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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03874884




Registration number
NCT03874884
Ethics application status
Date submitted
28/02/2019
Date registered
14/03/2019

Titles & IDs
Public title
177Lu-PSMA-617 Therapy and Olaparib in Patients With Metastatic Castration Resistant Prostate Cancer
Scientific title
177Lu-PSMA-617 Therapy and Olaparib in Patients With Metastatic Castration Resistant Prostate Cancer
Secondary ID [1] 0 0
Peter Mac project no.18/216
Universal Trial Number (UTN)
Trial acronym
LuPARP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Castration Resistant Prostate Cancer (mCRPC) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Olaparib
Other interventions - 177Lu-PSMA

Experimental: 177Lu-PSMA + olaparib - 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.


Treatment: Drugs: Olaparib
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.

Other interventions: 177Lu-PSMA
A fixed 7.4Gbq administered activity of 177Lu-PSMA will be given 6 weekly for up to 6 cycles.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose Limiting toxicities (DLTs)
Timepoint [1] 0 0
Dose escalation phase is expected to be completed 11 months from the time the first patient is recruited.
Primary outcome [2] 0 0
Maximum Tolerated dose (MTD)
Timepoint [2] 0 0
Dose escalation phase is expected to be completed 11 months from the time the first patient is recruited.
Primary outcome [3] 0 0
Recommended Phase 2 Dose (RP2D)
Timepoint [3] 0 0
Upto 30 months from the time the first patient is recruited.
Secondary outcome [1] 0 0
Adverse Events and Serious Adverse Events measured using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Timepoint [1] 0 0
Through study completion, up until 18 months after the last patient commences treatment.
Secondary outcome [2] 0 0
Radiographic progression-free survival (rPFS)
Timepoint [2] 0 0
Through study completion, up until 18 months after the last patient commences treatment.
Secondary outcome [3] 0 0
PSA progression free survival (PSA-PFS)
Timepoint [3] 0 0
Through study completion, up until 18 months after the last patient commences treatment.
Secondary outcome [4] 0 0
Objective response rate (ORR) by RECIST1.1 in patients with measurable disease
Timepoint [4] 0 0
Through study completion, up until 18 months after the last patient commences treatment.
Secondary outcome [5] 0 0
Overall survival (OS)
Timepoint [5] 0 0
Through study completion, up until 18 months after the last patient commences treatment.
Secondary outcome [6] 0 0
50% PSA response rate (PSA-RR)
Timepoint [6] 0 0
Through study completion, up until 78 weeks after the last patient commences treatment.
Secondary outcome [7] 0 0
Duration of response (DOR)
Timepoint [7] 0 0
Through study completion, up until 18 months after the last patient commences treatment.
Secondary outcome [8] 0 0
Time to treatment response (TTR) in the subset of patients who achieved a 50% PSA response
Timepoint [8] 0 0
Through study completion, up until 18 months after the last patient commences treatment.
Secondary outcome [9] 0 0
Treatment discontinuation due to toxicity
Timepoint [9] 0 0
Through study completion, up until 18 months after the last patient commences treatment.
Secondary outcome [10] 0 0
Rate of treatment discontinuation due to toxicity
Timepoint [10] 0 0
Through study completion, up until 18 months after the last patient commences treatment.

Eligibility
Key inclusion criteria
Patients must meet all of the following criteria for study entry:

1. Patient must be = 18 years of age and must have provided written informed consent.
2. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation.
3. Eastern Cooperative Oncology Group (ECOG) performance status of = 1 (see Appendix 1).
4. 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.
5. 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.
6. 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)
7. 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.
8. 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.
9. Serum testosterone levels = 50ng/dL (= 1.75nmol/L) within 28 days before registration.
10. Imaging evidence of metastatic disease documented with either bone scan or CT scan (Appendix 2).
11. 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.
12. 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).
13. Patients must have a life expectancy = 24 weeks.
14. 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).
15. 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.
16. 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).
17. 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Patients must not meet any of the following criteria for study entry:

1. Site(s) of disease that are FDG positive with low PSMA expression defined by PSMA SUVmax < 10.
2. Extensive marrow disease defined by a "Super Scan" on bone scintigraphy or diffuse marrow infiltration on PSMA PET.
3. 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.
4. Surgery or radiotherapy within < 3 weeks of registration (except for palliative reasons). Patients must have recovered from any effects of any major surgery.
5. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for = 4 weeks.
6. Any prior exposure to 177Lu-PSMA, cabazitaxel, platinums, PARP inhibitors, mitoxantrone or cyclophosphamide.
7. 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.
8. Persistent toxicities [Common Terminology Criteria for Adverse Event (CTCAE) = grade 2] caused by previous cancer therapy, excluding alopecia.
9. 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.
10. Previous history of interstitial lung disease or non-infectious pneumonitis.
11. Patients with a history or clinical features suggestive of myelodysplastic syndrome / acute myeloid leukaemia.
12. Patients unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with the absorption of the study medication.
13. 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.
14. Known hypersensitivity to olaparib or any of the excipients of olaparib.
15. 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/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 chemotherapy-induced 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 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.
16. 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.
17. 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.
18. 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.
19. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
20. Participation in another clinical study with an investigational product or another systemic therapy administered in the last 3 weeks.

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
9/07/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2026
Actual
Sample size
Target
70
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
St Vincent's Hospital Sydney - Sydney
Recruitment hospital [2] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 0 0
2010 - Sydney
Recruitment postcode(s) [2] 0 0
3000 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
Peter MacCallum Cancer Centre, Australia
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Shahneen Sandhu
Address 0 0
Peter MacCallum Cancer Centre, Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Shahneen Sandhu
Address 0 0
Country 0 0
Phone 0 0
+61 3 8559 7902
Fax 0 0
Email 0 0
Shahneen.Sandhu@petermac.org
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03874884