Mithramycin for Children and Adults With Solid Tumors or Ewing Sarcoma

Study Overview
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Brief Summary
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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 Ewings sarcoma - friend leukemia integration 1 transcription factor (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.

Detailed Description
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BACKGROUND: Mithramycin, an anti-tumor antibiotic, underwent broad clinical evaluation in solid tumors and leukemias in the 1960s 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. OBJECTIVES (PRIMARY): 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 (complete response (CR) and partial response (PR)) of Ewing sarcoma 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 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. ELIGIBILITY: 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. DESIGN: 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 maximum tolerated dose (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.

Official Title
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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)

Conditions
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Sarcoma, Ewing Sarcoma

Intervention / Treatment
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* Drug: Mithramycin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Diagnosis Patients 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 Ewings sarcoma - friend leukemia integration 1 transcription factor (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, National Cancer Institute (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, National Institutes of Health (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 Eastern Cooperative Oncology Group (ECOG) 1 or 2 (adults) Prior therapy greater than or equal to 2 weeks must have elapsed since local palliative radiation (XRT) (small port); greater than or equal to 24 weeks must have elapsed since prior total body irradiation (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 absolute neutrophil count (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 (packed red blood cell (PRBC) transfusions permitted) iv. Normal prothrombin time (PT)/partial thromboplastin time (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. Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (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 multi-gated acquisition scan (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 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 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 (nonsteroidal anti-inflammatory drugs (NSAIDs)) or aspirin or salicylate containing 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 human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (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.

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose Level -1<br>Dose Escalation Phase 9.0 mcg/kg.dose | Drug: Mithramycin<br>* 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. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. 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 Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Phase II Portion: 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.<br>|
| Experimental: Phase I Dose Level 1<br>Dose Escalation Phase 13.0 mcg/kg.dose | Drug: Mithramycin<br>* 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. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. 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 Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Phase II Portion: 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.<br>|
| Experimental: Phase I Dose Level 2<br>Dose Escalation Phase 17.5 mcg/kg.dose | Drug: Mithramycin<br>* 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. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. 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 Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Phase II Portion: 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.<br>|
| Experimental: Phase II - Expansion Phase<br>Expansion phase 17.5 mcg/kg.dose | Drug: Mithramycin<br>* 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. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. 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 Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Phase II Portion: 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Mithramycin | The MTD will be the maximum dose at which fewer than one-third of patients experience Dose Limiting Toxicity (DLT) (i.e., non-hematologic toxicity and hematologic toxicity) during cycle 1 (or 28 days) of therapy. | Cycle 1 of therapy (or 28 days) | 
| Number of Participants With Serious and Non-serious Adverse Events | Here is the number of participants with serious and non-serious adverse events. For a detailed list of serious and non-serious adverse events see the adverse event module. | 95 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (Complete Response (CR) + Partial Response (PR)) | Objective response in children and adolescents with Ewings sarcoma - friend leukemia integration 1 transcription factor to mithramycin is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. | 1-2 months | 
| Time to Progression (TTP) | TTP is defined as the number of days from enrollment until disease progression, death because of treatment complications, resection of measureable tumor, or last patient follow-up, whichever comes first, assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progressions). Stable disease (SD) is neither shrinkage to qualify for PR nor sufficient increase to qualify for PD. | At date of progression, an average of 56 days | 
| Count of Participants With NR0B1 Expression in Tumor Biopsies | Biopsies were to be obtained in adult patients who have disease that could be safely biopsied. | Pre-treatment and day 4 (+/- 1 day) | 
| Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) | Measurable disease were to be quantified using volumetric magnetic resonance imaging analysis per the RECIST, measuring soft tissue disease. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes. Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progressions). Stable disease (SD) is neither shrinkage to qualify for PR nor sufficient increase to qualify for PD. | ≥4 weeks from baseline | 
| Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria | Per the WHO criteria, progressive disease is a 25% increase in tumor lesions, or the appearance of any new measureable or non-measureable tumor lesions. Partial response is ≥50% decrease in tumor lesions. Complete response is disappearance of all tumor lesions. Stable disease is 50% decrease in tumor lesions compared to baseline, nor 25% increase compared with nadir. | ≥4 weeks from baseline | 
| Maximum Plasma Concentration (Cmax) of Mithramycin Using Non-Compartmental Methods | The maximum observed analyte concentration in serum was reported. Mithramycin plasma concentrations were measured using high-performance liquid chromatography tandem mass spectroscopic method, and analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method. | Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose | 
| Half-Life (HL) of Mithramycin | Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method. | Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose | 
| Area Under the Curve Extrapolated to Infinity (AUCinf) | AUC is a measure of the serum concentration of mithramycin over time. It is used to characterize drug absorption. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method. | Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose | 
| Area Under the Curve for the Dosing Interval (AUCtau) | AUCtau is AUC for the dosing interval. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method. | Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose | 
| Clearance at Steady State (CLss) | The CL is a quantitative measure of the rate at which a drug substance is removed from the body. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method. | Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose | 
| Volume of Distribution at Steady State (Vss) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method. | Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dose Limiting Toxicity, Maximum Tolerated Dose, Radiographic Response, Time to Progression, Bone Tumors