Cutaneous Squamous Cell Carcinoma, Squamous Cell Carcinoma of Head and Neck
Conditions
Keywords
intratumoral injection
Brief summary
This is a Phase 1 open-label, multi-center, dose-escalation study to evaluate the safety, PK, anti-tumor activity, and pharmacodynamic effects of SL-172154 administered by intratumoral injection in subjects with cutaneous squamous cell carcinoma (CSCC) or squamous cell carcinoma of the head and neck (SCCHN).
Detailed description
This Phase 1 trial will evaluate the safety, tolerability, pharmacokinetics, anti-tumor activity and pharmacodynamic effects of SL-172154 when administered as an intratumoral injection (ITI) and identify the dose and schedule i.e., recommended Phase 2 dose (RP2D) for future development. Eligible subjects must have unresectable or recurrent, locally advanced or metastatic squamous cell carcinoma of the skin or head and neck, that is not amenable to curative surgery or radiotherapy. The study design consists of four sequential dose-escalation cohorts and an optional pharmacodynamic cohort to obtain additional pharmacodynamic data at one or more dose levels that have completed evaluation for safety without exceeding the maximum tolerated dose (MTD).
Interventions
DRUGDrug: SL-172154
The investigational product (IP), SL-172154, is a novel fusion protein consisting of human SIRPα and CD40L (SIRPα -Fc-CD40L) linked via a human Fc.
Sponsors
Shattuck Labs, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants are eligible to be included in the study only if all the following criteria apply: * Subject has voluntarily agreed to participate by giving written informed consent in accordance with ICH/GCP guidelines and applicable local regulations. * Subject must have a histologically confirmed diagnosis of an unresectable or recurrent, locally advanced or metastatic cutaneous squamous cell carcinoma or squamous cell carcinoma of the head and neck that is not amenable to curative surgery or radiotherapy. * Subjects must have received, been intolerant to, or ineligible for standard therapy(ies) known to provide clinical benefit for their condition. * Subject has measurable disease by RECIST v1.1 using radiologic assessment. * Subject has at least 1 tumor lesion measuring between 1-6cm that is cutaneous and/or subcutaneous and/or nodal and is clinically accessible and safe for injection by direct visualization, palpation or by ultrasound guidance. PD Cohort Subjects Only: Must have a second lesion that is non-injected and is amenable to tumor biopsy collection. * Subject age is 18 years and older. * Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. * Has life expectancy of greater than 12 weeks. * Has adequate organ function. * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 72 hours of D1 of IP. * Male subjects of reproductive potential must use acceptable contraception. * Recovery from prior anti-cancer treatments including surgery, radiotherapy, chemotherapy or any other anti-cancer therapy to baseline or ≤ Grade 1. * Willing to consent to mandatory pre-treatment and on-treatment tumor biopsy(ies) of injected lesion (and non-injected lesion(s) for subjects enrolled in the PD cohort)
Exclusion criteria
* Prior treatment with an anti-CD47 or anti-SIRPα targeting agent or a CD40 agonist. * Any anti-cancer therapy within the washout period prior to first dose (D1) of SL-172154. * Concurrent chemotherapy, immunotherapy, biologic or hormonal/hormonal suppression therapy for cancer treatment is prohibited. Concurrent use of hormones for non-cancer related conditions is acceptable. * Use of corticosteroids or other immunosuppressive medication, current or within 14 days of D1 of SL-172154 treatment. * Receipt of live attenuated vaccine within 28 days of D1 of IP. * Hypersensitivity to the active drug substance or to any of the excipients for the agent to be administered or subjects with known hypersensitivity to Chinese hamster ovary cell products. * History of coagulopathy resulting in uncontrolled bleeding, eg, hemophilia, von Willebrand's disease. * Requires continuous anticoagulation therapy or antiplatelet therapy * Active or documented history of autoimmune disease. Exceptions include controlled Type I diabetes, vitiligo, alopecia areata or hypo/hyperthyroidism. * Active pneumonitis (i.e. drug-induced, idiopathic pulmonary fibrosis, radiation-induced, etc.). * Ongoing or active infection (e.g., no systemic antimicrobial therapy for treatment of infection within 5 days of D1 of IP). * Symptomatic peptic ulcer disease or gastritis, active diverticulitis, other serious gastrointestinal disease associated with diarrhea within 6 months of D1 of IP. * Clinically significant or uncontrolled cardiac/thromboembolic disease. * Untreated central nervous system or leptomeningeal metastases. * Women who are breastfeeding. * Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or compromised ability to provide written informed consent. * Another malignancy that requires active therapy and that in the opinion of the investigator and Sponsor would interfere with monitoring of radiologic assessments of response to IP. * Has undergone allogeneic stem cell transplantation or organ transplantation. * Known history or positive test for human immunodeficiency virus, or positive test for hepatitis B.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of SL-172154 When Administered Intratumorally | From Day 1 to Day 29. | Number of participants with dose limiting toxicities (DLTs) |
