Neoplasms

All Conditions

Digestive System Diseases

Symptoms and General Pathology

Rare Diseases

Carcinoma

Carcinoma, Hepatocellular

Recurrence

Cholangiocarcinoma

Carcinoma, Ductal

Gallbladder Neoplasms

Bile Duct Neoplasms

Liver Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Biliary Tract Neoplasms

Biliary Tract Diseases

Gallbladder Diseases

Bile Duct Diseases

Bile Duct Cancer

Biliary Tract Cancer

Gallbladder Cancer

Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Akt Inhibitor MK2206

Diagnostic Laboratory Biomarker Analysis

Pharmacological Study

Tanios Bekaii-Saab

This phase II trial is studying how well MD2206 works in treating patients with advanced refractory biliary cancer that cannot be removed by surgery.

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate (complete and partial response), as defined by the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria, in patients with advanced refractory biliary cancers (BC) receiving Akt inhibitor MK2206 (MK2206).

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of adverse events and tolerability of the regimen in patients with advanced refractory BC receiving MK2206.

II. To determine the overall and progression-free survival of patients with advanced refractory BC receiving MK2206.

III. To determine the presence of genetic mutations of PI3-kinase/ Akt pathway signaling-pathway genes relevant to BC and how these correlate with objective response to treatment with MK2206.

IV. To determine the pharmacokinetic and pharmacogenetic profile as a way of assessing inter-individual variability as well as how these relate to clinical outcomes.

V. To determine genetic variants and mutations in genes encoding drug-metabolizing enzymes and transporters, and genes involved in tumor biology, and how these may be related to response to treatment.

OUTLINE: This is a multicenter study.

Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for pharmacokinetic, pharmacogenetic, and other correlative studies. Previously collected tumor tissue is also analyzed.

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

MK2206 in Treating Patients With Advanced Refractory Biliary Cancer That Cannot Be Removed by Surgery

A Multi-Institutional Phase II Study of the Akt Inhibitor MK-2206 in Refractory Biliary Cancers

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) 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.

Severity of adverse events is graded according to the NCI CTCAE 4.0.

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), 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

National Cancer Institute (NCI)

NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 was utilized for Adverse Event reporting.

Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Akt Inhibitor MK2206: Given PO

Diagnostic Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Treatment (Akt Inhibitor MK2206)

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Intrahepatic

Gallbladder

Extrahepatic

Disease site

PS 0

PS 1

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

PS 0 defined as Normal activity. Fully active, able to carry on all pre-disease performance without restriction.

PS 1 defined as Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g. light housework, office work).

ECOG Performance Status

Tanios Bekaii-Saab, MD

Overall Response Rate (Complete and Partial Response) as Defined by RECIST 1.1

lymphopenia

rash

fatigue

fever

vomiting

diarrhea

Frequency of Adverse Events Related to MK-2206

Overall Survival

Progression-free Survival

Overall Study

Klatskin Tumor

Childhood Hepatocellular Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Bone Density Conservation Agents

Vitamins

Capecitabine

Leucovorin

Fluorouracil

Levoleucovorin

Calcium

Folic Acid

Calcium, Dietary

Trametinib

Vitamin B Complex

Hormones

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antidotes

Protective Agents

Trace Elements

Protein Kinase Inhibitors

Enzyme Inhibitors

Folinic Acid

Folate

Vitamin B9

Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15 (courses repeat every 28 days); or B) capecitabine PO BID on days 1-14 (courses repeat every 21 days). Patients treated until disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Leucovorin Calcium

Richard Kim

This randomized phase II trial studies how well trametinib or combination chemotherapy works in treating patients with refractory or advanced biliary or gallbladder cancer or that cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving trametinib is more effective than combination chemotherapy in treating patients with biliary or gallbladder cancer.

PRIMARY OBJECTIVES:

I. To assess overall survival (OS) in patients with refractory advanced biliary cancer randomized to Arm 1: trametinib compared to those randomized to Arm 2: chemotherapy (either 5-fluorouracil \[fluorouracil\] and leucovorin \[leucovorin calcium\] or capecitabine).

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of adverse events of trametinib in this patient population.

