Showing posts with label Ac-225. Show all posts
Showing posts with label Ac-225. Show all posts

Saturday, January 30, 2021

Avoiding radiation damage to salivary glands with Ac-225-PSMA-617 therapy

As we await the results of the VISION trial of Lu-177-PSMA-617, research continues into improving radiopharmeuticals. Ac-177-PSMA-617, which is more lethal to cancer cells within a more limited range, is one of several promising alternatives (see this link).

One of the serious side effects of the experimental Ac-225-PSMA-617 therapy is radiation damage to salivary glands. "Xerostomia" (dry mouth) also occurs with Lu-177-PSMA-617 therapy, but it is usually transient and less severe, although it does increase with the number of treatments. Sathkegke et al. reported occurrence in 85% of South African patients treated with Ac-225-PSMA-617, but no one stopped treatment entirely because of it. Kratchowil et al. reported occurrence of xerostomia in Heidelberg, Germany so severe in 4 of 40 treated patients that treatment had to be discontinued. Feuerrecker at al reported that all their treated German patients suffered from xerostomia; it was so severe as to curtail treatment in 6 of 26 patients.

Acute, low-grade xerostomia is caused by the temporary irritative inflammatory effects of the radiopharmaceutical on salivary tissue. Lasting damage may result from radioablation of the saliva-producing cells and the nerves that innervate them, and their replacement with and obstruction of the ducts with mucus and scar tissue. Loss of saliva can make chewing and swallowing almost impossible, leading to choking and vomiting. Digestion is impaired, and the ability to taste food may be lost. Saliva has antimicrobial properties, so its loss can lead to tooth decay, gum disease, and oral thrush. Speaking can become difficult.  It can feel like burning, and interfere with sleep. Humans normally produce about a liter of saliva each day.

Some simple therapies (local cooling with ice, Vitamin C, lemon juice, and PMPA) have been found to be ineffective. Taïeb et al. report that treatment with botulinum toxin, Vitamin E and MnBuOE may be more successful, but that regeneration of salivary glands with stem cells or genetic modification may ultimately be necessary. Riley et al. found very low quality of evidence that amifostine, pilocarpine, palifermin, biperidine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin) may be useful. More benefit may be accomplished with some of the following strategies:

Sialendoscopy

Rathke et al. reported the successful use of sialendoscopy in 11 patients. Sialendoscopy is a kind of endoscopic procedure involving the insertion of a thin probe into the salivary glands. It dilates the openings that have closed due to inflammation. They irrigated the glands with saline and prednisolone. It only worked when done immediately.

Pre-treatment with PSMA-11

PSMA-11 is the small molecule ligand used with Ga-68-PSMA-11. Taken without the radiotracer, it attaches to the salivary tissue, where it can block further uptake by the PSMA-617 ligand. Kalidindi et al. found that in mice, pretreatment with 1000 picomoles blocked uptake of Lu-177-PSMA-617 in the salivary glands and kidneys; but uptake, while reduced, was still at therapeutic levels in tumor tissue. This finding would have to be replicated in clinical trials.

Use only when there is significant PSMA-avidity

Damage to normal, healthy tissue increases when there is insufficient PSMA-avid tumor tissue to attach to. Gaertner et al. found that across 135 patients, uptake by normal tissues of the salivary glands, tear ducts, kidneys, and other vital organs was significantly reduced in men with high tumor load. While it is true for many pharmaceuticals that earlier use is more effective and less toxic, there is a balance to be struck between the tumor-killing effect and toxicity for the PSMA-targeted radiopharmaceuticals. We have seen that such treatment can be too late as well, when new metastases lose PSMA-avidity (see this link).

Mix Lu-177-PSMA-617 and Ac-225-PSMA-617

A cocktail of the two may increase the cancer-killing power of Lu-177-PSMA-617 while decreasing the toxicity of Ac-225-PSMA-617. Khreish et al. reported that only 5 of 20 patients given the cocktail reported mild xerostomia.

Use a PSMA antibody

PSMA-617 and PSMA-11 are small molecules that have been found to attach to the PSMA molecule on the surface of prostate cancer cells. They are not as specific as other ligands. Scott Tagawa is exploring the use of a PSMA antibody, called J591 in two clinical trials (this one and this one), that may be more specific than the small molecules. In a previous clinical trial, there were no reports of xerostomia.  The clinical trial of Th-227 targeting PSMA uses a highly specific antibody.