| Incidence of All Treatment Emergent Adverse Events | From Day 1 to 90 days after last injection of SL-172154, an average of 6 weeks. SL-172154 administration continued until disease progression or withdrawal of consent; there was no maximum treatment duration. | Number of participants with treatment-emergent adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate of SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | Number of participants with an objective response per investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1). Objective response includes complete response (disappearance of all target lesions) and partial response (\>/= 30% decrease in the sum of the longest diameter of target lesions). |
| Immunogenicity to SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | Proportion of participants with positive anti-drug antibody titer |
| Maximum Observed Concentration (Cmax) of SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | The Cmax is the maximum observed serum concentration of SL-172154 following single and multiple doses |
| Time at Which the Maximum Concentration is Observed (Tmax) of SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | The Tmax is the time at which the maximum concentration of SL-172154 is observed following single and multiple doses |
| Establish the Recommended Phase 2 Dose (RP2D) for SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | Based on review of all data, including safety, tolerability, PK, anti-tumor activity and PD effects |
| Terminal Elimination Half-life (t1/2) of SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | Terminal elimination half-life (t1/2) of SL-172154 |
| Clearance (CL) of SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | Clearance of Sl-172154 |
| Volume of Distribution of SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | Volume of distribtion of SL-172154 |
| Minimum Observed Concentration (Cmin) of SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | The Cmin is the minimum observed serum concentration of SL-172154 following single and multiple doses |
| Area Under the Serum Concentration Time Curve (AUC) of SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | The AUC is the area under the serum concentration time curve following single and multiple doses of SL-172154 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes From Baseline in Cell Counts to Assess Pharmacodynamic Biomarkers in Blood Prior to, On-treatment and Following SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | Circulating immune cells such as: T cells, B cells, natural killer (NK) cells, and myeloid cells and circulating chemokine and cytokine levels |
| Changes From Baseline in Cell Counts to Assess Pharmacodynamic Biomarkers in Tumor Tissue Prior to, On-treatment and Following SL-172154 When Administered by Intratumoral Injection (ITI) | Approximately 18-24 months | Presence of SL-172154 in tumor tissue, changes in T cells subsets, B cells and macrophages and assessment of SL-172154 in the tumor tissue, CD47 and CD40 expression and Programmed cell death ligand 1 (PD-L1) expression |
| To Estimate Progression-free Survival (PFS) | Approximately 18-24 months | PFS: time from first dose to progression by RECIST v1.1 or death, whichever comes first |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SL-172154 (0.003 mg) 0.003 mg of SL-172154 via intratumoral injection | 3 |
| SL-172154 (0.01 mg) 0.01 mg of SL-172154 via intratumoral injection | 2 |
| Total | 5 |
Baseline characteristics
| Characteristic | SL-172154 (0.003 mg) | Total | SL-172154 (0.01 mg) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 4 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Continuous | 70.0 years | 70.0 years | 63.5 years |
| Cancer type cutaneous squamous cell carcinoma | 3 participants | 4 participants | 1 participants |
| Cancer type squamous cell carcinoma of the head and neck | 0 participants | 1 participants | 1 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 5 Participants | 2 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 | 0 Participants | 0 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 | 3 Participants | 5 Participants | 2 Participants |
