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.

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.

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)

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.