Showing posts with label Lu-177. Show all posts
Showing posts with label Lu-177. Show all posts

Friday, April 30, 2021

First clinical trial of Lu-177-PSMA-617 in recurrent, hormone-sensitive men

While we expect only a few months of extra survival from the VISION trial of Lu-177-PSMA-617 in heavily pretreated, metastatic, castration-resistant men (see this link), we hope to get more out of the radiopharmaceutical if used earlier. Privé et al. reported the results of a pilot trial in 10 recurrent men treated with Lu-177-PSMA-617 at Radboud University in Nijmegen, The Netherlands. They were all:

  • Recurrent after prostatectomy ± salvage radiation (PSA>0.2 ng/ml) 
  • Rapid PSA doubling time (< 6 months)
  • Between 1-10 metastases detectable on a PSMA PET scan or USPIO MRI
  • At least 1 metastasis > 1 cm.
  • Unable to receive SBRT to metastases 
  • No visceral metastases 
  • Have not begun salvage ADT
  • Treated with a low dose (3 GBq) on day 1; second treatment (~6 GBq) after 8 weeks (compared to dose in VISION trial of 7.4 GBq in each of 4-6 cycles)

After 24 weeks of follow-up after Cycle 2:

  • 5 patients had PSA reduced by >50% (1 undetectable)
  • 2 patients had stable PSA
  • 3 patients had PSA progression
  • 6 patients had a radiographic response
  • 4 patients had radiographic progression
  • ADT-deferred survival was 9.5 months (median)
  • Those with lymph node only metastases had the best response
  • Those with any bone metastases had lesser response
After 2nd dose, comparing their 24-week PSA to their 12-week PSA:

  • PSA was continuing to decline in 3 patients
  • PSA was rising again in 6 patients

Side effects were mild (no grade 3) and transient:

  • fatigue in 7; nausea in 3
  • dry mouth (xerostomia) in 2

There are lots more questions than answers:
  • Would a higher dose and more treatments be more effective?
  • Would a higher dose and more treatments be more toxic?
  • Is it like Xofigo in that it's more effective with micrometatases? If so, would a combination with SBRT targeted at the larger metastases be more effective?
  • Since it was more effective on lymph nodes, would it make a good combination with Xofigo for patients who have both lymph node and bone metastases? (See also Th-227-PSMA)
  • Because there seems to be a continued abscopal effect for some patients, would combining it with Provenge be optimal?
  • Would pretreatment with ADT or a new anti-androgen (Xtandi, Erleada or Nubeqa) increase expression of PSMA, and increase radiosensitivity?
  • Can we predict who will benefit?
  • Use in other patient populations remains to be explored: high-risk, newly diagnosed metastatic, castration-resistant but chemo-naive. Optimal sequencing with other therapies remains to be explored.






Tuesday, August 11, 2020

PSMA-targeted radiopharmaceutical clinical trials in the US

(frequently updated)

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

Radiopharmaceutical

Adjuvant drugs

Extra criteria

Recruitment status/ contact

Locations

Ac-225-PSMA-R2


•After or without prior Lu-177-PSMA

Begins 10/23

TBD

Lu-177-PSMA-617

PSMACare

1. ADT

2.ARSi+ADT (ARSi=Zytiga, Xtandi,Erleada or Nubeqa)

•Metastatic with PSMA PET, but not with conventional imaging

•CRPC

•No prior ARSi or chemo

Begins 12/23

TBD

Lu-177-PNT2002

LUNAR

Before SBRT

Recurrent and oligometastatic

recruiting

UCLA


Lu-177-rhPSMA-10.1


±previous chemo

recruiting 

•Maryland

•St.Louis

•Omaha

•Mt Sinai-NYC

Lu-177-PSMA-I&T


Chemo naïve, failed one hormonal

recruiting

• 58 locations

Ac-225-PSMA-I&T

TATCIST



Recruiting

• Houston

Ac-225-J591

 

 

recruiting

• Weill Cornell

• Brooklyn Methodist

Pluvicto+ONC392 (a CTL4 blocking immunotherapy)



Begins 9/23

• NYU Langone

• Columbia

• Maryland

• Omaha

• Duke

• UTSW (Dallas)

•UWisc. Carbone

Ac-225-J591 + Lu-177-PSMA- I&T

 


Suspended

• Weill Cornell

• Brooklyn Methodist

Ac-225-J591

Keytruda

No chemo since castration resistant

recruiting

• Weill Cornell

• Brooklyn Methodist

• Dana Farber

• Columbia

Cu-67-SAR-bisPSMA

SECuRE

 

Previous chemo OK, not required

recruiting

• Johns Hopkins

•Mayo Rochester

•Mayo, AZ

•Tulane, N.O.