| Region of Enrollment United States | 3 participants | 5 participants | 2 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 2 |
| other Total, other adverse events | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 0 / 3 | 2 / 2 |
Outcome results
Primary
Incidence of All Treatment Emergent Adverse Events
Number of participants with treatment-emergent adverse events
Time frame: From Day 1 to 90 days after last injection of SL-172154, an average of 6 weeks. SL-172154 administration continued until disease progression or withdrawal of consent; there was no maximum treatment duration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SL-172154 (0.003 mg) | Incidence of All Treatment Emergent Adverse Events | 3 Participants |
| SL-172154 (0.01 mg) | Incidence of All Treatment Emergent Adverse Events | 2 Participants |
Primary
Maximum Tolerated Dose (MTD) of SL-172154 When Administered Intratumorally
Number of participants with dose limiting toxicities (DLTs)
Time frame: From Day 1 to Day 29.
Population: DLT evaluable population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SL-172154 (0.003 mg) | Maximum Tolerated Dose (MTD) of SL-172154 When Administered Intratumorally | 0 Participants |
| SL-172154 (0.01 mg) | Maximum Tolerated Dose (MTD) of SL-172154 When Administered Intratumorally | 0 Participants |
Secondary
Area Under the Serum Concentration Time Curve (AUC) of SL-172154 When Administered by Intratumoral Injection (ITI)
The AUC is the area under the serum concentration time curve following single and multiple doses of SL-172154
Time frame: Approximately 18-24 months
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| SL-172154 (0.003 mg) | Area Under the Serum Concentration Time Curve (AUC) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA hours*ng/mL |
| SL-172154 (0.01 mg) | Area Under the Serum Concentration Time Curve (AUC) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA hours*ng/mL |
Secondary
Clearance (CL) of SL-172154 When Administered by Intratumoral Injection (ITI)
Clearance of Sl-172154
Time frame: Approximately 18-24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SL-172154 (0.003 mg) | Clearance (CL) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA liters per hours |
| SL-172154 (0.01 mg) | Clearance (CL) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA liters per hours |
Secondary
Establish the Recommended Phase 2 Dose (RP2D) for SL-172154 When Administered by Intratumoral Injection (ITI)
Based on review of all data, including safety, tolerability, PK, anti-tumor activity and PD effects
Time frame: Approximately 18-24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SL-172154 (0.003 mg) | Establish the Recommended Phase 2 Dose (RP2D) for SL-172154 When Administered by Intratumoral Injection (ITI) | NA mg |
Secondary
Immunogenicity to SL-172154 When Administered by Intratumoral Injection (ITI)
Proportion of participants with positive anti-drug antibody titer
Time frame: Approximately 18-24 months
Population: Due to the small number of subjects and limited systemic exposure SL-172154 by ITI, samples were not analyzed for the presence of anti-drug antibodies to SL-172154.
Secondary
Maximum Observed Concentration (Cmax) of SL-172154 When Administered by Intratumoral Injection (ITI)
The Cmax is the maximum observed serum concentration of SL-172154 following single and multiple doses
Time frame: Approximately 18-24 months
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| SL-172154 (0.003 mg) | Maximum Observed Concentration (Cmax) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA ng/mL |
| SL-172154 (0.01 mg) | Maximum Observed Concentration (Cmax) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA ng/mL |
Secondary
Minimum Observed Concentration (Cmin) of SL-172154 When Administered by Intratumoral Injection (ITI)
The Cmin is the minimum observed serum concentration of SL-172154 following single and multiple doses
Time frame: Approximately 18-24 months
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| SL-172154 (0.003 mg) | Minimum Observed Concentration (Cmin) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA ng/mL |
| SL-172154 (0.01 mg) | Minimum Observed Concentration (Cmin) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA ng/mL |
Secondary
Objective Response Rate of SL-172154 When Administered by Intratumoral Injection (ITI)
Number of participants with an objective response per investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1). Objective response includes complete response (disappearance of all target lesions) and partial response (\>/= 30% decrease in the sum of the longest diameter of target lesions).
