Advanced/Metastatic NSCLCPhase 2NCT07224971
Impact of Circadian Rhythm on Immunotherapy
A Phase 2 study testing Immunotherapy - PD-1 Blocker in people with Advanced/Metastatic NSCLC, run by Liza Villaruz, MD at 1 site in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced/Metastatic NSCLC
- What is being tested?
- Immunotherapy - PD-1 Blocker
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 350 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Dec 2025to 1 May 2030
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
- 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).
Show all 10Show fewer
- 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.
- 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
- Must have the ability to understand and the willingness to sign a written informed consent document.
- Able to read and write in English.
Who cannot join
- 1. Participant unable to receive anti-PD-1/PD-L1 therapy due to prior allergic reactions to therapy or any therapy ingredients.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
Jennifer Ruth, RN, 412-623-8963, ruthj2@upmc.edu
Liza Villaruz, MD
About this study
Official title: 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).
Read the 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.
- Conditions
- Advanced/Metastatic NSCLC
- Being tested
- Immunotherapy - PD-1 Blocker
- Keywords
- anti-PD-1/PD-L1 Immunotherapy, Circadian Rhythm
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Immunotherapy - PD-1 BlockerDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Early Immunotherapy dosing | Experimental | 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) Receives: Drug: Immunotherapy - PD-1 Blocker |
| Late Immunotherapy dosing | Active comparator | 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) Receives: Drug: Immunotherapy - PD-1 Blocker |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 4.5 years
Secondary outcomes (11)
Overall Survival (OS) - Cohort A
Overall Survival (OS) defined as time from first dose of 1st line treatment to death from any cause.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: At Day 1 of Each Treatment Cycle (2-6-week cycles, per specific agent)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Nov 2025
- Study start2 Dec 2025
- Primary completion1 May 2027 (estimated)
- Study completion1 May 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced/Metastatic NSCLCStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 350 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Liza Villaruz, MD
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Liza Villaruz, MD, University of Pittsburgh
- Investigators
- Liza Villaruz, MD, Principal investigator, UPMC Hillman Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07224971
- Sponsor's protocol ID
- HCC 25-127
- Status last verified
- Dec 2025
- First submitted
- 31 Oct 2025
- Last updated
- 9 Dec 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assessing the Impact of Circadian Rhythm on Anti-PD-1/PD-L1 Immunotherapy
- ClinicalTrials.gov ID
- NCT07224971
- Acronym / sponsor ID
- HCC 25-127
- Conditions
- Advanced/Metastatic NSCLC
- Keywords
- anti-PD-1/PD-L1 Immunotherapy, Circadian Rhythm
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 350 participants (estimated)
- Lead sponsor
- Liza Villaruz, MDUniversity, hospital or other
- Study start
- 2 Dec 2025 (actual)
- Primary completion
- 1 May 2027 (estimated)
- Study completion
- 1 May 2030 (estimated)
- First posted
- 5 Nov 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Early Immunotherapy dosing | Experimental | Drug: Immunotherapy - PD-1 BlockerNSCLC 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) |
| Late Immunotherapy dosing | Active comparator | Drug: Immunotherapy - PD-1 BlockerNSCLC 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) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Cohort Specific Criteria
- 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).
- 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.
- 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
Key exclusion criteria (1 listed)
- 1. Participant unable to receive anti-PD-1/PD-L1 therapy due to prior allergic reactions to therapy or any therapy ingredients.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Immunotherapy - PD-1 BlockerStandard 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. | Drug | Early Immunotherapy dosing, Late Immunotherapy dosing |
Primary outcome
Real-world progression-free survival (rwPFS) - Cohort A
Time frame: Up to 4.5 years
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.
11 secondary outcomes
Overall Survival (OS) - Cohort A
Time frame: Up to 4.5 years
Real-world progression-free survival (rwPFS) - Cohort B
Time frame: Up to 4.5 years
Real-world progression-free survival (rwPFS) - Cohort C
Time frame: Up to 4.5 years
Overall Survival (OS) - Cohort B
Time frame: Up to 4.5 years
Overall Survival (OS) - Cohort C
Time frame: Up to 4.5 years
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort A
Time frame: At Screening - Up to 28 days after signed consent]
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort B
Time frame: At Screening - Up to 28 days after signed consent]
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort C
Time frame: At Screening - Up to 28 days after signed consent]
Health Related Quality of Life (HRQoL) - EQ-5D-5L - Cohort A
Time frame: 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
Time frame: 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
Time frame: At Day 1 of Each Treatment Cycle (2-6-week cycles, per specific agent)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Dec 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Liza Villaruz, MD principal investigator
UPMC Hillman Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Immunotherapy - PD-1 Blocker in people with Advanced/Metastatic NSCLC, run by Liza Villaruz, MD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 9 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Jennifer Ruth, RN (412-623-8963, ruthj2@upmc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Real-world progression-free survival (rwPFS) - Cohort A (time frame: Up to 4.5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Dec 2025.