Phase Ib Trial of 177Lu-PSMA-I&T Therapy in Combination With Olaparib and Pembrolizumab in Patients With Metastatic Castration Resistant Prostate Cancer

1. Prior chemotherapy for mCRPC. Prior docetaxel is permitted if given in the setting of hormone sensitive disease

2. Site(s) of disease that are FDG positive with low PSMA expression defined by PSMA SUVmax \< 10

3. Extensive marrow disease defined by a "Super Scan" on bone scintigraphy or diffuse marrow infiltration on PSMA PET

4. Active brain metastases or leptomeningeal metastases

5. Any prior exposure to anti-PD-1, anti-PD-L1/L2, anti-CD137, or anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathway

6. Any prior exposure to PARP inhibitors, platinum, or radionuclide therapy

7. Patients with a history or clinical features suggestive of myelodysplastic syndrome/acute myeloid leukaemia or previously known clonal haemopoiesis

8. Patients unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with the absorption of the study medication

9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography scan or psychiatric illness/social situations that is likely to impede participation and /or compliance in the study

10. Patients with active, known, or suspected autoimmune disease Note: Patients with vitiligo, type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol

11. Patients with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration Note: Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone are permitted in the absence of active autoimmune disease

12. Malignancy within the previous 2 years other than basal cell or squamous cell carcinomas, skin or melanoma in situ, or other cancers that are unlikely to recur within 24 months

13. Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C ribonucleic acid (HCV PCR) indicating acute or chronic infection

14. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable

15. Persistent toxicities (CTCAE ≥ Grade 2) caused by previous cancer therapy, excluding alopecia

16. Previous history of interstitial lung disease or non-infectious pneumonitis

17. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the Investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \> 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome

18. Known hypersensitivity to olaparib or pembrolizumab or any of the excipients of olaparib or pembrolizumab

19. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) 1/2. Only need to check this if there is a clinical history. HIV-infected (HIV1/2 antibody-positive) patients may participate if they meet all the following eligibility requirements:

* They must be on an anti-retroviral regimen with evidence of at least two undetectable viral loads within the past 6 months on this same regimen; the most recent undetectable viral load must be within 12 weeks prior to registration

* They must have a CD4 count ≥ 250 cells/µL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count \< 200 cells/µL over the past 2 years unless it was deemed related to the cancer and/or chemotherapyinduced bone marrow suppression

* For patients who have received chemotherapy in the past 6 months, a CD4 count \< 250 cells/µL during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy

* They must have an undetectable viral load and a CD4 count ≥ 250 cells/µL within 7 days prior to registration

* They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within 6 months prior to registration

20. Concomitant use of known strong cytochrome P450, family 3 (CYP3A) inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks

21. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for phenobarbital and enzalutamide, and 3 weeks for other agents

22. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation

23. Participation in another clinical study with an investigational product or another systemic therapy administered within 3 weeks prior to registration

What this study is about