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

Phase 2

Completed

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

Interventions: Other: Laboratory Biomarker Analysis
Drug: Selumetinib Sulfate

Registration Number: NCT03040986

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 8

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (selumetinib sulfate)	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
Treatment (selumetinib sulfate)	Laboratory Biomarker Analysis	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

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With an Objective Response (Partial Response + Complete Response)	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.

Secondary Outcome Measures

Name	Time	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	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.
Semi-quantitative Measurements of Connector Enhancer of the Kinase Suppressor of Ras-1 (CNKSR1)	Up to 52 weeks	Comparisons will be done to estimate the differences of the expression level in pancreas cancer tissues and clinical outcome variables.
Median Progression-free Survival (PFS)	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.
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	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.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).	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.
Predictive Biomarkers for Response to Selumetinib	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	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	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)	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	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)	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	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	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)	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	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	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	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%).

Trial Locations

Locations (9): Ohio State University Comprehensive Cancer Center
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Columbus, Ohio, United States
Los Angeles County-USC Medical Center
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Los Angeles, California, United States
University of Pittsburgh Cancer Institute (UPCI)
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Pittsburgh, Pennsylvania, United States
University of Kentucky/Markey Cancer Center
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Lexington, Kentucky, United States
USC / Norris Comprehensive Cancer Center
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Los Angeles, California, United States
University of California Davis Comprehensive Cancer Center
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Sacramento, California, United States
NCI - Center for Cancer Research
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Bethesda, Maryland, United States
Wayne State University/Karmanos Cancer Institute
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Detroit, Michigan, United States
Duke University Medical Center
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Durham, North Carolina, United States