Impact of Circadian Rhythm on Immunotherapy

Assessing the Impact of Circadian Rhythm on Anti-PD-1/PD-L1 Immunotherapy

This study aims to determine whether morning versus afternoon treatment impacts efficacy of (standard of care) immunotherapy in a broad patient population. Patients with any type of advanced/metastatic malignancy are eligible to enroll in this study, as long as first-line anti-PD-1/PD-L1 immunotherapy is on label for their condition. Participants will then be randomized to either the early treatment group (administration must start and conclude by 11:00 AM +1 hour window) or the late treatment group (administration must start after 12:00 PM).

Study Overview

• Status: Recruiting
• Conditions: Advanced/Metastatic NSCLC
• Intervention / Treatment: Drug: Immunotherapy - PD-1 Blocker

Detailed Description

The US market has many FDA approved options for anti-PD-1/PD-L1 immunotherapies, including pembrolizumab, nivolumab, cemiplimab, durvalumab, dostarlimab, avelumab, and atezolizumab, among others that are in development. With an estimated 56.55% of cancer patients eligible for treatment with anti-PD-1/PD-L1 immunotherapy (as of 2023), the impact of timing on immunotherapy efficacy should be delineated in order to provide the best care possible to patients This study will be implemented at a large regional cancer center in the United States. Three patient cohorts will be investigated: Non-Small Cell Lung Cancer (NSCLC) patients who receive first-line ICI therapy (Cohort A), NSCLC patients with stable disease or response after induction therapy receiving maintenance ICI therapy (Cohort B), and solid tumor patients receiving first-line ICI therapy (Cohort C).

To the best the knowledge of this principal investigator, this is the first prospective time-of-day immunotherapy study to take place in the US. Key endpoints include real-world progression free survival (rwPFS)[26], overall survival (OS), safety, quality of life (QoL), and pharmacoeconomic outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 350
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jennifer Ruth, RN; Phone Number: 412-623-8963; Email: ruthj2@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • UPMC Hillman Cancer Center
      • Contact: Jennifer Ruth, RN; Phone Number: 412-623-8963; Email: ruthj2@upmc.edu
      • Principal Investigator: Liza Villaruz, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Cohort Specific Criteria

   • Cohort A: Advanced/metastatic NSCLC patients for which 1st line PD-1/PD-L1 therapy is on-label either alone or in combination.
   • Cohort B: Advanced/metastatic NSCLC patients who have completed up to 4 cycles of induction therapy who have stable disease or responsive disease and for which maintenance anti-PD-1/PD-L1 therapy is on-label either alone or in combination.
   • Cohort C: Advanced/metastatic solid tumor malignancy for which first-line anti-PD-1/PD-L1 therapy is on-label either alone or in combination.

2. Prior and concurrent therapy criteria

   o Patients should be ICI-naïve (this should be first-line therapy) (Cohorts A and C), or should have received ICI induction therapy and are now eligible for ICI maintenance therapy (Cohort B).

3. Must be willing to be randomized to complete therapy at assigned time of day, which may be early in the morning OR later in the day/into the evening.
4. Must be eligible to receive anti-PD-1/PD-L1 therapy singly or in combination with other FDA-approved agents according to standard of care practices, as determined by the clinical judgment of the investigator but according to approved label indications
5. Must have the ability to understand and the willingness to sign a written informed consent document.
6. Able to read and write in English.

Exclusion Criteria:

1. Participant unable to receive anti-PD-1/PD-L1 therapy due to prior allergic reactions to therapy or any therapy ingredients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early Immunotherapy dosing; NSCLC and solid tumor patients who receive first-line or ICI therapy early in the day (prior to 11AM) versus late in the day (after 12PM) and NSCLC patients with stable or response disease after induction therapy receiving maintenance ICI therapy early in the day (prior to 11AM) versus late in the day (after 12PM)	Drug: Immunotherapy - PD-1 Blocker; Standard of Care Drugs (at investigator's discretion) may include: pembrolizumab, nivolumab, cemiplimab, durvalumab, dostarlimab, avelumab, and atezolizumab, or other immune checkpoint inhibitors used in cancer treatment that targets cancer cells by blocking the PD-1 receptor on T cells.
Active Comparator: Late Immunotherapy dosing; NSCLC and solid tumor patients who receive first-line or ICI therapy late in the day (started after 12 PM) and NSCLC patients with stable or response disease after induction therapy receiving maintenance ICI therapy late in the day (started after 12PM)	Drug: Immunotherapy - PD-1 Blocker; Standard of Care Drugs (at investigator's discretion) may include: pembrolizumab, nivolumab, cemiplimab, durvalumab, dostarlimab, avelumab, and atezolizumab, or other immune checkpoint inhibitors used in cancer treatment that targets cancer cells by blocking the PD-1 receptor on T cells.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Real-world progression-free survival (rwPFS) - Cohort A	Time from first dose of 1st line treatment to clinician documented clinical disease progression, initiation of new line of therapy, or death from any cause, whichever comes first. Real-world progression-free survival (rwPFS), defined as the time from first dose of 1st line treatment to clinician documented clinical disease progression, initiation of new line of therapy, or death from any cause, whichever came first. Per RECISIT v1.1, Progressive Disease: ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.	Up to 4.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) - Cohort A	Overall Survival (OS) defined as time from first dose of 1st line treatment to death from any cause.	Up to 4.5 years
Real-world progression-free survival (rwPFS) - Cohort B	Time from first dose of 1st line treatment to clinician documented clinical disease progression, initiation of new line of therapy, or death from any cause, whichever came first. Per RECISIT v1.1, Progressive Disease: ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.	Up to 4.5 years
Real-world progression-free survival (rwPFS) - Cohort C	Time from first dose of 1st line treatment to clinician documented clinical disease progression, initiation of new line of therapy, or death from any cause, whichever came first. Per RECISIT v1.1, Progressive Disease: ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.	Up to 4.5 years
Overall Survival (OS) - Cohort B	Overall Survival (OS) defined as time from first dose of 1st line treatment to death from any cause.	Up to 4.5 years
Overall Survival (OS) - Cohort C	Overall Survival (OS) defined as time from first dose of 1st line treatment to death from any cause.	Up to 4.5 years
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort A	Patient reported HRQoL scores using the EQ-5D-5L instrument. EQ-5D-5L is a preference-based measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Scores from each of the five dimensions range from 1 to 5. Total score ranges from 5 to 25, where higher scores indicate worse health status.	At Screening - Up to 28 days after signed consent]
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort B	Patient reported HRQoL scores using the EQ-5D-5L instrument. EQ-5D-5L is a preference-based measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Scores from each of the five dimensions range from 1 to 5. Total score ranges from 5 to 25, where higher scores indicate worse health status.	At Screening - Up to 28 days after signed consent]
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort C	Patient reported HRQoL scores using the EQ-5D-5L instrument. EQ-5D-5L is a preference-based measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Scores from each of the five dimensions range from 1 to 5. Total score ranges from 5 to 25, where higher scores indicate worse health status.	At Screening - Up to 28 days after signed consent]
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort A	Patient reported HRQoL scores using the EQ-5D-5L instrument. EQ-5D-5L is a preference-based measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Scores from each of the five dimensions range from 1 to 5. Total score ranges from 5 to 25, where higher scores indicate worse health status.	At Day 1 of Each Treatment Cycle (2-6-week cycles, per specific agent)
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort B	Patient reported HRQoL scores using the EQ-5D-5L instrument. EQ-5D-5L is a preference-based measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Scores from each of the five dimensions range from 1 to 5. Total score ranges from 5 to 25, where higher scores indicate worse health status.	At Day 1 of Each Treatment Cycle (2-6-week cycles, per specific agent)
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort C	Patient reported HRQoL scores using the EQ-5D-5L instrument. EQ-5D-5L is a preference-based measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Scores from each of the five dimensions range from 1 to 5. Total score ranges from 5 to 25, where higher scores indicate worse health status.	At Day 1 of Each Treatment Cycle (2-6-week cycles, per specific agent)

Collaborators and Investigators

• Sponsor: Liza Villaruz, MD
• Investigators: Principal Investigator: Liza Villaruz, MD, UPMC Hillman Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2025
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2030

Study Registration Dates

• First Submitted: October 31, 2025
• First Submitted That Met QC Criteria: November 3, 2025
• First Posted (Estimated): November 5, 2025

Study Record Updates

• Last Update Posted (Estimated): December 9, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Circadian Rhythm; anti-PD-1/PD-L1 Immunotherapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: HCC 25-127

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
• product manufactured in and exported from the U.S.: No