Use a non-PSMA-targeted ligand

Another strategy is to forgo the PSMA target entirely. Ac-225 has been attached to an antibody that very specifically targets hK2 (one of the 4 prostate cancer proteins detected by the 4KScore test). It has entered a clinical trial.

Beware of MSG and other supplements

Harsini et al. conducted a small clinical trial where patients were randomized to take tomato juice with and without monosodium glutamate (MSG). Glutamate is a known heavy-metal chelator. Each patient had two double-blinded PSMA PET scans -- one with MSG; the other without MSG. MSG did reduce the uptake of PSMA into the salivary glands and the kidneys. Unfortunately, it also blocked the uptake of PSMA into tumor tissue. Armstrong et al. reported a similar trial where patients could swish MSG in their mouths or ingest it. Each patient had Ga-68-PSMA-11 PET scans with and without MSG. Swishing had no effect. Oral ingestion reduced uptake in salivary glands and in tumors. Patients getting PSMA theranostics should avoid MSG and Chinese food.

Because the PSMA-targeted radiopharmaceuticals are very loosely held together (chelated) by a coordination complex, it is easily reversed by other heavy metals (like iron, cobalt, vanadium, etc. supplements) or other chelates or chelators (like those frequently found in multi-mineral tablets). Curcumin, a popular supplement, has been found to be a chelator. Use of such supplements may increase the toxicity of these radiopharmaceuticals, or render them ineffective. Antioxidants and free radical absorbers may interfere with the DNA damage that radiopharmaceuticals are trying to achieve. To be safe, and to maximize their effectiveness, patients should avoid all supplements during therapy.



Tuesday, August 11, 2020

PSMA-targeted radiopharmaceutical clinical trials in the US

Now that the VISION trial of Lu-177-PSMA-617 is no longer recruiting, some patients are wondering if they can still get PSMA-targeted radiopharmaceuticals in the US, without traveling to Germany, Australia, India, etc. Here is a list of trials that are active, still open to recruitment, or will soon be recruiting. 

Unless otherwise noted, they are all for men who are: 

  • metastatic
  • castration-resistant 
  • have had at least one taxane chemotherapy
  • at least one of the advanced androgen receptor therapies (e.g., Zytiga, Xtandi, Erleada, or Nubeqa)
  • no Xofigo
  • PSMA-avid on a PSMA PET/CT scan

Links that have contact information are provided.


Radiopharmaceutical

Adjuvant drugs

Extra criteria

Recruitment status/ contact

Locations

Lu-177-PSMA-617

Zytiga, Xtandi, or Erleada

mHSPC

Begins 5/3/21

Not yet announced

Lu-177-PSMA-PNT2002


Progressed on one second-line hormonal.

No chemo for CRPC

recruiting

Houston

Lu-177-PSMA-617

 

Chemo and immunotherapy naïve, failed one hormonal

Begins 4/30/21

Not yet announced

Lu-177-PSMA-617

Keytruda

No chemo since castration resistant

recruiting

UCSF

Lu-177-CTT1403

 

No Jevtana

recruiting

UCSF

Lu-177-PSMA-617

 

 

recruiting

•Weill Cornell

•Tulane (not yet)

Th-227-Antibody

(see article)

 

 

recruiting

• Royal Marsden (UK)

• Finland

• Tulane

• MSK

• Omaha, NE

Lu-177-J591

Ketoconazole

Prior RP or RT

Castration-resistant

Non-metastatic

recruiting

• Weill Cornell

• USC

• Georgetown

• IU

• U of Iowa

• UPMC

Lu-177-PSMA-R2

 

 

recruiting

• Stanford

• Yale

• Tulane

• Johns Hopkins

• Mt Sinai

• MD Anderson

• U of Wisconsin

• Phoenix

Ac-225-J591

 

 

recruiting

• Weill Cornell

• Tulane

Ac-225-J591

 

 

recruiting

• Weill Cornell

• Brooklyn Methodist

Lu-177-PSMA-617

(VISION)

 

 

