Head and Neck Squamous Cell Carcinoma (HNSCC)
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), intratumoral (IT), metastatic, unresectable, recurrent, ulevostinag, pembrolizumab
Brief summary
The purpose of this study is to assess the efficacy and safety of intratumoral (IT) ulevostinag PLUS pembrolizumab (MK-3475) compared to pembrolizumab alone as a first line treatment of adults with metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). The primary study hypotheses are that IT ulevostinag in combination with pembrolizumab results in a superior Objective Response Rate (ORR), per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), compared to pembrolizumab alone: 1. In participants with a tumor that has a programmed cell death-ligand 1 (PD-L1) Combined Positive Scoring (CPS) ≥ 1, and 2. In participants with a tumor that has a PD-L1 CPS ≥ 20.
Interventions
DRUGUlevostinag
IT injection
BIOLOGICALPembrolizumab
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically or cytologically confirmed diagnosis of metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC) that is considered incurable by local therapies * Has not had prior systemic therapy administered in the recurrent or metastatic setting * Has tumor PD-L1 expression of CPS ≥1. Tumor tissue must be provided for PD-L1 biomarker analysis * Has measurable disease per RECIST 1.1, as assessed by BICR * Has at least 1 measurable lesion which is amenable to injection * Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Demonstrates adequate organ function within 7 days prior to treatment initiation * Male participants of reproductive potential must agree to refrain from donating sperm and use a male condom plus partner use of an additional contraceptive method during sexual contact with females of childbearing potential during the intervention period with ulevostinag and for at least 120 days after the last dose of ulevostinag * Female participants of childbearing potential who are not pregnant or breastfeeding must be willing to use a highly effective method of birth control or be surgically sterile or abstain from heterosexual activity during the intervention period and for at least 120 days after the last dose of study intervention, and agree not to donate eggs (ova, oocytes) to others or freeze/store for personal use * Human immunodeficiency virus (HIV)-infected participants must meet these additional criteria: 1. Has HIV-1 infection documented by using any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry (Day 1) 2. Has well-controlled HIV on anti-retroviral therapy (ART)
Exclusion criteria
* Has disease that is suitable for local therapy administered with curative intent * Has progressive disease (PD) within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC * Has had chemotherapy or biological cancer therapy in the recurrent or metastatic setting for the treatment of HNSCC * Has had radiation therapy (or other non-systemic therapy) within 2 weeks prior to randomization or participant has not fully recovered from adverse events (AEs) due to a previously administered treatment * Is expected to require any other form of antineoplastic therapy while on study * Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for at least 2 years * Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis * Has an active autoimmune disease that has required systemic treatment in the past 2 years * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment * Has had an allogenic tissue/solid organ transplant * Has a history of vasculitis * Has a history of interstitial lung disease * Has an active infection requiring systemic therapy * Has a known history of active tuberculosis (TB; Bacillus tuberculosis) * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis * Has had a severe hypersensitivity reaction to treatment a monoclonal antibody/components of the study treatment * Has known Hepatitis B virus or Hepatitis C virus infections * Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti-PD-L2) agent or if the participant has previously participated in Merck Sharp & Dohme (MSD) MK-3475 clinical trials * HIV infected participant who has had an HIV-related opportunistic infection within 6 months * HIV infected participants who have a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease * Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment * Has not fully recovered from any effects of major surgery without significant detectable infection * Has a history of re-irradiation for HNSCC at the projected injection site in the head and neck * Has received a live-virus vaccine within 30 days of planned study treatment start * Has been treated with a stimulator of interferon genes (STING) agonist (e.g. ulevostinag, ADU-S100) * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, or used an investigational device, any of which occurred within 4 weeks of the first dose of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to 913.0 days | ORR was defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by blinded independent central review (BICR), and the 95% confidence interval (CI) was based on the exact method for binomial data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to 913.0 days | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. PFS was assessed by BICR and was based on the product-limit (Kaplan-Meier) method for censored data. |
| Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to 913.0 days | DOR was defined as the time from the first documented evidence of a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until Progressive Disease (PD) or death due to any cause, whichever occurs first, in participants demonstrating a CR or PR. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR was based on the product-limit (Kaplan-Meier) method for censored data. |
| Overall Survival (OS) | Up to 913.0 days | OS is defined as the time from randomization to the date of death from any cause, and is based on the product-limit (Kaplan-Meier) method for censored data. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to 913.0 days | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. |
| Number of Participants Discontinuing Study Treatment Due to an AE | Up to approximately 715.0 days | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. |
Countries
Australia, Austria, Brazil, France, Israel, Norway, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Adults with a confirmed diagnosis of metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC) with a tumor programmed cell death-1 ligand 1 (PD-L1) immunohistochemistry (IHC) combined positive scoring (CPS) ≥1 and had at least 1 measurable lesion that was amenable to intratumor (IT) injection were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Ulevostinag + Pembrolizumab Participants received ulevostinag 540 ug via IT injection on Day 1 of every week for two 3-week cycles (Cycles 1-2), then on Day 1 of each 3-week cycle for up 33 cycles (Cycles 3-35), for a total of 35 cycles PLUS pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment was up to approximately 2 years. | 8 |
| Pembrolizumab Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years. | 10 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 5 |
| Overall Study | Participation at the site terminated By Sponsor | 2 | 0 |
| Overall Study | Participation in the study terminated By Sponsor | 2 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab | Total | Ulevostinag + Pembrolizumab |
|---|---|---|---|
| Age, Continuous | 59.8 Years STANDARD_DEVIATION 9.8 | 62.2 Years STANDARD_DEVIATION 9.9 | 65.3 Years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 18 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 17 Participants | 8 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 17 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 8 | 5 / 10 |
| other Total, other adverse events | 8 / 8 | 9 / 10 |
| serious Total, serious adverse events | 5 / 8 | 4 / 10 |
Outcome results
Primary
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
ORR was defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by blinded independent central review (BICR), and the 95% confidence interval (CI) was based on the exact method for binomial data.
Time frame: Up to 913.0 days
Population: All randomized participants based on the treatment arm to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ulevostinag + Pembrolizumab | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 50.0 Percentage of participants |
| Pembrolizumab | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 10.0 Percentage of participants |
Secondary
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
DOR was defined as the time from the first documented evidence of a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until Progressive Disease (PD) or death due to any cause, whichever occurs first, in participants demonstrating a CR or PR. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR was based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 913.0 days
Population: All randomized participants based on the treatment arm to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ulevostinag + Pembrolizumab | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | NA Months |
| Pembrolizumab | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | NA Months |
Secondary
Number of Participants Discontinuing Study Treatment Due to an AE
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Time frame: Up to approximately 715.0 days
Population: All randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ulevostinag + Pembrolizumab | Number of Participants Discontinuing Study Treatment Due to an AE | 3 Participants |
| Pembrolizumab | Number of Participants Discontinuing Study Treatment Due to an AE | 2 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Time frame: Up to 913.0 days
Population: All randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ulevostinag + Pembrolizumab | Number of Participants Who Experienced an Adverse Event (AE) | 8 Participants |
| Pembrolizumab | Number of Participants Who Experienced an Adverse Event (AE) | 10 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time from randomization to the date of death from any cause, and is based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 913.0 days
Population: All randomized participants based on the treatment arm to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ulevostinag + Pembrolizumab | Overall Survival (OS) | NA Months |
| Pembrolizumab | Overall Survival (OS) | 11.1 Months |
Secondary
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. PFS was assessed by BICR and was based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 913.0 days
Population: All randomized participants based on the treatment arm to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ulevostinag + Pembrolizumab | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 6.4 Months |
| Pembrolizumab | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 1.5 Months |