The primary objective is to investigate whether the patient-specific adaptive treatment with AA/ENZ leads to a superior time to time to treatment failure (TTTF) while on treatment compared to continuous treatment with AA/ENZ. Secondary/tertiary…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the study is TTTF while on treatment.
Secondary outcome
Secondary endpoints are TTPP while on treatment, rPFS, overall survival,
quality of life and health-economic cost consequences.
Background summary
Despite rapid advances in the development of many potent and initially
effective treatments for cancer, the emergence of treatment resistance is
inevitable in almost all patients with metastatic cancer. Intra-tumor
heterogeneity and an evolving adaptation of the tumor under the selection
pressure of treatment lies at the core of the development of treatment
resistance. Clinically manifest progressive disease occurs when pre-existing
resistant cell populations can proliferate extensively. Maximum dosing and
continuation of treatment until the development of clinically manifest
progressive disease remains the prevailing philosophy in medical oncology.
Based on evolutionary principles this might be an unwise strategy because it
strongly selects for resistant cells and eliminates potential competitors.
Based on evolutionary principles, molecular mechanisms of resistance provide a
benefit during selection pressure from treatment, these mechanisms may
negatively impact the fitness of the cancer cells when treatment will be
stopped. Therefore, we hypothesize that the appropriately timed withdrawal of
treatment before all sensitive cancer cells are eliminated may allow residual
treatment sensitive cancer cells to regrow and out-compete the less fit
resistant cancer cells, thereby delaying the development of clinically manifest
treatment failure. Hormonal treatment with enzalutamide (ENZ) and abiraterone
acetate (AA) for metastatic castration-resistant prostate cancer (mCRPC) are a
very appropriate model to test this hypothesis for several reasons. Firstly,
evaluating treatment response by determining PSA is simple, cheap, and barely
invasive. Secondly, treatment with ENZ and AA is generally well-tolerated and
the duration is not limited by cumulative toxicity, which offers the
opportunity for long-term patient-specific adaptive treatment guided by PSA
response. Thirdly, for AA a pilot study has been performed with promising
results and a retrospective analysis may suggest beneficial outcomes in
patients in whom ENZ has been used intermittently. Nevertheless, a prospective
randomized study is warranted to test the hypothesis.
Study objective
The primary objective is to investigate whether the patient-specific adaptive
treatment with AA/ENZ leads to a superior time to time to treatment failure
(TTTF) while on treatment compared to continuous treatment with AA/ENZ.
Secondary/tertiary objectives are to investigate whether the patient-specific
adaptive treatment with AA/ENZ leads to a superior time to PSA progression
(TTPP) while on treatment, rPFS, OS, health-related quality of life and
cost-effectiveness.
Study design
An international, multicentre, open-label randomised phase II clinical trial.
Intervention
Patients will be randomly 1:1 assigned between the control group and the
experimental group. In the control group, patients will receive the standard
continuous treatment with AA/ENZ until criteria for treatment failure are met.
In the experimental group patients will start with AA/ENZ until achieving a
>50% decline in baseline PSA concentration. Upon achieving this decline,
treatment will be suspended. Patients will be monitored every month including
PSA concentration measurement. AA/ENZ will be reinitiated when the PSA
increases to or above the pre-treatment PSA baseline concentration. AA/ENZ
treatment will be stopped again after the PSA declines >50% from the baseline.
This pause/restart cycle of patient-individualized precision adaptive therapy
will be repeated presuming consent, tolerance and safety. Patients who do not
achieve a >50% decline of their baseline PSA concentration after restarting
AA/ENZ remain on treatment until the criteria for treatment failure are met.
Study burden and risks
Based on the existing evidence, we expect that the experimental treatment
regimen will lead to a superior rPFS compared to the standard continuous
treatment regimen. In case the hypothesis is wrong, a potential risk of this
study is that the experimental treatment regimen leads to a worse rPFS compared
to the standard treatment regimen. Based on the underlying hypothesis and
results from non-randomised and retrospective studies we estimate that it is
very unlikely that the investigational treatment regimen will leads to worse
outcomes compared to the standard treatment regimen.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
1. Willing and able to provide informed consent;
2. Aged 18 or older;
3. Histologically or cytologically confirmed adenocarcinoma of the prostate;
4. 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;
5. Presence of metastatic disease on WBBS and/or CT-scan;
6. 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:
a. PSA progression defined by a minimum of 2 rising (>=25%) PSA levels with an
interval of >=1 week between each determination. Patients who received an
anti-androgen must have PSA progression after withdrawal (>=4 6 weeks since last
cyproterone, flutamide, or >=6 weeks since last bicalutamide or nilutamide); OR
b. Radiographic PD on bone scintigraphy and/or CT-scan;
7. A PSA concentration of >=2 ng/mL.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
9. Controlled symptoms (opioids for cancer related pain stable for >4 weeks, no
need for urgent radiotherapy for symptomatic lesions);
10. Estimated life expectancy of >=12 months;
11. Patient has archival prostate cancer tissue available and which he consents
to share or is willing to undergo a new tumour biopsy;
12. 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 (>5.6 mmol/L);
total bilirubin <1.5 times ULN, alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) <2.5 times ULN; creatinine <175 µmol/L; albumin >30 g/L;
13. Any other therapies for CRPC (excluding denosumab and bisphosphonates) have
to be discontinued 3 weeks prior to study randomisation;
14. Able to swallow the study drug and comply with study requirements.
Exclusion criteria
1. Life-threatening or serious medical or psychiatric illness that could, in
investigator's opinion, potentially interfere with participation in this study;
2. 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;
3. Known or suspected brain metastasis or leptomeningeal disease;
4. Small-cell or neuroendocrine differentiation of prostate cancer;
5. Radiation therapy for treatment of the primary tumour within 3 weeks of
screening visit;
6. Radiation or radionuclide therapy for treatment of metastasis within 3 weeks
of screening visit, excluding radiation to reduce pain symptoms;
7. History of uncontrolled seizures (if patient and investigator wish to choose
treatment with enzalutamide)
8. Unstable symptomatic ischemic heart disease, ongoing arrhythmias or New York
Heart Association (NYHA) Class III or IV heart failure;
9. Known HIV infection, active chronic hepatitis B or C;
10. Known gastrointestinal (GI) disease that could interfere with GI
absorption/tolerance of study drugs;
11. Prior treatments with CYP17 inhibitors (e.g. ketoconazole) or novel
androgen receptor inhibitors (e.g. abiraterone, apalutamide, darolutamide or
enzalutamide). Bicalutamide, flutamide, cyproterone and nilutamide should be
stopped >6 weeks before first treatment. Prior treatment with docetaxel in the
mHSPC setting is allowed.
12. 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.
Design
Recruitment
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT05393791 |
| CCMO | NL79835.058.22 |