Annual Meeting Proceedings Part 1 - American Society of Clinical ...

4662 General Poster Session (Board #12E), Sun, 8:00 AM-12:00 PM
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC):
A phase I trial in metastatic castration-resistant prostate cancer (mCRPC)
previously treated with a taxane. Presenting Author: Anthony E. Mega,
Brown University Oncology Group, Providence, RI
Background: The abundant expression of prostate specific membrane
antigen (PSMA) type II transmembrane glycoprotein on prostate cancer
cells provides a rationale for antibody therapy. PSMA ADC, a fully
humanized antibody to PSMA linked to the potent antitubulin agent
monomethyl auristatin E (MMAE), binds PSMA and is internalized within
the prostate cancer cell where cleavage by lysosomal enzymes and releases
free MMAE, causing cell cycle arrest and apoptosis. We report results from
an ongoing phase 1 dose escalation study of PSMA ADC in subjects with
taxane-refractory mCRPC. Methods: Eligibility requirements include progressive
mCRPC following taxane-containing chemotherapy and ECOG status of
0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles.
Adverse events, pharmacokinetics (PK), PSA, circulating tumor cells,
clinical disease progression and immunogenic response to PSMA ADC were
assessed. Serum PSMA ADC and total antibody were measured by ELISA,
and free MMAE was measured by LC/MS/MS.The dosing cohorts range from
0.4 mg/kg to 2.8 mg/kg, with dose escalation continuing. Results: 40
subjects have been dosed in nine dose levels (0.4, 0.7, 1.1, 1.6, 1.8, 2.0,
2.2, 2.5, 2.8 mg/kg). To date, PSMA ADC has been well tolerated with the
most commonly seen adverse events being anorexia and nausea, and the
most common laboratory abnormalities being reversible hematologic parameters
and liver function tests. Antitumor activity has been manifested as
reductions either in PSA or circulating tumor cells in the higher dose
cohorts. Exposure to PSMA ADC increased with dose and was ~1,000-fold
greater than MMAE exposure. Similar PK metrics were observed after the
first and third doses. Dosing at the 2.8 mg/kg cohort is continuing and an
MTD has not yet been reached. Conclusions: PSMA ADC is generally well
tolerated in subjects with mCRPC, previously treated with taxane in doses
up to 2.8 mg/kg. Antitumor activity at higher dose levels has been observed.
The MTD has not yet been reached and enrollment is ongoing at higher dose
levels.
4664 General Poster Session (Board #12G), Sun, 8:00 AM-12:00 PM
Response to ketoconazole (keto) or docetaxel (D) following clinical progression
on abiraterone acetate (AA) in castrate-resistant prostate cancer
(CRPC). Presenting Author: Rahul Raj Aggarwal, University of California,
San Francisco, San Francisco, CA
Background: Patients (pts) with CRPC treated with keto often experience a
rise in serum adrenal androgen levels upon progression and may subsequently
respond to more potent adrenal suppression with AA. In contrast,
pts treated with AA do not have a rise in serum androgen levels upon
progression, and thus may not respond to further androgen synthesis
inhibition with keto but require other treatment modalities such as
chemotherapy instead. The goal of this analysis is to report the outcomes of
pts with CRPC progressing on AA subsequently treated with either keto or
D. Methods: Pts with chemotherapy-naïve CRPC were treated on previously
reported phase 1 and 2 trials of AA, with doses ranging from 250 to 1000
mg/day. Subsequent treatment following progression on AA was per
individual investigator discretion, including treatment with either keto or D.
Results: To date, following disease progression on AA, 6 and 14 pts have
been subsequently treated with either keto or D respectively. Of the 14 pts
treated with D, 11 (79%) had exposure to keto prior to AA. The keto- and
D-treated cohorts were similar with respect to other baseline factors,
including prior response to AA (4/6 (67%) pts with � 50% PSA decline on
AA in keto cohort; 10/14 (71%) pts in D cohort); though pts treated with D
were more likely to require opioid analgesics (0 pts in keto cohort; 7 (50%)
in D). For pts treated with keto, none experienced a decline in PSA,
improvement in bone scan, or an objective response; all had disease
progression by 12 weeks. In contrast, for pts treated with D, 10 (71%) had
a decline in PSA; 6 (43%) with a � 50% maximum PSA decline. Of 6 pts
with measurable disease, 2 (33%) had an objective response. The median
time to progression for the D cohort was 129 days (range 60 – 294).
Conclusions: Although the cohort size is small, and post-AA therapy was not
randomized, these data provide preliminary support for the hypothesis that
CRPC progressing on AA is cross-resistant to further androgen synthesis
inhibition with keto. Contrary to other reports, prior treatment with AA does
not appear to decrease the likelihood of subsequent response to D, but this
observation requires prospective validation.
