does work in triple-negative breast cancer. What we want to do is make it work better," said study researcher Dr. Hope Rugo.
Rugo is director of breast oncology and clinical trials education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.
Triple-negative cancers have cells that lack receptors for the hormones estrogen and progesterone. In addition, they don't have an excess of the protein known as HER2 on the cell surfaces. So, treatments that work on the receptors and drugs that target HER2 don't work in these cancers.
In two new studies, researchers got better results by adding drugs to the standard chemo regimen prior to surgery. However, both studies are phase 2 trials, so more research is needed.
Both studies are due to be presented Friday at the annual San Antonio Breast Cancer Symposium.
Rugo compared standard neoadjuvant therapy -- paclitaxel (Taxol, others), doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan, others) -- to standard therapy plus the drugs veliparib (investigational) and carboplatin (Paraplatin)....

Monday, December 26, 2016

Drug candidate delivered by plant-virus-based carrier shows promise for triple-negative breast cancer

In continuation of my update on phenanthriplatin

In a pair of firsts, researchers at Case Western Reserve University and Massachusetts Institute of Technology have shown that the drug candidate phenanthriplatin can be more effective than an approved drug in vivo, and that a plant-virus-based carrier successfully delivers a drug in vivo. 

Phenanthriplatin.svgphenanthriplatin

Triple-negative breast cancer tumors of mice treated with the phenanthriplatin -carrying nanoparticles were four times smaller than those treated either with cisplatin, a common and related chemotherapy drug, or free phenanthriplatin injected intravenously into circulation.
The scientists believe the work, reported in the journal ACS Nano, is a promising step toward clinical trials.

"We may have found the perfect carrier for this particular drug candidate," said Nicole Steinmetz, an assistant professor of biomedical engineering at Case Western Reserve, who has spent 10 years studying the use of plant viruses for medical purposes.

She teamed with Stephen J. Lippard, Arthur Amos Noyes Professor of chemistry at MIT, and an expert in biological interactions involving platinum-based chemotherapies.

Platinum-based drugs are used to treat more than half of cancer patients receiving chemotherapy. Two of the most commonly used drugs are cisplatin and carboplatin. They form bifunctional cross-links with DNA in cancer cells, which block the DNA from transcribing genes and result in cell death, Lippard explained.

Despite widespread use, cisplatin has been shown to cure only testicular cancer, and many cancers have or develop immunity to the drug.

Lippard's lab altered cisplatin by replacing a chloride ion with phenanthridine and found that the new molecule also binds to DNA. Instead of forming cross-links, however, phenanthriplatin binds to a single site but still blocks transcription.

In fact, his lab found that phenanthriplatin is up to 40 times more potent than traditional platins when tested directly against cancer cells of lung, breast, bone and other tissues. The molecule also appears to avoid defense mechanisms that convey resistance.

But when injected into mouse models of cancer, the drug candidate performed no better than standard platins.

Lippard realized phenanthriplatin wasn't reaching its target. He had a drug delivery problem.
He found a potential solution while visiting Case Western Reserve's campus and heard Steinmetz explain her work investigating tobacco mosaic virus (TMV) for drug delivery more than a year ago.

"I envisioned that TMV would be the perfect vehicle," Lippard said. "So we had a beer and formed a collaboration."

The long, thin tobacco mosaic virus nanoparticles are naturals for delivering the drug candidate into tumors, said Steinmetz, who was appointed by the Case Western Reserve School of Medicine.

The virus particles, which won't infect humans, are hollow. A central tube about 4 nanometers in diameter runs the length of the shell and the lining carries a negative charge.

Phenanthriplatin is about 1 nanometer across and, when treated with silver nitrate, has a strong positive charge. It readily enters and binds to the central lining.

The elongated shape of the nanoparticle causes it to tumble along the margins of blood vessels, remain unnoticed by immune cells and pass through the leaky vasculature of tumors and accumulate inside. Little healthy tissue is exposed to the toxic drug.

Inside tumors, the nanoparticles gather inside the lysosomal compartments of cancer cells, where they are, in essence, digested. The pH is much lower than in the circulating blood, Steinmetz explained. The shell deteriorates and releases phenanthriplatin.

The shell is broken down into proteins and cleared through metabolic or natural cellular processes within a day while the drug candidate starts blocking transcription, leading to greater amounts of cell death through apoptosis than cross-linking platins.

The researchers say delivery of the phenanthriplatin into the tumor led to its improved performance over cisplatin or free phenanthriplatin.

Lippard and Steinmetz continue to collaborate, investigating use of this system to deliver other drugs or drug candidates, use in other types of cancers, the addition of agents on the exterior of the shell to increase accumulation inside tumors and more.

Thursday, December 8, 2016

Fasnall drug appears to inhibit tumor growth by promoting cancer cell death

A promising new compound appears to impede a process that fuels breast cancer in mice, a discovery that could have implications in the treatment of a host of cancers.

On top of short-circuiting the proliferation of cancer cells, a new agent that the researchers called Fasnall also contributed to the death of existing cancer cells, according to scientists from The Ohio State University and Duke University.

