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Report for Clinical Trial NCT03040986

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Phase II Study of Selumetinib (AZD6244) for the Treatment of Advanced Pancreas Cancer Harboring KRAS G12R Mutations

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.

NCT03040986 KRAS NP_004976.2:p.G12R Stage III Pancreatic Cancer AJCC v6 and v7 Stage IV Pancreatic Cancer AJCC v6 and v7
MeSH:Pancreatic Neoplasms
HPO:Neoplasm of the pancreas

2 Interventions

Name: Laboratory Biomarker Analysis

Description: Correlative studies
Type: Other
Group Labels: 1

Treatment (selumetinib sulfate)

Name: Selumetinib Sulfate

Description: Given PO
Type: Drug
Group Labels: 1

Treatment (selumetinib sulfate)


Primary Outcomes

Description: 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).

Measure: Production of adequate numbers of clinical responses with selumetinib sulfate monotherapy

Time: Up to 52 weeks

Secondary Outcomes

Description: Will be calculated using the Kaplan-Meier method.

Measure: Progression-free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 52 weeks

Description: 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.

Measure: Incidence of adverse events graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Time: Up to 52 weeks

Description: 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.

Measure: Response to selumetinib sulfate (PR as defined by Response Evaluation Criteria in Solid Tumors)

Time: Up to 52 weeks

Description: Comparisons will be descriptively to estimate the differences of the expression level in pancreas cancer tissues and clinical outcome variables.

Measure: Semi-quantitative measurements of CNKSR1

Time: Up to 52 weeks

Description: Compared between baseline and repeat profiling (integrated biomarker; voluntary) will be evaluated for change from baseline levels and the estimated changes will be reported.

Measure: Change in circulating tumor deoxyribonucleic acid (ctDNA) and alteration in in somatic variants

Time: Baseline up to 52 weeks

Description: 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.

Measure: Predictive biomarkers for response to selumetinib

Time: Up to 52 weeks

Description: 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.

Measure: Longitudinal biomarker measuring response to treatment

Time: Up to 52 weeks

Purpose: Treatment

Allocation: N/A

Single Group Assignment


There is one SNP

SNPs


1 G12R

A Phase II Study of Selumetinib (AZD6244) for the Treatment of Advanced Pancreas Cancer Harboring KRAS G12R Mutations. --- G12R ---

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

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

This will be a descriptive presentation only.. 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 --- G12R ---

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 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 --- G12R ---

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

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

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



HPO Nodes


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