While it’s a long way off becoming reality, this is quite an exciting clinical trial. I have no idea if it will pick up Neuroendocrine disease but initially, patients with suspected oesophageal and stomach cancers will be asked to try the test. Later it will be extended to include prostate, kidney, bladder, liver and pancreatic cancers. It’s possible that Neuroendcorine tumours in these locations might be picked up or at least show up some abnormality that triggers further checks.
The fact that Cancer Research UK is involved gives me some confidence as they tend to back the strong horses.
I will keep this article live and track developments.
This is a ‘next generation’ Peptide receptor radionuclide therapy (PRRT) or more specifically the radiopharmaceutical that binds to both activated and unactivated somatostatin receptors which are upregulated on these tumours. There is far higher binding via this mechanism than standard octreotate. The technical name of the radiopharmaceutical is Satoreotide tetraxetan lutetium-177 (author’s note, I’m guessing but it could be a variant of Lanreotide). It was once named JR11.
What’s the difference to the current approved therapy?
Conventional PRRT (e.g. Lutathera, Lu177 Dotatate) is based on a somatostatin receptor ‘agonist’ approach, whereas 177Lu Ops 201 Satoreotide is a receptor ‘Antagonist’. The differences are quite technical but in the most layman terms , the antagonist has the capability of attaching (binding) to more receptors, including those in a ‘resting’ or ‘inactive’ state, spends more time on the tumor than agonist based therapies. The result is a higher number of receptor binding sites and greater tumor uptake. In addition it is said to show an improved tumor-to-kidney dose ratio compared to 177Lu-DOTA-TATE.
This would also be reflected in the theranostic use of the drug in Ga68 imaging (i.e. Ga68 Satoreotide).
The clinical trial is named “Study to Evaluate the Safety and Preliminary Efficacy of 177Lu-OPSC001 in NETs”. The protocol involves 3 cycles 8 weeks apart of intravenous Lu-177 OPS-201. All patients will have baseline Ga-68 octreotate imaging performed.
The treatment is available for all NET patients with a histologically confirmed diagnosis of:
unresectable GEP NET (Grade I and Grade II according to WHO classification (2010, Annex 01), functioning and non-functioning).
unresectable “typical lung NET” or “atypical lung NET” are acceptable (with the exception of Large Cell Bronchial Neuroendocrine Neoplasms and Small Cell Lung Cancers).
malignant, unresectable pheochromocytoma or paraganglioma
Patients who have previously had Lu-177 octreotate (e.g. Lutathera) are not eligible. Patients may have had any other treatment including chemotherapy, radiotherapy or Somatostatin Analogues (e.g. octreotide, landreotide).
There are other inclusion and exclusion criteria to be found within the clinical trial document. The trial is due to compete in May 2022.
Where is the Trial based?
At the time of writing and according to the Clinical Trial document, Australia (Melbourne and Perth), Austria (Vienna), Denmark (Aarhus), Switzerland (Basel), UK (Royal Free London). Two sites are also listed in France (Nantes and Toulouse) but trial document currently marked as not yet recruiting.
I have anecdotal evidence to suggest one more UK site is possible in 2019, Windsor in UK, a private healthcare provider but it will be open to public and private patients.
What about USA?
I also found an additional trial based in Memorial Sloan Kettering New York designed to take a theranostic approach by using Satoreotide (JR11) for the pre-treatment imaging, e.g. Ga68 satoreotide (JR11) and the 177Lu version for treatment. The clinical trial document indicates this trial is active but NOT RECRUITING and is entitled “Theranostics of Radiolabeled Somatostatin Antagonists 68Ga-DOTA-JR11 and 177Lu-DOTA-JR11 in Patients With Neuroendocrine Tumors”
Thanks for reading
You may also find these PRRT related articles useful:
Diarrhea is a huge subject for NET patients, whether it’s caused by the tumor itself (i.e. a syndrome), due to treatment, knock on effects of treatment, or some other reason, it can dramatically limit qualify of life. Working out the root cause can be problematic even for medical teams. I wrote about these issues before in my article Neuroendocrine Cancer – the diarrhea jigsaw. So when I saw the data from a trial of something called enterade®, I was immediately drawn to investigate. I don’t normally write articles on over the counter commercial products but this one is an exception given that it has been classed as a medical food since 2012 and is also used to rehydrate patients undergoing radiotherapy and chemotherapy for cancer (so not just for NETs).
What is enterade® ?
It’s a drink currently produced in 8oz bottles. It’s a first-in-class, glucose-free medical food i.e. it is intended to be used under the supervision of a healthcare provider. The solution comprises five critical amino acids – Valine, Aspartic Acid, Serine, Threonine, Tyrosine and electrolytes – potassium and sodium.
What does it do?
It’s designed to help manage debilitating gastrointestinal (GI) side effects. With no sugar to exacerbate the GI tract, enterade® supports the small bowel’s ability to absorb fluids, nutrients, and electrolytes and leads to improved digestive function. By helping to restore normal GI function, enterade® reduces diarrhea and dehydration, leading to a significant improvement in the patient’s overall quality of life and a healthier GI tract.
Is there evidence that it works?
Since May 2017, it’s been trialled by University of Kentucky Markey Cancer Center (MCC) for potential use by NET patients – trial coordinators include the well-known NET specialist Dr Lowell Anthony. The results so far are very interesting. The recent conference reported revised data as follows:
33 of 41 patients (80%) reported subjective improvement in diarrheal symptoms.
51% (21/41) reported more than 50% reduction in diarrhea frequency.
click here or on the poster below to see the trial poster data output.
As you will see from the poster, there were a wide range of patient types including (but not limited to) small intestinal NETs, bronchial NETs, NETs of unknown primary, gastric NETS, pancreatic NETs and one high grade neuroendocrine carcinoma of the prostate.
A follow on Phase 2 trial is now recruiting with the following detail available:
1. Up to 30 patients will be recruited.
2. The trial is coordinated by Markey Cancer Centre, Kentucky.
3. There will be two cohorts, those with carcinoid syndrome and those without.
4. The trial will run from December 2018 to August 2020.
Click here to see the trial information – important to note the inclusion and exclusion criteria.
Please also note there’s a plan for a follow on trial covering more locations. I will update further when known.
Can I buy Enterade now?
The product is available in North America on Amazon.com, www.enterade.com and 1-855-enterade. However, the parent company (Entrinsic Health) recently announced a partnership with global company Nestlé Health Science to provides worldwide commercial license and supply agreement for enterade®. The announcement is linked here:
NORWOOD, Mass., November 15, 2018 – Entrinsic Health Solutions (EHS), an innovative health sciences company, today announced that they have entered into a partnership with Nestlé Health Science (NHSc), a global innovative leader pioneering premium-quality, science-based nutritional health solutions. The partnership gives NHSc the exclusive rights to market EHS’s enterade® product.
Please note this is not a recommendation to go out and buy the product. It is actually described as a ‘medical food’ and is formulated to be consumed or administered under the supervision of a physician.
3. Recent output from ASCO 2018 – click here. (contact data update for 2018)
4. If you are interested in more information about how enterade® works, check out this short video
Please note this is not a recommendation to go out and buy the product. It is actually described as a ‘medical food’ and is formulated to be consumed or administered under the supervision of a physician.
On the heels of the approval of PRRT in USA and whilst we all wait on positive national announcements of PRRTapproval in UK and elsewhere, here’s news of a new PRRT compound undergoing a phase 3 clinical trial. Isotopen Technologien München AG (ITM), a specialized radiopharmaceutical company, today announced the enrolment of the first patient recruited in Europe for the COMPETE phase III clinical trial at theUniversity Hospital Marburg, Germany. The CEO of ITM said “This marks the starting point of COMPETE in Europe, whereby we expect a rapid increase in the number of recruits.” I actually met these guys at ENETS 2018 – sounds great.
What is the COMPETE trial?
