A Phase 1, Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous Dimethane Sulfonate (DMS612) in Advanced Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00923520
First received: June 17, 2009
Last updated: July 19, 2014
Last verified: July 2014
  Purpose

Background:

  • Dimethane sulfonate (DMS612) is an investigational drug that is being administered to humans for the first time in people with advanced tumors. More information on the maximum tolerated dose of DMS612 will help researchers identify whether the drug is suitable for use in treating certain kinds of cancer, particularly renal cell carcinoma.

Objectives:

  • To determine the maximum tolerated dose of DMS612 (the highest dose that does not cause unacceptable side effects) and evaluate any side effects.
  • To see if DMS612 has any effect on patients tumors through blood tests and laboratory studies.
  • To learn how the body processes DMS612.

Eligibility:

  • Patients 18 years of age and older who have been diagnosed with cancer that has not responded well to standard treatments.

Design:

  • Pre-treatment evaluation visit to determine eligibility:
  • Physical examination
  • Blood and urine tests
  • Chest X-ray; electrocardiogram; CAT scan of chest, abdomen, pelvis, and other areas of the body if needed
  • Other possible tests, such as magnetic resonance imaging (MRI) or positron emission tomography (PET)
  • Patients will receive one dose of DMS612 by intravenous infusion once a week for 3 weeks, followed by 1 week without the drug. Doses will be adjusted based on possible side effects and cancer response. The disease will be evaluated after three cycles of the drug.
  • Evaluations during the treatment period:
  • Physical examination and reviews of side effects.
  • Blood draws to evaluate the effectiveness of the drug, and how it is processed by the body.
  • CAT scan at the end of every two cycles (every 8 weeks).
  • Other scans and imaging procedures as required by the study doctors.

Condition Intervention Phase
Renal Cell Carcinoma
Breast Cancer
Colon Cancer
Lung Cancer
Non-Hodgkin Lymphoma
Drug: dimethane sulfonate (DMS612, NSC 281612)
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Dose Escalation Study of the Safety, Tolerability and Pharmacokinetics of Intravenous Dimethane Sulfonate (DMS612, NSC 281612) in Advanced Malignancies

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Determine the Maximum Tolerated Dose [ Time Frame: End of Cycle 1 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Evaluate non-dose limiting toxicity [ Time Frame: Treatment Completion ] [ Designated as safety issue: Yes ]
  • PK [ Time Frame: Collection of Samples ] [ Designated as safety issue: No ]
  • Anti-tumor Effects [ Time Frame: Disease Progression ] [ Designated as safety issue: No ]

Estimated Enrollment: 63
Study Start Date: March 2009
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
DMS 612 on day 1 and 2 with doses starting at 3.5mg/m2 to 18.5mg/m2 every 21 days until MTD is reached
Drug: dimethane sulfonate (DMS612, NSC 281612)
DMS 612 on day 1 and 2 with doses starting at 3.5mg/m2 to 18.5mg/m2 until MTD is reached

Detailed Description:

Background:

  • The dimethane sulfonates are a group of agents that were identified as active against renal cell carcinoma in the NCI anticancer drug screen.
  • In vitro studies showed that dimethane sulfonates have properties in common with alkylating agents, but are unlike conventional alkylators (such as nitrogen mustards, BCNU, or busulfan) in that they are active against renal cell carcinoma (RCC).

Objective:

Primary:

-To determine dose-limiting toxicity (DLT), MTD and recommended phase II dose (RPTD) of dimethane sulfonate (DMS612, NSC 281612) when administered by intravenous (IV) bolus on days 1 and 2 of a 21-day cycle.

Secondary:

  • To evaluate non-dose limiting toxicities of DMS612
  • To determine the pharmacokinetics of IV DMS612, NSC 281612 and its metabolites in humans.
  • To make a preliminary assessment of antitumor effect of IV DMS612, NSC 281612
  • To correlate dose and pharmacokinetics with molecular measures of DMS612, NSC281612 effect.

Eligibility:

  • Patients must have histologically confirmed solid tumor malignancy or lymphoma that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
  • Any prior chemotherapy therapy is allowed in this protocol. No more than 2 prior cytotoxic chemotherapy regimens are allowed.
  • Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of Dimethane sulfonate in patients less than 18 years of age, children are excluded from this study but will be eligible for future pediatric phase 1 single-agent trials.
  • ECOG performance status 0-2 (Karnofsky greater than or equal to 60%,).
  • Life expectancy of 3 months or greater.
  • Patients must have acceptable organ and marrow function as defined below: leukocytes greater than or equal to 3,000/mcL, absolute neutrophil count greater than or equal to 1,500/mm(3), platelets greater than or equal to 100,000/, mm(3) total bilirubin within normal institutional limits, AST(SGOT)/ALT(SGPT), less than or equal to 2.5 times the institutional upper limit of normal, creatinine within normal institutional limits or creatinine clearance> 50mL/min for patients with creatinine levels above institutional normal.

