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Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations

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ClinicalTrials.gov Identifier: NCT03040986
Recruitment Status : Suspended (Interim monitoring)
First Posted : February 2, 2017
Last Update Posted : December 25, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well selumetinib sulfate works in treating patients with pancreatic cancer with KRAS G12R mutations that has spread from where it started to nearby tissue or lymph nodes or other places in the body. Selumetinib sulfate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
KRAS NP_004976.2:p.G12R Stage III Pancreatic Cancer AJCC v6 and v7 Stage IV Pancreatic Cancer AJCC v6 and v7 Other: Laboratory Biomarker Analysis Drug: Selumetinib Sulfate Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the objective response rate to selumetinib sulfate (selumetinib) administered as 75 mg orally twice daily on a continuous schedule in patients with advanced pancreas cancer harboring KRAS G12R mutations.

SECONDARY OBJECTIVES:

I. To determine the progression free survival of patients with locally advanced, unresectable and stage IV pancreas cancer treated with selumetinib monotherapy.

II. To evaluate the safety of selumetinib in patients with advanced pancreas cancer.

III. To determine the impact of additional genetic alterations on the response to selumetinib in pancreas cancer harboring KRAS G12R mutations.

IV. To develop a clinically applicable biomarker predicting response to selumetinib in pancreas cancer harboring KRAS G12R mutations.

OUTLINE:

Patients receive selumetinib sulfate orally (PO) twice daily (BID). Treatment repeats every 28 days for up to 27 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 52 weeks.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Selumetinib (AZD6244) for the Treatment of Advanced Pancreas Cancer Harboring KRAS G12R Mutations
Actual Study Start Date : July 21, 2017
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (selumetinib sulfate)
Patients receive selumetinib sulfate PO BID. Treatment repeats every 28 days for up to 27 courses in the absence of disease progression or unacceptable toxicity
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Selumetinib Sulfate
Given PO
Other Names:
  • AZD-6244 Hydrogen Sulfate
  • AZD6244 Hydrogen Sulfate
  • AZD6244 Hydrogen Sulphate
  • Selumetinib Sulphate




Primary Outcome Measures :
  1. Production of adequate numbers of clinical responses with selumetinib sulfate monotherapy [ Time Frame: Up to 52 weeks ]
    Will determine whether this novel agent is able to be associated with a response rate (partial response [PR] + complete response) that can rule out 5% (p0=0.05) in favor of an improved response rate of 30% (p1=0.30).


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 52 weeks ]
    Will be calculated using the Kaplan-Meier method.

  2. Incidence of adverse events graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 52 weeks ]
    If there are 5 or more patients who experience grade 3 or greater toxicity attributable to the agent, then comparisons between this cohort and patients who tolerated the same course of selumetinib without toxicity across grades of toxicity with respect to outcome (response) and clinicopathological parameters (age, sex, type of metastatic involvement vs locally advanced) may be done using a Kruskal-Wallis test. Otherwise, toxicities will be tabulated and described.

  3. Response to selumetinib sulfate (PR as defined by Response Evaluation Criteria in Solid Tumors) [ Time Frame: Up to 52 weeks ]
    Will be associated with the presence of concomitant activating oncogene mutations or loss of tumor suppressor function will be presented descriptively to estimate the response rates according to those characteristics.

  4. Semi-quantitative measurements of CNKSR1 [ Time Frame: Up to 52 weeks ]
    Comparisons will be descriptively to estimate the differences of the expression level in pancreas cancer tissues and clinical outcome variables.

  5. Change in circulating tumor deoxyribonucleic acid (ctDNA) and alteration in in somatic variants [ Time Frame: Baseline up to 52 weeks ]
    Compared between baseline and repeat profiling (integrated biomarker; voluntary) will be evaluated for change from baseline levels and the estimated changes will be reported.

  6. Predictive biomarkers for response to selumetinib [ Time Frame: Up to 52 weeks ]
    Presence of variants identified in the 50-cancer gene panel will be compared with response, presenting the results in a 2x2 table with findings reported descriptively. Pre-treatment ctDNA levels will be divided into groups to separate aberrant values from the rest. The cutoffs will be > and < 2 standard deviations of the mean, with the cutoffs applied to both ctDNA levels. Based on these groups, resulting in patients with cell free deoxyribonucleic acid (cfDNA) transcripts levels > 2 standard deviation (SD) above the mean, patients with cfDNA transcripts levels < 2 SD below the mean, and the rest in between, the categorical results will be evaluated and reported relative to response vs. non-response in a descriptive manner.

  7. Longitudinal biomarker measuring response to treatment [ Time Frame: Up to 52 weeks ]
    cfDNA transcript levels will be followed from the start of treatment every (q)2 weeks and the change to pre-treatment will be plotted for each timepoint in a spider plot format. This will be a descriptive presentation only. Variant profile derived from voluntary repeat biopsies will be compared to pre-treatment variant profile and gain of variants (adjusted for similar sequencing depth) will be recorded. This will be a descriptive presentation only.



