Lymphoma, Solid Tumors
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Intratumoral (IT)
Brief summary
The purpose of this study is to identify a maximum tolerated dose (MTD) or maximum administered dose (MAD) of ulevostinag alone and of ulevostinag in combination with pembrolizumab in participants with advanced/metastatic solid tumors or lymphomas in Part 1, and to evaluate the safety and efficacy of ulevostinag via intratumoral (IT) injection in combination with pembrolizumab in selected solid tumors in Part 2. Ulevostinag will be administered IT; pembrolizumab (pembro) will be administered via intravenous (IV) infusion. In Part 1, participants will be allocated to one of three treatment arms: ulevostinag monotherapy (cutaneous/subcutaneous \[cut/subcut\] lesions), ulevostinag +pembro (cut/subcut lesions), or ulevostinag +pembro (visceral lesions). In Part 2, participants with head and neck squamous cell carcinoma (HNSCC) who are anti-programmed cell death-protein 1 or anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) refractory or with anti-PD-1/PD-L1 treatment (TrT)-naïve triple-negative breast cancer (TNBC) or with anti-PD-1/PD-L1 TrT-naïve solid tumors with liver metastases/lesions will receive ulevostinag via IT injection at the preliminary Recommended Phase 2 Dose (RP2D) determined in Part 1 PLUS pembrolizumab via IV infusion for up 35 cycles (up approximately 2 years).
Detailed description
Participants will receive either ulevostinag monotherapy or ulevostinag in combination with pembrolizumab for up to 35 cycles (approximately 2 years). Participants will undergo at least a 24-hour inpatient observation period following the first dose administration of ulevostinag on Cycle 1 Day 1 in Part 1. For Part 2, the length of the observation period following administration of the first dose of ulevostinag on Cycle 1 Day 1 is at least 8 hours.
Interventions
DRUGUlevostinag
IT injection
BIOLOGICALPembrolizumab
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All Arms and Cohorts (Parts 1 and 2): * Has ≥1 injectable lesion which is measurable and amenable to injection and biopsy. * Has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. * Demonstrates adequate organ function within 7 days prior to treatment initiation. * Female participants of childbearing potential must be using a contraceptive method that is highly effective or be abstinent from heterosexual intercourse (on a long-term and persistent basis) during the intervention period and for at least 130 days after the last dose of study intervention and agrees not to donate eggs to others or freeze/store for personal use for the purpose of reproduction during this period. Male participants must agree to refrain from donating sperm PLUS either be abstinent from heterosexual intercourse (on a long-term and persistent basis) OR agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse contraception, unless confirmed to be azoospermic (vasectomized) during the intervention period and for at least 130 days after the last dose of study intervention. * Human Immunodeficiency (HIV)-infected participants must meet these additional criteria: a) Has laboratory-test-documented HIV-1 infection; b) Has well-controlled HIV on anti-retroviral therapy (ART), defined as: 1) must have a cluster of differentiation (CD4+) T-cell count \>350 cells/mm\^3 at time of screening; 2) must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 or the lower limit of quantification (LLOQ) using the locally available assay at the time of screening and for ≥12 weeks prior to screening; and, 3) must have been on a stable regimen, without changes in drugs or dose modification, for ≥4 weeks prior to study entry (Day 1). All Part 1 Arms: -Has ≥1 distant, discrete non-injected lesion which is amenable to biopsy. This lesion must be measurable as defined by the response criteria used to assess the participant (RECIST 1.1 for solid tumors or revised International Working Group \[IWG\] criteria for lymphomas). Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) and Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions): * Has a histologically- or cytologically-confirmed advanced/metastatic solid tumor or lymphoma by pathology report and who has received, or been intolerant to, all treatment known to confer clinical benefit. Solid tumors and lymphomas of any type are eligible for enrollment. * Has stage III or stage IV disease that is not surgically resectable. Stage IIB (T3N0M0B0-1) cutaneous T cell lymphoma (CTCL) participants are eligible. Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions): * Has stage III or stage IV disease that is not surgically resectable. * Has metastatic liver involvement that does not exceed one third of the total liver volume in participants to be treated by liver IT injection. Hepatocellular carcinoma participants are excluded from eligibility of IT liver injection. All Part 2 Expansion Cohorts: Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory: * Has HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; anti-PD-1/PD-L1 refractory metastatic or recurrent. Participants may not have a primary tumor site of the nasopharynx (any histology). * Has histologically confirmed Stage III, IVa, or IVb disease per TNM (Tumor, Nodes, Metastasis) staging, American Joint Committee on Cancer (AJCC, 8th edition), with recurrent or persistent disease after definitive chemoradiation, deemed unresectable and considered refractory to both platinum-based combination chemotherapy and anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) antibody therapy. OR * Has histologically confirmed Stage IVc disease per TNM staging, AJCC 8th edition, considered refractory to platinum-based combination chemotherapy and anti-PD-1/PD-L1 antibody therapy. Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC: * Has confirmed unresectable locally advanced or metastatic TNBC as locally determined according to the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines on a newly obtained core or excisional biopsy from a metastatic, not previously irradiated, tumor lesion. * Has received at least one prior systemic treatment for metastatic breast cancer and has intolerance to, or documented disease progression on or after their most recent therapy. * Has been previously treated with an anthracycline and/or taxane in the (neo)adjuvant or metastatic setting unless there was a medical contraindication to this treatment regimen. * Have lactate dehydrogenase (LDH) \<2.5 × upper limit of normal (ULN) Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver: * Has histologically or cytologically confirmed Stage IV solid tumor that is not surgically resectable. * Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or baseline (except alopecia). If participant received major surgery or radiation therapy of \>30 Gray (Gy), they must have recovered from the toxicity and/or complications from the intervention.
Exclusion criteria
All Arms and Cohorts (Parts 1 and 2): * Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or has not recovered to Baseline or Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 from the adverse events due to cancer therapeutics administered \>4 weeks earlier. * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and has received study therapy or has used an investigational device within 28 days of administration of ulevostinag. Note: Prior exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 inhibitors * Is expected to require any other form of antineoplastic therapy while on study. * Is on chronic systemic steroid therapy in excess of replacement doses (prednisone ≤ 10 mg/day is acceptable), or on any other form of immunosuppressive medication. * Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 2 years. * Has clinically active central nervous system metastases and/or carcinomatous meningitis. * Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody. * Has an active autoimmune disease that has required systemic treatment in the past 2 years. * Has a history of vasculitis. * Has an active infection requiring therapy. * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. * Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. * Has Hepatitis B or C infection(s). * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study. * Has not fully recovered from any effects of major surgery, and is free of significant detectable infection. * Has received a live vaccine within 30 days prior to first dose of study drug. * Has a history of re-irradiation for squamous cell carcinoma of the head & neck (HNSCC) at the projected injection site. * Has a tumor(s) in direct contact or encases a major blood vessel, and has ulceration and/or fungation onto the skin surface at the projected injection site. * HIV-infected participants with history of Kaposi's sarcoma and/or multicentric Castleman's disease * HIV-infected participants who have had an HIV-related opportunistic infection within 6 months * Has been treated with a Stimulator of Interferon Genes (STING) agonist (e.g. ulevostinag, ADU-S100). All Part 2 Expansion Cohorts: * Has experienced weight loss \>10% over 2 months prior to first dose of study treatment. * Has clinically relevant ascites at baseline (defined as requiring paracentesis) or with moderate radiographic ascites. A minimal amount of radiographic ascites is allowed. * Has a history of interstitial lung disease. * For Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver, participants with MSI-H CRC are excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT) Per Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE 4.0) | Cycle 1 (21-day cycle) | DLTs were assessed during the first cycle (21 days) & are defined as: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia, Gr 4 thrombocytopenia, Gr 3 thrombocytopenia (if associated with clinically significant bleeding); nonhematologic adverse event (AE) ≥ Gr 3 (with exceptions); Gr 3 or 4 nonhematologic lab abnormality (if medical intervention is required, leads to hospitalization, or persists for \>1 week); Gr 3 or 4 febrile neutropenia; drug-related toxicity that causes treatment discontinuation or dose delay \>7 days between consecutive doses during Cycle 1; drug-related toxicity that causes a \>2 week delay in Cycle 2 initiation; elevated aspartate aminotransferase or alanine aminotransferase lab value that is ≥3× upper limit of normal (ULN) & an elevated total bilirubin value ≥2× ULN & an alkaline phosphatase value \<2× ULN, in which no alternative reasons can be found; ≥Gr 2 immune-mediated uveitis; or Gr 5 toxicity. |