II. To assess response rate (RR) and progression-free survival (PFS) in patients randomized to Arm 1: trametinib and patients randomized to Arm 2: chemotherapy (fluorouracil \[5-FU\] or capecitabine in this patient population).

TERTIARY OBJECTIVES:

I. To determine if a 16-gene expression signature is predictive of mitogen-activated protein kinase kinase (MEK) efficacy as evidenced by improved RR, PFS, and OS.

II. To evaluate the effects of trametinib on the inflammatory cytokine and explore potential associations with response rate and survival.

III. To estimate lean soft tissue and fat mass weight gain as a result of treatment with trametinib vs. capecitabine in patients with advanced refractory biliary cancer.

IV. To bank tissue samples for other future correlative studies including next generation sequencing and whole genome methylation assays. NOTE: These potential future correlative studies will not be performed until an amended protocol with relevant detailed information including specific arms and assays is approved by Cancer Therapy Evaluation Program (CTEP).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive trametinib orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive 1 of 2 treatment regimens at the discretion of the investigator.

ARM IIA: Patients receive leucovorin calcium intravenously (IV) over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM IIB: Patients receive capecitabine PO twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery

Randomized Phase II Trial of Single Agent MEK Inhibitor Trametinib (GSK1120212) Vs 5-Fluorouracil or Capecitabine in Refractory Advanced Biliary Cancer

From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.

Adverse event reporting followed the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.

Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.

From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact.

Eligible patients who received any treatment and were assessed for adverse events are included in the adverse event summaries. One patient was hospitalized prior to receiving protocol treatment and was not assessed for adverse events.

Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity or B) capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Chemotherapy

Total

Ethnicity (NIH/OMB)

5FU/LV

Planned Chemotherapy

Gall bladder

Site of Disease

All eligible and analyzable patients are included.

SWOG Statistician

Alanine aminotransferase increased

Anemia

Ascites

Aspartate aminotransferase increased

Blood bilirubin increased

Colitis

Fatigue

Gastric ulcer

Gastritis

Gastrointestinal disorders - Other, specify

Generalized muscle weakness

Hepatobiliary disorders - Other, specify

Hyponatremia

Infections and infestations - Other, specify

Mucositis oral

Neutrophil count decreased

Pain in extremity

Palmar-plantar erythrodysesthesia syndrome

Sepsis

Thromboembolic event

Urinary tract infection

Vomiting

Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity

Eligible patients who received any treatment and were assessed for adverse events are included in this summary. One patient was hospitalized prior to receiving protocol treatment and was not assessed for adverse events.

Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
MK2206 in Treating Patients With Advanced Refractory Biliary Cancer That Cannot Be Removed by Surgery	NCT01425879	Advanced Adult ... Localized Non-R... Recurrent Adult... Recurrent Gallb... Stage IV Distal... Stage IV Gallbl... Unresectable Ex... Unresectable Ga...	Akt Inhibitor M... Diagnostic Labo... Pharmacological...	18 Years -	National Cancer Institute (NCI)
Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery	NCT02042443	Adult Cholangio... Advanced Adult ... BCLC Stage C Ad... BCLC Stage D Ad... Hilar Cholangio... Localized Non-R... Recurrent Adult... Recurrent Child... Recurrent Extra... Recurrent Gallb... Stage II Gallbl... Stage III Child... Stage IIIA Gall... Stage IIIB Gall... Stage IV Childh... Stage IV Distal... Stage IVA Gallb... Stage IVB Gallb... Unresectable Ex...	Capecitabine Fluorouracil Laboratory Biom... Leucovorin Calc... Trametinib	-	National Cancer Institute (NCI)
Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery	NCT02042443	Adult Cholangio... Advanced Adult ... BCLC Stage C Ad... BCLC Stage D Ad... Hilar Cholangio... Localized Non-R... Recurrent Adult... Recurrent Child... Recurrent Extra... Recurrent Gallb... Stage II Gallbl... Stage III Child... Stage IIIA Gall... Stage IIIB Gall... Stage IV Childh... Stage IV Distal... Stage IVA Gallb... Stage IVB Gallb... Unresectable Ex...	Capecitabine Fluorouracil Laboratory Biom... Leucovorin Calc... Trametinib	-	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for stage iv distal bile duct cancer