COMPETE is led as an international pivotal multi-center phase III clinical trial evaluating the efficacy and safety of (no-carrier-added) n.c.a.177Lu-Edotreotide (Solucin®) and the trial is comparing it to Everolimus (Afinitor). The trial runs until Dec 2020. The enrolment requires patients with inoperable, progressive, somatostatin-receptor positive neuroendocrine tumors of gastroenteric or pancreatic origin (GEP-NET). The primary endpoint is progression-free survival (PFS). The study will be conducted predominantly in Europe, North America, South Africa and Australia (ITM is waiting on FDA clearance to include North American locations in the trial). The first patient to be enrolled and treated was in Australia. The clinical trial document (see references below) indicates its for non-functional GI tumours but for non-functional and functional pNETs. The list of locations can also be found in the clinical trial document. The usual inclusion/exclusion rules apply but the most notable would appear to be an exclusion for those with prior exposure to any PRRT or mTor inhibitor such as Everolimus (Afinitor).
What is 177Lu-Edotreotide (Solucin®) ?
The compound under investigation, Solucin®, is known as a Targeted Radionuclide Therapy (TRT) agent, which consists of the targeting molecule Edotreotide, an octreotide-derived somatostatin analogue and ITM´s EndolucinBeta® (no-carrier-added Lutetium-177). EndolucinBeta® is a synthetic, low-energy beta-emitting isotope of Lutetium, a recently EMA approved pharmaceutical precursor. The radiopharmaceutical Solucin® is administered as an intravenous infusion, specifically targeting and destroying the tumor cells with ionizing radiation. Solucin® received an Orphan Designation (EMA/OD/196/13) for the treatment of GEP-NET, based on early clinical experience, which has demonstrated a substantial clinical benefit with increased PFS and quality of life.
From ITM’s website … “Edotreotide contains DOTA which functions as a chelator for radioisotopes and TOC, a synthetic Somatostatin receptor ligand” (chelator and ligand are just fancy names for ‘bonding’ or ‘binding’). “The compound Edotreotide binds with high affinity Somatostatin receptors and retains both its receptor binding properties and its physiological function when labeled with 177Lu. Somatostatin receptors are predominantly overexpressed by neuroendocrine tumors. 177Lu-Edotreotide, upon binding to Somastotatin receptors in vivo is internalized and retained by tumor cells.”
“Compared to 90Y-Edotreotide, 177Lu-Edotreotide Targeted Radionuclide Therapy in NET was found to be less haematotoxic and associated with a longer median overall survival. That was highly significant for patients with low tumor uptake as well as for patients with extra hepatic and solitary metastases. In a retrospective Phase II trial 177Lu-Edotreotide showed a low uptake/dose delivered to normal organs and very high tumor-to-kidney ratio.”
Other Spin offs from ITM
Interestingly the company is also working on a ‘theranostic pair’ for imaging and treating bone metastases – see graphic below. It does not say whether this includes NET bone metastases but I don’t see why not given the connection with Solucin. However, please note this is some years away from fruition.
There’s been a lot of action in the area of what is termed Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP-NETs). It can therefore sometimes appear that Lung NETs are the poor relation. There are certainly some unmet needs in this area of the anatomy including a lack of research. Thus far, no prospective trials specifically for patients with lung NETs appear to have been reported.
However, there has been some recent movement. Last year, the use of Afinitor (Everolimus) was approved for progressive, non-functional NET of GI or Lung origin.
SPINET Trial for Lung NETs
In late 2016, I tipped you off about an Ipsen sponsored trial for Lung NETs involving Lanreotide (Somatuline). SPINET is a Phase 3, prospective, multi-center, randomized, double-blind, study evaluating the efficacy and safety of Lanreotide plus “Best Supportive Care” (BSC) versus placebo plus BSC for the treatment of well-differentiated, metastatic and/or unresectable, typical or atypical lung NETs. The aim of the SPINET study is to evaluate the safety and antitumor efficacy of Lanreotide 120 mg in patients with advanced lung NETs. I suspect that many Lung NET patients are already receiving somatostatin analogues (Octreotide/Lanreotide) but prescribed only for syndrome/symptom control.
SPINET is now recruiting in many locations (see below).
The countries involved in the SPINET trial are as follows (in case my post goes out of date – see the latest update to the trials document here). Please also check the inclusion and exclusion criteria.
USA, Austria, Canada, Denmark, France, Germany, Italy, Netherlands, Poland, Spain, UK.
In addition to the trial document linked above, you can read more about the SPINET trial here with commentary from a well-known NET Specialist – Dr Diane Reidy-Lagunes, who is the principal investigator for the trial.
How do I get on the trial?
