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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03874884
Registration number
NCT03874884
Ethics application status
Date submitted
28/02/2019
Date registered
14/03/2019
Date last updated
6/05/2024
Titles & IDs
Public title
177Lu-PSMA-617 Therapy and Olaparib in Patients With Metastatic Castration Resistant Prostate Cancer
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Scientific title
177Lu-PSMA-617 Therapy and Olaparib in Patients With Metastatic Castration Resistant Prostate Cancer
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Secondary ID [1]
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Peter Mac project no.18/216
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Universal Trial Number (UTN)
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Trial acronym
LuPARP
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Metastatic Castration Resistant Prostate Cancer (mCRPC)
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Condition category
Condition code
Cancer
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Prostate
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Olaparib
Combination Product - 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.
Combination Product: 177Lu-PSMA
A fixed 7.4Gbq administered activity of 177Lu-PSMA will be given 6 weekly for up to 6 cycles.
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Combination Product
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Dose Limiting toxicities (DLTs)
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Assessment method [1]
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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.
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Timepoint [1]
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Dose escalation phase is expected to be completed 11 months from the time the first patient is recruited.
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Primary outcome [2]
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Maximum Tolerated dose (MTD)
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Assessment method [2]
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The MTD is defined as the highest dose level at which the incidence of DLT was less than 2/6.
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Timepoint [2]
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Dose escalation phase is expected to be completed 11 months from the time the first patient is recruited.
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Primary outcome [3]
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Recommended Phase 2 Dose (RP2D)
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Assessment method [3]
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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.
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Timepoint [3]
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Upto 30 months from the time the first patient is recruited.
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Secondary outcome [1]
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Adverse Events and Serious Adverse Events measured using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
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Assessment method [1]
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Safety of the combination will be measured by AEs and SAEs.
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Timepoint [1]
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Through study completion, up until 18 months after the last patient commences treatment.
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Secondary outcome [2]
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Radiographic progression-free survival (rPFS)
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Assessment method [2]
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rPFS is defined as the time from treatment initiation to the first date of documented radiographic progression using conventional imaging or death due to any cause, whichever occurs first. The radiographic progression will be assessed by the investigator per RECIST1.1 for soft tissue and PCWG3 for bone lesions.
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Timepoint [2]
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Through study completion, up until 18 months after the last patient commences treatment.
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Secondary outcome [3]
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PSA progression free survival (PSA-PFS)
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Assessment method [3]
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PSA-PFS is defined as the time from treatment initiation to the date of PSA progression per PCWG3 or death due to any cause, whichever occurs first. The date of PSA progression is the date that an increase of 25% or more and an absolute increase of 2ng/mL or more from the nadir is documented. For patients who have an initial PSA decline during treatment, this must be confirmed by a second value 3 or more weeks later.
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Timepoint [3]
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Through study completion, up until 18 months after the last patient commences treatment.
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Secondary outcome [4]
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Objective response rate (ORR) by RECIST1.1 in patients with measurable disease
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Assessment method [4]
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Objective Response (OR) is only applicable for the subset of patients with measurable disease by RECIST1.1. OR is defined as a partial response (PR) or complete response (CR) at any stage from time of commencement of protocol treatment to the time of subsequent systemic anti-cancer treatment. The ORR is calculated as the proportion of patients with a best response of CR or PR.
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Timepoint [4]
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Through study completion, up until 18 months after the last patient commences treatment.
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Secondary outcome [5]
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Overall survival (OS)
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Assessment method [5]
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OS is defined as the time from treatment initiation to the date of death due to any cause.
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Timepoint [5]
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Through study completion, up until 18 months after the last patient commences treatment.
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Secondary outcome [6]
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50% PSA response rate (PSA-RR)
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Assessment method [6]
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PSA will be assessed at baseline and every 6 weeks from cycle 1 day 1 independent of olaparib and 177Lu-PSMA dosing. PSA response will be defined as a 50% or greater decrease in PSA from baseline to the lowest post-baseline PSA result. A second consecutive value obtained 3 or more weeks later is required to confirm the PSA response.
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Timepoint [6]
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Through study completion, up until 78 weeks after the last patient commences treatment.
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Secondary outcome [7]
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Duration of response (DOR)
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Assessment method [7]
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DOR-PCWG3 is defined as the time between the date of first response (CR/PR per RECIST1.1 for soft tissue and PCWG3 for bone lesions) to the date of first documented radiographic progression per RECIST1.1 for soft tissue and PCWG3 for bone lesions or cancer-related death.
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Timepoint [7]
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Through study completion, up until 18 months after the last patient commences treatment.
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Secondary outcome [8]
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Time to treatment response (TTR) in the subset of patients who achieved a 50% PSA response
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Assessment method [8]
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TTR-PCWG3 is defined as the time from treatment initiation to the date of the first documented CR or PR per RECIST1.1 for soft tissue and PCWG3 for bone lesions.
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Timepoint [8]
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Through study completion, up until 18 months after the last patient commences treatment.
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Secondary outcome [9]
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Treatment discontinuation due to toxicity
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Assessment method [9]
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The number of patients who discontinue treatment at any time due to treatment related toxicity (yes/no for each patient) will be reported.
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Timepoint [9]
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Through study completion, up until 18 months after the last patient commences treatment.
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Secondary outcome [10]
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Rate of treatment discontinuation due to toxicity
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Assessment method [10]
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The percentage of patients who discontinue treatment due to treatment related toxicity will be reported.
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Timepoint [10]
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Through study completion, up until 18 months after the last patient commences treatment.
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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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Males
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
9/07/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
1/06/2026
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Actual
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Sample size
Target
70
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
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St Vincent's Hospital Sydney - Sydney
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Recruitment hospital [2]
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Peter MacCallum Cancer Centre - Melbourne
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Recruitment postcode(s) [1]
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2010 - Sydney
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Recruitment postcode(s) [2]
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3000 - Melbourne
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Funding & Sponsors
Primary sponsor type
Other
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Name
Peter MacCallum Cancer Centre, Australia
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03874884
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Shahneen Sandhu
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Address
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Peter MacCallum Cancer Centre, Australia
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Shahneen Sandhu
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Address
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Country
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Phone
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+61 3 8559 7902
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03874884
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