Genitourinary Cancer
4663 General Poster Session (Board #12F), Sun, 8:00 AM-12:00 PM
Results of telomerase activity measurements from live circulating tumor
cells captured on a slot microfilter in a phase III SWOG-coordinated
prostate cancer trial (S0421). Presenting Author: Amir Goldkorn, University
of Southern California Norris Comprehensive Cancer Center, Los
Angeles, CA
Background: Analysis of circulating tumor cells (CTC) is a promising
biomarker strategy in advanced prostate cancer, and telomerase activity
(TA) is a recognized cancer marker. To test whether CTC TA is prognostic for
survival (OS), we developed a novel Parylene-C slot microfilter capable of
capturing live CTC and used it to measure CTC TA as part of a Phase III
SWOG-coordinated therapeutic trial in metastatic castration resistant
prostate cancer (S0421). Methods: Blood samples were drawn into EDTA
tubes and shipped overnight to a central processing site. After Ficoll
centrifugation, low constant pressure was used to pass the mononuclear
cell layer through two slot microfilters in series as published previously
(filter1 captures CTC � background white blood cells; filter2 captures only
background white blood cells). Filter-trapped cells were lysed in CHAPS
buffer and assayed for TA using qPCR-based telomeric repeat amplification.
In parallel, CTC were enumerated using CellSearch (J&J). Cox
regression was used to evaluate the association between baseline (pretreatment)
TA and OS overall, and within subgroups characterized by good
prognosis (�5) vs. poor prognosis (��5) baseline CTC counts. CART
regression was used to explore potential prognostic subgroups based on
baseline PSA, CTC, and TA cutpoints. Results: Samples were obtained from
263 patients. While no association was observed between TA and OS
overall, in patients with baseline CTC ��5 (108 of 263 or 41% of
patients), TAfilter2 –TAfilter1 representing high CTC TA relative to background
blood cells was associated with a hazard ratio (HR) of 1.14 (95% CI
1.05-1.23, p�0.001) for OS after adjusting for risk factors and remained
significant when also adjusting for CTC: HR 1.14 (95% CI 1.04-1.23;
p�0.005). Exploratory CART regression assessing baseline PSA, CTC, and
TA identified risk groups based only on CTC and TA values. Conclusions:
Baseline TA from CTC live-captured on a new slot microfilter is the first CTC
biomarker shown to be prognostic of OS in men with CTC counts ��5 ina
prospective clinical trial. CTC TA may be useful for further identifying
prognostic groups in this population.
4665 General Poster Session (Board #12H), Sun, 8:00 AM-12:00 PM
Phase I clinical trial of galeterone (TOK-001), a multifunctional antiandrogen
and CYP17 inhibitor in castration resistant prostate cancer (CRPC).
Presenting Author: Robert B. Montgomery, University of Washington,
Seattle, WA
Background: Galeterone is an oral steroid analog that suppresses prostate
cancer growth by inhibiting CYP17, blocking androgen receptor and
reducing androgen receptor levels. Methods: Open label, multicenter
dose-finding study assessing the safety, pharmacokinetics and clinical
effect of escalating doses of galeterone in chemotherapy naïve CRPC
patients (pts). Pts were enrolled in cohorts from 650-2,600mg of galeterone
daily for 12 wks. Study also explored effects of food supplement and
scheduling. Pts remained on study until disease progression or dose
limiting toxicity. Results: Pt characteristics included median age 69
(47-92), median PSA 24 (6-200), and 46.9% with metastases. 36 of 49
pts completed 12 wks of study with early discontinuation for toxicity (6),
progression (5), or withdrawal of consent (2). Maximal tolerated dose was
not reached. The frequency of AEs was 58% grade 1, 30% grade 2, 8%
grade 3 and 1% grade 4. Transient LFT elevations were seen in 15 men (5
with suspected or confirmed Gilberts). There was no trend for increasing
toxicity with dose escalation and no PK difference in Gilberts pts. 9 SAEs
were reported with one considered related to galeterone (rhabdomyolysis
with acute renal failure in the context of high dose statin use). Overall
11/49 pts (22%) demonstrated �50% PSA decline and an additional
13/49 (26%) had 30-50% declines. Partial response by RECIST was seen
in 2 pts. Consistent with lyase inhibition, increased corticosteroids and
suppressed androgens were seen with dose escalation. Analysis of limited
plasma collected 4 - 30 hours after dosing showed high interpatient
variability with no consistent relationship to dose or time after dosing.
Conclusions: Galeterone was well tolerated in CRPC pts and demonstrated
clinical activity. Galeterone is being reformulated with additional PK and
phase II trials planned.
PSA response to galeterone.
Dose (mg/day) N
Duration on
treatment
(months)
>50% PSA
decline
% (n)
317s
>30% PSA
decline
% (n)
650 6* 2-16 20% (1) 20% (1)
975 with and w/out supplement 12* 1-21 18% (2) 55% (6)
1,300 6 2-21 0% (0) 17% (1)
1,950 single/split 13 1-12 23% (3) 54% (7)
2,600 single/split
*One pt nonevaluable.
12 1-8 42% (5) 75% (9)
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