Cancer, Carcinoma, Melanoma, MSI-High, Non Small Cell Lung Cancer, Renal Cell Carcinoma, Solid Tumor, Squamous Cell Carcinoma of the Head and Neck, Triple-negative Breast Cancer
Conditions
Brief summary
This is a multiphase, multicenter study, which includes a Phase 1a open-label, dose escalation monotherapy study of ST-067 given as an SC injection with or without obinutuzumab \[Gazyva®\] pre-treatment, by IV infusion, and in combination with pembrolizumab. A Phase 2 monotherapy arm is also planned; the exact design of the Phase 2 study elements with respect to formulation and pre-treatment will be determined after completion of the Phase 1 study portion of the trial.
Detailed description
Phase 1a is designed to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ST067, administered by subcutaneous (SC) or intravenous (IV) dosing, in subjects with relapsed or refractory solid tumors, as well as to determine the MTD and recommended Phase 2 dose of ST067, administered SC with obinutuzumab (Gazyva®) as pretreatment in subjects with relapsed or refractory solid tumors using a modified toxicity probability interval (mTPI) design. There will be evaluations of ST-067 PK and PD effects. Phase 2 will evaluate the preliminary efficacy of ST-067 administered at the RP2D to patients with the following tumor types. A Simon 2 stage design is used to calculate the sample size and early stopping rules will be employed in the event of lack of efficacy in any of the cohorts. RECIST 1.1 will be used to assess tumor response every 8-12 weeks. * Melanoma (n=28) * Renal cell carcinoma (n=25) * Triple-negative best cancer (n=25) * Non-small cell lung cancer (n=25) * squamous cell carcinoma of the head and neck (n=28) * MSI-Hi tumors (n=25) A Simon 2 stage design is used to calculate the sample size and early stopping rules will be employed in the event of lack of efficacy in any of the cohorts. RECIST 1.1 will be used to assess tumor response every 8-12 weeks. Safety will be assessed for each patient throughout the study.
Interventions
BIOLOGICALST-067
ST-067 is an engineered variant of human interleukin-18.
BIOLOGICALObinutuzumab 25 MG/1 ML Intravenous Solution [GAZYVA]
Obinutuzumab is a humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It recognizes a specific epitope of the CD20 molecule found on B-cells.
BIOLOGICALpembrolizumab
Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody.
Sponsors
Merck Sharp & Dohme LLC
Simcha IL-18, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose escalation and expansion
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female patients aged ≥18 years 2. Must provide written informed consent and any authorizations required by local law 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 4. Have histologically or cytologically confirmed diagnosis of advanced/metastatic solid tumor For Phase 1a, the following solid tumors are allowed: Melanoma, Merkel cell, RCC, urothelial, NSCLC,TNBC, SCCHN, microsatellite instability high, high tumor mutation burden (Hi TMB) or mismatch repair deficient, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, hepatocellular carcinoma and platinum resistant ovarian cancer. 1. For patients who have developed disease progression through standard therapy, or 2. For patients whom standard of care therapy that prolongs survival is unavailable or unsuitable (according to the investigator and after consultation with the Medical Monitor) For Phase 1 combination therapy dose escalation, the following solid tumors are allowed: Melanoma, Merkel cell, RCC, urothelial, NSCLC (with no EGFR, TRK receptor, or ALK positive mutations/fusions), TNBC, SCCHN, MSI-Hi tumors, Hi TMB or mismatch repair deficient, gastric, cervical, endometrial, cutaneous squamous, small cell lung, esophageal, and HCC * TNBC is diagnosed in a tumor which does not express estrogen receptor or progesterone receptor, is not human epidermal growth factor receptor 2 (HER2) 3+ on IHC or is negative by fluorescence in situ hybridization (FISH). * MSI high tumor should have mutations in 30% or more microsatellites by PCR or be negative for MSH1/2/6 or PMS-2 by IHC. * Hi-TMB high tumor has 10 mut/Mb or greater calculated from whole genome sequencing or whole exome sequencing For Phase 2, the following solid tumors are allowed: Melanoma, RCC, TNBC, NSCLC, SCCHN, and MSI-Hi tumors 5. Has at least 1 measurable lesion per RECIST 1.1 criteria which has not been biopsied or received prior irradiation 6. Has an accessible tumor for biopsy pre- and on-treatment (mandatory).
Exclusion criteria
1. History of another malignancy 2. Known symptomatic brain metastases requiring \>10 mg/day of prednisolone or equivalent 3. Significant cardiovascular disease (MI, thrombotic events,) within 6 months prior to study treatmentSignificant ECG abnormalities (Phase 1a and 2 monotherapy only) including unstable cardiac arrhythmia requiring medication, second-degree atrioventricular block type II, third degree AV 4. Any degree of respiratory compromise (from either malignant or non-malignant disease) 5. Evidence of an ongoing systemic bacterial, fungal, or viral infection 6. Has received a live vaccine within 30 days 7. Major surgery within 4 weeks 8. Prior solid organ or bone marrow progenitor cell transplantation 9. Prior high dose chemotherapy requiring stem cell rescue 10. History of active autoimmune disorders 11. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids. 12. Treatment with an approved, systemic anticancer therapy or an investigational agent within 4 weeks of Day 1 13. A positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral test within 28 days prior to dosing, unless there is Investigator-confirmed clinical recovery on or before C1D1 14. Subjects with adrenal insufficiency 15. Subjects with any chemistry or hematology laboratory values that are ≥Grade 2 Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine the maximum tolerated dose of ST-067 in phase 1a monotherapy | Day 29 | Patients will be enrolled at a dose level that is predicted to be the MTD |
| Evaluate the overall safety and tolerability of ST-067 in combination with pembrolizumab | Day 29 | In patients experiencing insufficient response to a checkpoint inhibitor (PD-1) therapy administered alone or in combination. |
| Number of Participants With Treatment-Related Adverse Events | Day 29 | AE assessed by CTCAE 5.0 |
| Initial assessment of efficacy in phase 2 | At 8 weeks | Investigator-assessed ORR, defined as either a complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on computed tomography (CT) or magnetic resonance imaging (MRI) scans |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK | Day 29 | Peak Plasma Concentration (Cmax) |
| ADA | Day 29 | Incidence of ADA to ST-067 |
Countries
United States
Contacts
Primary ContactBeatrice McQueen, Ph.D.
Outcome results
None listed