ClinicalTrials.gov
ClinicalTrials.gov Menu

Disulfiram and Gemcitabine Hydrochloride in Treating Patients With Unresectable Solid Tumors or Metastatic Pancreatic Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02671890
Recruitment Status : Suspended (per protocol)
First Posted : February 2, 2016
Last Update Posted : November 20, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
This partially randomized phase I trial studies the side effects and best dose of disulfiram when given together with gemcitabine hydrochloride in treating patients with a solid tumor that cannot be removed by surgery (unresectable) or pancreatic cancer that has spread to other places in the body (metastatic) and to compare whether disulfiram and gemcitabine hydrochloride may reduce tumor induced muscle loss. Weight loss occurs in pancreatic cancer patients and is common in a multitude of other cancers. Patients with metastatic cancer and weight loss sometimes are not able to receive treatment due to physical weakness or debility. Disulfiram is a potential inhibitor of muscle degradation and may reduce tumor induced muscle wasting. Disulfiram may also help gemcitabine hydrochloride work better by making tumor cells more sensitive to the drug. Drugs used in chemotherapy, such as gemcitabine hydrochloride, 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 know whether giving gemcitabine hydrochloride with or without disulfiram is a better treatment for unresectable solid tumors or metastatic pancreatic cancer.

Condition or disease Intervention/treatment Phase
Metastatic Pancreatic Adenocarcinoma Recurrent Pancreatic Carcinoma Solid Neoplasm Stage IV Pancreatic Cancer Drug: Disulfiram Drug: Gemcitabine Hydrochloride Other: Laboratory Biomarker Analysis Other: Placebo Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose (MTD) of the combination of disulfiram and gemcitabine (gemcitabine hydrochloride) in unresectable solid tumor cancer patients (Cohort 1).

SECONDARY OBJECTIVES:

I. To describe the adverse event profile associated with this combination of disulfiram and gemcitabine (Cohort 2).

II. To describe changes in muscle area at the L3 level from baseline to 28 to 35 days of treatment with disulfiram/gemcitabine and with placebo/gemcitabine (Cohort 2).

III. To describe changes in fist-grip strength from baseline to 28 to 35 days of treatment with disulfiram/gemcitabine and with placebo/gemcitabine (Cohort 2).

IV. To describe overall survival of pancreas cancer patients who disulfiram/gemcitabine or placebo/gemcitabine (Cohort 2).

V. To estimate the response rate per Response Evaluation Criteria in Solid Tumors (RECIST) criteria around 1 month post-treatment in patients who receive disulfiram/gemcitabine and placebo/gemcitabine (Cohort 2).

TERTIARY OBJECTIVES:

I. To assess the effect of disulfiram and gemcitabine on the ubiquitin proteasome and autophagy pathways within muscle, as assessed by means of muscle biopsies performed at baseline and after 28 to 35 days of treatment (Cohort 2).

OUTLINE: This is a phase I, dose-escalation study of disulfiram.

COHORT I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15 and disulfiram orally (PO) on days 1-28 or days 1-35.

COHORT II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and disulfiram PO every other day or daily on days 1-28 or days 1-35.

ARM II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and placebo PO every other day or daily on days 1-28 or days 1-35.

After completion of study treatment, patients are followed up at 30 days, and then every 6 months for 3 years.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 74 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Phase 1 Trial and Randomized, Double-blinded, Placebo-Controlled Expansion Cohort Study of Disulfiram and Gemcitabine in Solid Tumor and Pancreas Cancer Patients
Actual Study Start Date : February 25, 2016
Estimated Primary Completion Date : May 5, 2021
Estimated Study Completion Date : May 5, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (gemcitabine hydrochloride and disulfiram)
Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and disulfiram PO every other day or daily on days 1-28 or days 1-35.
Drug: Disulfiram
Given PO
Other Names:
  • Antabuse
  • DS
  • Tetraethylthioperoxydicarbonic Diamide
  • Teturamin
  • TTD

Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
  • LY188011

Other: Laboratory Biomarker Analysis
Correlative studies

Placebo Comparator: Arm II (gemcitabine hydrochloride and placebo)
Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and placebo PO every other day or daily on days 1-28 or days 1-35.
Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
  • LY188011

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Placebo
Given PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Cohort I) [ Time Frame: 28 days ]
    MTD is defined as the dose level below the lowest dose that induces DLT in at least one-third of patients (at least 2 of a maximum of 6 new patients).


Secondary Outcome Measures :
  1. Adverse events profile (Cohort I and II) [ Time Frame: Up to 30 days post-treatment ]
    The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion. This will provide an indication of the level of tolerance for this treatment combination in this patient group.

  2. Change in muscle area at the L3 level using a computed tomography (CT) scan (Cohort II) [ Time Frame: Baseline to day 28 ]
    Changes will be described using summary statistics and graphical techniques. A grayscale pixel histogram of the remaining muscle in the image will be constructed and summed. The number of pixels will then be converted to an area measurement in squared centimeters. All measurements and calculations for each image will be undertaken by two independent study personnel, and the average will be used in the analyses. A Wilcoxon rank sum test may be used as appropriate to compare percent changes of biomarkers between the muscle clinical responders and the non-responders based on CT scan measurements

  3. Change in muscle area at the L3 level using a computed tomography scan (Cohort II) [ Time Frame: Baseline to day 35 ]
    Changes will be described using summary statistics and graphical techniques. A grayscale pixel histogram of the remaining muscle in the image will be constructed and summed. The number of pixels will then be converted to an area measurement in squared centimeters. All measurements and calculations for each image will be undertaken by two independent study personnel, and the average will be used in the analyses. A Wilcoxon rank sum test may be used as appropriate to compare percent changes of biomarkers between the muscle clinical responders and the non-responders based on CT scan measurements

  4. Changes in fist-grip strength as measured by hand dynamometer (Cohort II) [ Time Frame: Baseline to day 28 ]
    Changes will be described using summary statistics and graphical techniques. Patients will use 3 successive tries, and the average value will be used.

