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Aerosolized Azacytidine as Epigenetic Priming for Bintrafusp Alfa-Mediated Immune Checkpoint Blockade in Patients With Unresectable Pulmonary Metastases From Sarcomas, Germ Cell Tumors, or Epithelial Malignancies

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ClinicalTrials.gov Identifier: NCT04648826
Recruitment Status : Not yet recruiting
First Posted : December 2, 2020
Last Update Posted : February 24, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

About one-third to one-half of all people dying of extrathoracic malignant diseases have cancer that has spread to the lungs. Surgery may help some people. But most people with pulmonary metastases do not survive long. Researchers want to see if a combination of drugs can help.

Objective:

To find a safe dose of Azacytidine, when taken as a fine mist that is inhaled (aerosolized Azacytidine), together with Bintrafusp Alfa to treat cancers that have spread to the lungs.

Eligibility:

Adults ages 18 and older who have cancer that has spread to the lungs, cannot be cured with surgery, and has not responded to standard treatments.

Design:

Participants will get Azacytidine by breathing treatments once a day for 3 days each week, for 3 weeks. The 3-week period is 1 cycle. Each course of treatment is 3 cycles.

Once per cycle, participants will get Bintrafusp Alfa via IV. An IV is a small tube that is put into an arm vein.

Participants will keep a diary of any side effects.

Participants can take the study drugs for as long as they can continue treatment.

Participants will have medical histories and physical exams. They will give blood, urine, and lung lining fluid samples. Tumor samples will be taken via bronchoscopy. They will have lung function tests.

Participants will have an imaging scan that shows how spray particles move in their airway when they inhale. They will have tumor imaging scans of the chest and brain.

Participants will have a follow-up visit 30 days after they stop treatment.


Condition or disease Intervention/treatment Phase
Sarcomas Melanomas Germ Cell Tumors Epithelial Malignancies (Excluding Lung and Renal Cell Carcinomas) Pulmonary Metastases Device: AeroEclipse II Breath Actuated Nebulizer Drug: Bintrafusp alfa Drug: Azacytidine Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Evaluation of Aerosolized Azacytidine as Epigenetic Priming for Bintrafusp Alfa-Mediated Immune Checkpoint Blockade in Patients With Unresectable Pulmonary Metastases From Sarcomas, Germ Cell Tumors, or Epithelial Malignancies
Estimated Study Start Date : March 1, 2021
Estimated Primary Completion Date : December 30, 2027
Estimated Study Completion Date : December 30, 2028


Arm Intervention/treatment
Experimental: 1/ Phase I Dose Escalation
Azacytidine (aerosolized) at escalating doses (given on 3 consecutive days in the first week of every 3-week cycle) with a flat dose of Bintrafusp alfa 2400 mg (given on day 13 [+/- 3 days] of every 3-week cycle starting with Cycle 2)
Device: AeroEclipse II Breath Actuated Nebulizer
Patients will receive AZA via commercial device, AeroEclipse II Breath Actuated Nebulizer.

Drug: Bintrafusp alfa
Bintrafusp alfa will be administered on Day 13 (+/- 3 days) of every 3-week cycle (i.e., Q3W [once every 3 weeks]) at a fixed intravenous dose of 2400 mg; Bintrafusp alfa does not start until cycle 2 of the phase I portion.

Drug: Azacytidine
Patients will receive azacytidine (aersolized; via commercial AeroEclipse II Breath Actuated Nebulizer device) on 3 consecutive days in the first week of every 3-week cycle. Phase I: Azacytidine will be given at escalating doses. Phase II: Azacytidine will be given at the RP2D established in Phase I.

Experimental: 2/ Phase II Dose Expansion
Azacytidine (aerosolized) at the RP2D established in Phase I (given on 3 consecutive days in the first week of every 3-week cycle) with a flat dose of Bintrafusp alfa 2400 mg (given on day 13 [+/- 3 days] of every 3-week cycle)
Device: AeroEclipse II Breath Actuated Nebulizer
Patients will receive AZA via commercial device, AeroEclipse II Breath Actuated Nebulizer.