The mice injected with Fasnall survived for an average of 63 days, more than double the lifespan of the mice in the control group. After three weeks, tumors in the mice that received Fasnall were about two-thirds the size of those in the control group, the researchers report in a study published in the journal Cell Chemical Biology.

When researchers tried Fasnall alongside the chemotherapy drug carboplatin, they saw tumors shrink and survival increase more than with either agent by itself.

The study focused on mice with HER2-positive breast cancer, which is responsible for about one in five breast cancer diagnoses in women. But because of the critical role of an enzyme called fatty acid synthase in a variety of cancers, this work could have much broader implications, said Ohio State's Jesse Kwiek, an associate professor of microbiology and microbial infection and immunity.
The discovery, five years in the making, was speedy by drug development standards, he said.

"We started with an idea and got it to work in a mouse in a relatively short amount of time," Kwiek said.


"It's a promising starting point."

He and Duke's Timothy Haystead, a cancer biologist who co-led the study, are seeking a patent.

Fasnall inhibits the normal activity of fatty acid synthase, which regulates cell growth and proliferation.

"Tumor cells are quite dependent on that enzyme as a fuel source for survival," Haystead said. "If you nail this target, you're selectively striking the tumor rather than normal cells. And not only do you starve the tumor cell of its energy source, but also trigger changes that convince the cell to essentially kill itself."

Scientists exploring opportunities to close the doors on cancer growth have known for some time that many solid tumors depend on fatty acid synthase. Most other cells in the body are either less reliant on the enzyme, or don't need it at all, reducing the chances that harmful side effects would overshadow benefits.
All of that makes for an obvious, but thus far tricky, target for cancer fighters in the lab.

"It's always this balance where you try to identify molecules that are more important to the malignancy than to the host," Kwiek said. "You're looking for these little tweaks - little advantages."

In this case, that means interrupting fatty acid synthesis, effectively robbing the cancer of a molecule it needs in order to grow.

"Fasnall inhibits the ability of this enzyme to make palmitic acid, a molecule important for many cellular processes," Kwiek said.

And when the enzyme isn't doing its normal job, it appears to be diverted elsewhere - to a place where it has the added benefit of provoking the programmed death of cancer cells.

Before the mouse study, the research team sifted through a pool of 3,400 molecules looking for one that was efficient at knocking out fatty acid synthase in pig mammary glands without causing much residual harm. They first narrowed the field to about 1,300, then to 13 strong contenders.

Then the researchers examined each of the 13 finalists' activity within a cell. Fasnall rose to the top. Not only did it inhibit the tumor-fueling activity, it didn't take much of the compound for that to happen, which lowered the chances it would be toxic to the mice.

The discovery stemmed from an effort to look for novel treatments for cancer and HIV. Fatty acid synthase, disrupted by Fasnall, plays a role in both. The research team has not yet published results on their HIV work.

"Cancer is uncontrolled cell division, and fatty acid synthase helps make the raw materials that make the cells divide," Kwiek said.

The mice in the study showed no signs of major side effects, such as weight gain or loss or significant changes in liver enzymes, he said.

It appears the dose could be increased from the amount used in this research and that could produce more dramatic results, Kwiek said.

Fasnall needs more testing in animals before it can be employed in human studies, the researchers said. Other fatty acid inhibitors are under review, but thus far none has made it to market and none operates in precisely the way Fasnall does, Kwiek said.

The mechanism by which it works is less likely to run up against drug resistance in the cancer cells than some other approaches, Haystead said.

Its potential as one element of a cancer treatment cocktail is attractive, because it's possible Fasnall would offset the need for high doses of potent treatments that come with serious side effects, Haystead said.

"There are a huge gamut of implications and some may be better than others. Our job now is to sort of move this molecule down the clinical path," he said.
The researchers caution that this is the first, albeit big, step in a process that would take years if all goes well.

"This is just a mouse model of a single cancer," Kwiek said.

Tuesday, March 2, 2021

FDA Approves Cosela (trilaciclib) to Decrease the Incidence of Chemotherapy-Induced Myelosuppression

G1 Therapeutics, Inc. (Nasdaq: GTHX), a commercial-stage oncology company, announced   the U.S. Food and Drug Administration (FDA)   approval of  Cosela (trilaciclib) for injection to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC). It is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy. Cosela is expected to be commercially available through G1’s specialty distributor partner network in early March.




“The approval of trilaciclib (Cosela) is an important advance in the treatment of patients with extensive-stage small cell lung cancer receiving chemotherapy,” said Dr. Jeffrey Crawford, Geller Professor for Research in Cancer in the Department of Medicine and Duke Cancer Institute. “The most serious and life-threatening side effect of chemotherapy is myelosuppression, or damage to the bone marrow, resulting in reduced white blood cells, red blood cells and platelets. Chemotherapy-induced myelosuppression may lead to increased risks of infection, severe anemia, and/or bleeding. These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays. To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy. In clinical trials, the addition of trilaciclib to extensive-stage small cell lung cancer chemotherapy treatment regimens reduced myelosuppression and improved clinical outcomes. The good news is that these benefits of trilaciclib will now be available for our patients in clinical practice.”

