The primary objective of this study is to explore the PSA response to cabazitaxel in mCRPC patients who have progressed to docetaxel and have detectable AR-V7 expression in CTCs. Exploratory objectives include describing the toxicity of cabazitaxel…
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Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is PSA response, defined as a *50% PSA decline from
baseline during therapy.
Secondary outcome
Secondary endpoints include CTC response, progression-free survival and overall
survival to cabazitaxel in AR-V7 positive patients, as well as toxicity and
cumulative administered dose of cabazitaxel in second and third-line therapy.
Furthermore, we want to explore the relationship between systemic cabazitaxel
exposure and response.
Background summary
After failure on docetaxel, which has been the standard first line therapy for
patients with metastatic castration-resistant prostate cancer (mCRPC), several
treatment options are currently available. Two of the treatment options are
directed against the androgen receptor (AR), enzalutamide and abiraterone. A
third option is cabazitaxel, a next generation taxane. No head-to-head
comparisons have been done for these three therapies in second-line mCRPC and
as of yet, the optimal choice is unknown. Resistance to the AR-targeted
therapies is at least in part a consequence of signaling through constitutively
active AR splice variants (AR-Vs).
Because AR splice variants only occur after conversion to a
castration-resistant tumor, and can be acquired during systemic therapy for
mCRPC, analysis of the castration-naïve primary tumor is not informative in the
setting of second-line treatment of mCRPC. Circulating tumor cells (CTCs) can
be analyzed repetitively and in real-time. Recently, AR-V7 mRNA expression in
CTCs was shown to be associated with lack of response to AR-targeted therapy
(Antonarakis et al. N Engl J Med. 2014 Sep 11;371(11):1028-38). AR-V7 mRNA
expression does not seem to hinder response to cabazitaxel in our retrospective
pilot study (Onstenk et al. Eur Urol. 2015 Dec;68(6):939-45) nor in two
recently published retrospective studies (Antonarakis et al. JAMA Oncol. 2015
Aug;1(5):582-9; Scher at al. JAMA Oncol. 2016 Jun 4).
Therefore we hypothesize that the mRNA expression of AR-V7 in CTCs assessed
before start of second-line treatment for mCRPC does not affect PSA response to
cabazitaxel in patients who have progressed to docetaxel.
Study objective
The primary objective of this study is to explore the PSA response to
cabazitaxel in mCRPC patients who have progressed to docetaxel and have
detectable AR-V7 expression in CTCs. Exploratory objectives include describing
the toxicity of cabazitaxel in second and third-line treatment as well as
exploring if response measured by CTC counts and PSA is related to systemic
cabazitaxel exposure.
Study design
This is a multicenter, single arm phase 2 study.
Patients who are eligible to undergo second or third line treatment will be
asked to undergo prescreening consisting of a CTC count and, in case *3 CTCs
are detected, AR-V7 determination. Patients with *3 CTCs with AR-V7 expression
will be asked to sign a second informed consent to enter the treatment study.
In this study they will receive Cabazitaxel 25 mg/m² every 3 weeks plus
prednisone 10 mg daily, and undergo repeated blood sampling for biomarker
sample collection.
Intervention
During the prescreening in all patients, 2 x 10 mL blood will be drawn for
enumeration and isolation of CTCs.
All patients with *3 CTCs with AR-V7 expression will be asked to sign consent
for the treatment study.
All patients included in the treatment study will be administrated cabazitaxel
intravenously at a dose of 25 mg/m², during a one-hour infusion every 3 weeks,
as well as continuous treatment with prednisone 5 mg orally twice daily, or 10
mg once daily. In the treatment study patients, an additional 2 x 10 mL blood
will be drawn after the third cycle of treatment for CTC enumeration and
isolation. An additional 10 mL blood will be drawn for storage of plasma at
baseline and before start of every cycle (i.e., every 3 weeks) for analysis of
cell-free DNA (cfDNA). Moreover, 4 x 5 mL blood (baseline; end of infusion, 2
and 6 hours after end of the first cabazitaxel infusion) will be drawn for
pharmacokinetic studies, in order to explore a cabazitaxel exposure effect
relation.
Study burden and risks
In patients who are in prescreening only and do not proceed to the treatment
study, 20 mL additional blood will be drawn at the time of regular blood draws.
In patients included in the treatment study a total of 40 mL additional blood
will be drawn at the time of regular blood draws for CTC enumeration and
isolation,. For storage of plasma for cfDNA analysis, a total of 100 mL
additional blood will be drawn at the time of regular blood draws (at baseline
and before each treatment cycle). In case of study treatment discontinuation
without progression 10 mL additional blood will be drawn every 3 months until
progression, death, or study cut off, whichever comes first.