Drug: Bintrafusp alfa
Bintrafusp alfa will be administered on Day 13 (+/- 3 days) of every 3-week cycle (i.e., Q3W [once every 3 weeks]) at a fixed intravenous dose of 2400 mg; Bintrafusp alfa does not start until cycle 2 of the phase I portion.

Drug: Azacytidine
Patients will receive azacytidine (aersolized; via commercial AeroEclipse II Breath Actuated Nebulizer device) on 3 consecutive days in the first week of every 3-week cycle. Phase I: Azacytidine will be given at escalating doses. Phase II: Azacytidine will be given at the RP2D established in Phase I.




Primary Outcome Measures :
  1. Phase I: Determine pharmacokinetics, toxicities, maximum tolerated dose and recommended Phase 2 dose (RP2D) of aerosolized AZA in patients receiving IV Bintrafusp alfa for unresectable pulmonary metastases [ Time Frame: baseline, first treatment, end of each course ]
    DLTs at each Phase I dose level will be reported. Pharmacokinetic analysis will be conducted using non-compartmental methods. All patients will be evaluable for toxicity from the time of their first treatment with AZA/ Bintrafusp alfa. Dose limiting toxicities will be assessed during the first 3 cycles of AZA/ Bintrafusp alfa therapy. Patients who have measurable disease present at baseline, have received at least 9 weeks of AZA/Bintrafusp alfa therapy (three cycles), and have had their disease re-evaluated will be considered evaluable for response.

  2. Phase II: Determine frequency of intrathoracic objective clinical response in patients with unresectable pulmonary metastases following administration of aerosolized AZA at the RP2D and IV Bintrafusp alfa [ Time Frame: baseline, end of each course ]
    Patients who have measurable disease present at baseline, have received at least 9 weeks of AZA/Bintrafusp alfa therapy (three cycles), and have had their disease re-evaluated will be considered evaluable for response provided.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Histologically or cytologically confirmed, unresectable pulmonary metastases from sarcomas, melanomas, germ cell tumors, or epithelial malignancies excluding lung and renal cell carcinomas.
    2. Patients with extrathoracic disease may be eligible provided there are 5 or fewer low volume non-thoracic sites (less than or equal to 3 cm/nodule) that are not life-threatening and are potentially treatable with metastasis-directed therapy whether they are symptomatic or not.
    3. Patients with bone metastases (less than 5 sites) are potentially eligible for study.
    4. Patients must have received first line standard of care systemic treatment for their malignancies.
    5. Patients with tumors with potentially actionable mutations are eligible for study if their metastases are refractory to approved first-line targeted agents.
    6. Patient's PD-L1 expression in cancer cells may be positive or negative as quantitated by immunohistochemistry techniques.
    7. Patients must have measurable disease per RECIST 1.1.
    8. Patient's pulmonary disease can be safely accessed via bronchoscopic, thoracoscopic or transthoracic percutaneous biopsy, and patient must be willing to undergo biopsy as well as bronchoscopy before and after treatment.
    9. Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of aerosolized AZA in patients < 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
    10. ECOG performance status of less than or equal to 1
    11. Patients must be without evidence of unstable or decompensated myocardial disease, and have adequate pulmonary reserve evidenced by FEV1 and adjusted DLCO greater than or equal to 60% predicted and FEV1/FVC ratio greater than or equal to 60%; pCO2 less than or equal to 45 and pO2 greater than ir equal to 60 on room air.
    12. Normal organ and marrow function as defined below:

      • leukocytes greater than or equal to 3,000/mcL
      • absolute neutrophil count greater than or equal to 1,500/mcL (without transfusion or cytokine support)
      • absolute lymphocyte count > 800/mcL
      • platelets greater than or equal to 100,000/mcL
      • Hgb greater than or equal to 9 g/ dL
      • PT no more than 2 seconds above the ULN
      • total bilirubin < 1.5 X institutional upper limit of normal

      OR

      • direct bilirubin less than or equal to ULN for patients with total bilirubin > 1.5 ULN
      • serum albumin greater than or equal to 2.0 mg/dL
      • AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional ULN
      • creatinine less than or equal to 1.6 mg/mL

      OR

      --creatinine clearance (eGFR) greater than or equal to 30 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

      at the time AZA and M7824 treatment commences.

