Continuous 24h Intravenous Infusion of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in People With Primary Thoracic Malignancies or Carcinomas, Sarcomas or Germ Cell Neoplasms With Pleuropulmonary Metastases

• ClinicalTrials.gov Identifier: NCT02859415
• Recruitment Status: Recruiting
• First Posted: August 9, 2016
• Last Update Posted: January 12, 2021
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information

• First Submitted Date: August 6, 2016
• First Posted Date: August 9, 2016
• Last Update Posted Date: January 12, 2021
• Actual Study Start Date: August 8, 2019
• Estimated Primary Completion Date: August 3, 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 28, 2017)

• Maximum tolerated dose [ Time Frame: at the end of first 14 day cycle at each dose level ]
  The number of patients experiencing DLT.Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity.
• Overall response rate [ Time Frame: every 8 weeks until at disease progression ]
  Response rates will be calculated as the percent of patients whose best response is a CR or PR.

Original Primary Outcome Measures (submitted: August 6, 2016)

• Maximum tolerated dose [ Time Frame: at the end of first 14 day cycle at each dose level ]
• Overall response rate [ Time Frame: every 8 weeks until at disease progression ]

Current Secondary Outcome Measures (submitted: January 8, 2021)

• To ascertain if mithramycin inhibits stem cell gene expression in patients with thoracic malignancies [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
  Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1.Plasma and blood will also be collected.
• To evaluate gene expression, DNA methylation and micro- RNA profiles in pre- and post-treatment tumor biopsies [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
  Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1.
• To compare gene expression, DNA methylation, and microRNA profiles in patient tumor biopsies with treatment response profiles in pre-clinical studies [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
  Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1.
• To examine if mithramycin decreases pluripotent cancer stem cells (side population) [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
  Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1.
• To develop methodologies for assessing effects of mithramycin on cancer stem cells, hematopoietic stem cells, mesenchymal stem cells, and circulating tumor cells (CTC) [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
  Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1. Plasma and blood will also be collected.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Continuous 24h Intravenous Infusion of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in People With Primary Thoracic Malignancies or Carcinomas, Sarcomas or Germ Cell Neoplasms With Pleuropulmonary Metastases
• Official Title: Phase I/II Evaluation of Continuous 24h Intravenous Infusion of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in Patients With Primary Thoracic Malignancies or Carcinomas, Sarcomas or Germ Cell Neoplasms With Pleuropulmonary Metastases

Brief Summary

Background:

Mithramycin is a new cancer drug. In another study, people with chest cancer took the drug 6 hours a day for 7 straight days. Many of them had liver damage as a side effect. It was discovered that only people with certain genes got this side effect. Researchers want to test mithramycin in people who do not have those certain genes.

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Objectives:

To find the highest safe dose of mithramycin that can be given to people with chest cancer who have certain genes over 24 hours instead of spread out over a longer period of time. To see if mithramycin given as a 24-hour infusion shrinks tumors.

Eligibility:

People ages 18 and older who have chest cancer that is not shrinking with known therapies, and whose genes will limit the chance of liver damage from mithramycin

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Lung and heart function tests

X-rays or scans of their tumor

Liver ultrasound

Tumor biopsy

Participants will be admitted to the hospital overnight. A small plastic tube (catheter) will be inserted in the arm or chest. They will get mithramycin through the catheter over about 24 hours.

If they do not have bad side effects or their cancer does not worsen, they can repeat the treatment every 14 days.

Participants will have multiple visits for each treatment cycle. These include repeats of certain screening tests.

After stopping treatment, participants will have weekly visits until they recover from any side effects.

Detailed Description

Background:

Increasing evidence indicates that activation of stem cell gene expression is a common mechanism by which environmental carcinogens mediate initiation and progression of thoracic malignancies. Similar mechanisms appear to contribute to extra-thoracic malignancies that metastasize to the chest. Utilization of pharmacologic agents, which target gene regulatory networks mediating "stemness" may be novel strategies for treatment of these neoplasms. Recent studies performed in the Thoracic Epigenetics

Laboratory, NCI, demonstrate that under exposure conditions potentially achievable in clinical settings, mithramycin diminishes stem cell gene expression and markedly inhibits growth of lung and esophageal cancer and malignant pleural mesothelioma (MPM) cells in vitro and in vivo. These findings add to other recent preclinical studies demonstrating impressive anti-tumor activity of mithramycin in epithelial malignancies and sarcomas that frequently metastasize to the thorax.

