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

NCT03874884 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: Peter Mac project no.18/216
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 2

Brief 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).

Conditions

Metastatic Castration Resistant Prostate Cancer (mCRPC)

Outcome Measures

Primary Outcomes (3)

• Dose Limiting toxicities (DLTs)

  A DLT is defined as a toxicity that prevents further administration of the trial treatment at that dose level. Each cohort of 3 patients be assessed for DLTs in the first 6 weeks (cycle 1) of treatment and a dose for the next cohort will be determined.

  Dose escalation phase is expected to be completed 11 months from the time the first patient is recruited.

• Maximum Tolerated dose (MTD)

  The MTD is defined as the highest dose level at which the incidence of DLT was less than 2/6.

  Dose escalation phase is expected to be completed 11 months from the time the first patient is recruited.

• Recommended Phase 2 Dose (RP2D)

  After the MTD is established, additional patients will be treated at the MTD. Safety and efficacy data from the study will be used to define the RP2D.

  Upto 30 months from the time the first patient is recruited.

Secondary Outcomes (10)

• Adverse Events and Serious Adverse Events measured using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

  Through study completion, up until 18 months after the last patient commences treatment.

• Radiographic progression-free survival (rPFS)

  Through study completion, up until 18 months after the last patient commences treatment.

• PSA progression free survival (PSA-PFS)

  Through study completion, up until 18 months after the last patient commences treatment.

• Objective response rate (ORR) by RECIST1.1 in patients with measurable disease

  Through study completion, up until 18 months after the last patient commences treatment.

• Overall survival (OS)

  Through study completion, up until 18 months after the last patient commences treatment.

Study Arms (1)

177Lu-PSMA + olaparib

EXPERIMENTAL

Patients will receive a fixed 7.4 GBq of 177Lu-PSMA every 6 weeks together with olaparib on days 2-15 of each cycle. A cycle is 42 days long. Patients will receive 6 cycles of treatment.

Drug: Olaparib; Combination Product: 177Lu-PSMA

Interventions

Olaparib DRUG

During dose escalation doses of olaparib that can be administered are 50mg BD D2-15, 100mg BD D2-15, 150mg BD D2-15, 200mg BD D2-15,250mg BD D2-15, 300mg BD D2-15, 200mg BD D4-14, 300mg BD D-4-14 or 400mg D-4-18 of a 42 day cycle for up to 6 cycles. The recommended phase 2 dose of olaparib will be used in 2 consecutive dose expansion cohorts. The first cohort will received the recommended phase 2 dose of Olaparib on D4-14 of a 42 day cycle. Patients enrolled in the second dose expansion cohort will receive Olaparib continuously from cycle 1 day -4 to cycle 6 day 42.

177Lu-PSMA + olaparib

177Lu-PSMA COMBINATION_PRODUCT

A fixed 7.4Gbq administered activity of 177Lu-PSMA will be given 6 weekly for up to 6 cycles.

177Lu-PSMA + olaparib

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Men with mCRPC who are minimally symptomatic and have progressed on at least one line of novel AR targeted agents (e.g. enzalutamide, abiraterone acetate, apalutamide, etc) will be eligible for the study.Patients may have received docetaxel chemotherapy in the treatment naïve or castrate resistant setting. Prior prostate cancer vaccine therapy, radiation therapy, systemic therapies, diethylstilboestrol (DES) or other oestrogens, bicalutamide, flutamide or nilutamide are allowed up to 28 days prior to trial registration (bicalutamide, flutamide or nilutamide must be discontinued within 4 weeks of registration). Patients already receiving anti-bone resorptive therapy for management of skeletal related events (SREs) are permitted to continue with this treatment.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• For dose escalation (dose levels 1-9) and expansion cohorts, 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. For the continuous olaparib dose cohort (DE #2) patients can have had docetaxel however this is not required for eligibility.
• Patients must have progressed on a second generation AR targeted agent (e.g. enzalutamide, abiraterone, darolutamide 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.

You may not qualify if:

• 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, recent thromboembolic events (\<6 months ago), 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 \[Common Terminology Criteria for Adverse Event (CTCAE) ≥ grade 2\] 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.

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (2)

St Vincent's Hospital Sydney

Sydney, New South Wales, 2010, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

MeSH Terms

Interventions

olaparib

Study Officials

• Shahneen Sandhu

  Peter MacCallum Cancer Centre, Australia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 28, 2019
• First Posted: March 14, 2019
• Study Start: July 9, 2019
• Primary Completion: May 1, 2025
• Study Completion (Estimated): June 1, 2026
• Last Updated: May 14, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2)