Active, not recruiting

• 84 locations

Results expected August 2020

I-131-1095-MIPS

(see article)

Xtandi

Chemo naïve

Failed Zytiga

Active, not recruiting

• 17 locations

Results expected December 2021

 


 




Thursday, October 11, 2018

I-131-MIP-1095 has entered a phase 2 randomized clinical trial

As I reported last year, a new radiopharmaceutical has entered the pack. I-131-MIP-1095, a powerful beta-particle emitter attached to a PSMA-targeted ligand, will enter a multicenter phase 2 randomized clinical trial. Progenics®, the manufacturer, put out a press release, which can be read here. (Update 4/2020) The clinical trial has begun recruiting in 17 locations in the US and Canada.

They will be testing a combination of I-131-MIP-1095 with enzalutamide (Xtandi) in patients who are metastatic, castration resistant, have not yet had chemotherapy, and who have become resistant to Zytiga. It is hoped that Xtandi will radiosensitize the cancer to the radiopharmaceutical with a resultant PSA decrease.

175 evaluable patients will be recruited; half will get the radiopharmaceutical + Xtandi, half will get Xtandi alone. All patients will be screened using DCFPyL PET/CT to assure that their metastases are PSMA-avid. The primary endpoint - the percent who have greater than 50% PSA reduction - will be collected for a year. Secondary endpoints - radiographic response, progression-free survival, and overall survival - will be reported at the end of two years.

Another radiopharmaceutical in clinical trials is Lu-177-PSMA-617 .  There are various phase 1 and 2 clinical trials in the US and internationally (see list at the end of this link).

I recently reported about the very promising outcomes of Ac-225-PSMA-617 in Germany. Patients report that they are combining Ac-225-PSMA-617 and Lu-177-PSMA-617 to get the advantages of each. Weill Cornell in NYC is investigating Ac-225-J591 in a phase 1 trial.

For information on the trial of Th-227-PSMA, see this link.

Saturday, January 13, 2018

Ac-225-PSMA-617 (update)

We now have some details of the clinical trial of Ac-225-PSMA-617 in advanced prostate cancer patients. Kratchowil et al. reported on 40 patients who received this treatment at the University of Heidelberg. All patients had failed multiple therapies and were expected to have 2-4 months median survival (see this link). They received 3 cycles of Ac-225-PSMA in two-month intervals.

  • 11 patients did not complete 3 cycles
    • 5 discontinued due to non-response
    • 4 discontinued due to xerostomia (dry mouth)
    • 2 did not survive 8 weeks.
Among the 38 surviving patients:
  • 87% had some PSA decline
  • 63% had a PSA decline greater than 50%
  • Tumor control lasted 9.0 months (median)
  • 5 patients had a response lasting more than 2 years
  • Previous therapies with abiraterone lasted 10.0 months, docetaxel lasted for 6.5 months, enzalutamide for 6.5 months, and cabazitaxel for 6.0 months

These outcomes are impressive for a therapy given when all other therapies have failed. It is unclear whether it is better than Xofigo, the only approved radiopharmaceutical for metastatic castration-resistant prostate cancer. Xofigo only attacks cancer in bones, whereas Ac-225-PSMA attacks prostate cancer anywhere in the body.

(Update 5/19/2019)

Sathekge et al. reported the outcomes on 73 mostly chemotherapy-naive and abiraterone/enzalutamide-naive metastatic castration-resistant patients treated with Ac-225-PSMA-617 in South Africa. Most patients had 3 treatment cycles (every 2 months). Subsequent doses were lower to prevent side effects. PSA and metastatic activity was tracked using Ga-68-PSMA-617 PET scans.
  • 83% of patients responded to treatment
  • in 70% of patients, PSA declined by over 50%
  • PSA declines of over 50% predicted longer progression-free survival and overall survival
  • In 29% of patients, all lesions disappeared
  • During follow-up, 23 patients (32%) had disease progression and 13 (18%) died of prostate cancer
  • Progression-free survival was 15 months (median)
  • Overall survival was 18 months
  • Xerostomia (dry mouth) occurred in all 85% of patients, but it was not severe enough to stop treatment
  • Anemia occurred in 27 patients (37%); none grade 4
  • Grade 3 or 4 renal toxicity occurred in 5 patients with pre-existing renal impairment
This study suggests that Ac-225-PSMA-617 can be beneficial in patients who have not been heavily pre-treated. It also shows that xerostomia can be mitigated by reducing the subsequent doses given, and that for most patients, side effects are not severe enough to stop treatment. Lu-177-PSMA is now in a Phase 3 clinical trial at multiple sites in the US.