Time frame: Approximately 18-24 months
Population: Response Evaluable Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SL-172154 (0.003 mg) | Objective Response Rate of SL-172154 When Administered by Intratumoral Injection (ITI) | 0 Participants |
| SL-172154 (0.01 mg) | Objective Response Rate of SL-172154 When Administered by Intratumoral Injection (ITI) | 0 Participants |
Secondary
Terminal Elimination Half-life (t1/2) of SL-172154 When Administered by Intratumoral Injection (ITI)
Terminal elimination half-life (t1/2) of SL-172154
Time frame: Approximately 18-24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SL-172154 (0.003 mg) | Terminal Elimination Half-life (t1/2) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA hours |
| SL-172154 (0.01 mg) | Terminal Elimination Half-life (t1/2) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA hours |
Secondary
Time at Which the Maximum Concentration is Observed (Tmax) of SL-172154 When Administered by Intratumoral Injection (ITI)
The Tmax is the time at which the maximum concentration of SL-172154 is observed following single and multiple doses
Time frame: Approximately 18-24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SL-172154 (0.003 mg) | Time at Which the Maximum Concentration is Observed (Tmax) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA hours |
| SL-172154 (0.01 mg) | Time at Which the Maximum Concentration is Observed (Tmax) of SL-172154 When Administered by Intratumoral Injection (ITI) | NA hours |
Secondary
Volume of Distribution of SL-172154 When Administered by Intratumoral Injection (ITI)
Volume of distribtion of SL-172154
Time frame: Approximately 18-24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SL-172154 (0.003 mg) | Volume of Distribution of SL-172154 When Administered by Intratumoral Injection (ITI) | NA liters |
| SL-172154 (0.01 mg) | Volume of Distribution of SL-172154 When Administered by Intratumoral Injection (ITI) | NA liters |
Other Pre-specified
Changes From Baseline in Cell Counts to Assess Pharmacodynamic Biomarkers in Blood Prior to, On-treatment and Following SL-172154 When Administered by Intratumoral Injection (ITI)
Circulating immune cells such as: T cells, B cells, natural killer (NK) cells, and myeloid cells and circulating chemokine and cytokine levels
Time frame: Approximately 18-24 months
Population: Due to the small number of subjects and Sponsor decision to pursue development of SL-172154 by IV administration, a complete set of PD samples was not analyzed or reported.
Other Pre-specified
Changes From Baseline in Cell Counts to Assess Pharmacodynamic Biomarkers in Tumor Tissue Prior to, On-treatment and Following SL-172154 When Administered by Intratumoral Injection (ITI)
Presence of SL-172154 in tumor tissue, changes in T cells subsets, B cells and macrophages and assessment of SL-172154 in the tumor tissue, CD47 and CD40 expression and Programmed cell death ligand 1 (PD-L1) expression
Time frame: Approximately 18-24 months
Population: Due to the small number of subjects and Sponsor decision to pursue development of SL-172154 by IV administration, a complete set of PD samples was not analyzed or reported.
Other Pre-specified
To Estimate Progression-free Survival (PFS)
PFS: time from first dose to progression by RECIST v1.1 or death, whichever comes first
Time frame: Approximately 18-24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SL-172154 (0.003 mg) | To Estimate Progression-free Survival (PFS) | NA weeks |
| SL-172154 (0.01 mg) | To Estimate Progression-free Survival (PFS) | NA weeks |