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

• ClinicalTrials.gov Identifier: NCT03040986
• Recruitment Status: Completed
• First Posted: February 2, 2017
• Results First Posted: January 11, 2021
• Last Update Posted: February 9, 2021
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: February 1, 2017
• First Posted Date: February 2, 2017
• Results First Submitted Date: October 18, 2020
• Results First Posted Date: January 11, 2021
• Last Update Posted Date: February 9, 2021
• Actual Study Start Date: July 21, 2017
• Actual Primary Completion Date: August 10, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 16, 2020)

Proportion of Participants With an Objective Response (Partial Response + Complete Response) [ Time Frame: Approximately 1-8.2 months ]

Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm (<1 cm). Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Original Primary Outcome Measures (submitted: February 1, 2017)

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).

Current Secondary Outcome Measures (submitted: December 16, 2020)

• Median Progression-free Survival (PFS) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 52 weeks ]
  PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first and was calculated using the Kaplan-Meier method.
• Incidence of Grade 3 or Greater Adverse Events Using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Probably or Definitely Attributable to the Agent Selumetinib [ Time Frame: Date treatment consent signed to date off study, approximately 25 months and 6 days. ]
  Here are the grade 3 or greater adverse events assessed by the CTCAEv5.0 probably or definitely attributable to the agent Selumetinib. Grade 3 is defined as severe or medically significant, Grade 4 is life-threatening consequences, and Grade 5 is death related to adverse event. Probably is defined as likely related to the agent, and Definitely is defined as clearly related to the agent.
• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). [ Time Frame: Date treatment consent signed to date off study, approximately 25 months and 6 days. ]
  Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
• Semi-quantitative Measurements of Connector Enhancer of the Kinase Suppressor of Ras-1 (CNKSR1) [ Time Frame: Up to 52 weeks ]
  Comparisons will be done to estimate the differences of the expression level in pancreas cancer tissues and clinical outcome variables.
• 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 participants with cell free deoxyribonucleic acid (cfDNA) transcripts levels > 2 standard deviation (SD) above the mean, participants 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.
• Longitudinal Biomarker Measuring Response to Treatment [ Time Frame: start of treatment every (q)2 weeks, up to 52 weeks ]
  Circulating free deoxyribonucleic acid (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. 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.
• Change in the Somatic Circulating Tumor Deoxyribonucleic Acid (ctDNA) Mutation Profile and Its Correlation With Clinical Outcome [ Time Frame: Baseline up to 52 weeks ]
  The presence of mutant DNA copies and the fractional abundance of the mutant KRAS allele on circulating tumor DNA (ctDNA) in cell-free (cf) DNA isolated from plasma samples were to be determined.
• Mean Copy Number KRAS Wild Type Allele in Circulating Tumor DNA (ctDNA) [ Time Frame: Baseline and the last KRAS value before the participant came off treatment, approximately 1- 8.2 months. ]
  ctDNA copy number measurements of KRAS wild type alleles in circulating tumor DNA (ctDNA) from cell-free (cf) DNA isolated from plasma samples was determined from baseline and the last KRAS value (as a single value) before the participant came off treatment.
• Overall Percentage Change (%) of Copies KRAS Wild Type Allele [ Time Frame: Approximately 1- 8.2 months. ]
  Overall ctDNA copy number measurements of KRAS wild type alleles in circulating tumor DNA (ctDNA) from cell-free (cf) DNA isolated from plasma samples determined from a single percentage change for the group rather than a percentage change for each participant at baseline and last recorded value while on-treatment.
• Mean Copy Number KRAS Mutant Type Allele in Circulating Tumor DNA (ctDNA) [ Time Frame: Baseline and last recorded value while on treatment, approximately 1- 8.2 months. ]
  Mean ctDNA copy number measurements of KRAS mutant alleles in circulating tumor DNA (ctDNA) from cell-free (cf) DNA isolated from plasma samples was determined at baseline and the last recorded value while on treatment.
• Overall Percentage Change of Copies KRAS Mutant Type Allele [ Time Frame: Approximately 1- 8.2 months. ]
  Overall ctDNA copy number measurements of KRAS mutant alleles in circulating tumor DNA (ctDNA) from cell-free (cf) DNA isolated from plasma samples determined from a single percentage change for the group rather than a percentage change for each participant at baseline and last recorded value while on-treatment.
• Percentage of KRAS Allele in Circulating Tumor DNA (ctDNA) That is Identified as Variant From Cell-free (cf) DNA [ Time Frame: Between baseline and last recorded value while on-treatment, approximately 1- 8.2 months. ]
  This outcome measure is reporting the overall percentage of KRAS allele in circulating tumor DNA (ctDNA) that is identified as variant from cell-free (cf) DNA isolated from plasma samples between baseline and on-treatment.
• Overall Any Percent Change in (VAF, %), of KRAS Allele in Circulating Tumor Deoxyribonucleic Acid (ctDNA) [ Time Frame: Approximately 1- 8.2 months. ]
  Overall change in Variant Allele Fraction (VAF, %) of KRAS allele in circulating tumor DNA (ctDNA) from cell-free (cf) DNA isolated from plasma samples determined from a single percentage change for the group rather than a percentage change for each participant between baseline and last recorded value while on-treatment
• Mean Change in Variant Allele Fraction (VAF, %) of KRAS in Participants Who Had No Measurable KRAS Mutant Circulating Tumor Deoxyribonucleic Acid (ctDNA) at Baseline [ Time Frame: Baseline and last recorded value while on-treatment, approximately 1- 8.2 months. ]
  Any change in Variant Allele Fraction (VAF, %) of KRAS allele in circulating tumor DNA (ctDNA) from cell-free (cf) DNA isolated from plasma samples determined from a single percentage change for the group rather than a percentage change for each participant between baseline and while on-treatment in patients with no Mutant Fractional KRAS Abundency at baseline (VAF %, KRAS allele at baseline = 0% ).
• Overall Percent Change in Variant Allele Fraction (VAF, %) of KRAS in Participants Who Had No Measurable KRAS Mutant Circulating Tumor Deoxyribonucleic Acid (ctDNA) at Baseline [ Time Frame: Approximately 1- 8.2 months. ]
  Overall change in Variant Allele Fraction (VAF, %) of KRAS allele in circulating tumor DNA (ctDNA) from cell-free (cf) DNA isolated from plasma samples determined from a single percentage change for the group rather than a percentage change for each participant between baseline and while on-treatment in patients with no Mutant Fractional KRAS Abundency at baseline (VAF %, KRAS allele at baseline = 0% ).
• Percentage Change of KRAS Allele in Circulating Tumor Deoxyribonucleic Acid (ctDNA) That is Identified as Variant From Cell-free (cf) DNA at Baseline and After Treatment [ Time Frame: Baseline and last recorded value after treatment, approximately 1- 8.2 months. ]
  This outcome measure is reporting the percentage of KRAS allele in circulating tumor DNA (ctDNA) that is identified as variant from cell-free (cf) DNA isolated from plasma samples determined from a single percentage change for the group rather than a percentage change for each participant between baseline and last recorded value after treatment in patients with detectable KRAS Mutant Circulating Tumor Deoxyribonucleic Acid (ctDNA) (Mutant Fractional KRAS Abundency at baseline and after treatment (VAF %), KRAS allele at baseline > 0%).
• Overall Percent Change in Variant Allele Fraction (VAF, %) of KRAS in Participants With Detectable KRAS Mutant Circulating Tumor Deoxyribonucleic Acid (ctDNA) at Baseline and After Treatment [ Time Frame: Approximately 1- 8.2 months. ]
  Overall change in Variant Allele Fraction (VAF, %) of KRAS allele in circulating tumor DNA (ctDNA) from cell-free (cf) DNA isolated from plasma samples determined from a single percentage change for the group rather than a percentage change for each participant with detectable KRAS Mutant Circulating Tumor Deoxyribonucleic Acid (ctDNA) between baseline and last recorded value after treatment.

Original Secondary Outcome Measures (submitted: February 1, 2017)

• Change in pERK levels [ Time Frame: Baseline up to 52 weeks ]
  Will be evaluated with exploratory intent, and findings will be reported without formal adjustment for multiple comparisons, but in the context of a study with multiple exploratory analyses.
• 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.
• 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.
• 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 and examined in a Fisher's exact test.
• Semi-quantitative measurements of CNKSR1, ERK, and RSK3/4 [ Time Frame: Up to 52 weeks ]
  Comparisons will be made by determining the statistical significance of the difference of the expression level in pancreas cancer tissues and clinical outcome variables using a Fisher's exact test. Will be evaluated with exploratory intent, and findings will be reported without formal adjustment for multiple comparisons, but in the context of a study with multiple exploratory analyses.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations
• Official Title: A Phase II Study of Selumetinib (AZD6244) for the Treatment of Advanced Pancreas Cancer Harboring KRAS G12R Mutations
• Brief Summary: This phase II trial studies how well selumetinib sulfate works in treating patients with pancreatic cancer with Kirsten rat sarcoma (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.

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 Kirsten rat sarcoma (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
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• KRAS NP_004976.2:p.G12R
• Stage III Pancreatic Cancer AJCC v6 and v7
• Stage IV Pancreatic Cancer AJCC v6 and v7

Intervention

• Other: Laboratory Biomarker Analysis
  Correlative studies
• Drug: Selumetinib Sulfate
  Given by mouth (PO)
  Other Names:

  • AZD-6244 Hydrogen Sulfate
  • AZD6244 Hydrogen Sulfate
  • AZD6244 Hydrogen Sulphate
  • Selumetinib Sulphate

Study Arms

Experimental: Treatment (selumetinib sulfate)

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

Interventions:

• Other: Laboratory Biomarker Analysis
• Drug: Selumetinib Sulfate

• Publications *: Kenney C, Kunst T, Webb S, Christina D Jr, Arrowood C, Steinberg SM, Mettu NB, Kim EJ, Rudloff U. Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRAS(G12R)-mutant pancreatic ductal adenocarcinoma. Invest New Drugs. 2021 Jan 6. doi: 10.1007/s10637-020-01044-8. [Epub ahead of print]

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 16, 2020): 8
• Original Estimated Enrollment (submitted: February 1, 2017): 180
• Actual Study Completion Date: October 15, 2020
• Actual Primary Completion Date: August 10, 2018 (Final data collection date for primary outcome measure)

Eligibility 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 Kirsten rat sarcoma (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-Epidermal growth factor receptor (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 Selumetinib (AZD6244) or other agents used in study
• Previous Mitogen-activated protein kinase kinase (MEK), RAS, or Rapidly Accelerated Fibrosarcoma (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 magnetic resonance imaging (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 cluster of differentiation 4 (CD4) counts > 300, and after confirmation of eligibility after discussing with the study chair are eligible

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03040986
• 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 )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Udo Rudloff; National Cancer Institute LAO

• PRS Account: National Cancer Institute (NCI)
• Verification Date: January 2021