Phase 2 multicenter study determining the response to Cabazitaxel in metastatic prostate cancer (mCRPC) patients with AR-V7 positive or negative circulating tumor cells (CTCs): CARVE

After failure on Docetaxel, which has been the standard first line therapy for
patients with metastatic castration-resistant prostate cancer (mCRPC), three
treatment options are currently available. No head-to-head comparisons have
been done for the three therapies in second-line mCRPC treatment and as of yet,
the optimal choice is unknown. Two of treatment options are directed against
the androgen receptor (AR), enzalutamide and abiraterone. The third option is
cabazitaxel, a taxoid. Resistance to the anti-AR therapies is at least in part
a consequence of signaling through constitutively active AR splice variants
(AR-Vs) (1-8).
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 anti-AR therapy (9).
AR-V7 mRNA expression does not seem to hinder response to cabazitaxel in our
retrospective pilot study (Onstenk et al., submitted for publication).
Therefore we hypothesize that the mRNA expression of AR-V7 in CTCs assessed
before start of second-line treatment for mCRPC is associated with PSA response
rate to cabazitaxel in patients who have progressed to docetaxel.

The primary objective of this study is to explore the PSA response rate to
cabazitaxel in mCRPC patients who have progressed to docetaxel and to correlate
the PSA response to AR-V7 expression in CTCs. Exploratory objectives include
documenting the PSA response to cabazitaxel after enzalutamide or abiraterone
treatment in initially AR-V7 negative patients, describing the toxicity of
cabazitaxel in second and third-line treatment,exploring if response measured
by CTC counts and PSA is related to systemic cabazitaxel exposure, and to
confirm the impact of AR-V7 status in CTC on outcome to enzalutamide or
abiraterone.

This is a multicenter phase 2 study. All patients will receive physician's
choice of treatment.
AR-V7 negative patients who are treated with enzalutamide or abiraterone and
experience disease progression, can then again enter the screening phase and,
after additional eligibility check, subsequently be treated with cabazitaxel if
*3 CTCs are present and AR-V7 mRNA expression is now detected.

In all patients, 2 x 10 mL blood will be drawn for enumeration and isolation of
CTCs at baseline.

If physician's choice is cabazitaxel, cabazitaxel will be administrated
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, according to standard care. In these patients, an additional 2 x
10 mL blood will be drawn at start of fourth cycle of treatment for CTC
enumeration and isolation. Also, an additional 10 mL blood will be drawn for
storage of plasma at baseline and before every cycle (i.e., every 3 weeks) for
analyses of cell-free DNA (cfDNA) as part of a side-study. In patients treated
with cabazitaxel, 4 x 5 mL blood (baseline; end of infusion, 2 and 6 hours
after end of infusion) will be drawn for a pharmacokinetic side-study, to
explore a cabazitaxel exposure effect relation.

In patients treated with therapy other than cabazitaxel, an additional 10 mL
blood will be drawn for storage of plasma at baseline and at 12 weeks after
start of treatment for analyses of cell-free DNA (cfDNA) as part of a
side-study.

AR-V7 negative patients treated with abiraterone or enzalutamide that
subsequently experience disease progression can again enter the screening phase
of the study. An additional 2x 10 mL blood will be drawn for enumeration and
isolation of CTCs, as well as 1x 10 mL for analysis of cell-free DNA (cfDNA).

For the CTC enumeration and isolation, a total of 20 mL additional blood will
be drawn at baseline.. An additional 20 ml will be drawn 9 weeks after start of
treatment. Furthermore, in AR-V7 negative patients an additional 20 ml will be
drawn upon progression to abiraterone or enzalutamide.
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) from patients treated with cabazitaxel. . Patients not treated
with cabazitaxel will have a total of 30 mL additional blood drawn for storage
of plasma for cfDNA analysis (at baseline, at 12 weeks after start of
treatment, and upon disease progression).
For pharmacokinetic analysis, in patients treated with cabazitaxel, 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.
Cabazitaxel is standard second-line chemotherapy for mCRPC patients. In the
TROPIC trial, the most common observed grade 3-4 toxicity was neutropenia (82%)
(12). 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.
Cabazitaxel treated patients will have scheduled study visits frequently, in
accordance with standard-of-care cabazitaxel treatment. Patients will return
for regularly scheduled study visits for as long as they continue study
treatment, or discontinued study treatment but have not yet experienced disease
progression. All patients will be followed for survival after discontinuing
treatment. For the primary endpoint, serial blood samples will be collected
every three weeks to quantify PSA. Radiographic evaluations (bone scans and
CT/MRI-scans of the abdomen and pelvis) will be employed after four and eight
cycles of cabazitaxel to assess the status of the disease according to modified
RECIST 1.1 criteria.
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.