| Parts 1 and 2: Number of Participants Who Experienced One or More Adverse Events (AEs) | Up to approximately 2 years | AEs are defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment, is also an AE. |
| Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an AE | Up to approximately 2 years | AEs are defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment, is also an AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin) | Predose on Day 1 of Cycles 1, 2, and 4, and every 4 cycles thereafter up to Cycle 35 (up to 2 years). Each cycle was 21 days. | Cmin is a measure of the minimum amount of drug in the plasma after the dose is given. The Cmin of pembrolizumab IV infusion in combination with MK-1454 administered via IT injection was evaluated. |
| Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) | Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose. Each cycle was 21 days. | The AUC0-24 is a measure of the amount of drug in the blood over time for 0 hours to 24 hours. The AUC0-24 of ulevostinag administered via IT injection as monotherapy and the AUC0-24 of ulevostinag administered via IT injection as combination therapy with pembrolizumab IV infusion were evaluated. |
| Parts 1 and 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 2 years | ORR is 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, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR of ulevostinag at the preliminary RP2D in combination with pembrolizumab will be assessed by RECIST 1.1 modified to follow a maximum of 10 target lesions with a maximum of 5 target lesions per organ. |
| Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin) | Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, and 6 hours postdose. Each cycle was 21 days. | Cmin is a measure of the minimum amount of drug in the plasma after the dose is given. The Cmin of ulevostinag administered via IT injection as monotherapy and the Cmin of ulevostinag administered via IT injection as combination therapy with pembrolizumab IV infusion were evaluated. |
| Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax) | Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, and 6 hours postdose. Each cycle was 21 days. | Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. The Cmax of ulevostinag administered via IT injection as monotherapy and the Cmax of ulevostinag administered via IT injection as combination therapy with pembrolizumab IV infusion were evaluated. |
Countries
France, Israel, South Korea, United Kingdom, United States
Participant flow
Pre-assignment details
Evaluation of Part 2 Cohort C (anti-PD-1/PD-L1 treatment-naïve solid tumors with liver metastases/lesions) was not pursued. No participants were enrolled in Part 2 Cohort C.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) Participants with cutaneous (cut) or subcutaneous (subcut) lesions received escalating doses of ulevostinag monotherapy via IT injection on Days 1, 8, and 15 of each 21-day cycle for Cycles 1, 2, and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond for up to 35 cycles (up to approximately 2 years). | 32 |
| Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) Participants with cut or subcut lesions received escalating doses of ulevostinag via IT injection on Days 1, 8, and 15 of each 21-day cycle for Cycles 1, 2, and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond PLUS pembrolizumab (pembro) via intravenous (IV) infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). | 52 |
| Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) Participants with visceral lesions received escalating doses of ulevostinag via IT injection at escalating dose frequencies (Day 1 of each 21-day cycle for up to 35 cycles, then Days 1 and 8 of each 21-day cycle for two cycles, then Day 1 of each 21 day cycle up to 35 cycles, then Days 1, 8, and 15 of each 21-day cycle for two cycles followed by Day 1 of each 21-day cycle up to 35 cycles), PLUS pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (approximately 2 years). | 26 |
| Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory Participants with head and neck squamous cell carcinoma (HNSCC) who were anti-programmed cell death-1 (anti-PD-1) or anti-programmed cell death-ligand 1 (anti-PD-L1) refractory received ulevostinag via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). | 21 |
| Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC Participants with triple-negative breast cancer (TNBC) who were anti-PD-1/PD-L1 treatment (TrT)-naïve or who had refractory unresectable locally advanced or metastatic TNBC received ulevostinag via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). | 25 |
| Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver Participants with solid tumors with liver metastases/lesions who were anti-PD-1/PD-L1 treatment-naïve were to receive ulevostinag at the preliminary RP2D based on Part 1: ulevostinag+pembro (visceral lesions) treatment arm via IT injection in a to-be-determined dose and frequency, based on data from Arm 3, PLUS pembrolizumab mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). | 0 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Death | 21 | 35 | 19 | 19 | 14 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 4 | 0 | 1 | 0 | 0 |
