Neoplasms

Digestive System Diseases

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Gastrointestinal Agents

All Drugs and Chemicals

Pancrelipase

Pancreatin

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

Laboratory Biomarker Analysis

Selumetinib Sulfate

Udo Rudloff

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.

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.

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

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

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.

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.

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.

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.

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

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.

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.

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.

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 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 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 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.

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 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

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 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% ).

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 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.

National Cancer Institute (NCI)

Participants receive 75mg 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.

Dose Level 0: 75mg Selumetinib Sulfate Twice Daily

Participants receive 75mg selumetinib sulfate by mouth (PO) twice daily (BID) followed by 50mg twice daily. Treatment repeats every 28 days for up to 27 courses in the absence of disease progression or unacceptable toxicity.

75mg Selumetinib Sulfate Twice Daily Follow/by 50mg TwiceDaily

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Head/Body

Tail

Location of Primary Tumor

Radiation

Surgery

Multiple agents systemic chemotherapy

Previous Treatments

≥3

Number of Previous Lines of Systemic Chemotherapy

Number of Metastatic Sites (involved organs)

Dr. Udo Rudloff

Partial Response

Complete Response

Proportion of Participants With an Objective Response (Partial Response + Complete Response)

All participants that received 75mg selumetinib sulfate by mouth (PO) twice daily (BID); and 75mg Selumetinib sulfate twice daily followed by 50mg twice daily.

All Participants

All participants are grouped together as pre-specified in the protocol for this outcome measure.

Median Progression-free Survival (PFS)

Probably: Grade 3 Hypertension

Probably: Grade 3 Pancreatitis

Definitely: Grade 3 Alanine aminotransferase increased

Definitely: Grade 3 Dyspnea

Definitely: Grade 3 Heart failure

Definitely: Grade 3 Hypertension

Probably Attributable: 75mg Selumetinib Sulfate Twice Daily

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

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

This outcome measure was not done because only 1 out of the 8 enrolled participants agreed to undergo biopsy while on treatment. Tumoral biopsies were not mandatory but optional for participants enrolled onto the study. Because only one biopsy specimen was obtained, on the discretion of the PI, no analysis and no comparisons were performed.

Semi-quantitative Measurements of Connector Enhancer of the Kinase Suppressor of Ras-1 (CNKSR1)

Since no responses were observed in either Arm/Group, the planned correlation was not conducted for this outcome measure.

Predictive Biomarkers for Response to Selumetinib

This outcome measure was not done because of the lack of ctDNA copy number determinations in participants on-treatment compared to pre-treatment levels in the participants whose ctDNA levels were longitudinally evaluable. No variant profiling of baseline tumoral tissues was performed.

Longitudinal Biomarker Measuring Response to Treatment

No other somatic variants in ctDNA other than the KRAS allele were analyzed because the only available droplet digital PCR (ddPCR) assay was the one for the KRAS allele. Thus, the planned analysis change in the somatic ctDNA mutation profile and its correlation with clinical outcome was not conducted.

Change in the Somatic Circulating Tumor Deoxyribonucleic Acid (ctDNA) Mutation Profile and Its Correlation With Clinical Outcome

Baseline

Last recorded value

Mean Copy Number KRAS Wild Type Allele in Circulating Tumor DNA (ctDNA)

Overall Percentage Change (%) of Copies KRAS Wild Type Allele

On Treatment

Mean Copy Number KRAS Mutant Type Allele in Circulating Tumor DNA (ctDNA)

Overall Percentage Change of Copies KRAS Mutant Type Allele

Percentage of KRAS Allele in Circulating Tumor DNA (ctDNA) That is Identified as Variant From Cell-free (cf) DNA

Overall Any Percent Change in (VAF, %), of KRAS Allele in Circulating Tumor Deoxyribonucleic Acid (ctDNA)

Three out of 6 participants in dose level one and two out of 2 participants in dose level 2 had No Measurable KRAS Mutant Circulating Tumor Deoxyribonucleic Acid (ctDNA) at baseline.

Mean Change in Variant Allele Fraction (VAF, %) of KRAS in Participants Who Had No Measurable KRAS Mutant Circulating Tumor Deoxyribonucleic Acid (ctDNA) at Baseline

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

Two out of 6 participants in dose level one and 0 out of 2 participants in dose level 2 had detectable KRAS Mutant Circulating Tumor Deoxyribonucleic Acid (ctDNA) at baseline and after treatment

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

Two out of 6 participants in dose level one and 0 out of 2 participants in dose level 2 had detectable KRAS Mutant Circulating Tumor Deoxyribonucleic Acid (ctDNA) at Baseline and After Treatment

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations	NCT03040986	KRAS NP_004976.... Stage III Pancr... Stage IV Pancre...	Laboratory Biom... Selumetinib Sul...	18 Years -	National Cancer Institute (NCI)
Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations	NCT03040986	KRAS NP_004976.... Stage III Pancr... Stage IV Pancre...	Laboratory Biom... Selumetinib Sul...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for kras np 004976.2:p.g12r