Mithramycin for Children and Adults With Solid Tumors or Ewing Sarcoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 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:
NCT01610570
First received: May 31, 2012
Last updated: March 14, 2014
Last verified: February 2014
  Purpose

Background:

- Mithramycin is a drug that was first tested as a cancer therapy in the 1960s. It acted against some forms of cancer, but was never accepted as a treatment. Research suggests that it may be useful against some solid tumors, particularly Ewing sarcoma. Researchers want to see if mithramycin can be used to treat solid tumors in children and adults. It will be tested in different groups of people, including those with a type of Ewing sarcoma that contains a chemical called EWS-FLI1.

Objectives:

- To see if mithramycin is safe and effective against solid tumors and Ewing sarcoma in children and adults.

Eligibility:

  • Children and young adults between 1 and 17 years of age with solid tumors that have not responded to standard treatment.
  • Adults at least 18 years of age with EWS-FLI1 Ewing sarcoma that has not responded to standard treatment.
  • Children and young adults between 1 and 17 years of age with EWS-FLI1 Ewing sarcoma that has not responded to standard treatment.

Design:

  • Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and tumor tissue samples will be used to monitor the cancer before treatment. Individuals with solid brain tumors will not be eligible.
  • Participants will receive mithramycin every day for 7 days, followed by 14 days without treatment. Each 28-day round of treatment is called a cycle.
  • Treatment will be monitored with frequent blood tests and imaging studies.
  • Participants will continue to take the drug for as long as the side effects are not severe and the tumor responds to treatment.

Condition Intervention Phase
Ewing Sarcoma
Sarcoma
Drug: Mithramycin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Mithramycin in Children and Adults With Refractory Extracranial Solid Tumors (Phase I) or Ewing Sarcoma and EWSFLI1 Fusion Transcript (Phase II)

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Phase I: determine the tolerability, toxicity, and recommended dose of mithramycin in pediactric patients with extracranial tumors. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Phase II: determine response in children and adults with ewings sarcoma [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Evaluate NR0B1 expression in archival tumor tissue
  • Describe pharmacokinetic parameters for each dose level (phase1)

Estimated Enrollment: 44
Study Start Date: May 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Mithramycin
    Phase 1 dose escalation IV for six hours once daily for 7 days once every 28 days. Phase 2 25 mcg/kg IV over 6 hours once daily for 7 days, once every 28 days.
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   1 Year and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA
  • Diagnosis
  • Patient s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
  • Phase I Portion: Measurable or evaluable refractory or recurrent extracranial solid tumors, excluding brain tumors and cerebral metastases.
  • Phase II Portion adults and children: Refractory or recurrent extracranial Ewing sarcoma with EWS-FLI1 fusion transcript. Patients enrolled to this cohort must have measurable disease. Presence of the transcript will be determined during histologic confirmation of disease with a CLIA approved EWS-FLI paraffin assay in the Laboratory of Pathology CCR, NCI, unless a pathology report documenting presence of the transcript using a CLIA approved assay is obtained from the referring institution.
  • Histologic confirmation of disease in the Laboratory of Pathology, CCR, NCI, NIH.
  • Age
  • Phase I Portion: greater than or equal to 12 months to less than or equal to 17 years
  • Phase II Portion in adults initially: greater than or equal to 18 years
  • Phase II Portion expanded in pediatrics after determination of phase II dose in children will include children greater than or equal to 12 months to less than or equal to 17 years
  • Performance Score: Karnofsky (> 10-17 years old) or Lansky (less than or equal to 10 years old) greater than or equal to 50%, or ECOG 1 or 2 (adults)
  • Prior therapy
  • greater than or equal to 2 weeks must have elapsed since local palliative XRT (small port);
  • greater than or equal to 24 weeks must have elapsed since prior TBI, craniospinal XRT, or if greater than or equal to 50%
  • radiation of pelvis;
  • greater than or equal to 6 weeks must have elapsed since other substantial BM radiation;
  • greater than or equal to 12 weeks must have elapsed since stem cell transplant or infusion without TBI and no active graft vs. host disease;
  • greater than or equal to 3 weeks must have elapsed from last dose of myelosuppressive chemotherapy (six

weeks for nitrosoureas);

at least 3 half-lives must have elapsed since monoclonal antibody1;(https://members.childrensoncologygroup.org/Disc/devtherapeutics/default.asp for listing of monoclonal antibody half-lives.)

