Selumetinib in Treating Patients With Biliary Cancer That Cannot Be Removed By Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00553332
• Collaborator: (none)
• Enrollment: 29
• Locations: 7
• Arm: 1
• Duration (Months): 62
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial is studying how well selumetinib works in treating patients with biliary cancer that cannot be removed by surgery. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Liver and Intrahepatic Biliary Tract Cancer; Recurrent Extrahepatic Bile Duct Cancer; Unresectable Extrahepatic Bile Duct Cancer	Drug: selumetinib; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the objective response rate (complete response [CR] and partial response [PR]) in patients with unresectable biliary carcinoma treated with AZD6244 (selumetinib).

SECONDARY OBJECTIVES:

1. To evaluate the toxicity profile of this drug in these patients. II. To evaluate the 6- and 12-month survival, 6-month progression-free survival, and overall survival rates of patients treated with this drug.

2. To correlate genetic mutations, epigenetic silencing, and/or protein levels of RAS/RAF/MEK/ERK signaling pathway activation with therapeutic efficacy of AZD6244 in these patients.

3. To genotype tumors for the presence of RAS mutations (i.e., NRAS, KRAS, HRAS) and BRAF mutations (e.g., V600E) in biliary tumor samples from these patients.

4. To assess the presence of activation of the MEK1, MEK2, ERK, and/or Akt pathways in tumor samples from these patients.

5. To assess the epigenetic alterations (i.e., methylation) affecting the level of gene/protein expression of RASSF1A, NORE1A, and NORE1B in tumor samples from these patients.

OUTLINE:

Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Formalin fixed paraffin-embedded tissue blocks or fresh tissue samples are obtained from all patients prior to treatment. Tissue samples are analyzed by immunohistochemistry for the expression level of target proteins (MEK, p-MEK, ERK, p-ERK, Akt, p-AKT, RASSF1A, NORE1A and NORE1B); PCR for mutational status of target genes RAS, BRAF and EGFR); and in methylation-specific PCR for methylation of target gene promoters (promoters for RASSF1A, NORE1A and NORE1B). Samples are also analyzed by quantitative real-time PCR to compare methylation status. Fresh frozen tissue, when available, is evaluated by Western analysis to measure expression levels of target proteins.

After completion of study treatment, patients are followed up for 4 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of AZD6244 in Biliary Cancers
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (enzyme inhibitor therapy) Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: selumetinib; Given orally; Other Names: ARRY-142886 AZD6244 ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (CR and PR) [Every 8 weeks]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Secondary Outcome Measures

1. Toxicity Profile of AZD6244 [From the time of first treatment with AZD6244, assessed up to 4 weeks]

   Toxicitity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0

2. Median Progression Free Survival for Patients [Up to 6 months]

   Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

3. Overall Survival [Up to 12 months]

4. RAS/RAF/MEK/ERK Signaling Pathway Activation [At baseline]

5. Protein Levels of RAS/RAF/MEK/ERK Signaling Pathway Activation [At baseline]

   Measure the proteins levels of RAS/RAF/MEK/ERK signaling pathway activation to AZD6244

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed biliary tract carcinoma

• Surgically unresectable disease

• Meets any of the following criteria for biliary cancers only:

• Received ≤ 1 prior systemic anticancer therapy, including chemoembolization

• Received prior cryotherapy, radiofrequency ablation, ethanol injection, transarterial chemoembolization, or photodynamic therapy AND meets the following criteria:

• More than 6 weeks have elapsed since any of the prior therapy described above

• Indicator lesion(s) must be outside the area of prior treatment OR must demonstrate clear evidence of disease progression if the only indicator lesion is inside the prior treatment area

• Indicator lesion must have clearly distinct edges on CT scan

• Prior radiotherapy with or without the use of a fluoropyrimidine as a radiosensitizer is allowed, provided more than 12 weeks have elapsed since treatment

• Fresh or paraffin-embedded tissue from tumor blocks must be available for review

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion > 20 mm by conventional techniques or > 10 mm by spiral CT scan

• No known brain metastases

• Life expectancy > 12 weeks

• ECOG performance status (PS) 0-1 or Karnofsky PS 70-100%

• ANC ≥ 1,500/μL

• Platelet count ≥ 75,000/μL

• Total bilirubin ≤ 2 times upper limit of normal(ULN)

• AST or ALT ≤ 3 times ULN

• Serum albumin ≥ 2.5 mg/dL

• INR ≤ 1.5 (not receiving anticoagulation therapy)

• Creatinine normal or creatinine clearance ≥ 60 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile women must use effective contraception during and for four weeks after the last dose of AZD6244

• Fertile men must use effective contraception during and for 16 weeks after the last dose of AZD6244

• No significant traumatic injury within the past 3 weeks

• No uncontrolled symptoms consistent with encephalopathy

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 or its excipient, Captisol®

• No QTc interval > 500 msecs or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., hypokalemia or family history of long QT interval syndrome), including NYHA class III-IV heart failure