Chemotherapy is an effective and important weapon against cancer. However, chemotherapy does not differentiate between healthy cells and cancer cells. It kills both, including important hematopoietic stem and progenitor cells (HSPCs) in the bone marrow that produce white blood cells (immune cells that help fight infection), red blood cells (cells that carry oxygen from the lungs to the tissues), and platelets (cells that prevent bleeding from cancer, surgeries, chronic diseases, and injuries). This chemotherapy-induced bone marrow damage, known as myelosuppression, can lead to increased risk of infection, anemia, thrombocytopenia, and other complications. Myeloprotection is a novel approach of protecting HSPCs in the bone marrow from chemotherapy-induced damage. This approach can help reduce some chemotherapy-related toxicity, making chemotherapy safer and more tolerable, while also reducing the need for reactive rescue interventions.

“Chemotherapy is the most effective and widely used approach to treating people diagnosed with extensive-stage small cell lung cancer; however, standard of care chemotherapy regimens are highly myelosuppressive and can lead to costly hospitalizations and rescue interventions,” said Jack Bailey, Chief Executive Officer at G1 Therapeutics. “Cosela will help change the chemotherapy experience for people who are battling ES-SCLC. G1 is proud to deliver Cosela to patients and their families as the first and only therapy to help protect against chemotherapy-induced myelosuppression.”

Cosela is administered intravenously as a 30-minute infusion within four hours prior to the start of chemotherapy and is the first FDA-approved therapy that helps provide proactive, multilineage protection from chemotherapy-induced myelosuppression. The approval of Cosela is based on data from three randomized, placebo-controlled trials that showed patients receiving Cosela prior to the start of chemotherapy had clinically meaningful and statistically significant reduction in the duration and severity of neutropenia. Data also showed a positive impact on red blood cell transfusions and other myeloprotective measures. The trials evaluated Cosela in combination with carboplatin/etoposide (+/- the immunotherapy atezolizumab) and topotecan chemotherapy regimens. Approximately 90% of all patients with ES-SCLC will receive at least one of these regimens during the course of their treatment.

The majority of adverse reactions reported with Cosela were mild to moderate in severity. The most common adverse reactions (≥10%) were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia. Serious adverse reactions occurred in 30% of patients receiving Cosela. Serious adverse reactions reported in >3% of patients who received Cosela included respiratory failure, hemorrhage, and thrombosis. Grade 3/4 hematological adverse reactions occurring in patients treated with Cosela and placebo included neutropenia (32% and 69%), febrile neutropenia (3% and 9%), anemia (16% and 34%), thrombocytopenia (18% and 33%), and leukopenia (4% and 17%), respectively.

“Quite often, people diagnosed with extensive-stage small cell lung cancer rely on chemotherapy to not only extend their lives, but also to acutely alleviate their symptoms,” said Bonnie J. Addario, lung cancer survivor, co-founder and board chair of the Go2 Foundation for Lung Cancer. “Unfortunately, the vast majority will experience chemotherapy-induced side effects, resulting in dose delays and reductions, and increased utilization of healthcare services. G1 shares our organization’s goal to improve the quality of life of those diagnosed with lung cancer and to transform survivorship among people living with this insidious disease. We are thrilled to see new advancements that can help improve the lives of those living with small cell lung cancer.”

Approximately 30,000 small cell lung cancer patients are treated in the United States annually. G1 is committed to helping patients with extensive-stage small cell lung cancer in the U.S. gain access to treatment with Cosela. For more information on access and affordability programs, patients and providers should call the G1toOne support center at 833-G1toONE (833-418-6663) from 8:00 a.m. to 8:00 p.m. Eastern time.

G1 received Breakthrough Therapy Designation from the FDA in 2019 based on positive data in small cell lung cancer patients from three randomized Phase 2 clinical trials. As is common with breakthrough-designated products that receive priority review, G1 will conduct certain post-marketing activities, including in vitro drug-drug interaction and metabolism studies, and a clinical trial to assess impact of trilaciclib on disease progression or survival in patients with ES-SCLC with chemotherapy-induced myelosuppression treated with a platinum/etoposide-containing or topotecan-containing regimen with at least a two year follow up. G1 intends to initiate the post-approval clinical trial in 2022.

Cosela (trilaciclib) Co-Promotion Agreement with Boehringer Ingelheim

In June 2020, G1 announced a three-year co-promotion agreement with Boehringer Ingelheim for Cosela in small cell lung cancer in the U.S. and Puerto Rico. G1 will lead marketing, market access and medical engagement initiatives for Cosela. The Boehringer Ingelheim oncology commercial team, well-established in lung cancer, will lead sales force engagement initiatives. G1 will book revenue and retain development and commercialization rights to Cosela and pay Boehringer Ingelheim a promotional fee based on net sales. The three-year agreement does not extend to additional indications that G1 is evaluating for trilaciclib. Press release details of the G1/ Boehringer Ingelheim agreement can be found here.


Ref : https://en.wikipedia.org/wiki/Trilaciclib