You may be interested in this organisation – Trialbee. They are a company helping Ipsen to raise awareness of the SPINET trial using a cloud based platform to connect patients, investigators and sponsors (I’ve authenticated their participation with Ipsen). There is no fee for using their services. There’s a useful questionnaire which can help you decide if this trial is for you – here.
Please note, if you are concerned about participating in clinical trials, you should always consult your specialist for advice.
If you are a patient advocate or an advocate organisation, please share with your communities in order that Lung NET patients are at least made aware of the trial.
I recently wrote a blog called Neuroendocrine Cancer – Exciting Times Ahead! I wrote that on a day I was feeling particularly positive and at the time, I wanted to share that positivity with you. I genuinely believe there’s a lot of great things happening. Don’t get me wrong, there’s a lot still to be done, particularly in the area of diagnosis and quality of life after being diagnosed. However, this is a really great message from a well-known NET expert.
In an interview with OncLive, Jonathan R. Strosberg, MD, associate professor at the H. Lee Moffitt Cancer Center in Florida, discussed his presentation on NETs at a recent 2016 Symposium, and shed light on the progress that has been made in this treatment landscape.
OncLive: Please highlight some of the main points from your presentation.
Strosberg: The question I was asked to address is whether we’re making progress in the management of NETs, and I think the answer is unequivocally yes. Prior to 2009, there were no positive published phase III trials.
Since then, there have been 8 trials, 7 of which have reached their primary endpoints. So it’s been a decade of significant improvement. And even though none of these studies were powered to look at overall survival as an endpoint, we’re certainly seeing evidence of improvement in outcomes.
OncLive: What are some of the pivotal agents that you feel have impacted the paradigm in the past several years?
Strosberg: The first group is the somatostatin analogs. We use them to control hormonal symptoms like carcinoid syndrome, but with the CLARINET study, we now know that they substantially inhibit tumor growth.
The next significant drug we use in this disease is everolimus (Afinitor), an oral mTOR inhibitor, which is now approved in several indications based on positive phase III studies. The first was in pancreatic NETs and subsequently, based on the RADIANT-4 trial, it was also approved in lung and gastrointestinal NETs. So that was an important advance.
The next important category of treatment is radiolabeled somatostatin analogs, otherwise known as peptide receptor radiotherapy. The one that’s been tested in a phase III trial is lutetium dotatate, also known as Lutathera. It was tested in patients with progressive midgut NETs and showed a very substantial 79% improvement in progression-free survival, and a very strong trend toward improvement in overall survival, which we hope will be confirmed upon final analysis.
OncLive: Are we getting better at diagnosing and managing the treatment of NETs?
Strosberg: Certainly. I think pathologists are better at making the diagnosis of a NET, rather than just calling a cancer pancreatic cancer or colorectal cancer. They’re recognizing the neuroendocrine aspects of the disease, and doing the appropriate immunohistochemical staining.
We also have better diagnostic tools. We used to rely primarily on octreoscan, and in many cases we still do, but there is a new diagnostic scan called Gallium-68 dotatate scan, also known as Netspot, which has substantially improved sensitivity and specificity. It’s not yet widely available, but it is FDA approved and hopefully will enable better diagnosis as well as staging in the coming years.
And, with the increase in number of phase III studies, we’re developing evidence-based guidelines, which will hopefully lead to more standardization, although knowing how to sequence these new drugs is still quite challenging.
OncLive: With sequencing, what are the main questions that we’re still trying to answer?
Strosberg: If we take, for example, NETs of the midgut, beyond first-line somatostatin analogs, physicians and patients often face decisions regarding where to proceed next, and for some patients with liver-dominant disease, liver-directed therapies are still an option.
For others, everolimus is a systemic option, and then hopefully lutetium dotatate will be an option based on approval of the drug, which is currently pending. Knowing how to choose among those 3 options is going to be a challenge, and I think there will be debates. Hopefully, clinical trials that compare one agent to another can help doctors make that choice. It’s even more complicated for pancreatic NETs. Beyond somatostatin analogs, we have about 5 choices—we have everolimus, sunitinib (Sutent), cytotoxic chemotherapy, liver-directed therapy, and peptide receptor radiotherapy. It’s even more challenging in that area.