For pharmacokinetic analysis a total of 20 mL (4 x 5 mL) additional blood will
be drawn at baseline, end of infusion, 2 and 6 hours after the first
cabazitaxel infusion. All other evaluations are part of the standard of care
treatment.
Cabazitaxel is standard second-line chemotherapy for mCRPC patients. In the
TROPIC trial, the most common observed grade 3-4 toxicity was neutropenia
(82%). Despite the high incidence of neutropenia, febrile neutropenia was rare
(8%). The most frequent non-hematologic adverse event (AE) was diarrhea,
occurring in 47% (grade *3 6%) of patients treated with cabazitaxel, compared
to 11% (grade *3 <1%) of patients treated with mitoxantrone. In the TROPIC
trial, a total of 18 (5%) patients treated with cabazitaxel died within 1 month
of the last drug infusion due to adverse effects. This compares to 3
drug-related deaths (2%) in the mitoxantrone group. The most common cause of
death in patients treated with cabazitaxel was neutropenia and its clinical
consequences. The frequency of hematological adverse events and related deaths
demonstrates that cabazitaxel treatment requires careful monitoring and
management of emerging symptoms. Dose reductions as well as supportive
treatment (i.e. the administration of granulocyte colony-stimulating factor
[G-CSF]) will be considered to manage the toxic effects of treatment. The
toxicity profile of cabazitaxel is well known and manageable in daily practice.
In this study the treatment will not divert from the standard of care.
The safety of cabazitaxel in second and third-line treatment will be assessed
by monitoring the frequency of treatment related (serious) adverse events,
which will be recorded according to the Common Terminology Criteria (CTCAE)
scale version 4.03.
The recent PROSELICA study, randomizing patients between a cabazitaxel dose of
20mg/m2 and 25mg/m2 in the second line treatment setting, presented at the 2016
ASCO Annual meeting, suggests that a dose reduction to 20mg/m2 might improve
the toxicity profile and is results in equivalent progression free survival.
However, the data regarding the endpoint we chose (PSA response) showed a clear
difference in favor of the 25mg/m2 group. Therefore, awaiting the full
publication we choose to mandate a 25mg/m2 cabazitaxel dose for this study.
Dr. Molenwaterplein 40
Rotterdam 3015GD
NL
Dr. Molenwaterplein 40
Rotterdam 3015GD
NL
Listed location countries
Age
Inclusion criteria
Histologically or cytologically confirmed adenocarcinoma of the prostate
without neuroendocrine differentiation or small cell features.
- Continued androgen deprivation therapy either by LHRH
agonists/antagonists or orchiectomy.
- Serum testosterone <50 ng/ml (1.7 nmol/L) within 21 days of
treatment start (if patient enters treatment phase of the study)
- Age *18 years
progression for study entry is defined as one or more of the following
criteria:
* At least 3 consecutive PSA rises over a reference value, with an
interval of * 1 week between each determination. PSA at screening visit
should be * 2.0 *g/l.
* Bone disease progression defined by the appearance of *2 new
lesions on a bone scan (confirmed by a second bone scan 6 weeks later).
* Soft tissue disease progression defined by modified RECIST 1.1.
- ECOG performance status 0-2
- Written informed consent according to ICH-GCP
Exclusion criteria
* Geographical, psychological or other non-medical conditions interfering with follow-up
* Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus or active systemic or local bacterial, viral, fungal - or yeast infection)
* Symptomatic CNS metastases or history of psychiatric disorder that would prohibit the understanding and giving of informed consent.
* Chemotherapy or immunotherapy (other than LHRH analogues) within the last 4 weeks before study inclusion.
* Prior treatment with cabazitaxel
* Successive treatment with both abiraterone and enzalutamide in the post-docetaxel setting
* Radiotherapy to 40% or more of the bone marrow
* Known hypersensitivity to corticosteroids
* History of severe hypersensitivity reaction (*grade 3) to docetaxel
* History of severe hypersensitivity reaction (*grade 3) to polysorbate 80 containing drugs
* 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) (see Appendix C of protocol)
* Concomitant vaccination with yellow fever vaccine
* Abnormal liver functions consisting of any of the following (within 21 days before treatment group allocation):
* Total bilirubin > 1.5 x ULN (except for patients with documented Gilbert's disease)
* If total bilirubin > 1 x ULN or AST > 1.5 x ULN inclusion is permitted but cabazitaxel dose should be reduced 20mg/m2
* Abnormal hematological blood counts consisting of any of the following (within 21 days before treatment group allocation):
* Absolute neutrophil count < 1.5 x 109/L
* Platelets < 100 x 109/L
* Hemoglobin < 6.2 mmol/L
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 | EUCTR2016-002993-11-NL |
| CCMO | NL58639.056.16 |