Primary: * To assess Clinical Benefit Rate (CBR) in patients with mCRPC and poor prognostic factors treated with cabazitaxel or novel hormonal agents (abiraterone OR enzalutamide) as second-line therapy.Secondary: * To formally compare CBR in both…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
- Prostatic disorders (excl infections and inflammations)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
To establish the Clinical Benefit Rate (CBR) in both study arms:
Percentage of patients that fulfill the criteria of clinical benefit. Patients
are considered to have had a clinical benefit if they have a radiological
response of any duration or stable disease for * 12 weeks, in the absence of
symptomatic progression, or objective disease progression.
Radiological Response
Subjects that have measurable disease at screening will be evaluated for
response on the basis of RECIST criteria v1.1, Tumor measurements using
physical examination, chest, abdomen, pelvic CT scan, and/or MRI or other
appropriate techniques deemed suitable by the investigator will be performed at
screening within 28 days of subject registration and repeated at week 6, 12, 18
and 24 followed by every 12 weeks.
Symptomatic or objective disease Progression
Disease Progression is defined as the development of symptomatic or
radiological progression at any time. Progression will be classified as any of
the following:
1. Symptomatic progression: worsening of cancer-related symptoms mandating a
stop of all treatments, a change in anti-cancer therapy (radiation,
chemotherapy or antihormonal therapy), or * 2 level decrease in WHO PS or death
of any cause. Radiotherapy does not account for symptomatic progression when
administered in the first 4 weeks of this study.
2. Radiological progression: RECIST criteria v1.1 for measurable disease and/or
appearance of * 2 new bone lesions on whole body bone scan confirmed on a
subsequent scan. All radiological images will be assessed by an independent
radiologist for central review of the RECIST criteria.
Secondary outcome
Secondary endpoints:
1. Formal comparison of the CBR in both study arms.
2. Rate of PSA >50% decrease from baseline
3. Duration of treatment; time from randomization to last day of treatment.
All time to event endpoints are met at death and censored at last follow-up;
4. Time To Symptomatic Progression TTSP;time from randomization to day of
worsening of cancer-related symptoms mandating a stop of all treatments, a
change in anti-cancer therapy (radiation, chemotherapy or antihormonal therapy)
or * 2 level decrease in WHO PS. Radiotherapy does not account for symptomatic
progression when administered in the first 4 weeks of this study.
5. Time To Radiological Progression (TTRP); time from randomization to day of
radiological progression: RECIST criteria v1.1 for measurable disease or
appearance of * 2 new bone lesions on whole body bone scan confirmed on a
subsequent scan.
6. Time To PSA Progression (TTPP); time from randomization to PSA progression
(PCWG3 criteria: at least 2 rises at a minimum of 1-week intervals. The first
PSA value must be * 2 ng/ml).
7. Progression Free Survival (PFS); time from randomization to the first date
of progression on study medication as measured by PSA progrression (PCWG3
criteria), tumor progression (RECIST 1.1 criteria and PCWG3 criteria),
symptomatic progression; stop of all treatments, a change in anti-cancer
therapy (radiotherapy, chemotherapy or antihomonal therapy), >2 level decrease
in WHO PS or death of any cause. Radiotherapy does not account for symptomatic
progression when administered in the first 4 weeks of this study. PFS
isassessed in patients who are treated with either arms as second line
treatment and in patients who crossed over to the other treatment arm.
8. Overall Survival; time from randomization to date of death. Follow up will
be maximum 3 years.
9. To evaluate safety and toxicity profile of cabazitaxel and novel hormone
agents (abiraterone OR enzalutamide) all Adverse Events (AEs; assessed by CTCAE
4.03 grading) and Serious Adverse Events (SAEs) will be recorded during second
line cabazitaxel/abiraterone OR enzalutamide treatment.
