Symptoms and General Pathology

All Conditions

Neoplasms

Digestive System Diseases

Rare Diseases

Recurrence

Carcinoma

Cholangiocarcinoma

Adenocarcinoma

Klatskin Tumor

Carcinoma, Ductal

Metaplasia

Gallbladder Neoplasms

Bile Duct Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Biliary Tract Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Biliary Tract Diseases

Gastrointestinal Diseases

Gallbladder Diseases

Bile Duct Diseases

Bile Duct Cancer

Gallbladder Cancer

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Sorafenib

Erlotinib Hydrochloride

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Patients receive sorafenib tosylate PO twice daily and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Sorafenib Tosylate

Anthony El-Khoueiry

This phase II trial is studying how well giving sorafenib tosylate together with erlotinib hydrochloride works in treating patients with locally advanced, unresectable, or metastatic gallbladder cancer or cholangiocarcinoma. Sorafenib tosylate and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor.

OBJECTIVES:

I. To assess the progression-free survival in patients with unresectable or metastatic gallbladder carcinoma or cholangiocarcinoma treated with the combination of sorafenib (sorafenib tosylate) and erlotinib (erlotinib hydrochloride).

II. To assess the overall survival in patients with unresectable or metastatic gallbladder carcinoma or cholangiocarcinoma treated with the combination of sorafenib and erlotinib.

III. To assess the objective response rate. IV. To assess the frequency and severity of toxicities. V. To collect specimens for banking for future research.

OUTLINE: This is a multicenter study.

Patients receive sorafenib tosylate orally (PO) twice daily and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 6 months for 3 years.

Sorafenib Tosylate and Erlotinib Hydrochloride in Treating Patients With Locally Advanced, Unresectable, or Metastatic Gallbladder Cancer or Cholangiocarcinoma

Phase II Study of Sorafenib (NSC-724772) and Erlotinib (NSC-718781) in Patients With Advanced Gallbladder Carcinoma or Cholangiocarcinoma

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

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.

Complete response (CR) is complete disappearance of all target and non-target lesions, no new lesions and no disease related symptoms. Partial response (PR) is a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Confirmed response is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response 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.

Only adverse events that are possibly, probably or definitely related to study drug are reported.

National Cancer Institute (NCI)

Patients receive sorafenib tosylate 400 mg PO twice daily and erlotinib hydrochloride 100 mg PO once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Sorafenib and Erlotinib

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Zubrod Performance Status Scale: 0 - Fully active, able to carry on all pre-disease performance without restriction; 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light sedentary nature; 2 - Ambulatory and capable of self-care but unable to carry out any work activities; up and about more than 50% of waking hours; 3 - Capable of limited self-care, confined to bed or chair more than 50% of waking hours; 4 - Completely disabled, cannot carry on any self-care, totally confined to bed or chair

Zubrod Performance Status

Chemotherapy, multiple agents

Prior Surgery

Distant Metastatic

Locally Advanced

Current Status of Disease

Gallbladder

Primary Cancer

Prior Radiation Therapy

Adjuvant

Neoadjuvant

None

Setting of Prior Chemotherapy

Eligible patients who began protocol therapy

The first stage of accrual was met with 40 registered patients. Insufficient number of patients were alive and free from progression at four months to warrant accruing to a second stage.

Study Statistician

Overall Survival

Progression-free Survival

Objective Response

Abdominal pain

Alanine aminotransferase increased

Alkaline phosphatase increased

Allergic reaction

Aspartate aminotransferase increased

Blood bilirubin increased

Death NOS

Dehydration

Diarrhea

Erythema multiforme

Fatigue

Gastric perforation

Hepatic failure

Hepatic infection

Hepatic necrosis

Hypertension

Hypoalbuminemia

Hypokalemia

Hypophosphatemia

Hypoxia

Lymphocyte count decreased

Mucositis oral

Nausea

Pain

Palmar-plantar erythrodysesthesia syndrome

Platelet count decreased

Rash acneiform

Rash maculo-papular

Thromboembolic event

Eligible patients who received any treatment and were assessed for toxicity were included in the adverse event summaries. Any CTCAE v4.0 event of Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal) which were deemed to be related to protocol treatment are included.

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

Overall Study

Carcinoma, Hepatocellular

Liver Neoplasms

Liver Diseases

Biliary Tract Cancer

Childhood Hepatocellular Carcinoma

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

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

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

5FU/LV

Planned Chemotherapy

Gall bladder

Site of Disease

All eligible and analyzable patients are included.

SWOG Statistician

Anemia

Ascites

Colitis

Gastric ulcer

Gastritis

Gastrointestinal disorders - Other, specify

Generalized muscle weakness

Hepatobiliary disorders - Other, specify

Hyponatremia

Infections and infestations - Other, specify

Neutrophil count decreased

Pain in extremity

Sepsis

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
Sorafenib Tosylate and Erlotinib Hydrochloride in Treating Patients With Locally Advanced, Unresectable, or Metastatic Gallbladder Cancer or Cholangiocarcinoma	NCT01093222	Extrahepatic Bi... Gallbladder Ade... Gallbladder Ade... Hilar Cholangio... Recurrent Extra... Recurrent Gallb... Undifferentiate... Unresectable Ex... Unresectable Ga...	Erlotinib Hydro... Sorafenib Tosyl...	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)
Sorafenib Tosylate and Erlotinib Hydrochloride in Treating Patients With Locally Advanced, Unresectable, or Metastatic Gallbladder Cancer or Cholangiocarcinoma	NCT01093222	Extrahepatic Bi... Gallbladder Ade... Gallbladder Ade... Hilar Cholangio... Recurrent Extra... Recurrent Gallb... Undifferentiate... Unresectable Ex... Unresectable Ga...	Erlotinib Hydro... Sorafenib Tosyl...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for recurrent extrahepatic bile duct carcinoma