177Lu-PSMA-617 Therapy and Olaparib in Patients With Metastatic Castration Resistant Prostate Cancer (LuPARP)

  • STATUS
    Recruiting
  • days left to enroll
    74
  • participants needed
    52
  • sponsor
    Peter MacCallum Cancer Centre, Australia
Updated on 12 February 2022

Summary

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

Description

This phase 1, open label, multicentre, dose-escalation and dose-expansion study is designed to evaluate the safety and tolerability of olaparib in combination with 177Lu-PSMA in patients with mCRPC. Patients with mCRPC who have previously progressed on a novel AR targeted agent (abiraterone and/or enzalutamide and/or apalutamide) and have not had prior exposure to platinums, PARP inhibitors or 177Lu-PSMA will be eligible for the study. Patients can have had prior exposure to docetaxel in the chemotherapy nave setting or castrate setting.

Patients will be enrolled in two stages: a dose escalation and a dose expansion phase. The clinical and translational outcomes from this study will inform the design of future phase 2/3 clinical trials of this combination.

This is a single arm study where patients will receive 177Lu-PSMA and olaparib for upto 4 cycles.

Details
Condition Metastatic Castration Resistant Prostate Cancer (mCRPC)
Treatment olaparib, 177Lu-PSMA
Clinical Study IdentifierNCT03874884
SponsorPeter MacCallum Cancer Centre, Australia
Last Modified on12 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients must meet all of the following criteria for study entry
Patient must be 18 years of age and must have provided written informed consent
Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation
Eastern Cooperative Oncology Group (ECOG) performance status of 1 (see Appendix 1)
Patients must have had at least one prior line of taxane (docetaxel) chemotherapy either in the hormone sensitive or castrate resistant setting unless the patient is deemed medically unsuitable for chemotherapy. If a patient has had docetaxel chemotherapy twice, this will be considered one line
Patients must have progressed on a second generation AR targeted agent (e.g. enzalutamide, abiraterone and/or apalutamide). Determination of disease progression on second generation AR targeted agent will be made by the local investigator
Patients must have progressive disease for study entry. This is defined by PCWG3 as any one of the following
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 10ng/ml
Soft tissue or visceral disease progression as per RECIST 1.1 criteria (see Appendix 2)
Bone progression: 2 new lesions on bone scan (Appendix 2)
At least 3 weeks since the completion of surgery or radiotherapy prior to registration. Any clinically relevant sequelae from the surgery or radiotherapy must have improved to grade 1 prior to registration
Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist). Patients without prior surgical castration must be currently taking and willing to continue luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) therapy throughout the duration of study treatment
Serum testosterone levels 50ng/dL ( 1.75nmol/L) within 28 days before registration
Imaging evidence of metastatic disease documented with either bone scan or CT scan (Appendix 2)
Prior prostate cancer vaccine therapy, radiation therapy, systemic therapies, diethylstilboestrol (DES) or other estrogens, bicalutamide, flutamide or nilutamide are allowed up to 28 days prior to trial registration. Note: bicalutamide, flutamide or nilutamide must be discontinued within 4 weeks of registration
Significant PSMA avidity on 68Ga/18F-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)
Patients must have a life expectancy 24 weeks
Patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception (see section 11.7.4 for acceptable methods)
Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled assessments including completing Patient Reported Outcomes (PRO) instruments
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 1.5x109/L
Platelets 150 x109/L
Total bilirubin 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome where this applies for the unconjugated bilirubin
Aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGPT) 2.5 x ULN if there is no evidence of liver metastasis or 5 x ULN in the presence of liver metastases
Albumin 30 g/L
Adequate renal function: patients must have creatinine clearance estimated of 51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test to appendix 5)
Patients who are deemed by PSMA imaging to have readily accessible disease will be required to consent to 3 serial tumour biopsies - at screening, post combination treatment (at any time between weeks 2-4) and in the event of disease progression

Exclusion Criteria

Patients must not meet any of the following criteria for study entry
Site(s) of disease that are FDG positive with low PSMA expression defined by PSMA SUVmax < 10\
Extensive marrow disease defined by a "Super Scan" on bone scintigraphy or diffuse marrow infiltration on PSMA PET
Previous history or presence of brain metastases or leptomeningeal metastases. A scan to confirm the absence of brain metastases is not required if there is no clinical history of this
Surgery or radiotherapy within < 3 weeks of registration (except for palliative reasons). Patients must have recovered from any effects of any major surgery
Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for 4 weeks
Any prior exposure to 177Lu-PSMA, cabazitaxel, platinums, PARP inhibitors, mitoxantrone or cyclophosphamide
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 (HRCT) scan or psychiatric illness/social situations that is likely to impede participation and /or compliance in the study
Persistent toxicities [Common Terminology Criteria for Adverse Event (CTCAE) grade
caused by previous cancer therapy, excluding alopecia
Other malignancies within the previous 2-years other than basal cell or squamous cell carcinomas of skin or other cancers that are unlikely to recur within 24 months
Previous history of interstitial lung disease or non-infectious pneumonitis
Patients with a history or clinical features suggestive of myelodysplastic syndrome / acute myeloid leukaemia
Patients unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with the absorption of the study medication
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
Known hypersensitivity to olaparib or any of the excipients of olaparib
Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV1/2). 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 the past 12 weeks
They must have a CD4 count 250 cells/L over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count < 200 cells/l over the past 2 years, unless it was deemed related to the cancer and/or chemotherapy-induced bone marrow suppression
For patients who have received chemotherapy in the past 6 months, a CD4 count < 250 cells/l 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/L within 7 days of enrolment
They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months
Patients with known active hepatitis (i.e. Hepatitis B or C). Only need to check this if there is a clinical history
Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
Concomitant use of known strong 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
Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for phenobarbital and enzalutamide and 3 weeks for other agents
Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
Participation in another clinical study with an investigational product or another systemic therapy administered in the last 3 weeks
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