OncLive: Are there any other ongoing clinical trials with some of these agents that you’re particularly excited about?
Strosberg: There’s a trial that is slated to take place in Europe which will compare lutetium dotatate with everolimus in advanced pancreatic NETs, and I think that’s going to be a very important trial that will help us get some information on both sequencing of these drugs, as well as the efficacy of Lutathera in the pancreatic NET population, based on well-run prospective clinical trials. I’m particularly looking forward to that trial.
OncLive: Looking to the future, what are some of the immediate challenges you hope to tackle with NETs?
Strosberg: One area of particular need is poorly differentiated neuroendocrine carcinomas. That’s a field that’s traditionally been understudied. There have been very few prospective clinical trials looking at this particular population, and we’re hoping that will change in the near future. There are a number of trials taking place looking at immunotherapy drugs. If these agents work anywhere in the neuroendocrine sphere, they are more likely to work in poorly differentiated or high-grade tumors, in my opinion, given the mutational profile of these cancers. So that’s something I’m particularly looking forward to being able to offer these patients something other than the cisplatin/etoposide combination that goes back decades, and is of short-lasting duration.
See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-24/expert-discusses-recent-progress-in-net-management#sthash.ypkilX2A.dpuf
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Cabozantinib is an oral drug which works by blocking the growth of new blood vessels that feed a tumour. In addition to blocking the formation of new blood cells in tumours, Cabozantinib also blocks pathways that may be responsible for allowing cancers cells to become resistant to other “anti-angiogenic” drugs. It is a type of drug called a growth blocker. Cabozantinib has been studied or is already in research studies as a possible treatment for various types of cancer, including prostate cancer, ovarian cancer, brain cancer, thyroid cancer, lung cancer, and kidney cancer. During my research, I found that it has a connection to Medullary Thyroid Cancer (MTC) which is a type of Neuroendocrine Cancer, frequently associated with Multiple Endocrine Neoplasia (MEN). Cabozantinib, under the brand name of ‘Cometriq’ was approved by the FDA in 2012 for use in MTC. Read more about Cometriq here. It’s also been approved by the FDA for advanced renal cell carcinoma (RCC) (branded as Cabometyx). I also discovered that there is an exclusive licensing Agreement with the manufacturers (Elelixis) and Ipsen (of Lanreotide fame) to commercialize and develop Cabozantinib in regions outside the United States, Canada and Japan
Growth blockers are a type of biological therapy and include tyrosine kinase inhibitors, proteasome inhibitors, mTOR inhibitors, PI3K inhibitors, histone deacetylase inhibitors and hedgehog pathway blockers. Cabozantinib is a tyrosine kinase inhibitor (TKI). They block chemical messengers (enzymes) called tyrosine kinases. Tyrosine kinases help to send growth signals in cells so blocking them stop the cell growing and dividing. Some TKIs can block more than one tyrosine kinase and these are known as multi-TKIs.
So Capozantinib is a tyrosine kinase inhibitor and is therefore a biological therapy and growth blocker just like Everolimus (Afinitor) and Sunitinib (Sutent) – some texts describe thelattero two as chemotherapy but this is just not accurate.
Very technical process but in the simplest of terms, Cabozantinib is designed to disrupt the actions of VEGF (a growth factor) and MET (a growth factor receptor) which promote spread of cancerous cells through the growth of new blood vessels. Whilst we are on this subject, please note Everolimus (Afinitor) is an mTOR inhibitor and Sunitinib (Sutent) is a tyrosine kinase inhibitor. Many people think these drugs are a type of chemo – that is incorrect, these are targeted biological therapies. See more on this by clicking here.
What is the current trial status of Capozantinib?
A Phase III trial is now recruiting entitled “Cabozantinib S-malate in Treating Patients With Neuroendocrine Tumors Previously Treated With Everolimus That Are Locally Advanced, Metastatic, or Cannot Be Removed by Surgery”.
The trial has 172 locations across the US (see link below). The primary study (final data) is scheduled Jan 1st 2021.
A funded piece of research by the NET Research Foundation – check it out here – looks like they are trying to figure out what patients might benefit from Cabozantinib using biomarker data to predict response.
BOSTON — Cabozantinib (Cabometyx) may benefit patients with malignant pheochromocytomas and paragangliomas, according to results of a phase II trial presented here.