    13. Patients with history of brain metastases except those with meningeal carcinomatosis or leptomeningeal disease may be eligible for treatment a minimum of 2 weeks following completion of gamma knife or whole brain radiotherapy, or 4 weeks following surgical resection of brain metastasis; provided post-treatment MR scan reveals no evidence of active disease, and no ongoing need for systemic steroids.
    14. The effects of AZA and Bintrafusp alfa on the developing human fetus are unknown. For this reason and because the agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 125 days following the last dose of Bintrafusp alfa for males, and 65 days following the last dose of Bintrafusp alfa for females.
    15. Ability of subject to understand and the willingness to sign a written informed consent document.
    16. Ability of subject and the willingness to co-enroll and sign a written informed consent document for 06C0014 "Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic Malignancies".

EXCLUSION CRITERIA:

  1. Patients with cancers harboring mutations targetable with approved agents who have not progressed on targeted therapy.
  2. Patients with primary lung cancers are excluded from study due to potential exacerbation of pulmonary toxicities from investigational therapy due to evolution or treatment of their malignancies.
  3. Patients with renal cancers are excluded from study due to potential bleeding from these highly vascular metastases.
  4. Active smokers
  5. Patients either receiving systemic steroids other than physiologic replacement doses, or inhaled corticosteroids.
  6. Previous treatment with targeted therapy, immune checkpoint inhibitor, DNA demethylating agent, systemic chemotherapy, or radiation therapy to an index lesion within three weeks prior to starting protocol therapy. Patients with prior treatment with immune checkpoint inhibitors, and DNA demethylating agents may be eligible for study provided more than three weeks have elapsed since treatment and they did not experience serious immune adverse events that required discontinuation of the immune checkpoint

    inhibitor.

  7. History of allergic reactions attributed to compounds of chemical or biologic composition similar to Bintrafusp alfa and AZA.
  8. Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class greater than or equal to II), serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism.
  9. History of pneumonitis (idiopathic or drug induced) unless cleared by pulmonary consultants.
  10. Receipt of any organ transplantation, including allogeneic stem-cell transplantation, except for transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
  11. Active Hepatitis A, Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  12. Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness due to unknown effects of AZA on systemic immunity.
  13. Other active infection requiring systemic therapy, including COVID-19 (testing will be required as part of screening).
  14. Pregnant women are excluded from this study because AZA and Bintrafusp alfa may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Bintrafusp alfa and AZA, breastfeeding should be discontinued if the mother is treated with Bintrafusp alfa and AZA.
  15. Other severe acute or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
  16. Recent major bleeding events considered by the Investigator as high risk for investigational drug treatment.
  17. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with the exceptions:

    • Diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment;
    • Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses less than or equal to 10 mg of prednisone or equivalent per day;
    • Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or intra-articular).
  18. Patients receiving another investigational agent.
  19. An additional malignancy that is progressing or requires active treatment.
  20. Administration of live vaccines with 28 days prior to enrollment. Administration of inactivated vaccines (e.g., inactivated influenza vaccines) is permitted during the study.
  21. Emotional, psychiatric or substance abuse disorders that would interfere with cooperation with the requirements and safety of the trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04648826


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

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: David S Schrump, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04648826    
Other Study ID Numbers: 210004
21-C-0004
First Posted: December 2, 2020    Key Record Dates
Last Update Posted: February 24, 2021
Last Verified: December 9, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
M7824
AZA
unresectable pulmonary metastases
inhalational epigenetic priming regimen
aerosol drug delivery
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplasms
Sarcoma
Neoplasms, Germ Cell and Embryonal
Lung Neoplasms
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Neoplasms, Connective and Soft Tissue
Neoplasms by Site
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors