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

4654 General Poster Session (Board #11E), Sun, 8:00 AM-12:00 PM
A phase II study of KX2-391, an oral inhibitor of Src kinase and tubulin
polymerization, in men with bone-metastatic castration-resistant prostate
cancer (CRPC): A PCCTC trial. Presenting Author: Emmanuel S. Antonarakis,
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
University, Baltimore, MD
Background: KX2-391 is an oral small molecule inhibitor of Src kinase and
tubulin polymerization. In phase 1 trials, PSA declines were seen in men
with advanced prostate cancer. Methods: A single-arm phase 2 study of
KX2-391 in 31 men with chemo-naïve bone-metastatic CRPC was conducted
at 5 PCCTC sites. Men received oral KX2-391 (40 mg BID) until
disease progression or unacceptable toxicity. The primary endpoint was
progression-free survival (PFS) at 24 wk (progression � clinical/
radiographic progression or death, but not rising PSA; PCWG2 criteria); a
50% success rate was predefined as clinically significant. Secondary
endpoints were PSA progression-free survival (PPFS) at 24 wk (PSA
progression � 25% PSA rise above nadir; PCWG2 criteria); median PFS;
median PPFS; and max PSA decline. Exploratory outcomes included PK
studies, CTC enumeration, and analysis of markers of bone resorption
(urinary N-telopeptide [uNTx]; C-telopeptide [CTx]) and formation (bone
alk phos [BAP]; osteocalcin). Results: The trial closed early after accrual of
31 men, due to a prespecified futility rule. In all, 26/31 men were
evaluable for the primary endpoint; efficacy results are shown below. Also,
2/11 men (18%) with unfavorable (�5) CTCs at baseline converted to
favorable (�5) CTC counts on study, and 18/19 men (95%) with baseline
favorable CTC counts maintained them. The proportion of men with
declines in bone turnover markers was 32% (8/25) for uNTx, 21% (6/29)
for CTx, 10% (3/29) for BAP, and 25% (7/28) for osteocalcin. In PK
studies, median Cmax was 61 (range 16–129) ng/mL, and AUC was 156
(35–348) ng*hr/mL. Common toxicities (�10%) included LFT elevations,
leukopenia, thrombocytopenia, fatigue, nausea and constipation.
Conclusions: KX2-391 dosed at 40 mg BID lacks antitumor activity in men
with CRPC, but modulates bone turnover markers in some men. Because a
Cmax of �142 ng/mL is required for tubulin polymerization inhibition,
higher once-daily dosing will be used in future trials.
Endpoint Value 95% CI
Primary
PFS at 24 wk (%) 7.7 2.3 – 24.3
Secondary
PPFS at 24 wk (%) 0 0 – 13.2
Median PFS (wk) 18.6 12.1 – 24.0
Median PPFS (wk) 5.0 4.1 – 11.4
>30% PSA decline (%) 9.7 3.5 – 25.0
4656 General Poster Session (Board #11G), Sun, 8:00 AM-12:00 PM
Phase I results from a phase I/II study of orteronel, an oral, investigational,
nonsteroidal 17,20-lyase inhibitor, with docetaxel and prednisone (DP) in
metastatic castration-resistant prostate cancer (mCRPC). Presenting Author:
Daniel Peter Petrylak, Columbia University Medical Center, New York,
NY
Background: The investigational agent orteronel (ortl, TAK-700) is a
selective 17,20-lyase inhibitor that blocks androgen production. Since DP
is standard chemotherapy in mCRPC, this phase 1/2 study examined ortl �
DP in men with mCRPC. Methods: The primary phase I objective was to
determine the maximum dose of ortl 200–400 mg BID that can be
administered safely with DP in castrate men (testosterone [T] �50 ng/dL)
with mCRPC, �1 prior chemotherapy and no ketoconazole/abiraterone
�30 d prior. A 3�3 dose escalation was used with ortl 200 then 400 mg
BID. Ortl dosed daily and D (75 mg/m2 q3w) � P (5 mg BID) was started on
d8 of cycle 1 (28 d); cycles �2 � 21 d. Results: 14 men, median age 68 yrs
(range 53–81), ECOG PS 0/1 (71%/29%), median PSA 59.4 ng/mL
(5.2–1052), T 8.1 ng/dL (1.2–16.7), 9 with measurable disease, were
treated. Median ortl exposure was 33.3 wks (6.3–59); 6 and 8 men
received ortl 200 and 400 mg BID � DP, in cohorts 1 and 2, respectively.
No dose-limiting toxicities (DLTs) occurred in cohort 1 (2 x 3 pts); in cohort
2 (2 x 4 pts), 1 pt in group 1 had DLT (Gr3 related febrile neutropenia); no
DLTs occurred in group 2. 3 pts discontinued due to AEs (2 D infusion
reactions, 1 at each dose; 1 unrelated cardiorespiratory death at 200 mg).
All men had at least 1 AE Gr �3 which were treatment-related in 11 men.