Patients receiving cabozantinib (Cometriq) treatment experienced notable tumor shrinkage in the lymph nodes, liver, and lung metastases, according to Camilo Jimenez, MD, of the MD Anderson Cancer Center in Houston, and colleagues.
Additionally, progression-free survival significantly increased after treated to 12.1 months (range 0.9-28) compared with just 3.2 months prior to treatment, they reported at the American Association of Clinical Endocrinologists (AACE) annual meeting.
Cabozantinib treatment was also tied to an improvement in blood pressure and performance status, as well as remission of diabetes among these patients.
“Malignant pheochromocytomas and paragangliomas are frequently characterized by an excessive secretion of catecholamines. [Patients] have a large tumor burden and they have a decreased overall survival,” explained Jimenez. “Tumors are frequently very vascular and frequently associated with bone metastases. In fact, up to 20% of patients who have malignancy of pheochromocytomas and paragangliomas may have predominant bone metastases.”
He added that “an interesting aspect of this tumor is that C-MET receptor mutation have been found in occasional patients with malignant pheochromocytomas and paragangliomas.”
Cabozantinib is an anti-angiogenic tyrosine kinase inhibitor, which also targets RET, MET, and AXL. It is approved for metastatic medullary thyroid cancer, and was more recently approved for first-line treatment of advanced renal cell carcinoma.
“MET pathway is also involved in the development of bone metastases. In fact, cabozantinib is a very effective medications for patients who have bone metastases in the context of cancer of different origins,” Jimenez said.
In order to be eligible for the trial, patients with confirmed pheochromocytoma or paraganglioma had to be ineligible for curative surgery, have ≥3 months life expectancy, no risk for perforation or fistula, and adequate organ functioning. Prior to cabozantinib initiation, patients could not receive chemotherapy or biologic agents within 6 weeks, radiation within 4 weeks, or MIBG within 6 months.
Following histological confirmation of disease progression >1 year according to RECIST 1.1, the trial included 14 patients with measurable disease and eight patients with predominant/exclusive bone metastases. Fifteen patients subsequently enrolled into the trial, six of whom had germline mutations of the SDHB gene.
All participants were all started at an initial daily dose of 60 mg of cabozantinib, which was subsequently reduced down to between 40 to 20 mg due to toxicity in 13 patients based on tolerance.
The majority of these patients with measurable disease experienced some level of disease response. Six patients reported a partial response, defined as over a 30% reduction, while three patients achieved moderate response, marked by a 15%-30% reduction. Five of the patients with predominant bone metastases reported disease stabilization, according to results of an FDG-PET scan. One patient experienced disease progression while on treatment.
Overall, cabozantinib was generally well-tolerated without any grade 4 or 5 treatment-related adverse events reported. Some of the most common adverse events reported included grade mild dysgeusia, hand and foot syndrome, mucositis, fatigue, weight loss, and hypertension, according to the authors.
Primary Source – American Association of Clinical Endocrinologists meeting – AACE 2018; Abstract 142. attended my Medscape writers
I generated this blog article to add value rather than just post the outputs for your own perusal. I hope you find it useful.
Please note that taking part in a clinical trial is a big decision and must be considered carefully in conjunction with your specialists if necessary. This article is not suggesting this trial is right for you. Please check the inclusion and exclusion criteria in the trials document carefully. (Pheo/Para patients see other clinical trial link above)
I recently posted an ‘Onc Live’ video series about Neuroendocrine Tumour (NET) treatments and the final episode talked about combination treatments i.e. where more than one treatment is administered simultaneously. An interesting and exciting area to watch for the treatment of NET patients.
Thought you’d be interested in a potential new treatment being developed in Australia. The use of PRRT and chemo (in particular CAPTEM) or ‘PRCRT’. The attached video is a presentation by Dr Michael Hofman who I see regularly on twitter posting some very interesting stuff. He’s a great advocate for NET patients. The video will explain in some detail how the treatment is thought to work together. Additionally, it also provides excellent PRRT information. Dr Hofman has some really interesting things to say. 20 minutes – definitely recommended watching! CLICK HERE
‘CONTROLNETS’ involving PRRT and CAPTEM. The details of the trial can be read here: CLICK HERE
From ASCO 2019 conference extract: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients; abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. All evaluable patients except one had stable disease at 3 months. One patient showed SD but non target lesion demonstrated PD. One patient had > 30% decrease in tumor size but overall sum of lesions showed SD. A detailed table with all grade toxicities and waterfall plot of RR will be presented at the meeting. Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. Early clinical data suggests clinical activity and stable disease in all but one patient at 3 months. Read full text from ASCO 2019 here.
