|Phase II, Phase I||Biomarker/Laboratory analysis, Treatment||Active||1 and over||NCI||120135|
- 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.
- To see if mithramycin is safe and effective against solid tumors and Ewing sarcoma in children and adults.
- 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.
- 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.
Further Study Information
- Mithramycin, an anti-tumor antibiotic, underwent broad clinical evaluation in solid tumors and leukemias in the 1960 s and demonstrated activity in some leukemias, lymphomas, and solid tumors. In particular, mithramycin was found to have activity against testicular cancers and was briefly used in the clinic for this tumor prior to the development of the currently used treatment regimen.
- The Ewing Sarcoma Family of Tumors (ESFT) is the second most common malignant bone tumor of childhood. There has been very little improvement in overall patient survival in past years, particularly for patients with high risk metastatic or relapsed disease. Therefore, there is a need for effective novel agents for the treatment of this disease.
- Multiple studies have shown that suppressing the expression of EWS-FLI1 effectively limits the tumorigenicity of ESFT cells. Laboratory studies have shown that mithramycin effectively suppresses the activity of EWS-FLI1 both in vitro and in vivo.
- Phase I portion of this study is to: determine the tolerability, toxicity, and the recommended phase II dose of mithramycin in children and adolescents with refractory extracranial solid tumors.
- Phase II portion of this trial is to: determine the objective response rate (CR and PR) of Ewing sarcoma to mithramycin in children and adults using 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 portion of this trial to: evaluate if mithramycin inhibits NR0B1 in tumor tissue and determine changes in gene expression signature pre-treatment and at steady state on day +4 of treatment in patients greater than or equal to 18 years old with Ewing sarcoma and EWS/FLI1 fusion transcript with disease amenable to percutaneous biopsy.
- Phase I Portion: children (greater than or equal to 12 months) and adolescents (less than or equal to 17 years) with recurrent or refractory extracranial solid tumors.
- Phase II Portion in adults: adults (greater than or equal to 18 years of age at enrollment) with recurrent or refractory measurable extracranial Ewing sarcoma and the EWS-FLI1 fusion transcript.
- Phase II Portion in children and adolescents: Once the adult dose is deemed safe, children
(greater than or equal to 12 months) and adolescents (less than or equal to 17 years) with recurrent or refractory measurable
extracranial Ewing sarcoma and the EWS-FLI1 fusion transcript will begin enrollment to the Phase II portion.
- Participants must meet safety laboratory criteria and prior therapy limitations.
Phase I Portion: Mithramycin will be administered in escalating doses to children and adolescents intravenously over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. The cohort at the recommended dose or MTD will be expanded up to 12 patients, and attempts will be made to enroll 6 patients that are greater than or equal to 12 years of age and 6 patients that are < 12 years of age to gain experience with a broad age range of patients. A maximum of 18 evaluable patients will be enrolled on the phase I portion.
- Phase II Portion: Using a Simon two stage design, mithramycin will be administered intravenously 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 to children and adults with Ewing sarcoma with EWS-FLI1 fusion transcript. Up to 24 evaluable patients will be enrolled on the phase II portion.
- The Phase I and Phase II portions of the protocol will enroll patients simultaneously.
- 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 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.
- 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
- 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
- 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.
Trial Lead Organizations/Sponsors
National Cancer Institute
|Brigitte C. Widemann||Principal Investigator|
|Lauren M Long, R.N.||Ph: (301) 451-9921|
|NIH - Warren Grant Magnuson Clinical Center|
|For more information at the NIH Clinical Center contact National Cancer Institute Referral Office||Ph: 888-624-1937|
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01610570
ClinicalTrials.gov processed this data on March 16, 2014
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