Primary Objectives:

• Phase I component: To determine pharmacokinetics, toxicities, and maximum tolerated dose (MTD) of mithramycin administered as a continuous 24h infusion in patients with primary thoracic malignancies or carcinomas, sarcomas or germ cell tumors metastatic to the chest.
• Phase II component: To determine objective response rates (CR+PR) of mithramycin administered as 24h intravenous infusions in patients with primary thoracic malignancies or carcinomas, sarcomas or germ cell tumors metastatic to the chest.

Eligibility:

• Patients with measurable inoperable, histologically confirmed lung and esophageal carcinomas, thymic neoplasms, germ cell tumors, malignant pleural mesotheliomas or chest wall sarcomas, as well as patients with gastric, colorectal or renal cancers and sarcomas metastatic to the thorax are eligible.
• Patients with favorable germline SNPs in ABCB4, ABCB11, RALBP or CYP8B1 that are associated with resistance to mithramycin-induced hepatotoxicity.
• Patients must have had or refused first-line standard therapy for their malignancies.
• Patients must be 18 years or older with an ECOG performance status of 0 - 2, without evidence of unstable or decompensated myocardial disease. Patients must have adequate pulmonary reserve evidenced by FEV1 and DLCO equal to or greater than 30% predicted; Oxygen saturation >= 92% on room air. ABG will be drawn if clinically indicated.
• Patients must have a platelet count greater than or equal to 100,000, an ANC equal to or greater than 1500 without transfusion or cytokine support, a normal PT/PTT, and adequate hepatic function as evidenced by a total bilirubin of < 1.5 x upper limits of normal (ULN) and AST/ALT <= 3 X ULN.
• Serum creatinine within normal institutional limits or creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.

Design:

• Single arm Phase I dose escalation to define pharmacokinetics, toxicities and MTD.
• Patient cohorts will receive 24h infusions of mithramycin targeting total doses previously administered during 7 daily six hour infusions at 30-50 mcg/kg.
• The 24h infusions will be administered every 14 days (1 cycle). Four cycles will constitute one course of therapy.
• Pharmacokinetics and toxicity assessment to define MTD will be assessed during Cycle 1 of the first course of therapy.
• Due to uncertainties regarding potential cumulative toxicities, no intra-patient dose escalation will be allowed.
• Once MTD has been defined, patients will be enrolled into two cohorts (primary thoracic malignancy vs neoplasm of non-thoracic origin metastatic to the chest) to determine clinical response rates at the MTD, using a Simon Optimal Two Stage Design for Phase II Clinical Trials targeting an objective response rate (RECIST) of 30%.
• Following each course of therapy, patients will undergo restaging studies. Patients exhibiting objective response to therapy or stable disease by RECIST criteria will be offered an additional course of therapy.
• Patients exhibiting disease progression will be removed from study.
• Biopsies of index lesions will be obtained at baseline and on Day 4 of the first cycle of therapy for analysis of pharmacodynamic endpoints. Optional tumor biopsies may be requested at the completion of Course 1 (4 cycles) and in patients exhibiting objective responses.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Esophageal Neoplasms
• Lung Neoplasms
• Mesothelioma
• Thymus Neoplasms
• Neoplasms, Germ Cell and Embryonal

Intervention

Drug: Mithramycin

Phase 1: 24 hour intravenous infusion of mithramycin given once every 14 days at escalating doses; Phase 2: 24 hour intravenous infusion of mithramycin given once every 14 days at MTD established in phase 1