| Overall Study | Sponsor Decision | 0 | 4 | 4 | 1 | 6 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 9 | 3 | 0 | 4 | 0 |
Baseline characteristics
| Characteristic | Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) | Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) | Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory | Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC | Total | Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) | Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.1 Years STANDARD_DEVIATION 14 | 59.1 Years STANDARD_DEVIATION 10.1 | 60.2 Years STANDARD_DEVIATION 8.5 | 49.3 Years STANDARD_DEVIATION 10.9 | 57.5 Years STANDARD_DEVIATION 12.7 | 56.9 Years STANDARD_DEVIATION 14.1 | — |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 25 Participants | 20 Participants | 12 Participants | 131 Participants | 30 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 1 Participants | 1 Participants | 12 Participants | 21 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 6 Participants | 6 Participants | 3 Participants | 19 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 13 Participants | 16 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 50 Participants | 20 Participants | 12 Participants | 7 Participants | 115 Participants | 26 Participants | 0 Participants |
| Sex: Female, Male Female | 31 Participants | 8 Participants | 4 Participants | 25 Participants | 88 Participants | 20 Participants | 0 Participants |
| Sex: Female, Male Male | 21 Participants | 18 Participants | 17 Participants | 0 Participants | 68 Participants | 12 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 21 / 32 | 45 / 66 | 19 / 26 | 19 / 21 | 15 / 25 |
| other Total, other adverse events | 32 / 32 | 65 / 66 | 26 / 26 | 21 / 21 | 25 / 25 |
| serious Total, serious adverse events | 14 / 32 | 33 / 66 | 10 / 26 | 11 / 21 | 7 / 25 |
Outcome results
Primary
Part 1: Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT) Per Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE 4.0)
DLTs were assessed during the first cycle (21 days) & are defined as: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia, Gr 4 thrombocytopenia, Gr 3 thrombocytopenia (if associated with clinically significant bleeding); nonhematologic adverse event (AE) ≥ Gr 3 (with exceptions); Gr 3 or 4 nonhematologic lab abnormality (if medical intervention is required, leads to hospitalization, or persists for \>1 week); Gr 3 or 4 febrile neutropenia; drug-related toxicity that causes treatment discontinuation or dose delay \>7 days between consecutive doses during Cycle 1; drug-related toxicity that causes a \>2 week delay in Cycle 2 initiation; elevated aspartate aminotransferase or alanine aminotransferase lab value that is ≥3× upper limit of normal (ULN) & an elevated total bilirubin value ≥2× ULN & an alkaline phosphatase value \<2× ULN, in which no alternative reasons can be found; ≥Gr 2 immune-mediated uveitis; or Gr 5 toxicity.
Time frame: Cycle 1 (21-day cycle)
Population: All participants who received at least 1 dose of study treatment and were either observed for safety for 21 days after the first dose of treatment or experienced a DLT prior to 21 days after the first dose of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) | Part 1: Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT) Per Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE 4.0) | 15.1 Percentage of participants |
| Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) | Part 1: Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT) Per Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE 4.0) | 10.4 Percentage of participants |
| Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) | Part 1: Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT) Per Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE 4.0) | 0 Percentage of participants |
Primary
Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an AE
AEs are defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment, is also an AE.
Time frame: Up to approximately 2 years
Population: All participants who received at least 1 dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) | Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an AE | 3 Participants |
| Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) | Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an AE | 7 Participants |
| Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) | Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an AE | 3 Participants |
| Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory | Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an AE | 3 Participants |
| Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC | Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an AE | 2 Participants |
Primary
Parts 1 and 2: Number of Participants Who Experienced One or More Adverse Events (AEs)
AEs are defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment, is also an AE.
