Disulfiram and Gemcitabine Hydrochloride in Treating Patients With Unresectable Solid Tumors or Metastatic Pancreatic Cancer
| Status: | Suspended |
|---|---|
| Conditions: | Cancer, Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/21/2019 |
| Start Date: | February 25, 2016 |
| End Date: | May 5, 2021 |
Phase 1 Trial and Randomized, Double-blinded, Placebo-Controlled Expansion Cohort Study of Disulfiram and Gemcitabine in Solid Tumor and Pancreas Cancer Patients
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.
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.
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.
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.
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
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