Everolimus, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients With Unresectable Solid Tumors Refractory to Standard Therapy

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Brian A. Costello, M.D., Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00949949
First received: July 30, 2009
Last updated: February 18, 2014
Last verified: February 2014
  Purpose

This randomized phase I trial is studying the side effects and best dose of everolimus, gemcitabine hydrochloride, and cisplatin in treating patients with unresectable solid tumors refractory to standard therapy. Drugs used in chemotherapy, such as everolimus, gemcitabine hydrochloride, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.


Condition Intervention Phase
Cholangiocarcinoma of the Gallbladder
Localized Gallbladder Cancer
Unresectable Gallbladder Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: everolimus
Drug: gemcitabine hydrochloride
Drug: cisplatin
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Everolimus, Gemcitabine, and Cisplatin for Patients With Solid Tumors Refractory to Standard Therapy

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Adverse events profile [ Time Frame: Up to 3 months post-treatment ] [ Designated as safety issue: Yes ]
    Tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.

  • Toxicity profile per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 [ Time Frame: Up to 3 months post-treatment ] [ Designated as safety issue: Yes ]
    Defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. Non-hematologic toxicities will be evaluated via the ordinal Common Toxicity Criteria (CTC) standard toxicity grading. Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.

  • MTD of the combination of everolimus, gemcitabine hydrochloride, and cisplatin [ Time Frame: 3 weeks ] [ Designated as safety issue: Yes ]
    Toxicity assessed by NCI CTCAE v3.0.


Secondary Outcome Measures:
  • Response profile [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Best response is defined to be the best objective status recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria will be used for tumor evaluation. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group).

  • Timed endpoints [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    The data on time-related variables will be summarized descriptively. These include time until any treatment related toxicity, time until treatment related grade 3+ toxicity, time until hematologic nadirs (white blood cells [WBC], ANC, platelets), time to progression and time to treatment failure, where time to treatment failure is defined as the time from registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient.


Estimated Enrollment: 52
Study Start Date: September 2009
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort I (everolimus and gemcitabine hydrochloride)
Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and everolimus PO once daily or 3 times weekly.
Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar
Experimental: Cohort II (everolimus, gemcitabine hydrochloride, cisplatin)
Patients receive gemcitabine hydrochloride IV over 30 minutes and cisplatin IV over 1 hour on days 1 and 8 and everolimus PO once daily or 3 times weekly.
Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Experimental: Cohort III (MTD)
Patients receive treatment as in cohort II.
Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP

Detailed Description:

OBJECTIVES:

I. To determine the maximally tolerated dose (MTD) of concurrently administered everolimus and gemcitabine (gemcitabine hydrochloride) in patients with advanced, refractory solid tumors (two-agent MTD).

II. To determine the maximally tolerated dose of concurrently administered everolimus, gemcitabine and cisplatin in patients with advanced, refractory solid tumors (three-agent MTD).

III. To describe the toxicity of the two treatment combinations. IV. To describe any evidence of the antitumor activity of the two treatment combinations.

V. To obtain pilot data on toxicity and efficacy outcome of everolimus, gemcitabine and cisplatin in patients with cholangiocarcinoma or gallbladder carcinoma. (Cohort III)

OUTLINE: This is a dose-escalation study of gemcitabine hydrochloride and everolimus.

COHORT I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8 and everolimus orally (PO) once daily or 3 times weekly.

COHORT II: Patients receive gemcitabine hydrochloride IV over 30 minutes and cisplatin IV over 1 hour on days 1 and 8 and everolimus PO once daily or 3 times weekly.

COHORT III: Patients receive treatment as in cohort II.

Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologic proof of cancer that is now unresectable and refractory to or refused all standard treatment for the disease; exception: cancers in which gemcitabine is considered an appropriate initial treatment option
  • Cohort III (MTD) Only: Patients with histologic proof of metastatic cholangiocarcinoma or gallbladder carcinoma who have not had previous treatment for metastatic disease or who received gemcitabine >= 6 months ago as part of adjuvant therapy
  • Absolute neutrophil count (ANC) >= 1500/uL
  • Platelet (PLT) >= 100,000/uL
  • Total bilirubin =< 1.5 x Institutional upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) (=< 5x ULN in patients with liver metastases)
  • Creatinine =< 1.5 x Institutional ULN
  • Alkaline phosphatase =< 5 x Institutional ULN
  • Hemoglobin (Hgb) >= 9.0 g/dL
  • International normalized ratio (INR) and Partial thromboplastin time (PTT) =< 3.0 x ULN (anticoagulation is allowed if target INR =< 3.0 x ULN on a stable dose of warfarin or on a stable dose of low-molecular-weight [LMW] heparin for > 2 weeks at time of registration)
  • Fasting serum glucose < 1.5 x ULN
  • Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN; NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2
  • Ability to provide informed consent
  • Willingness to return to Mayo Clinic for follow up
  • Life expectancy >= 12 weeks
  • Women of childbearing potential only: Negative serum pregnancy test done =< 7 days prior to registration

Exclusion Criteria:

  • Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy
  • 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
  • Clinically significant cardiac disease, especially history of myocardial infarction =< 6 months, or congestive heart failure (New York Heart Association [NYHA] classification III or IV) requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Patients taking strong inhibitors or inducers of CYP3A4
  • Prior therapy with everolimus
  • Any of the following prior therapies:

    • Chemotherapy =< 4 weeks prior to registration
    • Mitomycin C/nitrosoureas =< 6 weeks prior to registration
    • Immunotherapy =< 4 weeks prior to registration
    • Biological therapy =< 4 weeks prior to registration
    • Radiation therapy =< 4 weeks prior to registration
    • Radiation to > 25% of bone marrow prior to registration
  • Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment
  • CNS metastases that are not stable for at least 4 weeks prior to registration based on imaging, clinical assessment, and use of steroids
  • Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation)
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
  • Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive
  • Current active other malignancy, except non-melanoma skin cancer or carcinoma-in-situ of the cervix
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
  • Severely impaired lung function (i.e., forced expiratory volume in one second [FEV1] < 1 liter)
  • Received immunization with attenuated live vaccines =< 7 days prior to study entry or during study period; NOTE: close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus; examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines
  • Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C); Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients; hepatitis B virus (HBV) deoxyribonucleic acid (DNA) and hepatitis C virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection
  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: NCT00949949

Locations
United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Brian Costello Mayo Clinic
  More Information

No publications provided

Responsible Party: Brian A. Costello, M.D., Principal Investigator, Mayo Clinic
ClinicalTrials.gov Identifier: NCT00949949     History of Changes
Other Study ID Numbers: MC0812, NCI-2009-01151, 09-000809, MC0812, P30CA015083
Study First Received: July 30, 2009
Last Updated: February 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Cholangiocarcinoma
Gallbladder Neoplasms
Neoplasms
Adenocarcinoma
Biliary Tract Diseases
Biliary Tract Neoplasms
Carcinoma
Digestive System Diseases
Digestive System Neoplasms
Gallbladder Diseases
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Cisplatin
Everolimus
Gemcitabine
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antiviral Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 23, 2014