Selumetinib and Akt Inhibitor MK-2206 in Treating Patients With Refractory or Advanced Gallbladder or Bile Duct Cancer That Cannot Be Removed By Surgery

NCT01859182 | Withdrawn Phase 2

• 4 other identifiers: NCI-2013-01014OSU 121819178N01CM00070
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase II trial studies how well selumetinib and Akt inhibitor MK-2206 work in treating patients with refractory or advanced gallbladder or bile duct cancer that cannot be removed by surgery. Selumetinib and Akt inhibitor MK-2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conditions

Adenocarcinoma of the Gallbladder; Adenocarcinoma With Squamous Metaplasia of the Gallbladder; Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Localized Unresectable Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Stage II Gallbladder Cancer; Stage IIIA Gallbladder Cancer; Stage IIIB Gallbladder Cancer; Stage IVA Gallbladder Cancer; Stage IVB Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer

Outcome Measures

Primary Outcomes (1)

• Proportion of patients who have a response (PR or CR), assessed by the RECIST v1.1

  Calculated with corresponding 95% binomial confidence intervals.

  6 months

Secondary Outcomes (2)

• Frequency and severity of adverse events as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

  Up to 4 weeks

• Changes in QOL evaluated using the Functional Assessment of Cancer Therapy - General (FACT-G)

  Baseline to 8 weeks

Study Arms (1)

Treatment (selumetinib, Akt inhibitor MK2206)

EXPERIMENTAL

Patients receive Akt inhibitor MK-2206 PO on days 1, 8, 15, and 22 (days 8, 15, and 22 of course 1) and selumetinib PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: selumetinib; Drug: Akt inhibitor MK2206; Other: laboratory biomarker analysis; Other: pharmacogenomic studies; Procedure: quality-of-life assessment

Interventions

selumetinib DRUG

Given PO

Treatment (selumetinib, Akt inhibitor MK2206)

Akt inhibitor MK2206 DRUG

Given PO

Treatment (selumetinib, Akt inhibitor MK2206)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (selumetinib, Akt inhibitor MK2206)

pharmacogenomic studies OTHER

Correlative studies

Treatment (selumetinib, Akt inhibitor MK2206)

quality-of-life assessment PROCEDURE

Ancillary studies

Treatment (selumetinib, Akt inhibitor MK2206)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have surgically unresectable histologically confirmed biliary tract adenocarcinoma (defined as gallbladder cancer, extrahepatic and intrahepatic cholangiocarcinoma; this definition excludes ampullary cancers and all tumors of mixed histology); cytological confirmation is not allowed on this study, as tissue is needed for correlative science; fresh tissue (mandatory) AND paraffin embedded tissue (positron emission tomography \[PET\]) from tumor blocks (if available) will be required from patients before enrolling on this study
• Patients will be required to undergo a biopsy prior to enrolling on the study and will be given the option to have another biopsy around 4 weeks from initiation of treatment
• Patients must have measurable disease by RECIST 1.1 criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 10 mm with spiral computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm); malignant lymph nodes will be considered measurable if they are \>= 15 mm in short axis
• All of the following:
• Patients must have received only one prior line of systemic therapy for recurrent or advanced disease
• Prior adjuvant therapy (chemotherapy +/- radiation) completed within 6 months of diagnosis of recurrence/metastases is equivalent to one line of prior therapy for metastatic disease
• For patients who completed adjuvant therapy \> 6 months prior to diagnosis of recurrence/metastases, progression on 1 prior line of systemic therapy for metastatic disease is required
• No prior Akt inhibitors or mitogen-activated protein kinase kinase (MEK) inhibitors allowed
• For patients who had having prior cryotherapy, radiofrequency ablation, ethanol injection, transarterial chemoembolization (TACE) or photodynamic therapy, the following criteria must be met
• weeks must have elapsed since that therapy
• Indicator lesion(s) is/are outside the area of prior treatment or, if the only indicator lesion is inside the prior treatment area, there must be clear evidence of disease progression associated with that lesion
• Edges of the indicator lesion are clearly distinct on CT scanning
• Prior radiation therapy with or without the use of a fluoropyrimidine as a radiosensitizer in the adjuvant setting will be allowed on study if \> 12 weeks have elapsed since therapy
• Prior palliative radiation therapy will be allowed as long as \> 2 weeks have elapsed since therapy
• Life expectancy of greater than 12 weeks

You may not qualify if:

• Patients who have had chemotherapy, biologic therapy, or immunotherapy, within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events to a grade 1 or less due to agents administered more than 4 weeks earlier
• Patients may not be receiving any other investigational agents
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or AZD6244 hydrogen sulfate or other agents used in the study
• Preclinical studies demonstrated the potential of MK-2206 for induction of hyperglycemia in all preclinical species tested; patients with diabetes or in risk for hyperglycemia should not be excluded from trials with MK-2206, but the hyperglycemia should be well controlled on oral agents before the patient enters the trial
• Preclinical studies indicated transient changes in corrected QT (QTc) interval during MK-2206 treatment; prolongation of QTc interval is potentially a safety concern while on MK-2206 therapy; cardiovascular: baseline corrected QT by Fridericia's formula (QTcF) \> 450 msec (male) or QTcF \> 470 msec (female) will exclude patients from entry on study; a list of medications that may cause QTc interval prolongation should be avoided by patients entering on trial
• Patients with clinically significant bundle branch block or pre-existing clinically significant bradycardia will be excluded from the study
• History of any other malignancy other than biliary cancer in the last 3 years, except for adequately treated basal cell carcinoma, and squamous cell carcinoma of the skin or cervix
• 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
• Pregnant women are excluded from this study; developmental and reproductive toxicity studies of MK-2206 and AZD6244 hydrogen sulfate have not been performed thus far; women of child-bearing potential and men participating in clinical studies of AZD6244 hydrogen sulfate and MK-2206 must use appropriate contraception, including abstinence and double-barrier methods, throughout AZD6244 hydrogen sulfate and MK-2206 therapy; in preclinical mutagenicity studies, ADZ6244 hydrogen sulfate and MK-2206 were neither genotoxic or mutagenic; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD6244 hydrogen sulfate and MK-2206, breastfeeding should be discontinued if the mother is treated with AZD6244 hydrogen sulfate and MK 2206
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD6244 hydrogen sulfate and MK-2206; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• Patients requiring strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) or those receiving any medications or substances that are inhibitors or inducers of CYP 450 3A4 are ineligible

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

MeSH Terms

Conditions

Bile Duct Neoplasms; Carcinoma, Hepatocellular; Gallbladder Neoplasms

Interventions

AZD 6244; MK 2206; Pharmacogenomic Testing

Condition Hierarchy (Ancestors)

Biliary Tract Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Liver Neoplasms; Liver Diseases; Gallbladder Diseases

Intervention Hierarchy (Ancestors)

Genetic Testing; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Tanios Bekaii-Saab

  Ohio State University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 17, 2013
• First Posted: May 21, 2013
• Study Start: January 1, 2013
• Primary Completion: May 1, 2013
• Study Completion: May 1, 2013
• Last Updated: September 9, 2014

Record last verified: 2013-10