• No other malignancy within the past 3 years, except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

• No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption

• No uncontrolled concurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situation that would limit compliance with study requirements

• No malignant hypertension within the past year

• No prior sorafenib or MEK inhibitors

• More than 4 weeks since prior chemotherapy, biologic therapy, or immunotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered to ≤ grade 1 adverse events

• No major surgery within the past 3 weeks

• No other concurrent investigational agents

• No concurrent requirement for medication that can prolong the QT interval

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No concurrent consumption of grapefruit or grapefruit juice

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
2	Emory University	Atlanta	Georgia	United States	30322
3	University of Michigan Cancer Center (UMCC) Research Base	Ann Arbor	Michigan	United States	48109-0352
4	Wayne State University	Detroit	Michigan	United States	48202
5	University of North Carolina	Chapel Hill	North Carolina	United States	27599
6	Ohio State University Medical Center	Columbus	Ohio	United States	43210
7	Vanderbilt University	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Tanios Bekaii-Saab, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00553332
• Other Study ID Numbers: NCI-2009-00251; OSU 07056; OSU-07056; CDR0000573452; N01CM62208; N01CM62207; NCT01645644
• First Posted: Nov 4, 2007
• Last Update Posted: Apr 22, 2016
• Last Verified: Mar 1, 2016

• Additional relevant MeSH terms: Biliary Tract Neoplasms; Bile Duct Neoplasms; Cholangiocarcinoma

Study Results

Participant Flow

Recruitment Details	Patients were enrolled to the trial between December 2007 and January 2009

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. selumetinib: Given orally laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	29
COMPLETED	28
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. selumetinib: Given orally laboratory biomarker analysis: Correlative studies
Overall Participants	28
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55.6
Sex: Female, Male (Count of Participants)
Female	9 32.1%
Male	19 67.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3.6%
White	27 96.4%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (patients) [Number]
United States	28
Eastern Cooperative Oncology Group (ECOG) (patients) [Number]
0 (Fully active)	11
1 (Restricted activity)	17
Disease site (patients) [Number]
Intrahepatic	17
Gallbladder	7
Extrahepatic	4
Metastasis site (patients) [Number]
Liver only	7
Liver and other sites	16
Other (soft tissue, lymph nodes and lung)	5
Number of target lesions (lesions) [Median (Full Range) ]
Median (Full Range) [lesions]	4

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (CR and PR)
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	Every 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. selumetinib: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	25
Complete Response	0
Partial Response	3

2. Secondary Outcome

Title	Toxicity Profile of AZD6244
Description	Toxicitity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0
Time Frame	From the time of first treatment with AZD6244, assessed up to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. selumetinib: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	28
Rash	90
Xerostomia	54
Nausea	50

3. Secondary Outcome

Title	Median Progression Free Survival for Patients
Description	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. selumetinib: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	28
Median (95% Confidence Interval) [months]	3.7

4. Secondary Outcome

Title	Overall Survival
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Kaplan-Meier

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. selumetinib: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	28
Median (95% Confidence Interval) [months]	9.8

5. Secondary Outcome

Title	RAS/RAF/MEK/ERK Signaling Pathway Activation
Time Frame	At baseline

Outcome Measure Data

Analysis Population Description

Data was not collected and analyzed

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. selumetinib: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	0

6. Secondary Outcome

Title	Protein Levels of RAS/RAF/MEK/ERK Signaling Pathway Activation
Description	Measure the proteins levels of RAS/RAF/MEK/ERK signaling pathway activation to AZD6244
Time Frame	At baseline

Outcome Measure Data

Analysis Population Description

Only 27 patients had pAKT and pERK performed due to 2 samples not available for analysis

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. selumetinib: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	28
pAKT	1.23 (0.98)
pERK	1.36 (1.09)

Adverse Events

Time Frame	All patients were evaluated for toxicity using the NCI Common Toxicity Criteria version 3.0 from the time of their first treatment until the end of treatment.
Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. selumetinib: Given orally laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	0/28 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	28/28 (100%)
Gastrointestinal disorders
Xerostomia	15/28 (53.6%)	15
Nausea	14/28 (50%)	14
Vomiting	14/28 (50%)	14
Diarrhea	13/28 (46.4%)	13
Bloating	12/28 (42.9%)	12
Mucositis	7/28 (25%)	7
Flatulence	6/28 (21.4%)	6
Injury, poisoning and procedural complications
Thrombocytopenia	3/28 (10.7%)	3
Metabolism and nutrition disorders
Hypokalemia	3/28 (10.7%)	3
Nervous system disorders
Dysgeusia	8/28 (28.6%)	8
Skin and subcutaneous tissue disorders
Rash	25/28 (89.3%)	25
Dry Skin	11/28 (39.3%)	11
Pruritus	4/28 (14.3%)	4
Alopecia	3/28 (10.7%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.