Selumetinib and Erlotinib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well giving selumetinib and erlotinib hydrochloride together works in treating patients with locally advanced or metastatic pancreatic cancer that is refractory to chemotherapy. Selumetinib and erlotinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
-----------------
PRIMARY OBJECTIVES: l. To assess overall survival (as measured by median survival and proportion of patients alive at 24 weeks) in patients with advanced pancreatic cancer who have received one prior line of systemic therapy when treated with the combination of AZD6244 (selumetinib) and erlotinib (erlotinib hydrochloride). SECONDARY OBJECTIVES: I. Progression-free survival (median progression-free survival [PFS] and proportion of patients with PFS at 12 and 24 weeks). II. Cancer antigen (CA)19-9 biomarker response (defined as a 50% decline in serum CA19-9 level from baseline in patients with > 2 x upper limit of normal [ULN] CA19-9 measurement). III. Objective radiographic response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. IV. Safety and toxicity profile of the combination of AZ6244 and erlotinib. OUTLINE: Patients receive selumetinib orally (PO) once daily (QD) and erlotinib hydrochloride PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 2-3 months.

Official Title
-----------------
A Phase 2 Study of AZD6244 Plus Erlotinib for the Second-Line Treatment of Advanced Pancreatic Adenocarcinoma

Conditions
-----------------
Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: erlotinib hydrochloride
* Drug: selumetinib
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically proven adenocarcinoma of the pancreas Patients must have locally advanced unresectable disease not amenable to curative resection or extrapancreatic metastases; patients must have EITHER radiographically measurable disease (defined as at least one lesion that can be accurately measured in at least one dimension [longest diameter to be recorded] as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography [CT] scan) AND/OR a serum CA19-9 measurement > 2 x ULN One prior line of systemic therapy for advanced disease (locally advanced or metastatic) The following represent acceptable examples meeting the definition of one prior line of therapy: Gemcitabine as a single agent or in combination with other agents; patients receiving (a) gemcitabine initially alone, with the eventual addition of a second agent; or (b) gemcitabine as part of a combination regimen, followed by gemcitabine alone; are eligible A non-gemcitabine-based regimen, including (but not limited to) leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin (FOLFIRINOX) or any combination of components therein Treatment as part of a clinical trial involving cytotoxic agents, small molecule inhibitors, monoclonal antibodies, and/or immunomodulatory agents For patients with locally advanced disease, prior radiation to the primary tumor is allowable as long as there is clear evidence of disease progression (either radiographic locoregional disease progression and/or a rising CA19-9 level); patients may have received chemotherapy both concurrently and/or sequentially with (either before or after) the radiation and still be eligible for the study, as this would be considered all part of the same course of treatment Treatment given in the adjuvant setting (radiation and/or chemotherapy, given either concurrently or sequentially) does not count as prior therapy as long as progressive disease occurs > 6 months following completion of treatment Life expectancy of greater than 8 weeks Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Absolute neutrophil count (ANC) >= 1500/uL Platelet count >= 100,000/uL International normalized ratio (INR) =< 1.5 (except those subjects who are receiving full-dose warfarin) Total bilirubin =< 2.0 mg/dL Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 times the upper limit of normal for subjects Serum creatinine of =< 2.0 mg/dL Pregnancy test for women of childbearing potential (serum or urine beta-human chorionic gonadotropin [HCG]) All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for four weeks after dosing with AZD6244 ceases; women of child-bearing potential must have a negative pregnancy test prior to entry; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; please note that the AZD6244 manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Patients may not be receiving any other investigational agents Patients with known brain metastases should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 (or its excipient Captisol) or erlotinib Previous mitogen-activated protein kinase kinase (MEK) or epidermal growth factor receptor (EGFR) inhibitor use Patients with corrected QT (QTc) interval > 480 msecs or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that (i) meets New York Heart Association (NYHA) class III and IV definitions or (ii) is demonstrated by an left ventricular (LV) ejection fraction < 55% on baseline echocardiogram, are excluded Required use of a concomitant medication that can prolong the QT interval There are potential interactions between erlotinib and cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and CYP3A4 promoters; although caution and careful monitoring are recommended when use of these compounds is necessary, use of these compounds does not exclude patients from participating in this trial Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study; therefore, a negative pregnancy test is required for women of childbearing potential; breastfeeding should be discontinued if the mother is treated with AZD6244 Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (erlotinib hydrochloride, selumetinib)<br>Patients receive selumetinib PO QD and erlotinib hydrochloride PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: erlotinib hydrochloride<br>* Given PO<br>* Other names: OSI-774;Drug: selumetinib<br>* Given PO<br>* Other names: AZD6244;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Survival will be calculated according to the method of Kaplan and Meier. Both actual and estimated probability of being alive (along with a 95% confidence interval) at 24 weeks (6 months) and for any multiple of 6 months will be calculated for which the number of uncensored subjects is not smaller than 10. | Up to 2 years | 
| Survival at 24 Weeks | Percent survival at 24 weeks (6 months) | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Calculated according to the method of Kaplan and Meier. Actual and estimated probability of being alive and progression-free, along with a 95% confidence interval, will be calculated. Response and progression are evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 92(Macdonald et al.):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used. Progressive Disease is defined as a 20% or higher increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). | From first dose of study treatment to the date of objective progression, or death due to cancer or unknown cause, or to the date of withdrawal from the trial from unknown reasons, assessed up to 2 years | 
| CA19-9 Biomarker Response (Defined as a 50% Decline in Serum CA19-9 Level From Baseline in Patients With > 2 x ULN CA19-9 Measurement) | The proportion of patients with CA19-9 response. | Up to 2 years | 
| Objective Radiographic Response by RECIST Criteria | Patient's best overall response will be tabulated by level; proportions of complete response (CR) and of CR+partial response will be calculated along with 95% confidence intervals. Per Response Evaluation Criteria In Solid Tumors (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR, >= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR+PR. | Up to 2 years | 
| Incidence of Toxicities Graded Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Tabulation of type of adverse events (AE) and the incidence of grade 3 and 4 for each AE | Up to 30 days after completion of study treatment | 
| Number of Patients With Dose Modifications and Reason for Dose Modification. | Tabulation of the reasons for dose modification with number of patients | Up to final day of study treatment |