•Barnes Jewish, St. Louis

•Omaha, NE

•Weill Cornell

Lu-177-PSMA-617

PSMAddition


mHSPC

(M1 or N1)

Treatment naive

Recruiting

• 188 sites

Lu-177-PSMA-617

Keytruda

No chemo since castration resistant

active, not recruiting

UCSF

Lu-177-CTT1403

 

No Jevtana

active, not recruiting

UCSF

Lu-177-PSMA-617

 

 

Active, not recruiting

•Weill Cornell

•Tulane

Th-227-Antibody

(see article)

 

 

active, not recruiting

• Royal Marsden (UK)

• Finland

• Tulane

• MSK

• Omaha, NE

Lu-177-J591

Ketoconazole

Prior RP or RT

CRPC

Non-metastatic

active, not recruiting

• Weill Cornell

• USC

• Georgetown

• IU

• U of Iowa

• UPMC

Lu-177-PSMA-R2

 

 

Active, not recruiting

• Stanford

• Yale

• Tulane

• Johns Hopkins

• Mt Sinai

• MD Anderson

• U of Wisconsin

• Phoenix

Lu-177-PSMA-617

PSMAfore

 

Chemo and immunotherapy naïve, failed one hormonal

Active, not recruiting

(Phase 3 RCT)

• 72  sites

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



Sunday, May 31, 2020

Lu-177-PSMA-617 vs Jevtana (cabazitaxel): which should I do next?

We saw recently (see this link) that of chemo and hormonal medicines for metastatic castration-resistant prostate cancer (mCRPC), Jevtana (cabazitaxel) is the preferred third treatment after Taxotere (docetaxel) and Zytiga (abiraterone) or Xtandi (enzalutamide). But when should radiopharmaceuticals, either approved ones like Xofigo (Ra-223), or prospective ones like Lu-177-PSMA-617, be used in the optimal sequencing?

Michael Hofman reported the results of the TheraP randomized clinical trial (RCT). They randomized some well-selected patients to receive either Lu-177-PSMA-617 or Jevtana. Patients were selected according to the following criteria;
  • mCRPC (PSA≥20 ng/ml and rising)
  • must have had docetaxel
  • must have had either Zytiga or Xtandi or both
  • healthy, with good liver, kidney, and blood function
In addition, all patients received both an FDG PET scan and a PSMA PET scan. They were excluded from the trial if either:
  • Their metastases were insufficiently PSMA-avid - (10% excluded)
  • There were many metastases that showed up on FDG but not on PSMA PET scans (as described here) - (18% excluded)
  • 85 patients were treated with Jevtana
  • 98 patients were treated with Lu-177-PSMA-617

The endpoint used was the percent of patients whose PSA declined by at least 50% (PSA50) from baseline after the treatment. After a median follow-up of 13 months:
  • Lu-177-PSMA-617 had a PSA50 of 66% vs 37% for Jevtana
  • The percent who had PSA progression was 31% less in those getting Lu-177-PSMA-617 relative to those getting Jevtana
  • At 12 months, progression-free survival was 19% for Lu-177-PSMA-617 vs 3% for Jevtana
  • Pain improvement was better for Lu-177-PSMA-617 (60%) than Jevtana (43%)
  • It is too early for data on overall survival (see below for update)
  • Serious/life-threatening adverse events occurred in 33% of those taking Lu-177-PSMA-617 vs. 53% of those taking Jevtana
  • The most common adverse events reported by those taking Lu-177-PSMA-617 were fatigue, pain, nausea, dry mouth/eyes, low platelets, and anemia. Only 1 patient discontinued for toxicity.
  • The most common adverse events reported by those taking Jevtana were fatigue, pain, diarrhea, nausea, loss of taste, neuropathy, dry mouth, and neutropenia, 3 patients discontinued for toxicity
(update 12/23) With longer term follow-up, it became apparent that although Lu-177-PSMA-617 was quicker to reduce PSA, there was no survival difference. After a follow-up of 36 months:
  • Overall survival was 19.1 months for those starting with Jevtana vs 19.6 months for those starting with Lu-177-PSMA-617 (not statistically different)

This study further highlights the importance of getting both an FDG and a PSMA  PET scan at about the same time. (update 10/17/22) SUVmean>10 was a good biomarker for predicting whether Lu-177-PSMA-617 will succeed. High FDG PET predicted poor treatment response.

PSMA expression is highly variable. It is not expressed in low-grade cancer in the prostate. Expression increases as metastases develop, reach a peak, and then decreases. PSMA expression also increases when second-line hormonals are first used, but then decreases with continued use. Given this variation over time and treatment, several questions about PSMA-targeted therapy remain unanswered:
  • Should it be used soon after second-line hormonals?
  • Should it be used before or soon after docetaxel? (see this link)
  • Would the problem of heterogeneity be minimized if Jevtana and Lu-177-PSMA were given simultaneously?
  • Should it be used in minimally metastatic patients?
  • Should it be used in newly diagnosed metastatic patients?
  • Should it be used with immunotherapies (e.g., Provenge, Checkpoint inhibitors)?
  • Will PARP inhibitors enhance the cell-kill rate?
  • Is PSA the best biomarker of effectiveness?
  • What are the best radionuclides to use (e.g., Ac-225, Th-227)?
  • What are the best/most specific ligands to use? (e.g., PSMA-617, PSMA-I&T)
  • Are there better surface proteins to target, perhaps simultaneously (e.g., FAPI)
  • How do they compare to PSMA BiTE therapies?
  • How does it compare to Xofigo for bone metastases?