For further information about the clinical trial, please visit www.clinicaltrials.gov, Study NCT03014297
I will get a better picture but this is what they tweeted from ASCO 2019
added 19 Apr 2017
Mateon Therapeutics, Inc. a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, today announced that the Markey Cancer Center at the University of Kentucky has enrolled the first patient into a new phase 1 study of CA4P in combination with everolimus for the treatment of neuroendocrine tumors.
“The combination of CA4P and everolimus has the potential to decrease the ability of tumor cells to recover between CA4P treatment cycles,” stated Lowell B. Anthony, M.D., Professor of Medicine and Chief, Division of Medical Oncology, Markey Cancer Center, University of Kentucky. “This is the first trial testing this hypothesis in neuroendocrine tumors – with CA4P disrupting the existing tumor blood supply and everolimus preventing a new tumor blood supply from re-forming. Our findings from this trial should lead to a larger clinical study once we have identified the optimal dose and schedule for the combination of these two agents.”
Study MCC-2016-088 is designed to demonstrate whether the addition of CA4P to everolimus may improve tumor control without additional toxicity. Everolimus has been approved by the U.S. Food and Drug Administration for the treatment of advanced pancreatic neuroendocrine tumors and progressive gastrointestinal neuroendocrine tumors, among other indications, and is marketed by Novartis under the tradename AFINITOR®. Mateon has previously demonstrated initial evidence of efficacy for CA4P in patients with neuroendocrine tumors when CA4P was provided as a single agent.
Study MCC-2016-088 is being sponsored, funded, and conducted by the Markey Cancer Center, with Mateon providing the investigational drug. The study is designed as a single center, open label, phase 1 clinical trial for patients with grade 1-3 gastroenteropancreatic neuroendocrine tumors. In the first part of the study, up to 15 patients will be treated with everolimus in combination with two different dosing regimens of CA4P to establish appropriate CA4P dosing levels and evaluate the safety of the drug combination. The second part of the study is designed to enroll 15 additional patients for assessment of additional safety and efficacy data. Patients enrolled in MCC-2016-088 will be treated with CA4P and everolimus for 12 weeks.
For further information about the clinical trial, please visit www.clinicaltrials.gov, Study NCT03014297. (see also ‘added 23 Dec 2016’ below)
added 23 Jan 2017
Mateon Therapeutics, a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, today announced the presentation of final data from Study OX4218 in patients with neuroendocrine tumors (NETs) at a poster session at the ASCO Gastrointestinal Cancers Symposium being held today in San Francisco (20 Jan 17).
Study OX4218 was a multi-center, open label, phase 2 clinical trial to investigate the safety and activity of combretastatin A4-phosphate (CA4P) in the treatment of well-differentiated, low-to-intermediate-grade unresectable, recurrent or metastatic pancreatic or gastrointestinal neuroendocrine tumors/carcinoid (PNETs or GI-NETs) with elevated biomarkers. Following patients’ completion of Study OX4218, patients were eligible to enroll in Study OX4219, a long-term extension study, if they achieved a biomarker or symptom response. In OX4218 patients were treated with CA4P 60 mg/m2 on Days 1, 8, and 15 of a 21-day cycle for 3 cycles, and in OX4219 patients received CA4P maintenance on Day 1 of a 21-day cycle until disease progression or up to one year.
A total of 18 patients were enrolled in OX4218. One patient (6%) experienced significant symptomatic improvement as measured by ECOG Status and had a partial response per investigator-assessed RECIST and an additional 7 patients (39%) had stable disease. In addition, a majority of patients (53%) experienced an improvement in patient-reported quality of life. A statistically significant mean change in biomarkers from baseline, the primary endpoint of the study, was not achieved in OX4218 due to the small sample size along with a high intra- and inter-patient variability observed in the biomarkers. A total of 7 patients were enrolled in OX4219, of which 5 patients (71%) had stable disease, including one that continued for 14 months. The partial response and stable disease analyses, as well as other measures from the trial, suggest that CA4P monotherapy has activity in this indication.