10. Quality of Life (QoL) as assessed by FACT-P questionnaire and Pain response
as assessed by BPI-S questionnaire and opiate use will be recorded during
second line cabazitaxel/abiraterone OR enzalutamide treatment
Background summary
There are multiple treatment options for mCRPC patients previously treated with
docetaxel. Treatment options include chemotherapy e.g. cabazitaxel,
bone-seeking radionuclides e.g. radium-223, and the new hormonal agents
abiraterone and enzalutamide. Currently, there are no prospective data to
support an optimal choice for second line treatment in the post-docetaxel
space. Retrospective cohorts suggest a relation between patient
characteristics, choice of second line treatment and patient benefit and
survival. Patients with poor prognosis mCRPC might benefit more from
cabazitaxel as a second line treatment then from novel hormonal treatment
(abiraterone OR enzalutamide). Hallmarks of poor prognosis might be, among
others, liver metastases, short duration of responsiveness to androgen
deprivation therapy, short duration of response on docetaxel or progression
during docetaxel treatment, elevated LDH and ALP and low serum albumin. In this
prospective randomized trial, poor prognosis mCRPC patients, previously treated
with docetaxel, will be randomized between cabazitaxel and abiraterone OR
enzalutamide. Cabazitaxel, abiraterone and enzalutamide will be used according
to the registered doses and schedules. Abiraterone, enzalutamide and radium-223
treatment prior to docetaxel is allowed, but not within the imposed
docetaxel-cabazitaxel or novel hormonal treatment sequence. Cross-over to the
other treatment arm is allowed at the time the patient meets the criteria for
progressive disease, however, is no part of the randomization.
The aim of this study is to identify the optimal second line treatment option
for patients with a poor prognosis mCRPC with respect to clinical benefit rate
and quality of life.
Study objective
Primary:
* To assess Clinical Benefit Rate (CBR) in patients with mCRPC and poor
prognostic factors treated with cabazitaxel or novel hormonal agents
(abiraterone OR enzalutamide) as second-line therapy.
Secondary:
* To formally compare CBR in both study arms.
* Rate of PSA>50% decrease from baseline
* To determine duration of treatment
All time to event endpoints are met at death and censored at last follow-up;
* Time To Symptomatic Progression (TTSP), Time To PSA Progression (TTPP), and
Time To Radiologic Progression (TTRP) in mCRPC patients treated with
cabazitaxel or novel hormone agents (abiraterone OR enzalutamide) as
second-line therapy and for those who cross over to the other study arm as a
third-line therapy.
* To determine the Progression Free Survival (PFS) of mCRPC patients treated
with cabazitaxel or novel hormone agents (abiraterone OR enzalutamide) as
second-line therapy and for those who cross over to the other study arm as a
third-line therapy.
* To determine the Overall Survival (OS) of mCRPC patients treated with
cabazitaxel or novel hormone agents (abiraterone OR enzalutamide) as
second-line therapy.
* To evaluate safety and toxicity profile of cabazitaxel and novel hormone
agents (abiraterone OR enzalutamide) as a second line treatment.
* Quality of Life (QoL) as assessed by FACT-P questionnaire and Pain response
as assessed by BPI-S questionnaire and opiate use of metastatic CRPC patients
treated with cabazitaxel or novel hormone agents (abiraterone OR enzalutamide)
as second-line therapy.
Exploratory Objectives
Three biomarker studies are included in this randomized trial. The value of the
neutrophil to lymphocyte ratio, mutations in cfDNA and epigenetic modifications
of cfDNA as predictive biomarkers will be explored.
(See page 28-31 of the study protocol)
Study design
This trial is a prospective, multicenter, national, randomized, open label
phase IIB study, with optional cross over to the other study arm after primary
endpoint has met.
In this study the efficacy in terms of CBR of cabazitaxel after docetaxel will
be compared to enzalutamide OR abiraterone acetate after docetaxel treatment.
Patients with a progressive poor prognosis mCRPC and fulfilling all in- and
exclusion criteria can be enrolled in the trial.
Study burden and risks
There will be no benefit for the patients who are willing to participate in the
study.
They will receive a treatment with cabazitaxel, enzalutamide of abiraterone; a
treatment they would have received if they did not participate in the study.
The risks of participation are low (as high as usual, since there is no
difference from the standard of care).
Extra blood will be drawn during the usual blood drawings (38.5 ml, 3 times),
and the patient will get extra scans during the study.
Patients are also asked to fill in questionnaires about pain, pain medication
use and quality of life.
This will all cost extra time (approximately 9 hours per patient).