Design:

This is a Phase I study of the safety, pharmacokinetics, pharmacodynamics and antitumor activity of IV DMS612, NSC 281612, designed as an open-label, dose-escalation study to determine the RPTD of DMS612, NSC 281612 based on safety and pharmacokinetics.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients must have histologically confirmed solid tumor malignancy or lymphoma that is metastatic or unresectable and for which effective therapy does not exist or is no longer effective.
  • Any prior chemotherapy therapy is allowed in this protocol. No more than 2 prior cytotoxic chemotherapy regimens are allowed for eligibility. Non-myelotoxic therapies such as sunitinib and sorafenib or everolimus are not considered "cytotoxic chemotherapies".Patients must be greater than or equal to 4 weeks from prior radiation or cytotoxic chemotherapy, except greater than or equal to 6 weeks for mitomycin C and nitrosoureas; greater than or equal to 2 weeks from hormonal therapy; greater than or equal to 4 weeks from prior experimental therapy; greater than or equal to 4 weeks from monoclonal antibody therapy (cetuximab, bevacizumab), greater than or equal to 2 weeks from sorafenib, sunitinib or temsirolimus and greater than or equal to 8 weeks from prior UCN01 treatment. Patients with prostate cancer may continue ongoing LHRH agonist therapy. Patients with bone metastases or hypercalcemia who began intravenous bisphosphonate treatment prior to study entry may continue this treatment.
  • Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of dimethane sulfonate in patients less than 18 years of age, children are excluded from this study but will be eligible for future pediatric phase 1 single-agent trials.
  • ECOG performance status 0-2 (Karnofsky greater than or equal to 60%,).
  • Life expectancy of 3 months or greater.
  • Patients must have acceptable organ and marrow function as defined below:

    • leukocytes greater than or equal to 3,000/mm(3)
    • absolute neutrophil count greater than or equal to 1,500/ mm(3)
    • platelets greater than or equal to 100,000/ mm(3)
    • total bilirubin within normal institutional limits
    • AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of normal
    • creatinine within normal institutional limits OR
    • 24 hour urine creatinine clearance greater than 50 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal (may use creatinine clearance Cockcroft-Gault Equation).
  • The effects of dimethane sulfonate on the developing human fetus are unknown. For this reason and because alkylating agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least 3 months after study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Willing to comply with study procedures and follow-up.

EXCLUSION CRITERIA:

  • Patients who have not recovered (CTC less than or equal to grade I) from adverse events due to prior treatments
  • Patients may not have received more than 2 prior cytotoxic regimens.
  • Patients may not be receiving any other investigational agent with therapeutic anticancer intent.
  • Patients with history of CNS metastasis, unless control has been achieved with either radiation or surgical resection at least 3 months prior to enrollment on study.
  • Patients who have had radiation to the pelvis or other bone marrow-bearing sites will be considered on a case by case basis and may be excluded if the bone marrow reserve is not considered adequate (greater than 25% of bone marrow irradiated).
  • Uncontrolled medical illness including, but not limited to, ongoing or active infection, chronic or acute hepatitis, renal failure, symptomatic congestive heart failure, myocardial infarction within the last 6 months, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because DMS612 is likely to have toxicities similar to the alklyating agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DMS612, breastfeeding should be discontinued if the mother is treated with DMS612.
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with DMS612. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  • Patients are not eligible for the study if taking cytochrome P450-inducing anticonvulsants. This applies to patients with brain metastasis or those taking anticonvulsant for another reason (ie. Epilepsy).
  • Patients diagnosed with alcoholism may not be treated with disulfiram.
  • Patients may not be receiving agents thought to inhibit or induce the cytochrome p450 isoenzyme CYP3A4.
  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: NCT00923520

Contacts
Contact: Christine M Bryla, R.N. (301) 451-7868 christina.bryla@nih.gov
Contact: Susan E Bates, M.D. (301) 402-0984 sebates@helix.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
United States, Pennsylvania
Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15261
Sponsors and Collaborators
Investigators
Principal Investigator: Susan E Bates, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT00923520     History of Changes
Obsolete Identifiers: NCT00888121
Other Study ID Numbers: 090111, 09-C-0111
Study First Received: June 17, 2009
Last Updated: July 19, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Solid Tumors
Phase I
Lymphoma
Dimethane Sulfonate (DMS612, NSC 281612)
Cancer
Solid Tumor
Renal Cell Cancer
Kidney Cancer
Breast Cancer
Colon Cancer
Lung Disease
Non-Hodgkin Lymphoma
NHL

Additional relevant MeSH terms:
Thoracic Neoplasms
Breast Neoplasms
Carcinoma
Colonic Neoplasms
Carcinoma, Renal Cell
Lung Neoplasms
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Respiratory Tract Neoplasms
Lung Diseases

ClinicalTrials.gov processed this record on September 14, 2014