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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01222689
Recruitment Status : Completed
First Posted : October 18, 2010
Results First Posted : November 7, 2016
Last Update Posted : July 31, 2020
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
Adenocarcinoma of the Pancreas Recurrent Pancreatic Cancer Stage III Pancreatic Cancer Stage IV Pancreatic Cancer Drug: erlotinib hydrochloride Drug: selumetinib Other: laboratory biomarker analysis Phase 2

Detailed Description:


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).


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.


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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of AZD6244 Plus Erlotinib for the Second-Line Treatment of Advanced Pancreatic Adenocarcinoma
Study Start Date : November 2010
Actual Primary Completion Date : April 2013
Actual Study Completion Date : September 2014

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Treatment (erlotinib hydrochloride, selumetinib)
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
Given PO
Other Names:
  • CP-358,774
  • erlotinib
  • OSI-774

Drug: selumetinib
Given PO
Other Names:
  • ARRY-142886
  • AZD6244

Other: laboratory biomarker analysis
Correlative studies

Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Up to 2 years ]
    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.

  2. Survival at 24 Weeks [ Time Frame: 24 weeks ]
    Percent survival at 24 weeks (6 months)

Secondary Outcome Measures :
  1. Progression-free Survival (PFS) [ Time Frame: 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 ]

    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).

  2. 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) [ Time Frame: Up to 2 years ]
    The proportion of patients with CA19-9 response.

  3. Objective Radiographic Response by RECIST Criteria [ Time Frame: Up to 2 years ]

    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.

  4. Incidence of Toxicities Graded Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ]
    Tabulation of type of adverse events (AE) and the incidence of grade 3 and 4 for each AE

  5. Number of Patients With Dose Modifications and Reason for Dose Modification. [ Time Frame: Up to final day of study treatment ]
    Tabulation of the reasons for dose modification with number of patients

Other Outcome Measures:
  1. Protein Expression Levels in Pretherapeutic Core Biopsies [ Time Frame: Up to 2 years ]
    Logistic regression models will be used to associate baseline protein markers and best objective response. Cox models will be used to associate baseline protein markers with overall and progression-free survival. Each selected protein markers will be evaluated individually and ranked by the corresponding p-values. Combinations of markers will also be explored.

  2. Circulating Tumor Cell (CTC) Analysis [ Time Frame: Up to 2 years ]
    The association between baseline CTC numbers, their longitudinal changes, and patient outcomes as measured by OS, PFS, and radiographic and biomarker response will be evaluated. The association between expression level of protein markers in CTC with biopsy samples using Pearson's correlation and by unsupervised hierarchical clustering of samples using Pearson correlation as the distance metric will be assessed. Association of longitudinal protein markers in CTC with patient OS will be evaluated using the joint models of longitudinal observations.

  3. Plasma Biomarkers Potentially Predictive of Dual MEK/EGFR Inhibition [ Time Frame: Up to 2 years ]

    The association between candidate plasma biomarkers of interest, their longitudinal changes, and patient outcomes as measured by OS, PFS, and radiographic and biomarker response.

    Specifically, correlation of the relative change in allelic frequency of mutations present in both pre-treatment and on-treatment blood samples versus percent change in CA19-9.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01222689

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United States, California
UCSF-Mount Zion
San Francisco, California, United States, 94115
United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Andrew Ko UCSF-Mount Zion
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Responsible Party: National Cancer Institute (NCI) Identifier: NCT01222689    
Other Study ID Numbers: NCI-2011-01266
NCI-2011-01266 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10454 ( Other Identifier: UCSF-Mount Zion )
8598 ( Other Identifier: CTEP )
N01CM00070 ( U.S. NIH Grant/Contract )
R21CA149939 ( U.S. NIH Grant/Contract )
First Posted: October 18, 2010    Key Record Dates
Results First Posted: November 7, 2016
Last Update Posted: July 31, 2020
Last Verified: July 2020
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Erlotinib Hydrochloride
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action