Thursday, December 22, 2016

Ac-225-PSMA-617 extends survival (update)

The nuclear medicine group at the University of Heidelberg recently reported a complete response in two patients treated with Ac-225-PSMA-617 (see this link). Now they have treated 80 patients with at least 24 weeks of follow-up, and report impressive results (here).

The 80 patients had failed on multiple therapies and were only expected to have 2-4 months of median survival.
  • The response rate (PSA reduction and tumor shrinkage) was 75%
  • Most were still alive 6 months after the therapy
  • Dry mouth was the only side effect of treatment
This is a report from a media release, and not a peer-reviewed journal. I will certainly report more details as they become available.

Anyone interested in medical tourism to try this experimental therapy can contact Dr. Haberkorn at the University of Heidelberg (he speaks English):
Email: Uwe_Haberkorn@med.uni-heidelberg.de
Phone: 06221 56-7731

There is a Phase 1 (dose finding) clinical trial of Ac-225-J591(a PSMA ligand) at Weill Cornell in NYC. It involves 8 visits over 12 weeks. Eligible patients must be metastatic and castration-resistant. They must have tried Zytiga, Xtandi and Taxotere or Jevtana. Scott Tagawa is the Principal Investigator.
Email: guonc@med.cornell. edu

(BTW - Scott Tagawa is also leading a trial combining two Lu-177-PSMA radiopharmaceuticals at Weill Cornell)

Thursday, August 25, 2016

First in-human trial of Actinium-225-PSMA-617


Among the more interesting developments in radiation oncology/nuclear medicine in recent years are novel therapies created by attaching radioactive isotopes to molecules (called ligands) that attach to the prostate-specific membrane antigen (PSMA) that is found on the surface of most metastatic prostate cancer cells.

We have seen several small studies conducted throughout Germany using Lu-177-PSMA (see this link for latest update).  Lu-177 is a beta (β) particle emitter – its radioactivity is produced when a neutron decays into a proton and an energetic electron – a beta particle. Xofigo is an alpha (α) particle emitter – its radioactivity occurs when the radium 223 nucleus releases 2 protons and 2 neutrons – an alpha particle or helium nucleus. There are advantages and disadvantages to each (see table in this link).

Lu-177-PSMA was developed at the University of Heidelberg. Those researchers have developed a targeted therapy using an alpha emitter called actinium 225. Ac-225-PSMA-617 can potentially be used in some situations where Xofigo or Lu-177-PSMA cannot. Xofigo only treats bone metastases because radium is biologically similar to calcium and replaces it in areas of active bone growth, like metastases. Ac-225-PSMA-617 has several theoretical advantages:
  • ·      It can target metastases in any tissue or fluid, including undetectable, systemic micrometastases.
  • ·      Because its alpha particles are very short range, it doesn’t destroy very much healthy bone marrow.
  • ·      Because the alpha particles are highly energetic, they destroy nearby cells very effectively.
  • ·      Because it attaches to PSMA instead of calcium-active sites in bone or other tissue, it may be less toxic to other healthy tissue.

Kratochwil et al. report a proof-of-concept in two patients treated with Ac-225-PSMA-617. They used Ga-68-PSMA-11, which shows up on a PET scan, to detect metastases that were positive for PSMA and to detect response to the alpha- emitter. The two patients selected had progressed under other treatments and were in “highly challenging clinical situations,” which included tumor infiltration into the red bone marrow. After bi-monthly treatments, both patients:
  • ·      Exhibited complete PSA response, becoming undetectable
  • ·      Exhibited complete tumor response on PET imaging
  • ·      Exhibited no hematological toxicity; that is, no bone marrow suppression
  • ·      Exhibited dry mouth from decreased saliva (xerostomia)

This is a first-in-human trial, and larger trials will be needed to prove efficacy and safety. However, it is an early encouraging development worth taking note of.