Study Arms

• Experimental: Phase I
  Escalating doses of Mithramycin
  Intervention: Drug: Mithramycin
• Experimental: Phase II
  Mithramycin administered at MTD
  Intervention: Drug: Mithramycin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 7, 2020): 60
• Original Estimated Enrollment (submitted: August 6, 2016): 100
• Estimated Study Completion Date: August 3, 2028
• Estimated Primary Completion Date: August 3, 2028 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:
• Patients with measurable inoperable, histologically confirmed non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), esophageal carcinomas, thymic neoplasms, germ cell tumors, malignant pleural mesotheliomas or chest wall sarcomas, as well as patients with gastric, colorectal, pancreas or renal cancers, and sarcomas metastatic to thorax.
• Histologic confirmation of disease in the Laboratory of Pathology, CCR, NCI, NIH.
• Disease amenable to biopsy via percutaneous approach or other minimally invasive procedures such as thoracoscopy, bronchoscopy, laparoscopy, or GI endoscopy.
• Age >= 18.
• ECOG status 0-2.
• Patients must have had, or refused first-line standard chemotherapy for their inoperable malignancies.
• Patients must have had no chemotherapy, biologic therapy, or radiation therapy for their malignancy for at least 30 days prior to treatment. Patients may have received localized radiation therapy to non-target lesions provided that the radiotherapy is completed 14 days prior to commencing therapy, and the patient has recovered from any toxicity. At least 3 half-lives must have elapsed since monoclonal antibody treatment. At least 6 weeks must have elapsed between mitomycin C or nitrosourea treatment.

• Patients must have adequate organ and marrow function as defined below:

  1. Hematologic and Coagulation Parameters

     • Peripheral ANC greater than or equal to 1500/mm(3)
     • Platelets greater than or equal to 100,000/ mm(3) (transfusion independent)
     • Hemoglobin greater than or equal to 8 g/dL (PRBC transfusions permitted)
     • PT/PTT within normal limits (patient may be eligible for trial if abnormality is deemed clinically insignificant and cleared for protocol therapy by Hematology Consult service)

  2. Hepatic Function

     • Bilirubin (total) < 1.5 times upper limit of normal (ULN)
     • ALT (SGPT) less than or equal to 3.0 times ULN
     • Albumin > 2 g/dL

  3. Renal Function

     • Creatinine within normal institutional limits or creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.
     • Normal ionized calcium, magnesium and phosphorus (can be on oral supplementation)
• Cardiac Function: Left ventricular ejection fraction (EF) >40% by echocardiogram, MUGA, or cardiac MR.
• Ability of subject to understand, and be willing to sign informed consent.
• Female and male patients (and when relevant their partners) must be willing to practice birth control (including abstinence) during and for 2 months after treatment if female of childbearing potential or male having sexual contact with a female of childbearing potential.
• Patients must be willing to undergo 2 tumor biopsies.

EXCLUSION CRITERIA:

• Patients with unfavorable ABCB4, ABCB11, RALBP or CYP8B1 genotypes associated with mithramycin-mediated hepatotoxicity
• 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 cerebral metastases.
• Patients with any of the following pulmonary function abnormalities will be excluded: FEV, < 30% predicted; DLCO, < 30% predicted (post-bronchodilator); Oxygen saturation less than or equal to 92% on room air (per vital sign measurement). Arterial blood gas will be drawn if clinically indicated.
• Patients with evidence of active bleeding, intratumoral hemorrhage or history of bleeding diatheses, unless specifically occurring as an isolated incident during reversible chemotherapy-induced thrombocytopenia.
• Patients on therapeutic anticoagulation. Note: Prophylactic anticoagulation (i.e. intralumenal heparin) for venous or arterial access devices is allowed.

• Patients who are concurrently receiving or requiring any of the following agents, which may increase the risk for mithramycin related toxicities, such as hemorrhage:

  • Thrombolytic agents
  • Aspirin or salicylate-containing products, which may increase risk of hemorrhage
  • Dextran
  • Dipyridamole
  • Sulfinpyrazone
  • Valproic acid
  • Clopidogrel
• 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 mithramycin.
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Tricia Kunst, R.N.; (240) 760-6234; tricia.kunst@nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02859415
• Other Study ID Numbers: 160152; 16-C-0152
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: David S Schrump, M.D.; National Cancer Institute (NCI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: January 8, 2021