5-Azacitidine with PD-1/PD-L1 Inhibitor in PD-1/PD-L1 Refractory Tumors

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

What this trial studies

This is a Phase I trial to find the optimal biological dose of 5-azacitidine when given with a PD-1/PD-L1 inhibitor in patients whose tumors are refractory to PD-1/PD-L1 therapy. Six dose levels of 5-azacitidine (5 to 75 mg/m2) will be explored alongside standard-of-care PD-1/PD-L1 agents (pembrolizumab, nivolumab, or cemiplimab). The PD-1/PD-L1 inhibitor will be administered at approved FDA dosing for the indication. Eligible participants have locally advanced or metastatic unresectable solid tumors with a prior FDA-approved PD-1/PD-L1 therapy, adequate organ function, and measurable disease. Safety and preliminary signals of activity will guide dose selection for future studies.

Why it matters

Who can join: the full rules

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.

Where it's running

• University of Iowa Health Care
  Iowa City, Iowa, United States Recruiting

Study contacts

• Principal investigator: Mohammed Milhem, MD — University of Iowa
• Study coordinator: Mohammed Milhem, MD
• Email: mohammed-milhem@uiowa.edu
• Phone: +1 319 356 2324

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.