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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02042443
First received: January 20, 2014
Last updated: October 17, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
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 Childhood Liver Cancer
Recurrent Extrahepatic Bile Duct Cancer
Recurrent Gallbladder Cancer
Stage C Adult Primary Liver Cancer (BCLC)
Stage D Adult Primary Liver Cancer (BCLC)
Stage II Gallbladder Cancer
Stage III Childhood Liver Cancer
Stage IIIA Gallbladder Cancer
Stage IIIB Gallbladder Cancer
Stage IV Childhood Liver Cancer
Stage IVA Gallbladder Cancer
Stage IVB Gallbladder Cancer
Unresectable Extrahepatic Bile Duct Cancer
Drug: trametinib
Drug: leucovorin calcium
Drug: fluorouracil
Drug: capecitabine
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial of Single Agent MEK Inhibitor Trametinib (GSK1120212) vs 5-Fluorouracil or Capecitabine in Refractory Advanced Biliary Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • OS [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    The final analysis will be based on a stratified log rank test.


Secondary Outcome Measures:
  • Objective response (complete response, unconfirmed complete response, partial response, unconfirmed partial response) using the RECIST 1.1 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Rate of toxicities, using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • Change in plasma cytokine levels [ Time Frame: Baseline to up to 8 weeks post-randomization ] [ Designated as safety issue: No ]
    Pre- and post-treatment levels will be compared within each arm using a paired t-test. The difference in change from baseline at week 4 between treatment arms using a two sample t-test will also be compared. Potential associations between cytokines and clinical outcomes will be assessed using regression models (logistic regression for response, Cox regression for PFS and OS). Odds ratios and hazard ratios for each cytokine variable will be estimated within each arm, and differential effects of the cytokines on clinical outcomes between arms will also be explored.

  • Change in lean soft tissue [ Time Frame: Baseline to 6 weeks ] [ Designated as safety issue: No ]
    Standard abdominal CT scans or MRI from baseline and restaging at 6 weeks will be analyzed using regression equations. These changes will be summarized using descriptive statistics and compared between treatment arms using a two sample t-test or non-parametric Mann-Whitney U test. Potential associations between changes in lean soft tissue and fat mass with changes in levels of interleukin-6 and other cytokines implicated in cancer cachexia will be explored. For each cytokine, the correlation with the Spearman rank correlation coefficient will be estimated.

  • Change in fat mass weight [ Time Frame: Baseline to 6 weeks ] [ Designated as safety issue: No ]
    Standard abdominal CT scans or MRI from baseline and restaging at 6 weeks will be analyzed using regression equations. These changes will be summarized using descriptive statistics and compared between treatment arms using a two sample t-test or non-parametric Mann-Whitney U test. Potential associations between changes in lean soft tissue and fat mass with changes in levels of interleukin-6 and other cytokines implicated in cancer cachexia will be explored. For each cytokine, the correlation with the Spearman rank correlation coefficient will be estimated.


Estimated Enrollment: 89
Study Start Date: February 2014
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (trametinib)
Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • Mekinist
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm IIA (leucovorin calcium, fluorouracil)
Patients receive 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.
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm IIB (capecitabine)
Patients receive capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: capecitabine
Given PO
Other Names:
  • CAPE
  • Ro 09-1978/000
  • Xeloda
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • DISEASE RELATED CRITERIA
  • Patients must have histologically or cytologically documented carcinoma primary to the intra- or extra-hepatic biliary system or gall bladder with clinical and/or radiologic evidence of unresectable, locally advanced or metastatic disease; patients with ampullary carcinoma are not eligible
  • Patients must have measurable disease; computed tomography (CT) scans or magnetic resonance imaging (MRI)s used to assess measurable disease must have been completed within 28 days prior to registration; CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
  • PRIOR/CONCURRENT THERAPY CRITERIA
  • Patients must have completed any prior chemotherapy at least 21 days prior to registration and have recovered from any of the effects AND