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
1. Histological diagnosis of prostate adenocarcinoma., 2. Able and willing
to provide informed consent and to comply with the study procedures, 3. Age
*18, 4. Evidence of bone, visceral and/or lymph node metastases on bone scan,
CT-scan or MRI., 5. Must have received at least one prior regimen of docetaxel
treatment for at least 12 weeks (four courses) and no other prostate cancer
treatments between docetaxel and randomization, other than prednisone., 6.
Continued androgen deprivation therapy either by LHRH agonist/ antagonist or
orchiectomy., 7. Treatment with curative intent is not an option and patient
has an indication for systemic treatment as judged by the medical care
provider, 8. Evidence of progressive metastatic disease by PSA progression
(Prostate Cancer Working Group 3 (PCWG3) criteria: at least 2 rises at a
minimum of 1-week intervals. The first PSA value must be * 2 ng/ml) and/or
radiological progression as evaluated by chest, abdominal, or pelvic CT/MRI
scan and/or bone scan within 28 days of registration (see Appendix III), 9.
Poor prognosis disease as defined by any of the following:, a) The presence of
liver metastases AND/OR, b) Development of castration-resistance within 12
months of orchiectomy or commencement of LHRH antagonist/agonist for metastatic
disease AND/OR, c) Progressive disease during docetaxel treatment or <6
months after completion of docetaxel treatment, 10. WHO PS 0-2., 11. Serum
testosterone < 50 ng/dL (< 1.7 nmol/L) within 28 days before treatment
group allocation, 12. At least 21 days have passed since completing
radiotherapy (exception for a single fraction of * 800 cGy to a restricted
field or limited-field radiotherapy to non-marrow bearing area such as an
extremity or orbit: at least 7 days prior to randomization)., 13. At least 21
days have passed since major surgery. , 14. Neuropathy * grade 1 at the time of
registration. , 15. Has recovered from all therapy-related toxicity to * grade
2 (except alopecia, anemia and any signs or symptoms of androgen deprivation
therapy) at the time of registration., 16. Eligible for cabazitaxel,
abiraterone acetate or enzalutamide as per standard of care practices., 17. Men
treated with cabazitaxel should use effective contraception throughout
treatment and are recommended to continue this for up to 6 months after the
last dose of cabazitaxel. Due to potential exposure via seminal liquid, men
treated with cabazitaxel should prevent contact with the ejaculate by another
person throughout treatment. Men being treated with cabazitaxel are advised to
seek advice on conservation of sperm prior to treatment.
Exclusion criteria
1. Histologic evidence of small cell/neuroendocrine prostate cancer, 2. Any
treatment other than prednisone between docetaxel and cabazitaxel/abiraterone
OR enzalutamide sequence , 3. Uncontrolled severe illness or medical condition
(including uncontrolled diabetes mellitus). , 4. History of severe
hypersensitivity reaction (* grade 3) to docetaxel, abiraterone or enzalutamide
(whichever applies)., 5. History of severe hypersensitivity reaction (* grade
3) to polysorbate 80 containing drugs., 6. Concurrent or planned treatment with
strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week
wash-out period is necessary for patients who are already on these
treatments)., 7. Patients who have a concurrent yellow fever vaccination
(several weeks before start of treatment) must be excluded., 8. Dementia,
altered mental status, or any psychiatric condition, if this is in conflict
with the study., 9. Unable to swallow a whole tablet or capsule, 10.
Contraindications to the use of corticosteroid treatment, 11. Symptomatic
peripheral neuropathy Grade *2 (National Cancer Institute Common Terminology
Criteria [NCI CTCAE] v.4.0). , 12. Prior malignancy active within the previous
3 years except for locally curable cancers that have been apparently cured and
needing no subsequent therapy., 13. Inadequate organ and bone marrow function
as evidenced by:, a. Hemoglobin <10.0 g/dL, b. Absolute neutrophil count
<1.5 x 109/L, c. Platelet count < 100 x 109/L, d. AST/ SGOT and/ or ALT/
SGPT > 1.5 x ULN, Total bilirubin >1 x ULN (except for patients with
documented Gilbert*s disease).
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EudraCT | EUCTR2016-004963-38-NL |
| CCMO | NL60114.031.16 |