Clinical Trials /

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

NCT04648826

Description:

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.

Related Conditions:
  • Epithelial Neoplasm
  • Germ Cell Tumor
  • Melanoma
  • Sarcoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 210004
  • SECONDARY ID: 21-C-0004
  • NCT ID: NCT04648826

Conditions

  • Sarcomas
  • Melanomas
  • Germ Cell Tumors
  • Epithelial Malignancies (Excluding Lung and Renal Cell Carcinomas)
  • Pulmonary Metastases

Interventions

DrugSynonymsArms
Bintrafusp alfa1/ Phase I Dose Escalation
Azacytidine1/ Phase I Dose Escalation

Purpose

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.

Detailed Description

      Background:

      While malignancies of diverse histologies express a variety of cancer-testis antigens (CTAs),
      immune responses to these proteins appear uncommon in cancer patients due to low-level,
      heterogeneous antigen expression, as well as local and systemic immunosuppression.

      CTAs such as NY-ESO-1 and MAGE-A3 can be up-regulated in tumor cells of various histologies,
      but not in normal cells, by DNA demethylating agents such as decitabine (DAC) and azacytidine
      (AZA). Up-regulation of these CTAs facilitates CTL-mediated lysis of tumor cells.

      Clinical trials have demonstrated impressive regressions of tumors expressing NY-ESO-1
      following adoptive immunotherapy targeting this CTA.

      In addition to shared CTAs, unique neoantigens are major targets for immune eradication of
      cancer cells.

      DNA demethylating agents not only up-regulate cancer-testis (CT) genes but also induce
      expression of endogenous retroviruses (ERV) which further augments immunogenicity of cancer
      cells.

      Additionally, DNA demethylating agents enhance antigen processing and presentation by cancer
      cells, and inhibit activity of myeloid derived suppressor cells (MDSC), thereby increasing
      the efficacy of immune checkpoint inhibitors in murine tumor models.

      Despite these provocative preclinical results, epigenetic priming for immune checkpoint
      blockade has yet to be translated to humans due to systemic toxicities and
      pharmacokinetic/pharmacodynamic limitations that prevent optimal dosing of DNA demethylating
      agents.

      One potential strategy to enhance delivery of DNA demethylating agents to pulmonary
      malignancies while minimizing systemic toxicities is to administer these drugs by inhalation
      techniques.

      Preclinical studies have demonstrated that aerosolized AZA mediates epigenetic activation of
      gene expression in orthotopic lung cancers, and significantly prolongs survival of mice
      bearing these tumors without systemic toxicities.

      Conceivably, inhaled AZA may help to prime pulmonary malignancies for immune checkpoint
      blockade.

      In this study, the optimal dose of inhaled AZA will be established in patients with
      unresectable pulmonary metastases who are receiving the dual immune checkpoint
      inhibitor-TGF-Beta trap, Bintrafusp alfa (M7824).

      This trial is intended to establish the rationale for further evaluation of inhalational
      epigenetic priming regimens in combination with immune checkpoint inhibitors or adoptive cell
      transfer regimens in patients with locally advanced pulmonary malignancies.

      Objectives:

      Phase I component: To determine pharmacokinetics, toxicities, maximum tolerated dose (MTD)
      and recommended Phase 2 dose (RP2D) of aerosolized AZA in patients receiving Bintrafusp alfa
      for unresectable pulmonary metastases

      Phase II component: To determine frequency of intrathoracic clinical responses in these
      patients following administration of aerosolized AZA at the RP2D and Bintrafusp alfa.

      Both components: To determine safety of aerosolized AZA and Bintrafusp alfa in patients with
      unresectable pulmonary metastases.

      Eligibility Criteria:

      Patients with histologically or cytologically proven, unresectable pulmonary metastases from
      sarcomas, melanomas, germ cell tumors, or epithelial malignancies (except lung or kidney
      cancers) who have received first line standard of care treatment for their metastatic
      disease.

      Measurable disease by RECIST

      Patients are eligible irrespective of intratumoral PD-L1 expression.

      Patients with prior treatment with an immune checkpoint inhibitor and DNA demethylating
      agents may be eligible for study provided they did not experience serious immune adverse
      events that required discontinuation of the drug, and more than three weeks have elapsed
      since treatment

      Patients greater than or equal to 18 years; ECOG performance status of 0-1 without evidence
      of unstable or decompensated myocardial disease; adequate pulmonary reserve evidenced by FEV1
      greater than or equal to 60% predicted, FEV1/FVC ratio greater than or equal to 60%, and
      adjusted DLCO greater than or equal to 60% predicted; pCO2 less than or equal to 45 mm Hg and
      pO2 greater than or equal to 60 mm Hg on room air ABG

      Adequate renal, hepatic and hematopoietic function

      Design:

      Subjects will receive aerosolized AZA on three consecutive days (i.e.; Days 1, 2, and 3, or
      Days 3, 4, 5) of a 21-day cycle. Three cycles constitute one course of treatment.

      Bintrafusp alfa will be administered at a fixed dose of 2400 mg. During Phase I, Bintrafusp
      alfa will be administered on Day 13 (i.e., once every 3 weeks, one week after AZA) of each
      cycle starting from Cycle 2 of Course 1 (i.e., no Bintrafusp alfa in the first cycle of
      Course 1). During Phase II, Bintrafusp alfa will be administered the day after the last AZA
      treatment, during Week 1 of each treatment cycle.

      The dose of AZA will be escalated during Phase I using a 3+3 design with no intrapatient dose
      escalation.

      The dose of AZA will be sequentially increased to maximize intra-tumoral DNMT1 depletion
      while avoiding Grade 3 or greater pulmonary or systemic toxicities attributable to this agent
      during the first cycle of therapy.

      Treatment evaluation will be three weeks +/- one week following completion of each course of
      therapy.

      Once the RP2D of aerosolized AZA has been defined, that dose level will be expanded to a
      total of 9 patients to determine response rates at the RP2D using a Simon two stage design
      for Phase II trials.

      Approximately 42 patients will be accrued to this trial.
    

Trial Arms

NameTypeDescriptionInterventions
1/ Phase I Dose EscalationExperimentalAzacytidine (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)
  • Bintrafusp alfa
  • Azacytidine
2/ Phase II Dose ExpansionExperimentalAzacytidine (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)
  • Bintrafusp alfa
  • Azacytidine

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • M7824
  • AZA
  • unresectable pulmonary metastases
  • inhalational epigenetic priming regimen
  • aerosol drug delivery

Last Updated

December 14, 2020