  5. Changes in fist-grip strength as measured by hand dynamometer (Cohort II) [ Time Frame: Baseline to day 35 ]
    Changes will be described using summary statistics and graphical techniques. Patients will use 3 successive tries, and the average value will be used.

  6. Overall survival (OS) (Cohort II) [ Time Frame: From registration until death due to any cause, assessed up to 3 years ]
    OS will be summarized descriptively using the Kaplan-Meier estimate up to 3 years of follow-up in all alive patients.

  7. Response rate assessed using standard Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria (Cohort II) [ Time Frame: At 1 month post-treatment ]
    Response rate will be assessed using standard RECIST 1.1 criteria.

  8. Toxicity profile defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment (Cohorts I and II) [ Time Frame: Up to 30 days post-treatment ]
    Non-hematologic toxicities will be evaluated via the ordinal Common Terminology Criteria (CTC) standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via 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.


Other Outcome Measures:
  1. Change in muscle protein expression level of total and phosphorylated (phosph)-signal transducer and activator of transcription 3 (STAT3) via immunohistochemistry [ Time Frame: Baseline to up to 35 days ]
    Changes will be made at baseline and 28 to 35 days.

  2. Changes in muscle messenger ribonucleic acid (mRNA) levels via real-time polymerase chain reaction [ Time Frame: Baseline to up to 35 days ]
    Changes in mRNA transcripts of the muscle ubiquitin proteasome system (atrogin and muscle-specific RING finger protein 1) and STAT3 target genes (suppressor of cytokine signaling 3 and early growth response 1) will be made at baseline and 28 to 35 days.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Cohort 1 (dose escalation): histologic or cytologic proof of any solid tumor that is incurable with no standard therapy that is likely to make a major impact on clinical outcomes
  • Cohort 2 (MTD) only: metastatic adenocarcinoma of the pancreas; prior systemic treatment for metastatic disease is allowed
  • Cohort 2 (MTD) only: patient is thought to be a short- or long-term candidate for gemcitabine in the opinion of the treating oncologist
  • Cohort 2 (MTD) only: weight loss of > 5% at any point after a cancer diagnosis or within 3 months prior to this cancer diagnosis; Note: no documentation from the medical record is necessary
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelet >= 100,000/ mm^3
  • Total bilirubin =< 2 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x ULN
  • Creatinine =< 1.5 x ULN
  • Hemoglobin >= 9.0 g/dL
  • Cohort 2 (MTD) only: prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN
  • Ability to provide written informed consent
  • Willing to return to Mayo clinic for follow up
  • Life expectancy >= 12 weeks
  • Cohort 2 (MTD) only: patient willing to undergo muscle biopsies at baseline and after 28 to 35 days of disulfiram/gemcitabine or gemcitabine/placebo therapy as required by the protocol
  • Cohort 2 (MTD) only: patient willing to have paraffin-embedded slides of the primary pancreas tumor or metastatic site, if available, sent to Mayo investigators for this study
  • For women of childbearing potential only: negative urine or serum pregnancy test done =< 7 days prior to registration
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
  • Able to swallow or have medication administered through a gastrostomy tube (G-tube) and absorb the medication
  • Patient willing to complete a medication diary
  • Patient agrees to use acceptable form of contraception during the study and for up to 30 days after last study drug dose if female partner is of childbearing potential

    • Acceptable forms of contraception:

      • Latex condom (always used with spermicide)
      • Diaphragm (always used with spermicide)
      • Cervical cap (always used with spermicide)
    • Acceptable forms of secondary contraception, when used along with a barrier method:

      • Hormonal contraception methods, including pills, patches, rings, or injections except progestin-only containing pills (i.e. ?Mini-pill?)
      • Tubal ligation
      • Partner?s vasectomy
      • Intrauterine device (non-progesterone T)
      • Vaginal sponge (containing spermicide)
    • Other acceptable forms:

      • 100% commitment to abstinence
    • Unacceptable forms of contraception for women of childbearing potential:

      • Oral contraception containing progestins only
      • Intrauterine device (IUD) progesterone T
      • Female condom
      • Natural family planning (rhythm method) or breastfeeding
      • Fertility awareness
      • Withdrawal
      • Cervical shield

Exclusion Criteria:

  • Known standard therapy for the patient?s disease that is potentially curative
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, including localized infections, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements
  • Untreated brain metastases
  • Any of the following:

    • Pregnant women
    • Nursing women
  • Other concurrent chemotherapy, immunotherapy, radiotherapy, any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) or receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Baseline of grade 2 or worse peripheral sensory neuropathy
  • Daily oral or intravenous corticosteroids for 7 days or longer within one week of enrollment and patient is anticipated to have an increase in dose after study enrollment
  • Receiving phenytoin
  • Unable to abstain from alcohol for the duration of the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02671890


Locations
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
Principal Investigator: Aminah Jatoi Mayo Clinic

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT02671890     History of Changes
Other Study ID Numbers: MC1512
NCI-2016-00007 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
15-003194
MC1512 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: February 2, 2016    Key Record Dates
Last Update Posted: November 20, 2017
Last Verified: December 2016

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Disulfiram
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors