Transcript ASCO_GI_2010_files/Baklund Sora_Erlot ASCO GI 2010

Primary Objective
1.1.1.1 To determine the maximum tolerated dose (MTD) of nab-paclitaxel when combined concurrently with carboplatin and radiation followed by two cycles of nab-paclitaxel/carboplatin as consolidation
A Phase II Trial of Sorafenib (S) and Erlotinib (E) in Unresectable Pancreas Cancer (UPC): Preliminary
Results
DC Backlund, LW Goff, E Chan, Y Shyr, WA Conkright, L Cornelius, S Pakron, M Holloway, P McClanahan, J Berlin.
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Abstract
Background: The MAP kinase pathway is known to
play a central role in PC pathogenesis, and blocking
this pathway at multiple levels using S and E is
attractive from a mechanistic standpoint. S also
targets VEGF receptors and there is evidence
suggesting that blockade of both EGFR and VEGF
pathways simultaneously has potential for additive, if
not synergistic effects. This phase II trial is designed
to evaluate the efficacy of the combination of S and E
in patients with UPC.
Methods: Patients (pts) with UPC are eligible to receive
S 400mg twice daily along with E 150mg once daily, on
a continuous basis as either 1st or 2nd line therapy.
Primary endpoint is 8-week progression free survival
rate (PFS) and secondary endpoints include response
rate, 4-month PFS and safety. In addition, DNA from
peripheral blood will be interrogated by analysis of
single nucleotide polymorphisms to see if any predict
for response and toxicity with these agents.
Results: Fourteen pts have enrolled to date, and 13
have received study drug. Median age is 62 (range 5275), 8 female, 6 male. Thirteen patients have received
prior regimens, and 3 pts had ECOG PS=2 upon
starting therapy. Grade 3 related toxicities reported
thus far include nausea, vomiting and abdominal pain
(4 pts each), diarrhea (3 pts), hypertension,
constitutional symptoms and low blood counts (2 pts
each), and 1 pt each with rash, constipation and
dehydration. There have been 7 deaths, all due to
progressive disease. Eleven pts were off-treatment at
the time of this assessment, 7 due to disease
progression, 2 due to pt request or withdrawal, and 2
due to toxicities or complications.
Conclusions: The combination of full-dose S and E is
often poorly tolerated by UPC pts, and this protocol
has been amended to begin pts at an S dose of 400mg
q day. For several patients, there was a delay in start of
therapy due to problems getting insurance coverage
for erlotinib on study, and for patients with aggressive
disease, this delay may have had an impact on
tolerance of therapy and survival. Efficacy data and
toxicity of the revised dosing regimen will be reported
at the meeting after an interim analysis.
Data included in this poster reflects updated
information since abstract submission.
Trial Design
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Cancer Center, Vanderbilt University Medical Center, Nashville, TN; 2Purchase Cancer Group, Paducah, KY.
Patient Demographics
Toxicity
Methods
•Phase II, nonrandomized, single arm, multiinstitutional study
Inclusion Criteria
•Microscopic confirmation of diagnosis of unresectable pancreatic
adenocarcinoma (excluding neuroendocrine tumors and cystadenocarcinoma)
•Measurable or evaluable disease by RECIST criteria
•Age > 18 years
•ECOG PS 0-2
•Adequate bone marrow, liver and renal function
•Normal coagulation parameters in pts not receiving anticoagulants such as
warfarin or heparin
Exclusion Criteria
•Prior treatment with antiangiogenics
•Patients who received more than one line of therapy for advanced disease
•Underlying heart failure > class II NYHA, unstable angina or MI in prior 6
months
•Ventricular arrhythmias requiring antiarrhythmic therapy
•Uncontrolled hypertension
•Known HIV or chronic Hepatitis B or C
•Any arterial thrombotic event in prior 6 months
•Pulmonary hemorrhage or other bleeding event within 4 weeks of beginning
study drug, or prior evidence of a bleeding diathesis or coagulopathy (except
cancer-related blood clots)
•Serious non-healing wound, infection, ulcer or bone fracture
•Known brain metastasis
•Patients who require therapy with known strong CYP3A4 inhibitors or inducers
•Major surgery, open biopsy or significant traumatic injury within 4 weeks of
first study drug
•Known allergy to sorafenib or erlotinib
•A known, untreated malabsorption problem, or inability to swallow whole pills
•Pregnant or nursing women
Characteristic
N value
Consented
18
Enrolled (received study drug)
Vanderbilt-Ingram Cancer Center
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15
Vanderbilt Cool Springs
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Purchase Cancer Group
Age (median)
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62
Range
51-74
Gender
Male
Female
9
9
*ECOG PS-Prestudy
4
12
2
0
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2
Line of therapy for unresectable disease
1st
2nd
Stage at start of therapy
Locally advanced
Metastatic
2
16
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16
* 1 patient went from PS=1 to 2 between prestudy visit and C1D1
•Primary: To determine the efficacy of the combination of sorafenib and
erlotinib in patients with unresectable pancreas cancer. Primary endpoint is
8-week progression free survival rate.
•Secondary: To determine the response rate, the progression free survival at
4 months, and evaluate the safety profile of this combination in this patient
population.
•Correlative: To evaluate change in serum Ca 19-9 at baseline and at 8-week
intervals, to gather blood and plasma at baseline and 8 weeks for future DNA
and proteomic assessments.
Patients with ≥ Grade 2 Toxicities Possibly, Probably or
Definitely Related to Treatment
Grade 2
Grade 3*
Anemia
1
1
Lymphopenia
0
1
Hypertension
2
3
Fatigue
5
2
Weight Loss
1
0
Constipation
1
0
Skin toxicity
3
3
Dehydration
2
1
Diarrhea
3
3
Anorexia
3
0
Oral mucositis
1
0
Nausea
2
0
Vomiting
1
1
Abdominal Pain
1
2
Chest Pain
1
0
LFT/amylase
1
1
abnormalities
Hyperbilirubinemia
2
0
Hypophosphatemia
1
0
Dry eye syndrome
1
0
*No Grade 4 related toxicities observed
Results to Date
•Between October 2008 and December
2009 18 patients were accrued
•Full dose sorafenib and erlotinib
were poorly tolerated in this patient
population, with 12 of the first 15
patients accrued requiring dose
delays or dose reductions. This
protocol has been amended to begin
sorafenib at a lower dose, (400mg qd)
with option of titration to full dose if
patient tolerates modified dose well
after one month of combined therapy
•Toxcities seen in this patient
population appear slightly more
severe than in the lung cancer
population reported by Lind, et al
•There
were
no
unanticipated
toxicities seen in this study, and no
deaths to date attributable to study
interventions
•It is too early to draw conclusions
regarding efficacy. Trial accrual is
ongoing at the modified dose.
Current Patient status
Pts no longer receiving study drug
Best Response
--Disease progression or relapse
7
--Withdrawal or refusal to continue
therapy
--Toxicity, side effects or complications
3
--Clinical Deterioration (decline in PS)
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2
--Died before receiving study drug
1
# of patient deaths *
11
* No deaths to date due felt due to study intervention
Efficacy
14
Reason for treatment discontinuation
Objectives
Summary
Stable Disease
Progressive Disease
Not Assessed*
Not Evaluable
Improvement in Ca 199 on therapy
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8
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3
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*3 patients not due for first assessment at this time
**Research support provided by Bayer-Onyx
Pharmaceuticals; additional drug support
provided by OSI Pharmaceuticals.
This research was also supported by the
Vanderbilt-Ingram Cancer Center Support Grant
CA 068485-14.