Phase 1a and Phase 2 Study for Safety, Preliminary Efficacy, PK and PD of ST-067

Cancer Clinical Trial

Official title:

A First-In-Human Phase 1/2 Open-Label Study of Intravenous ST-067, Subcutaneous ST-067 With or Without Obinutuzumab Pre-Treatment, and ST-067 in Combination With Pembrolizumab in Subjects With Advanced Solid Malignancies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04787042
• Other study ID #: ST-067-001
• Secondary ID: KEYNOTE-E64
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 6, 2021
• Est. completion date: January 30, 2025

Study information

• Verified date: June 2023
• Source: Simcha IL-18, Inc.
• Contact: Beatrice McQueen, Ph.D.
• Phone: 805-300-3912
• Email: beatrice[@]simchatherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 316
• Est. completion date: January 30, 2025
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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 exclusion criteria for Phase 1 combination therapy only:

16. Presence of known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.

17. Prior radiotherapy within 2 weeks of start of study treatment or history of radiation pneumonitis.

18. Presence of an active documented autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine or insulin) is not considered a form of systemic treatment and is allowed. Subjects may use topical and/or inhaled corticosteroids. However, subjects with adrenal insufficiency on replacement doses of steroids are not allowed.

19. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX40, CD137), and was discontinued from that treatment due to a Grade 3 or higher irAE

20. Severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients. Subjects who have been retreated after such a reaction may be allowed after discussion with the Simcha Medical Monitor

21. History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

22. NSCLC subjects that have received radiation therapy to the lung that is >30Gy within 6 months of the first dose of study treatment

Related Conditions & MeSH terms

• Cancer
• Carcinoma
• Carcinoma, Renal Cell
• Melanoma
• Non Small Cell Lung Cancer
• Renal Cell Carcinoma
• Solid Tumor
• Squamous Cell Carcinoma of Head and Neck
• Squamous Cell Carcinoma of the Head and Neck
• Triple Negative Breast Neoplasms
• Triple-negative Breast Cancer

Intervention

Biological:
• ST-067
ST-067 is an engineered variant of human interleukin-18.
• Obinutuzumab 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.
• pembrolizumab
Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody.

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Sarah Cannon Research Institute at HealthONE	Denver	Colorado
United States	Yale Cancer Center	New Haven	Connecticut
United States	Providence Cancer Institute Franz Clinic	Portland	Oregon
United States	HonorHealth Research Institute	Scottsdale	Arizona
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Simcha IL-18, Inc.	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Determine the maximum tolerated dose of ST-067 in phase 1a monotherapy	Patients will be enrolled at a dose level that is predicted to be the MTD	Day 29
Primary	Evaluate the overall safety and tolerability of ST-067 in combination with pembrolizumab	In patients experiencing insufficient response to a checkpoint inhibitor (PD-1) therapy administered alone or in combination.	Day 29
Primary	Number of Participants With Treatment-Related Adverse Events	AE assessed by CTCAE 5.0	Day 29
Primary	Initial assessment of efficacy in phase 2	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	At 8 weeks
Secondary	PK	Peak Plasma Concentration (Cmax)	Day 29
Secondary	ADA	Incidence of ADA to ST-067	Day 29