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

NCT02859415 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 16015216-C-0152
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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. 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.

Conditions

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

Keywords

Metastatic Colorectal Cancer; Sarcoma; ABCB4 Liver Toxicity; ABCB11 Hepatotoxicity; Metastatic Renal Cancer

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD)

  MTD is defined as the number of participants experiencing a dose-limiting toxicity (DLT). A DLT is defined as Grade 4 or greater anemia or neutropenia exceeding 5 days duration, thrombocytopenia requiring transfusion, or Grade 3 or greater nonhematologic toxicity possibly, probably, or definitely related to the investigational therapy excluding alopecia during Cycle 1 of therapy.

  At the end of first 14 day cycle at each dose level

• Number of Participants Whose Best Response is a Complete Response (CR) or Partial Response (PR)

  Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

  every 8 weeks until at disease progression, approximately 3.5 months

Secondary Outcomes (5)

• To Ascertain if Mithramycin Inhibits Stem Cell Gene Expression in Participants With Thoracic Malignancies

  baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1

• To Evaluate Gene Expression, Deoxyribonucleic Acid (DNA) Methylation and Micro-ribonucleic Acid (RNA) Profiles in Pre- and Post-treatment Tumor Biopsies

  baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1

• To Compare Gene Expression, Deoxyribonucleic Acid (DNA) Methylation and Micro-ribonucleic Acid (RNA) Profiles in Participant Tumor Biopsies With Treatment Response Profiles in Pre-clinical Studies

  baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1

• To Examine if Mithramycin Decreases Pluripotent Cancer Stem Cells (Side Population)

  baseline, 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)

  baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1

Other Outcomes (2)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, approximately 1 month and 4 days, and 3 months and 17 days for the first and second group respectively.

• Number of Participants With a Dose-limiting Toxicity (DLT)

  Cycle 1

Study Arms (2)

Phase I/Escalating doses of Mithramycin

EXPERIMENTAL

Escalating doses of Mithramycin

Drug: Mithramycin

Phase II/Mithramycin administered at Maximum Tolerated Dose (MTD)

EXPERIMENTAL

Mithramycin administered at MTD

Drug: Mithramycin

Interventions

Mithramycin DRUG

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

Also known as: Plicamycin

Phase I/Escalating doses of Mithramycin; Phase II/Mithramycin administered at Maximum Tolerated Dose (MTD)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH).
• Disease amenable to biopsy via percutaneous approach or other minimally invasive procedures such as thoracoscopy, bronchoscopy, laparoscopy, or gastrointestinal (GI) endoscopy.
• Age \>= 18.
• Eastern Cooperative Oncology Group (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:
• Hematologic and Coagulation Parameters
• Peripheral absolute neutrophil count (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)
• Prothrombin Time (PT)/partial thromboplastin time (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)
• Hepatic Function
• Bilirubin (total) \< 1.5 times upper limit of normal (ULN)

You may not qualify if:

• Patients with unfavorable ATP Binding Cassette Subfamily B Member 4 (ABCB11), Ral binding protein (RALBP) or Cytochrome P450 Family 8 Subfamily B Member 1 (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: forced expiratory volume (FEV), \< 30% predicted; diffusing capacity for carbon monoxide (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. intraluminal 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).

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Esophageal Neoplasms; Lung Neoplasms; Mesothelioma; Thymus Neoplasms; Neoplasms, Germ Cell and Embryonal; Colorectal Neoplasms; Sarcoma; Kidney Neoplasms

Interventions

Plicamycin

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial; Lymphatic Diseases; Hemic and Lymphatic Diseases; Intestinal Neoplasms; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplasms, Connective and Soft Tissue; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital 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. David S. Schrump
• Organization: National Cancer Institute

schrumpd@mail.nih.gov

240-858-7000

Study Officials

• David S Schrump, 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: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 6, 2016
• First Posted: August 9, 2016
• Study Start: August 8, 2019
• Primary Completion: December 6, 2019
• Study Completion: December 1, 2021
• Last Updated: April 5, 2022
• Results First Posted: April 5, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF

Locations

US (1)