Phase II Randomised Controlled Trial of Patient-specific Adaptive vs. Continuous Abiraterone or eNZalutamide in mCRPC

NCT05393791 | Recruiting Phase 2 DMC

• 2 other identifiers: 79835ANZUP 2101
• Study Type: interventional
• Target: 168
• Locations: 2 countries
• Sites: 19

Brief Summary

Hormone tablets, abiraterone (Zytiga®) and enzalutamide (Xtandi®) are approved to treat advanced prostate cancer. However, even if these drugs are helpful, their effectiveness usually diminishes over time. Small pilot studies have indicated that using hormone tablets sparingly, for just long enough to control the cancer, followed by a break in treatment and restarting them later, seems to improve how long hormone tablets can control the cancer. This study aims to find out if this pause/restart strategy is better than taking hormone tablets every day continuously. The study will include 168 people with metastatic castrate resistant prostate cancer in the Netherlands and Australia. Patients will be randomly 1:1 assigned between the control group and the experimental group. In the control group, patients will take the treatment with AA/ENZ every day until the prostate cancer doesn't respond anymore to the treatment. In the experimental group, patients will start with daily AA/ENZ until the PSA has declined for \>50%. The treatment will then be paused and monthly PSA measurements will be performed. The treatment will be re-initiated when the PSA has increased to the level of before starting treatment. The treatment will be continued daily until the PSA has again dropped for \>50%. This pause/restart cycle will be repeated until the prostate cancer doesn't respond anymore to the treatment.

Conditions

Prostatic Neoplasms, Castration-Resistant

Keywords

Antineoplastic Agents, Hormonal; Evolution; Quality of Life; Prostatic Neoplasms, Castration-Resistant / drug therapy

Outcome Measures

Primary Outcomes (1)

• Time to treatment failure

  Defined as the time from randomization until death by any cause, or the occurrence of ≥2 of the following events: * Radiographic progression according to RECIST 1.1 and/or PWCG3 criteria on the CT-scan and/or WBBS while a subject received treatment with AA/ENZ during the whole period between the imaging tests. NB: Radiologic progression while a subject is off treatment in the experimental arm will trigger the endpoint, but may be an indication to restart treatment and continue with the adaptive dosing strategy * PSA progression, defined as an increase of PSA of \>25% and \>2 ng/mL occurring while a patient is on consecutive treatment with AA/ENZ for at least 8 weeks. * Clinical progression in the judgment of the treating clinician occurring while a patient is on consecutive treatment with AA/ENZ for at least 8 weeks.

  Time from randomization until death by any cause, or until criteria for treatment failure are met. PSA progression and clinical progression will be measured every 4 weeks, radiographic progression every 12 weeks, both up to 3 years after randomization.

Secondary Outcomes (8)

• Time to PSA progression while on treatment

  Time from randomization until an increase of PSA of >25% and >2 ng/mL persisting while a patient is on consecutive treatment for at least 8 weeks or death. PSA will be measured every 4 weeks until 3 years after randomization.

• Radiographic progression-free survival while on study treatment

  Time from randomization to death or the first occurrence of radiographic progression while a subject received treatment between the imaging tests. Bone scan and CT-scan will be measured every 12 weeks until 3 years after randomization.

• Overall survival

  Time from randomization to the date of death due to any cause. Measured every 4 weeks up to 3 years after randomizaton and after end of treatment visit every 6 months until 2 years after end of treatment visit.

• Time to first skeletal-related event

  Time from randomization to first skeletal-related event or death. Bone scan and CT-scan will be measured every 12 weeks up to 3 years after randomization.

• Health Related Quality of Life - FACT-P

  FACT-P questionnaire will be obtained every 12 weeks up to 3 years after randomization

Other Outcomes (3)

• Cost-effectiveness analysis

  QoL and adverse events will be measured every 12 weeks up to 3 years after randomization. Treatment duration will be evaluated every 4 weeks up to 3 years after randomization.

