Clinical Trial · NCT07090369

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

Overview

This phase 1b trial is designed to evaluate the safety and tolerability of olaparib in combination with 177Lutetium-Prostate Specific Membrane Antigen (177 Lu-PSMA) and pembrolizumab in patients with metastatic castration resistant prostate cancer (mCRPC).

Sponsor

Peter MacCallum Cancer Centre

Phase

Phase 1

Contacts

Ramin Alipour, ramin.alipour@petermac.org (CONTACT)

ramin.alipour@petermac.org

+61 3 8559 7000

Shahneen Sandhu (CONTACT)

shahneen.sandhu@petermac.org

+61 3 8559 7902

ClinicalTrials.gov

NCT07090369

Drug / Compound

PSMA-I&T

Isotope(s):

Target(s):

PSMA

Ligand Class: Small Molecules

Chelator: DOTAGA

Eligibility

Inclusion

Albumin ≥ 30 g/L
Patients must have progressive disease defined as any one of the following:
Bone progression: ≥ 2 new lesions on bone scan (Appendix 2)
Patients who are deemed to have disease that is safe and amenable to biopsy based on screening PSMA PET scans will be mandated to consent to paired tumour biopsies at Screening and on treatment
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
Radiographic evidence of metastatic disease documented with either bone scan or CT scan (Appendix 2)
PSA \> 5 ng/mL
Platelets ≥ 150 x 109/L
Prior surgical orchiectomy or chemical castration maintained on ongoing luteinizing hormone-releasing hormone analogue (agonist or
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome
PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement. The PSA value at screening should be ≥ 5 ng/mL
Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation
Adequate renal function: Patients must have creatinine clearance (CrCl) estimated of ≥ 51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test
Patients must have adequate bone marrow, hepatic and renal function documented within 28 days prior to registration, defined as:
Haemoglobin ≥ 100 g/L independent of transfusions (no red blood cell transfusion in last 8 weeks)
Absolute neutrophil count ≥ 1.5 x 109/L
Non-sterilised male patients who are sexually active with a female partner of childbearing potential must use a condom from screening to approximately 3 months after the last dose of treatment. Female partners of male patients should also use a highly effective form of contraception throughout this period
Willing and able to comply with treatment schedule, laboratory testing, and other requirements of the study
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN if there is no evidence of liver metastasis or ≤ 5 x ULN in the presence of liver metastases
At least 2 weeks since the completion of prior therapy, including surgery or radiotherapy
Soft tissue or visceral disease progression as per modified RECIST 1.1 criteria (Appendix 2)
Patients must have progressed on an ARPI (e.g. enzalutamide, abiraterone, darolutamide/or apalutamide). Determination of disease progression on an ARPI will be made by the local Investigator
Patients must have a life expectancy ≥ 24 weeks
Significant PSMA avidity on PSMA PET/CT, defined as a minimum uptake of SUVmax 15 at a site of disease, and SUVmax \> 10 at other sites of disease ≥ 10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact)

Exclusion

Site(s) of disease that are FDG positive with low PSMA expression defined by PSMA SUVmax \< 10
Patients unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with the absorption of the study medication
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
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
Any prior exposure to PARP inhibitors, platinum, or radionuclide therapy
Persistent toxicities (CTCAE ≥ Grade 2) caused by previous cancer therapy, excluding alopecia
Previous allogenic bone marrow transplant or double umbilical cord blood transplantation
Known hypersensitivity to olaparib or pembrolizumab or any of the excipients of olaparib or pembrolizumab
Extensive marrow disease defined by a "Super Scan" on bone scintigraphy or diffuse marrow infiltration on PSMA PET
Patients with a history or clinical features suggestive of myelodysplastic syndrome/acute myeloid leukaemia or previously known clonal haemopoiesis
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
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
Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable
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
Prior chemotherapy for mCRPC. Prior docetaxel is permitted if given in the setting of hormone sensitive disease
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
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
Participation in another clinical study with an investigational product or another systemic therapy administered within 3 weeks prior to registration
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
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 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
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:
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
Previous history of interstitial lung disease or non-infectious pneumonitis
Active brain metastases or leptomeningeal metastases
Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C ribonucleic acid (HCV PCR) indicating acute or chronic infection
They must have an undetectable viral load and a CD4 count ≥ 250 cells/µL within 7 days prior to registration