Plicamycin in Treating Patients with Refractory Extracranial Solid Tumors or Ewing Sarcoma

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase II, Phase IBiomarker/Laboratory analysis, Treatment1 and over12-C-0135
NCI-2013-01528, 120135, P11887, NCT01610570

Trial Description



This phase I/II trial studies the side effects and best dose of plicamycin and to see how well it works in treating patients with extracranial solid tumors or Ewing sarcoma that does not respond to treatment. Plicamycin may kill cancer cells by blocking a gene that helps cancer form and grow.

Further Study Information


I. Determine the tolerability, toxicity, and recommended dose of mithramycin (plicamycin) in children and adolescents with refractory extracranial solid tumors. (Phase I)

II. Determine the objective response rate (complete response [CR] and partial response [PR]) of Ewing sarcoma with Ewing sarcoma (EWS)-friend leukemia virus integration 1 (FLI1) fusion transcript to mithramycin in children and adults using Response Evaluation Criteria in Solid Tumors (RECIST) criteria when administered at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. (Phase II)

III. Evaluate if mithramycin inhibits nuclear receptor subfamily 0, group B, member 1 (NR0B1) in tumor tissue, and determine changes in EWS/FLI1 gene expression signature by obtaining mandatory tumor biopsies pre treatment and at steady state on day +4 of treatment in patients >= 18 years old with Ewing sarcoma and EWS/FLI1 fusion transcript and disease amenable to percutaneous biopsy. (Phase II)


I. Describe pharmacokinetic parameters for each dose level using non-compartmental methods. (Phase I and II)

II. Evaluate NR0B1 expression in patients with Ewing sarcoma using immunohistochemistry on archival tumor tissue, if available. (Phase I and II)

III. To prospectively evaluate the feasibility and utility of volumetric analysis of target lesions, and descriptively compare volumetric measurements to 1-dimensional (1D) (RECIST), and 2-dimensional (2D) (World Health Organization [WHO]) measurements. (Phase I and II)

IV. Define preliminarily time to progression (TTP) in patients with Ewing sarcoma. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive plicamycin intravenously (IV) over 6 hours for 7 days. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days.

Eligibility Criteria

Inclusion Criteria:

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 Clinical Laboratory Improvement Amendments (CLIA) approved EWS-FLI paraffin assay in the Laboratory of Pathology Center for Cancer Research (CCR), National Cancer Institute (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, National Institutes of Health (NIH)

Phase I portion: >= 12 months to =< 17 years

Phase II portion in adults initially: >= 18 years; Phase II portion expanded in pediatrics after determination of phase II dose in children will include children >= 12 months to =< 17 years

Karnofsky (> 10-17 years old) or Lansky (=< 10 years old) >= 50%, or Eastern Cooperative Oncology Group (ECOG) 1 or 2 (adults)

Prior therapy:

>= 2 weeks must have elapsed since local palliative external beam radiation therapy (XRT) (small port) or other substantial bone marrow (BM) radiation

>= 24 weeks must have elapsed since prior total-body irradiation (TBI), craniospinal XRT, or if >= 50% radiation of pelvis

>= 12 weeks must have elapsed since stem cell transplant or infusion without TBI and no active graft vs. host disease

>= 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 antibody

>= 7 days must have elapsed from the last dose of biologic agents

>= 7 days since the completion of therapy with a growth factor

Recovered from acute toxicities of prior therapy to =< grade 1

Peripheral absolute neutrophil count (ANC) >= 1000/mcL

Platelets >= 75,000/mcL (transfusion independent)

Hemoglobin >= 8 g/dL (packed red blood cells [PRBC] transfusions permitted)

Normal prothrombin time (PT)/partial thromboplastin time (PTT) with the exception of a lupus anti-coagulant, which is permitted, may be corrected with vitamin K administration or transfusion; fibrinogen >= the lower limit of normal

Bilirubin (total) =< 1.5 X upper limit of normal (ULN)

Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN

Albumin > 2 g/dL

Creatinine clearance >= 60 mL/min/1.73 m^2, or serum creatinine based on age and gender as follows:

Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for males and 0.8 mg/dL for females

Age 6 to < 10 years: maximum serum creatinine 1 mg/dL for males and 1 mg/dL for females

Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for males and 1.2 mg/dL for females

Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females

Age >= 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females

Normal calcium (can be on oral supplementation)

Normal magnesium (can be on oral supplementation)

Normal phosphorus (can be on oral supplementation)

Left ventricular ejection fraction (EF) within normal institutional limits by echocardiogram or multigated acquisition scan (MUGA) or cardiac magnetic resonance imaging (MRI)

Ability to give informed consent; for patients < 18 years of age their legal guardian must give informed consent; pediatric patients will be included in age-appropriate 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 >= 18 years old


Age: >= 18 years old

Ewing sarcoma with EWS-FLI1 fusion transcript

Normal PT/PTT with exception of lupus anticoagulant

Platelets >= 75,000/mcL

Peripheral ANC >= 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 principal investigator (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

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 salicylate containing products, which may increase risk of hemorrhage




Valproic acid

Patients who are currently receiving other anti-cancer agents

Lactating or pregnant females

Patients with history of human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

NCI - Center for Cancer Research

  • National Cancer Institute
Brigitte C. Widemann, Principal Investigator

Trial Sites



Mark O Hatfield-Warren Grant Magnuson Clinical Center

Brigitte C. Widemann
Ph: 301-496-7387

Brigitte C. Widemann
Principal Investigator

Link to the current record.
NLM Identifer NCT01610570

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