“The results of OX4218 and OX4219 confirm that CA4P monotherapy has efficacy in the indications studied, as we have seen with the investigational drug in a number of other monotherapy trials,” said William D. Schwieterman, M.D., President and Chief Executive Officer of Mateon. “However, we believe that the efficacy of CA4P only becomes compelling when it is used in combination with an anti-angiogenic agent, due to the complementary mechanisms of action for the two agents. Based on the evidence of efficacy observed in this trial, plus an understanding of the benefits of combination therapy, a lead investigator in this trial is sponsoring a 20 patient study in NETs using CA4P in combination with everolimus (AFINITOR®, marketed by Novartis), an anti-angiogenic agent which is already approved and commonly used in this indication.”
Overall CA4P monotherapy was well tolerated. Treatment related adverse events were reported in 77% of subjects. The most common Grade 3-5 AEs (>10%) included: anemia, abdominal pain, fatigue, hypertension, and ALT and AST increases. One Grade 5 adverse event, carcinoid syndrome, was reported and attributed to the underlying disease.
added 23 Dec 2016
There is news of a trial involving this drug which I first published in Jan 2016. The trial is based at Markey Cancer Centre and is led by Dr Lowell Anthony. The trial’s primary objective is to establish the maximum tolerated dose of the combination of Everolimus (Afinitor) plus Fosbretabulin in Neuroendocrine Tumors (Grades 1-3) who have progressed after at least one prior regimen for metastatic disease. Read more here.
The original blog published on 10 Jan 2016 follows:
It’s always nice to hear that another treatment for Neuroendocrine Cancer is in the pipeline. This drug is in the news because it has just been granted designated orphan drug status by the FDA in the US for the treatment of Neuroendocrine Tumours.
My initial thoughts are that it looks promising but it’s very early days.The new drug is formally known as Fosbretabulin Tromethamine or just Fosbretabulin.It also goes by the name of Combretastatin or CA4P which translates to Combretastatin A4-phosphate.In the most basic of terms, it’s a type of vascular disrupting agent (VDA) (note – it’s not chemotherapy).
It appears to be something currently targeted at patients with Advanced Pancreatic or GI Neuroendocrine Tumours with elevated biomarkers. This is not a new drug and has been around for some years. According to Cancer Research UK, it has already been used for advanced and recurrent ovarian and thyroid cancers.
So how does it work? The drug makes the cells that line the smallest blood vessels (capillaries) swell up and this has the effect of blocking the blood flow to a tumour. All tumours need a blood supply so that they can get the oxygen and food they need to survive and Neuroendocrine Tumours can be highly vascular. It follows that if the blood flow to a tumour is blocked, there is a chance that it could stop growing or at best kill the tumour (necrosis). Sounds like the same principles used in Liver Embolization except that this drug has a greater anatomical reach plus a vastly different delivery mechanism via a 10 minute IV infusion.
So why is it a targeted treatment? The drug will only affect blood vessels that supply cancer cells. Cells lining normal blood vessels contain a protein called actin and this protects the blood vessels from the drug’s effects. Cells lining blood vessels that supply a cancer don’t have actin.
Does it work alongside other treatments? Interestingly, it appears to be a recommendation to use the drug in combination with anti-angiogenic drugs (i.e. those that can stop the growth of new blood vessels rather than block the blood supply). Also, according to the manufacturer Mateon, Fosbretabulin has demonstrated broad potential therapeutic value when combined with mainstay oncology modes of treatment including chemotherapy, radiation therapy and the more recent ‘molecularly-targeted therapies’. In fact if you read the trial addition above dated 23 Dec 16, you will see it’s being tested alongside Everolimus (Afinitor).
So when can we expect to see this drug? Phase 2 trials were completed at the end of 2016 (results above). I guess it would still be some years ahead if they wish to proceed. You can see the trial information by clicking here.
I’ll keep this blog live adding to it when I find new or updated information.
Thanks for reading
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