Time frame: Up to approximately 2 years
Population: All participants who received at least 1 dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) | Parts 1 and 2: Number of Participants Who Experienced One or More Adverse Events (AEs) | 32 Participants |
| Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) | Parts 1 and 2: Number of Participants Who Experienced One or More Adverse Events (AEs) | 66 Participants |
| Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) | Parts 1 and 2: Number of Participants Who Experienced One or More Adverse Events (AEs) | 26 Participants |
| Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory | Parts 1 and 2: Number of Participants Who Experienced One or More Adverse Events (AEs) | 21 Participants |
| Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC | Parts 1 and 2: Number of Participants Who Experienced One or More Adverse Events (AEs) | 25 Participants |
Secondary
Parts 1 and 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
ORR is 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, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR of ulevostinag at the preliminary RP2D in combination with pembrolizumab will be assessed by RECIST 1.1 modified to follow a maximum of 10 target lesions with a maximum of 5 target lesions per organ.
Time frame: Up to approximately 2 years
Population: All participants with a baseline scan that demonstrated measurable disease by investigator assessment, and who received a dose of study medicine
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) | Parts 1 and 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 0.0 Percentage of participants |
| Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) | Parts 1 and 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 16.1 Percentage of participants |
| Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) | Parts 1 and 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 3.8 Percentage of participants |
| Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory | Parts 1 and 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 4.8 Percentage of participants |
| Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC | Parts 1 and 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 4.0 Percentage of participants |
Secondary
Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin)
Cmin is a measure of the minimum amount of drug in the plasma after the dose is given. The Cmin of pembrolizumab IV infusion in combination with MK-1454 administered via IT injection was evaluated.
Time frame: Predose on Day 1 of Cycles 1, 2, and 4, and every 4 cycles thereafter up to Cycle 35 (up to 2 years). Each cycle was 21 days.
Population: All participants who complied with the protocol sufficiently to ensure that the data they generated were likely to exhibit the effects of treatment, according to the underlying scientific model
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) | Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin) | 14.5 ng/mL |
| Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) | Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin) | 14.25 ng/mL |
| Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) | Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin) | 17.7 ng/mL |
| Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory | Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin) | 13.6 ng/mL |
Secondary
Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24)
The AUC0-24 is a measure of the amount of drug in the blood over time for 0 hours to 24 hours. The AUC0-24 of ulevostinag administered via IT injection as monotherapy and the AUC0-24 of ulevostinag administered via IT injection as combination therapy with pembrolizumab IV infusion were evaluated.
Time frame: Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose. Each cycle was 21 days.
Population: All participants who complied with the protocol sufficiently to ensure that the data they generated were likely to exhibit the effects of treatment, according to the underlying scientific model
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) | Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) | 8.62 nM*hr |
| Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) | Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) | 6.59 nM*hr |
| Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) | Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) | 5.88 nM*hr |
| Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory | Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) | 6.24 nM*hr |
| Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC | Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) | 7.98 nM*hr |
Secondary
Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax)
Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. The Cmax of ulevostinag administered via IT injection as monotherapy and the Cmax of ulevostinag administered via IT injection as combination therapy with pembrolizumab IV infusion were evaluated.
Time frame: Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, and 6 hours postdose. Each cycle was 21 days.
Population: All participants who complied with the protocol sufficiently to ensure that the data they generated were likely to exhibit the effects of treatment, according to the underlying scientific model
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) | Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax) | 6.56 nM |
| Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) | Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax) | 5.38 nM |
| Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) | Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax) | 7.08 nM |
| Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory | Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax) | 6.75 nM |
| Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC | Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax) | 8.4 nM |
Secondary
Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin)
Cmin is a measure of the minimum amount of drug in the plasma after the dose is given. The Cmin of ulevostinag administered via IT injection as monotherapy and the Cmin of ulevostinag administered via IT injection as combination therapy with pembrolizumab IV infusion were evaluated.
Time frame: Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, and 6 hours postdose. Each cycle was 21 days.
Population: All participants who complied with the protocol sufficiently to ensure that the data they generated were likely to exhibit the effects of treatment, according to the underlying scientific model
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) | Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin) | 0.18 ng/mL |
| Part 1 Arm 2: Ulevostinag+Pembro (Cut/Subcut Lesions) | Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin) | 0.12 ng/mL |
| Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions) | Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin) | 0.08 ng/mL |
| Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory | Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin) | 0.09 ng/mL |
| Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC | Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin) | 0.13 ng/mL |