The most common Gr �3 AEs were seen at both doses and included
neutropenia 50% (n � 7), hyperglycemia 21% (n � 3), febrile neutropenia,
infusion reaction, hyponatremia, decreased neutrophil count (2 each); at
400 mg only: fatigue, hypophosphatemia, and decreased WBC count (2
each). 7 men had serious AEs (SAEs), which were drug-related in 5. The
most common SAE was febrile neutropenia in 2 men. At 3 mo, PSA50 and
PSA90 rates were 86% and 36%, respectively; 12/14 men had a median
PSA decline �70%; and median T declined to �0.2 ng/dL (0–10.7). The
Cmax of D � ortl was similar to D alone. Conclusions: Ortl 200 mg and 400
mg BID � DP appears safe and tolerable with androgen-lowering activity at
the maximum planned dose in mCRPC. There is no evidence of AE
potentiation when ortl is administered with DP. The phase II portion of the
study will use ortl 400 mg BID � DP.
Genitourinary Cancer
315s
4655 General Poster Session (Board #11F), Sun, 8:00 AM-12:00 PM
Liver metastases (LM) to predict for short overall survival (OS) in metastatic
castration-resistant prostate cancer (mCRPC) patients (pts). Presenting
Author: William Kevin Kelly, Kimmel Cancer Center at Thomas Jefferson
University, Philadelphia, PA
Background: Patients withCRPC with LM represent a subset of patients with
a poor prognosis. An exploratory analysis was performed to evaluate the
difference in baseline characteristics and clinical outcomes in patients
with and without LM from a randomized phase III trial (CALGB 90401) in
men with mCRPC. Methods: Data from 1,050 men treated with docetaxel,
prednisone with either bevacizumab or placebo were used. Pts were
chemotherapy naïve, and had evidence of progressive mCRPC despite
castrate testosterone levels and anti-androgen withdrawal, ECOG performance
status � 2, and adequate bone marrow, hepatic and renal functions.
The proportional hazards model was used to assess the prognostic significance
of LM in predicting OS and progression free survival (PFS) adjusting
for stratification factors. Results: Fifty-nine (5.6%) of the 1045 pts with a
complete data set had documented LM. Patients with LM had higher
baseline alkaline phosphatase (ALK, 167 vs 117 U/L, p �0.0205) and
lactate dehydrogenase (LDH, 262 vs 205 U/L, p �0.0001) compared to
patients without LM. There were strong associations between LM status
and lung metastasis (p�0.0004) and other visceral disease (p��0.001)
but not with bone disease. Clinical outcomes as a function of LM status are
listed in the table. The median OS time in LM pts was 14.4 compared to
22.6 months, with a hazard ratio (HR) 1.4. The HR for treatment effect
(DP�B vs. DP) for LM was not statistically significant for either group.
Conclusions: Compared to pts without LM, mCRPC with LM are characterized
by higher LDH and ALK and have a poor OS despite having similar PFS
and objectivebiochemical response to docetaxel based therapy.
Clinical outcomes Liver mets at baseline
No
Yes
HR*
(n�986) (n�59) (95% CI) p value
Median OS (months) 22.6
14.4
1.4 0.019*
(95% CI )
(21.5-24.1) (13.3-17.8) (1.1-1.8)
Median PFS (months) 7.6
5.7
1.1 0.672*
(95% CI)
(7.2-8.1) (2.5-7.1) (0.7-1.7)
>50% decline in PSA 64%
55%
0.216
(95% CI)
(60-67) (42-69)
Objective response
41%
53%
0.097
(95% CI)
(37-46) (39-67)
* stratified log-rank p value
4657 General Poster Session (Board #11H), Sun, 8:00 AM-12:00 PM
A national survey of radiation oncologists and urologists on active surveillance
for low-risk prostate cancer. Presenting Author: Simon P. Kim, Mayo
Clinic, Rochester, MN
Background: While active surveillance (AS) is well recognized as an
acceptable treatment strategy for low-risk prostate cancer (PC), the extent
to which radiation oncologists and urologists perceive AS as effective and
routinely recommend it to patients is unknown. Therefore, we sought to
assess the attitudes and treatment recommendations for low-risk PC from a
national survey of PC specialists. Methods: A mail survey was sent to a
population-based sample of 1,439 physicians in the U.S. from late 2011
and early 2012. Physicians were queried about their attitudes regarding AS
and treatment recommendations for patients diagnosed with low-risk PC
(PSA�10 ng/dl; T1c; Gleason 6 in one of twelve cores). Pearson Chi-square
and multivariate logistic regression were used to test for differences in
attitudes and treatment recommendations by physician demographics,
compensation structure, primary place of employment, and specialty.
Results: Overall, 321 radiation oncologists and 322 urologists completed
the survey for a 45% response rate. Most physicians reported that AS is
effective for low-risk PC (71%) and stated that they were comfortable
routinely recommending AS (67%). Urologists were more likely to agree
that AS is effective (77% vs. 67%; p�0.005) and were comfortable
recommending AS (74% vs. 61%; p�0.001) compared with radiation
oncologists. Most physicians recommended radical prostatectomy (47%)
or radiation therapy (32%), but fewer endorsed AS (21%) for low-risk
disease. After adjusting for physician covariates, radiation oncologists were
more likely to recommend radiation therapy (OR: 10.97; p�0.001), while
urologists were more likely to recommend surgery (OR: 4.69; p�0.001)
and AS (OR: 2.18; p�0.001) for low-risk PC. Conclusions: Although AS is
widely viewed as effective by both radiation oncologists and urologists,
most urologists continue to recommend surgery, while most radiation
oncologists recommend radiation therapy. Our results may explain in part
the relatively low contemporary use of AS in the U.S.
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