• Cumulative duration on treatment

  Every 4 weeks up to 3 years after randomization

• Translational Biospecimens

  Baseline and every 12 weeks

Study Arms (2)

Experimental group

EXPERIMENTAL

In the experimental group, treatment will be paused if there is a \>50% decline in baseline PSA. AA/ENZ will be restarted if the PSA rises to the same level or higher than the pre-treatment PSA. AA/ENZ treatment will be paused again after the PSA declines \>50% from the baseline. This pause/restart cycle of adaptive therapy will be repeated presuming consent, tolerance and safety. Patients who do not have a \>50% decline of their baseline PSA level after restarting AA/ENZ remain on treatment until the criteria for treatment failure are met.

Other: Patient-specific adaptive therapy; Drug: Abiraterone acetate; Drug: Enzalutamide

Control group

ACTIVE COMPARATOR

In the control group, patients will receive the standard continuous treatment with abiraterone or enzalutamide (AA/ENZ) until criteria for treatment failure are met.

Drug: Abiraterone acetate; Drug: Enzalutamide

Interventions

Patient-specific adaptive therapy OTHER

Patients will start taking abiraterone or enzalutamide (AA/ENZ) daily. PSA will be measured every month as well as radiological evaluation by CT-scan and bone scan. Treatment will be continued until PSA has dropped \>50%. The treatment will then be paused. Once the PSA has risen again above the pretreatment baseline, treatment will be re-initiated. AA/ENZ will be stopped again after the PSA declines \>50% from the baseline. This will be continued until criteria for treatment failure are met (death by any cause or at least 2 out of 3 of the following events while on treatment: radiographic progression on CT-scan and/or bone scan, PSA progression or clinical progression).

Experimental group

Abiraterone acetate DRUG

Use of abiraterone or enzalutamide

Also known as: Zytiga

Control group; Experimental group

Enzalutamide DRUG

Use of abiraterone or enzalutamide

Also known as: Xtandi

Control group; Experimental group

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: As the investigated disease is prostate cancer, only males are eligible for inclusion.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide informed consent;
• Aged 18 or older;
• Histologically or cytologically confirmed adenocarcinoma of the prostate;
• Ongoing androgen deprivation therapy with a GnRH analogue or bilateral orchiectomy (i.e. surgical or medical castration with testosterone at screening ≤1.7 nmol/L (\<0.5 ng/mL)); patients who have not had a bilateral orchiectomy, must have a plan to maintain effective GnRH-analogue therapy for the duration of the trial;
• Presence of metastatic disease on WBBS and/or CT-scan;
• Progressive disease at study entry defined as per PCWG3 as one or more of the following criteria that occurred while the patient was on ADT:
• PSA progression defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each determination. Patients who received an anti-androgen must have progression after withdrawal (≥4 weeks since last flutamide or ≥6 weeks since last bicalutamide or nilutamide); OR
• Radiographic PD on bone scintigraphy and/or CT-scan;
• A PSA concentration of ≥2 ng/mL.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
• Controlled symptoms (opioids for cancer related pain stable for \>4 weeks, no need for urgent radiotherapy for symptomatic lesions);
• Estimated life expectancy of ≥12 months;
• Patient has archival prostate cancer tissue available and which he consents to share or is willing to undergo a new tumour biopsy;
• Adequate organ function: absolute neutrophil count \> 1,500/μL (\> 1.5\*109/L); platelet count \> 100,000/μL (\> 100\*109/L), haemoglobin \> 90 g/L; total bilirubin \< 1.5 times ULN, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \< 3 times ULN; creatinine \< 175 μmol/L; albumin \> 30 g/L;
• Any other therapies for CRPC (excluding denosumab and bisphosphonates) have to be discontinued 3 weeks prior to study randomisation;

You may not qualify if:

• Life-threatening or serious medical or psychiatric illness that could, in investigator's opinion, potentially interfere with participation in this study;
• Diagnosis or treatment for another systemic malignancy within 2 years before the first dose of study drugs. Potential participants with non-melanoma skin cancer, non-muscle invasive bladder cancer, or carcinoma in situ of any type are allowed if they have undergone complete resection;
• Known or suspected brain metastasis or leptomeningeal disease;
• Small-cell or neuroendocrine differentiation of prostate cancer;
• Radiation therapy for treatment of the primary tumour within 3 weeks of screening visit;
• Radiation or radionuclide therapy for treatment of metastasis within 3 weeks of screening visit, excluding radiation to reduce pain symptoms;
• History of uncontrolled seizures (if patient and investigator wish to choose treatment with enzalutamide)
• Unstable symptomatic ischemic heart disease, ongoing arrhythmias or New York Heart Association (NYHA) Class III or IV heart failure;
• Known HIV infection, active chronic hepatitis B or C;
• Known gastrointestinal (GI) disease that could interfere with GI absorption/tolerance of study drugs;
• Prior treatments with CYP17 inhibitors (e.g. ketoconazole) or novel androgen receptor inhibitors (e.g. abiraterone, apalutamide, darolutamide or enzalutamide). Bicalutamide and nilutamide should be stopped \>6 weeks before screening visit. Prior treatment with docetaxel in the mHSPC setting is allowed.
• Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data.

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Australian and New Zealand Urogenital and Prostate Cancer Trials Group: collaborator
• Anticancer Fund, Belgium: collaborator

Study Sites (19)

Border Medical Oncology Research Unit / The Border Cancer Hospital

Albury, New South Wales, 2460, Australia

RECRUITING

Chris O'Brien Lifehouse

Camperdown, New South Wales, 2050, Australia

RECRUITING

St George Hospital

Kogarah, New South Wales, Australia

RECRUITING

Calvary Mater Newcastle

Newcastle, New South Wales, 2298, Australia

RECRUITING

Genesis Care North Shore

St Leonards, New South Wales, 2065, Australia

RECRUITING

Sydney Adventist Hospital

Wahroonga, New South Wales, 2076, Australia

RECRUITING

Sunshine Coast University Hospital

Birtinya, Queensland, Australia

RECRUITING

Mater Hospital Brisbane

South Brisbane, Queensland, 4101, Australia

RECRUITING

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

RECRUITING

ICON Cancer Centre

Adelaide, South Australia, Australia

RECRUITING

Eastern Health Box Hill

Box Hill, Victoria, Australia

RECRUITING

Fiona Stanly Hospital

Murdoch, Western Australia, 6150, Australia

RECRUITING

Radboud Univeristy Medical Centre

Nijmegen, Gelderland, 6525 GA, Netherlands

RECRUITING

Spaarne Gasthuis

Hoofddorp, North Holland, 2134 TM, Netherlands

RECRUITING

Isala Ziekenhuis

Zwolle, Overijssel, 8025 AB, Netherlands

RECRUITING

Groene Hart Ziekenhuis

Gouda, South Holland, 2803 HH, Netherlands

RECRUITING

Leids Universitair Medisch Centrum

Leiden, South Holland, 2333 ZA, Netherlands

RECRUITING

Meander Medical Centre

Amersfoort, Utrecht, 3813 TZ, Netherlands

RECRUITING

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

RECRUITING

MeSH Terms

Conditions

Prostatic Neoplasms, Castration-Resistant; Prostatic Neoplasms

Interventions

Abiraterone Acetate; enzalutamide

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Tom van der Hulle, MD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

• A/Prof. Craig Gedye, MBChB,FRACP

  Australian and New Zealand Urogenital and Prostate Cancer Trials Group

  STUDY CHAIR

• Dr. Laurence Krieger, MBChB,FRACP

  Australian and New Zealand Urogenital and Prostate Cancer Trials Group

  PRINCIPAL INVESTIGATOR

• Dr. Amy Rieborn

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tom van der Hulle, MD PhD

CONTACT

0031715263464; t.van_der_hulle@lumc.nl

Samantha Oakes, Prof.

CONTACT

+61 2 90543600; trials@anzup.org.au

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Control group and experimental group

Study Record Dates

• First Submitted: May 18, 2022
• First Posted: May 26, 2022
• Study Start: November 10, 2022
• Primary Completion (Estimated): November 10, 2027
• Study Completion (Estimated): November 10, 2027
• Last Updated: November 26, 2024

Record last verified: 2024-11

Locations

NL (7); AU (12)