Clinical Trials /

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

NCT03040986

Description:

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.

Related Conditions:
  • Pancreatic Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00118
  • SECONDARY ID: NCI-2017-00118
  • SECONDARY ID: 10050
  • SECONDARY ID: 10050
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT03040986

Conditions

  • KRAS NP_004976.2:p.G12R
  • Stage II Pancreatic Cancer
  • Stage IIA Pancreatic Cancer
  • Stage IIB Pancreatic Cancer
  • Stage III Pancreatic Cancer
  • Stage IV Pancreatic Cancer

Interventions

DrugSynonymsArms
Selumetinib SulfateAZD-6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulphate, Selumetinib SulphateTreatment (selumetinib sulfate)

Purpose

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.

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the objective response rate to selumetinib sulfate (selumetinib) administered as 100 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.

Trial Arms

NameTypeDescriptionInterventions
Treatment (selumetinib sulfate)ExperimentalPatients receive selumetinib sulfate PO BID. Treatment repeats every 28 days for up to 27 courses in the absence of disease progression or unacceptable toxicity
    • Selumetinib Sulfate

Eligibility Criteria

Inclusion Criteria:

- Patients must have histologically confirmed locally advanced or metastatic pancreas cancer

- 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 confirmed somatic KRAS G12R mutation as determined by sequence analysis of matched normal deoxyribonucleic acid (DNA) from any specimen obtained from the individual (prior Clinical Laboratory Improvement Act [CLIA] genotyping results from surgical resection specimens are acceptable)

- 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 fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (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 (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 16 weeks post-last dose due to sperm life cycle; NOTE: breastfeeding should be discontinued if the mother is treated with selumetinib; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform the treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have received prior treatment with tyrosine kinase inhibitors (e.g. erlotinib, or cetuximab)

- 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

- 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

- Normal 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

- 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; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Production of adequate numbers of clinical responses with selumetinib sulfate monotherapy
Time Frame:Up to 52 weeks
Safety Issue:
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).

Secondary Outcome Measures

Measure:Change in pERK levels
Time Frame:Baseline up to 52 weeks
Safety Issue:
Description: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.
Measure: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
Safety Issue:
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:Progression-free survival
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 52 weeks
Safety Issue:
Description:Will be calculated using the Kaplan-Meier method.
Measure:Response to selumetinib sulfate (PR as defined by Response Evaluation Criteria in Solid Tumors)
Time Frame:Up to 52 weeks
Safety Issue:
Description: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.
Measure:Semi-quantitative measurements of CNKSR1, ERK, and RSK3/4
Time Frame:Up to 52 weeks
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

    Last Updated

    February 9, 2017