Mithramycin for Children and Adults With Solid Tumors or Ewing Sarcoma

NCT01610570 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 12013512-C-0135
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

Ewing Sarcoma; Sarcoma

Keywords

Dose Limiting Toxicity; Maximum Tolerated Dose; Radiographic Response; Time to Progression; Bone Tumors

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (11)

• Objective Response Rate (Complete Response (CR) + Partial Response (PR))

  1-2 months

• Time to Progression (TTP)

  At date of progression, an average of 56 days

• Count of Participants With NR0B1 Expression in Tumor Biopsies

  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)

  ≥4 weeks from baseline

• Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria

  ≥4 weeks from baseline

Other Outcomes (1)

• Number of Participants With Dose Limiting Toxicity (DLT)

  Cycle 1 of therapy (or 28 days)

Study Arms (4)

Phase I Dose Level -1

EXPERIMENTAL

Dose Escalation Phase 9.0 mcg/kg.dose

Drug: Mithramycin

Phase I Dose Level 1

EXPERIMENTAL

Dose Escalation Phase 13.0 mcg/kg.dose

Drug: Mithramycin

Phase I Dose Level 2

EXPERIMENTAL

Dose Escalation Phase 17.5 mcg/kg.dose

Drug: Mithramycin

Phase II - Expansion Phase

EXPERIMENTAL

Expansion phase 17.5 mcg/kg.dose

Drug: Mithramycin

Interventions

Mithramycin DRUG

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.

Phase I Dose Level -1; Phase I Dose Level 1; Phase I Dose Level 2; Phase II - Expansion Phase

Eligibility Criteria

• Age: 1 Year+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Esiashvili N, Goodman M, Marcus RB Jr. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol. 2008 Jun;30(6):425-30. doi: 10.1097/MPH.0b013e31816e22f3.

  PMID: 18525458 BACKGROUND

• Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, Ambros PF, Sheer D, Turc-Carel C, Triche TJ, et al. The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med. 1994 Aug 4;331(5):294-9. doi: 10.1056/NEJM199408043310503.

  PMID: 8022439 BACKGROUND

• Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992 Sep 10;359(6391):162-5. doi: 10.1038/359162a0.

  PMID: 1522903 BACKGROUND

• Grohar PJ, Glod J, Peer CJ, Sissung TM, Arnaldez FI, Long L, Figg WD, Whitcomb P, Helman LJ, Widemann BC. A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript. Cancer Chemother Pharmacol. 2017 Sep;80(3):645-652. doi: 10.1007/s00280-017-3382-x. Epub 2017 Jul 22.

  PMID: 28735378 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Sarcoma, Ewing; Sarcoma; Bone Neoplasms

Interventions

Plicamycin

Condition Hierarchy (Ancestors)

Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Bone Diseases; Musculoskeletal Diseases

Intervention Hierarchy (Ancestors)

Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Dr. Brigitte Widemann
• Organization: National Cancer Institute

widemanb@mail.nih.gov

301-496-7387

Study Officials

• Brigitte C Widemann, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 31, 2012
• First Posted: June 4, 2012
• Study Start: May 10, 2012
• Primary Completion: May 21, 2014
• Study Completion: May 21, 2014
• Last Updated: March 2, 2018
• Results First Posted: February 15, 2016

Record last verified: 2017-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)