5-Azacitidine Plus PD-1/PD-L1 Inhibitor With PD-1/PD-L1 Refractory Tumors

Phase I Study of 5-Azacitidine Plus PD-1/PD-L1 Inhibitor in Patients With PD-1/PD-L1 Refractory Tumors

This is a Phase I study to determine the optimal biological dose (OBD) of 5-Azacitidine in combination with PD-1/PD-L1 inhibitors in patients with tumors refractory to PD-1/PD-L1 inhibitors, for which such treatments have been approved.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor; Locally Advanced Solid Tumor; Metastatic Tumor
• Intervention / Treatment: Drug: 5 Azacytidine; Drug: Pembrolizumab; Drug: Nivolumab; Drug: Cemiplimab

Detailed Description

This is a Phase I study to determine the optimal biological dose (OBD) of 5-Azacitidine in combination with PD-1/PD-L1 inhibitors in patients with tumors refractory to PD-1/PD-L1 inhibitors, for which such treatments have been approved.

This Phase I study will assess 6 doses of 5-Azacitidine (5, 10, 15, 25, 50 and 75 mg/m2) in combination with a PD1/PD-L1 inhibitor. The PD1/PD-L1 inhibitor will be given at standard of care dosing approved by the FDA for this indication.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Mohammed Milhem, MD; Phone Number: +1 319 356 2324; Email: mohammed-milhem@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa Health Care
      • Contact: Mohammed Milhem, MD; Phone Number: +1 319 356 2324; Email: mohammed-milhem@uiowa.edu
      • Contact: Milhem

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written and voluntary informed consent.
• At least 18 years of age or older.
• Histologically and radiologically confirmed locally advanced or metastatic unresectable solid tumor malignancy for which PD-1 or PD-L1 therapy is already approved by the FDA. Locally advanced is defined as unresectable in the opinion of the treating physician. A repeat biopsy is required if previous biopsy tissue is unavailable.
• At least one Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - defined target lesion.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able to carry on all pre-disease performance without restriction), 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, such as light housework or office work), or 2 (ambulatory and capable of self-care but unable to carry out any work activities, spending more than 50% of waking hours up and about).
• Documented progression on PD1 or PD-L1 inhibitors.
• Recovery from any acute toxicity associated with prior therapy to grade 1.
• Renal function (creatinine level within normal institutional limit, or creatinine clearance >15 mL/min/1.73 m2 for patients with creatinine levels above institutional normal, calculated using the Cockcroft-Gault formula).
• Liver function (AST/ALT <3.0 X institutional upper limit of normal OR <5 X institutional upper limit of normal in cases of liver metastasis; total bilirubin ≤ 1.5 times upper limit of normal).

• Adequate hematological lab values including:

  • Absolute Neutrophil Count (ANC) ≥ 1.0 X 109/L
  • Platelets ≥ 100X109/L
  • Hemoglobin ≥ 7.0 g/dL
• Female subjects of childbearing potential and non-sterilized male subjects who intend to be sexually active during the study must agree to use a highly effective method of contraception from time of screening, throughout the whole duration of the drug treatment, and during the 6-month post-treatment washout period.
• Patients may have previously received a hypomethylating agent, as long as it was not given in combination with ipilimumab.
• Patients may have previously received ipilimumab but must have relapsed or progressed while on therapy.
• Patients must have adequate archival tissue available for the purpose of downstream methylation status assessment, immunohistochemistry, RNA expression (10 slides at 5µM). If archival tissue is not available, a repeat biopsy is required.

Exclusion Criteria:

• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
• Patients with active, untreated metastases in the central nervous system.
• Patients who are pregnant or breastfeeding.
• Patients who have an active infection.
• Patients with significant hematologic, hepatic, and renal function impairment.
• Patients who are being treated for any concurrent medical condition requiring the use of systemic steroids or history of long-term use of systemic steroids.
• Patients who have a history of inflammatory bowel disease or a history of symptomatic autoimmune disease.
• Patients who have had any major surgical procedure or significant traumatic injury within 28 days prior to study enrollment.
• Patients who have received chemotherapy, immunosuppressive agents or any investigational drug within 28 days prior to starting the study drugs.
• Patients who have any underlying medical condition which, in the treating physician's opinion, will make the administration of study drugs hazardous or obscure the interpretation of adverse events.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 5-Azacitidine Plus PD-1/PD-L1 inhibitor; This Phase I study will assess 6 doses of 5-Azacitidine (5, 10, 15, 25, 50 and 75 mg/m2) in combination with a PD1/PD-L1 inhibitor. The PD1/PD-L1 inhibitor will be given at standard of care dosing approved by the FDA for this indication. Inhibitors approved for study indications include Pembrolizumab, Nivolumab, and Cemiplimab.

Drug: 5 Azacytidine; 5-Azacitidine (Azacitidine) is a nucleoside analogue chemotherapy drug; Drug: Pembrolizumab; Pembrolizumab is a high-affinity humanized monoclonal antibody that functions as immune checkpoint inhibitor; Drug: Nivolumab; Nivolumab is a high-affinity humanized monoclonal antibody that functions as immune checkpoint inhibitor; Drug: Cemiplimab; Cemiplimab is a high-affinity humanized monoclonal antibody that functions as immune checkpoint inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose-limiting toxicities and responses as defined by CTCAE v5.0	Assess the safety and tolerability of 5-Azacitidine Plus PD-1/PD-L1 inhibitor	Treatment initiation through 30 days +/- 7 days post completion of therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with a complete response (CR)	The proportion of patients with a pathologic complete response, defined as disappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor marker level	Treatment initiation through five years
Proportion of participants with a partial response (PR)	At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD	Treatment initiation through five years
Overall Survival (OS)	Time from study treatment initiation to death due to any cause	Treatment initiation through five years
Progression Free Survival (PFS)	Time from study treatment initiation to disease progression or death due to any cause	Treatment initiation through five years

Collaborators and Investigators

• Sponsor: Mohammed Milhem
• Investigators: Principal Investigator: Mohammed Milhem, MD, University of Iowa

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2026
• Primary Completion (Estimated): February 28, 2028
• Study Completion (Estimated): February 28, 2031

Study Registration Dates

• First Submitted: February 4, 2026
• First Submitted That Met QC Criteria: February 4, 2026
• First Posted (Actual): February 11, 2026

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Nivolumab; Azacitidine; pembrolizumab; cemiplimab
• Other Study ID Numbers: 202511023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No