    • Patients must have experienced progression to no more than 1 prior regimen of systemic chemotherapy for advanced biliary cancer OR
    • Patients who received adjuvant chemotherapy and had evidence of disease recurrence within 6 months of completion of the adjuvant treatment are also eligible; if patient received adjuvant treatment and had disease recurrence after 6 months, patients will only be eligible after failing one regimen of systemic chemotherapy used to treat the (unresectable or metastatic) disease recurrence
  • Patients must not have been treated with prior MEK inhibitors; prior 5-FU or capecitabine treatment is allowed only if given as a radiosensitizer concurrently with radiation therapy at least 12 weeks prior to registration or if given as part of any adjuvant therapy regimen >= 12 months prior to study enrollment
  • Patients must have no plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy or any other type of therapy (including herbal or natural supplements) for treatment of cancer while on this treatment protocol
  • For patients who have received prior cryotherapy, radiation therapy, radiofrequency ablation, therasphere, ethanol injection, transarterial chemoembolization (TACE) or photodynamic therapy, the following criteria must be met:

    • 28 days have elapsed since that therapy (lesions that have not been treated with local therapy must be present and measureable)
  • CLINICAL/LABORATORY CRITERIA
  • Patients must have a Zubrod performance status of 0-1
  • Absolute neutrophil count (ANC) > 1000/mcL
  • Platelets > 100000/mcL
  • Total bilirubin =< 2.0 x the institutional upper limit of normal limits (IULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 3 x IULN; if liver metastases are present, AST and ALT must be =< 5 x IULN
  • If the patient has had decompression of the biliary tree within the last 14 days, stability of the bilirubin level needs to be confirmed with two measurements that are within 5 to 7 days of each other; (the second measurement must be obtained within 7 days prior to registration;) both the first and second measurement must be =< 2.0 X IULN; stability is defined as the second measurement being no more than one point higher than the first
  • Patients must have adequate kidney function as evidenced by at least ONE of the following:

    • Serum creatinine =< 1.5 mg/dL within 28 days prior to registration
    • Calculated creatinine clearance >= 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 28 days prior to registration
  • Patients with known history or current evidence of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) are not eligible:

    • History of RVO or RPED, or predisposing factors to RVO or RPED (e.g. such as uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
    • Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as:

      • Evidence of new optic disc cupping
      • Evidence of new visual field defects
      • Intraocular pressure > 21 mmHg
    • NOTE: ophthalmic exam is required for all patients; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration
  • Patients must have echocardiogram and left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) within 28 days prior to registration; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration
  • Patients must not have uncontrolled or clinically significant cardiovascular disease including: myocardial infarction within past 6 months; uncontrolled angina within past 6 months; class II-IV New York Heart Association (NYHA) congestive heart failure; grade 3 cardiac valve dysfunction; cardiac arrhythmia not controlled by medication; history of stroke or transient ischemic attack within 6 months; history of arterial thrombotic event (ATE) of any type in the past 6 months; treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled with anti-hypertensive therapy; known intra-cardiac defibrillators; known cardiac metastases
  • Patients must have an electrocardiogram (ECG) within 28 days prior to registration; patients must have QT interval corrected for Fridericia (QTcF) =< 500 msec; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration
  • Must be able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
  • Must not have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO) or other agents used in study
  • Must not have active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible)
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 4 months after discontinuation of study drug; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
  • SPECIMEN SUBMISSION CRITERIA
  • Patients must submit paraffin-embedded tissue and blood for banking within 28 days after registration; paraffin-embedded tissue from prior surgical resection or from a diagnostic biopsy is acceptable
  • REGULATORY CRITERIA
  • Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02042443

  Show 218 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Richard Kim Southwest Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02042443     History of Changes
Other Study ID Numbers: NCI-2013-02485, NCI-2013-02485, SWOG-S1310, S1310, S1310, U10CA032102, U10CA180888
Study First Received: January 20, 2014
Last Updated: October 17, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Gallbladder Neoplasms
Bile Duct Neoplasms
Cholangiocarcinoma
Liver Neoplasms
Adenocarcinoma
Bile Duct Diseases
Biliary Tract Diseases
Biliary Tract Neoplasms
Carcinoma
Digestive System Diseases
Digestive System Neoplasms
Gallbladder Diseases
Liver Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Capecitabine
Fluorouracil
Leucovorin
Levoleucovorin
Trametinib
Antidotes
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Growth Substances
Immunologic Factors
Immunosuppressive Agents

ClinicalTrials.gov processed this record on October 21, 2014