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

Inclusion Criteria:

  • Patients must have histologically confirmed locally advanced or metastatic pancreas cancer
  • Patients must have received at least 6 months fluorouracil (5-FU)- or gemcitabine-based treatments for pancreas cancer (fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin [FOLFIRINOX], fluorouracil, leucovorin calcium and oxaliplatin [FOLFOX], 5-FU+ nal-IRI [MM-398; nanoliposomal irinotecan], or 5-FU [including capecitabine], gemcitabine-based gemcitabine plus abraxane, gemcitabine monotherapy among others)
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed somatic KRAS G12R mutation as determined by sequence analysis of matched normal deoxyribonucleic acid (DNA) from any specimen obtained from the individual; patients must provide tumor sample for KRAS analysis or be willing to undergo mandatory screening biopsy
  • Patients must not have had chemotherapy, molecular therapy with erlotinib, radiation therapy, or experimental biological or molecular therapy for at least 4 weeks prior to starting study medication; patients who received FOLFIRINOX must be 6 weeks from the last administration of therapy; patients must have recovered from any acute toxicity related to prior therapy or surgery, to a grade 1 or less unless specified
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 or Karnofsky >= 70%
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 75,000/mcL
  • Hemoglobin (Hgb) >= 9.0 g/dL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) < 3 x institutional upper limit of normal
  • Creatinine =< institutional upper limit of normal OR
  • Creatinine clearance > 60 mL/min/1.73 m^2 by either Cockcroft-Gault formula or 24-hour urine collection analysis
  • Patients must be willing to return to the clinic for follow-up visits
  • Women of child-bearing potential 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 4 weeks after dosing with selumetinib sulfate (AZD6244) ceases; women of child-bearing potential must have a negative pregnancy test within 14 days prior to study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform her treating physician immediately; please note that the AZD6244 manufacturer recommends that adequate contraception for male patients should be used for 12 weeks post-last dose due to sperm life cycle; NOTE: breastfeeding should be discontinued if the mother is treated with selumetinib
  • Ability to understand and the willingness to sign a written informed consent document or patients with Impaired Decision Making Capacity (IDMC) if they are represented by a Legally Authorized Representative (LAR)
  • Patient must be able to reliably swallow oral medications

Exclusion Criteria:

  • Patients who have received prior treatment with tyrosine kinase inhibitors (e.g. erlotinib), or anti-EGFR agents (e.g. cetuximab, panitumumab)
  • Patients currently receiving any medication known to induce central serous chorioretinopathy which in the opinion of the principal investigator, would make the administration of study drug hazardous
  • Patients with active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
  • Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events
  • Patients who are receiving any other investigational agents
  • Patients with known brain metastases should be excluded from this clinical trial; no additional workup is needed to exclude brain metastases if the patient is asymptomatic or has no history of brain metastases
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 or other agents used in study
  • Previous MEK, RAS, or RAF inhibitor use
  • Patients with the following cardiac conditions are excluded:

    • Uncontrolled hypertension (blood pressure [BP] of >= 150/95 despite medical support/management)
    • Acute coronary syndrome within 6 months prior to starting treatment
    • Uncontrolled angina - Canadian Cardiovascular Society grade II-IV despite medical support/management
    • Heart failure New York Heart Association (NYHA) class II or above
    • Prior or current cardiomyopathy (within 6 months) including but not limited to the following:

      • Known hypertrophic cardiomyopathy
      • Known arrhythmogenic right ventricular cardiomyopathy
      • Abnormal ejection fraction (echocardiogram [ECHO]) =< 53% (if a range is given then the upper value of the range will be used) or cardiac MRI
      • Previous moderate or severe impairment of left ventricular systolic function (left ventricular ejection fraction [LVEF] < 45% on echocardiography or equivalent on multi-gated acquisition scan [MUGA]) even if full recovery has occurred; echocardiogram (Echo) and additional cardiac studies not indicated unless clinically symptomatic or patient has significant cardiac history
      • Severe valvular heart disease
      • Atrial fibrillation with a ventricular rate > 100 beats per minute (bpm) on electrocardiogram (ECG) at rest
      • Fridericia's corrected QT interval (QTcF) >= 450 msec 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) are excluded; the use of medication(s) that can prolong QTc interval is prohibited while treated on this study
  • Patients with known ophthalmologic conditions, such as:

    • Current or past history of central serous retinopathy
    • Current or past history of retinal vein occlusion
    • Known intraocular pressure (IOP) > 21 mmHg (or upper limit of normal [ULN] adjusted by age) or uncontrolled glaucoma (irrespective of IOP); patients with controlled glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) may be eligible after discussion with the study chair
    • Subjects with any other significant abnormality on ophthalmic examination (performed by an ophthalmologist) should be discussed with the study chair for potential eligibility
    • Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal plexiform neurofibroma (PN) (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
  • Patients with refractory nausea and vomiting, chronic gastrointestinal (GI) diseases (e.g., inflammatory bowel disease) or significant bowel resection
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; HIV-positive patients not on antiviral therapy with undetectable viral loads and CD4 counts > 300, and after confirmation of eligibility after discussing with the study chair are eligible

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 ClinicalTrials.gov identifier (NCT number): NCT03040986


Locations
United States, California
Los Angeles County-USC Medical Center
Los Angeles, California, United States, 90033
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States, 95817
United States, Kentucky
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States, 40536
United States, Maryland
NCI - Center for Cancer Research
Bethesda, Maryland, United States, 20892
United States, Michigan
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Udo Rudloff National Cancer Institute LAO

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03040986     History of Changes
Other Study ID Numbers: NCI-2017-00118
NCI-2017-00118 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
17C0144
10050 ( Other Identifier: National Cancer Institute LAO )
10050 ( Other Identifier: CTEP )
ZIABC011078 ( U.S. NIH Grant/Contract )
First Posted: February 2, 2017    Key Record Dates
Last Update Posted: December 25, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases