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NCT04648826 | Withdrawn Phase 1 FDA Drug

• 2 other identifiers: 21000421-C-0004
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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....

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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

  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.

  baseline, first treatment, end of each course

• 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

  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.

  baseline, end of each course

Study Arms (2)

1/ Phase I Dose Escalation

EXPERIMENTAL

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; Drug: Bintrafusp alfa; Drug: Azacytidine

2/ Phase II Dose Expansion

EXPERIMENTAL

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; Drug: Bintrafusp alfa; Drug: Azacytidine

Interventions

AeroEclipse II Breath Actuated Nebulizer DEVICE

Patients will receive AZA via commercial device, AeroEclipse II Breath Actuated Nebulizer.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

Bintrafusp alfa DRUG

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.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

Azacytidine DRUG

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.

1/ Phase I Dose Escalation; 2/ Phase II Dose Expansion

Eligibility Criteria

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

You may qualify if:

• Histologically or cytologically confirmed, unresectable pulmonary metastases from sarcomas, melanomas, germ cell tumors, or epithelial malignancies excluding lung and renal cell carcinomas.
• 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.
• Patients with bone metastases (less than 5 sites) are potentially eligible for study.
• Patients must have received first line standard of care systemic treatment for their malignancies.
• Patients with tumors with potentially actionable mutations are eligible for study if their metastases are refractory to approved first-line targeted agents.
• Patient's PD-L1 expression in cancer cells may be positive or negative as quantitated by immunohistochemistry techniques.
• Patients must have measurable disease per RECIST 1.1.
• 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.
• 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.
• ECOG performance status of less than or equal to 1
• 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.
• 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

You may not qualify if:

• Patients with cancers harboring mutations targetable with approved agents who have not progressed on targeted therapy.
• 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.
• Patients with renal cancers are excluded from study due to potential bleeding from these highly vascular metastases.
• Active smokers
• Patients either receiving systemic steroids other than physiologic replacement doses, or inhaled corticosteroids.
• 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.
• History of allergic reactions attributed to compounds of chemical or biologic composition similar to Bintrafusp alfa and AZA.
• 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.
• History of pneumonitis (idiopathic or drug induced) unless cleared by pulmonary consultants.
• Receipt of any organ transplantation, including allogeneic stem-cell transplantation, except for transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
• Active Hepatitis A, Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
• Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness due to unknown effects of AZA on systemic immunity.
• Other active infection requiring systemic therapy, including COVID-19 (testing will be required as part of screening).
• 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.

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

Sarcoma; Melanoma; Neoplasms, Germ Cell and Embryonal; Carcinoma, Renal Cell

Interventions

bintrafusp alfa protein, human; Azacitidine

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; 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)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• David S Schrump, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2020
• First Posted: December 2, 2020
• Study Start: December 14, 2021
• Primary Completion: December 14, 2021
• Study Completion: December 14, 2021
• Last Updated: December 17, 2021

Record last verified: 2021-12

Locations

US (1)