Mithramycin for Children and Adults With Solid Tumors or Ewing Sarcoma

Phase 1

Terminated

Conditions: Ewing Sarcoma
Sarcoma

Interventions: Drug: Mithramycin

Registration Number: NCT01610570

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 8

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase II - Expansion Phase	Mithramycin	Expansion phase 17.5 mcg/kg.dose
Phase I Dose Level 1	Mithramycin	Dose Escalation Phase 13.0 mcg/kg.dose
Phase I Dose Level -1	Mithramycin	Dose Escalation Phase 9.0 mcg/kg.dose
Phase I Dose Level 2	Mithramycin	Dose Escalation Phase 17.5 mcg/kg.dose

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Mithramycin	Cycle 1 of therapy (or 28 days)	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.
Number of Participants With Serious and Non-serious Adverse Events	95 days	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.

Secondary Outcome Measures

Name	Time	Method
Maximum Plasma Concentration (Cmax) of Mithramycin Using Non-Compartmental Methods	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	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.
Objective Response Rate (Complete Response (CR) + Partial Response (PR))	1-2 months	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.
Time to Progression (TTP)	At date of progression, an average of 56 days	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.
Count of Participants With NR0B1 Expression in Tumor Biopsies	Pre-treatment and day 4 (+/- 1 day)	Biopsies were to be obtained in adult patients who have disease that could be safely biopsied.
Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST)	≥4 weeks from baseline	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.
Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria	≥4 weeks from baseline	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.
Half-Life (HL) of Mithramycin	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	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.
Area Under the Curve Extrapolated to Infinity (AUCinf)	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	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.
Area Under the Curve for the Dosing Interval (AUCtau)	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	AUCtau is AUC for the dosing interval. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method.
Clearance at Steady State (CLss)	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	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.
Volume of Distribution at Steady State (Vss)	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 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.