  • greater than or equal to 7 days must have elapsed from the last dose of biologic agents.
  • greater than or equal to 7 days since the completion of therapy with a growth factor
  • Recovered from acute toxicities of prior therapy to less than or equal to Grade 1; specifically

    a) Hematologic and Coagulation Parameters

    i. Peripheral ANC greater than or equal to 1000/mcL

ii. Platelets greater than or equal to 75,000/ mcL (transfusion independent)

iii. Hemoglobin greater than or equal to 8 g/dL (PRBC transfusions permitted)

iv. Normal PT/PTT with the exception of a lupus anticoagulant, which is permitted, may be corrected with Vitamin K administration or transfusion. Fibrinogen greater than or equal to the lower limit of normal.

b) Hepatic Function

i. Bilirubin (total) less than or equal to 1.5 times upper limit of normal (ULN)

ii. ALT (SGPT) less than or equal to 3.0 times ULN

iii. Albumin > 2 g/dL

c) Renal Function

i. Creatinine clearance greater than or equal to 60 mL/min/1.73 m(2), or serum creatinine base on age and gender as follows:

Age (years) Maximum Serum Creatinine (mg/dL)

2 to < 6 0.8 0.8

6 to < 10 1 1

10 to < 13 1.2 1.2

13 to < 16 1.5 1.4

greater than or equal to 16 1.7 1.4

  • Normal calcium, magnesium and phosphorus (can be on oral supplementation
  • Cardiac Function: Left ventricular ejection fraction (EF) within normal institutional limits by Echocardiogram or MUGA
  • Ability to give informed consent. For patients < 18 years of age their legal guardian must give informed consent. Pediatric patients will be included in ageappropriate discussion in order to obtain verbal assent.
  • Female and male patients (and when relevant their partners) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of childbearing potential during sexual contact with a female of childbearing potential.
  • A durable power of attorney (DPA) will be offered to all patients greater than or equal to 18 years old.
  • Eligibility criteria for mandatory serial tumor biopsies
  • Age: greater than or equal to 18 years old
  • Ewing sarcoma with EWS-FLI1 fusion transcript
  • Hematologic and coagulation parameters within 2 days prior to each biopsy: Normal PT/PTT with exception of lupus anticoagulant, platelets greater than or equal to 75,000/mcL, peripheral ANC greater than or equal to 750/mcL
  • Willing to undergo biopsies, which will only be performed on tumors amenable to percutaneous biopsy

EXCLUSION CRITERIA:

  • Clinically significant systemic illness (e.g. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the PI would compromise the patient s ability to tolerate protocol therapy or significantly increase the risk of complications.
  • Patients with a history intracranial Ewing sarcoma including cerebral metastases
  • Patients with evidence of active bleeding, intratumoral hemorrhage or history of bleeding diatheses
  • Patients who are receiving anticoagulants other than prophylactic anticoagulation of venous or arterial access devices, provided that requirements for PT, PTT and fibrinogen are met, as described
  • Investigational Drugs: Patients who are currently receiving another investigational drug
  • Patients who are concurrently receiving agents, which may increase the risk for mithramycin related toxicities, such as hemorrhage including:
  • Thrombolytic agents
  • Anti-inflammatory drugs, nonsteroidal (NSAIDs) or aspirin or salicylatecontaining products, which may increase risk of hemorrhage
  • Dextran
  • Dipyridamole
  • Sulfinpyrazone
  • Valproic acid
  • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents
  • Lactating or pregnant females (due to risk to fetus or newborn, and lack of testing for excretion in breast milk).
  • Patients with history of HIV, HBV or HCV due to potentially increased risk of mithramycin toxicity in this population.
  • Hypersensitivity to plicamycin (mithramycin)
  • Requirement for any of the contraindicated medications: nonsteroidal anti-inflammatory drugs, aspirin, dextran or other iron containing solutions (due to incompatibility), dipyridamole, sulfinpyrazone or valproic acid
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
  • Patients receiving concurrently other therapies directed at their cancer.
  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: NCT01610570

Contacts
Contact: Lauren M Long, R.N. (301) 451-9921 longl@pbmac.nci.nih.gov
Contact: Brigitte C Widemann, M.D. (301) 496-7387 widemanb@pbmac.nci.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    888-624-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Brigitte C Widemann, 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: NCT01610570     History of Changes
Other Study ID Numbers: 120135, 12-C-0135
Study First Received: May 31, 2012
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Dose Limiting Toxicity
Maximum Tolerated Dose
Radiographic Response
Time to Progression
Bone Tumors

Additional relevant MeSH terms:
Sarcoma, Ewing
Sarcoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Bone Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms, Connective Tissue
Osteosarcoma
Plicamycin
Antibiotics, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Protein Synthesis Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014