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

Primary Purpose

Cancer, Solid Tumor, Melanoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ST-067
Obinutuzumab 25 MG/1 ML Intravenous Solution [GAZYVA]
pembrolizumab
Sponsored by
Simcha IL-18, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 not available or suitable (according to the investigator and after consultation with the Medical Monitor)

    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
  3. Significant cardiovascular disease
  4. Significant ECG abnormalities i
  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.

Sites / Locations

  • HonorHealth Research InstituteRecruiting
  • Sarah Cannon Research Institute at HealthONERecruiting
  • Yale Cancer CenterRecruiting
  • Moffitt Cancer CenterRecruiting
  • Massachusetts General HospitalRecruiting
  • Roswell Park Cancer InstituteRecruiting
  • Providence Cancer Institute Franz ClinicRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Phase 1a, Dose Escalation

Phase 2, Expansion

Phase 1a, Dose Escalation, ST-067 SC + Obinutuzumab Pre-treatment

Phase 1 combination therapy

Arm Description

In the Phase 1a monotherapy study, the starting dose of ST-067 will be 30 μg/kg, with a total of 7 dose level cohorts planned. The starting dose for the IV infusion monotherapy dosing will be 60 µg/kg. Patients will be treated every week with ST-067 in all cohorts. The DLT period is 28 days after the initial dose of ST-067. According to the mTPI schema initially there will be 3 patients per cohort until the first DLT is observed at which point cohorts will be expanded according to the predetermined mTPI design. Up to 12 patients will be treated at the RP2D.

Phase 2 will enroll patients aged 18 years or older diagnosed with the following solid tumors: melanoma, renal cell carcinoma (RCC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and microsatellite instability-high (MSI-Hi) tumors at the RP2D.

Patients will be treated every week with ST-067 in all cohorts. The DLT period is 28 days after the initial dose of ST-067. According to the mTPI schema initially there will be 3 patients per cohort until the first DLT is observed at which point cohorts will be expanded according to the predetermined mTPI design. The starting dose for ST-067 with obinutuzumab pre-treatment will be 120µg/kg. Obinutuzumab will be administered at 1000 mg daily via IV infusion on 2 consecutive days, with the first dose given at least 7 days prior to first dose of SC ST-067.

Phase 1 dose escalation in combination with pembrolizumab will start at a dose of 30 µg/kg of ST-067 and 200 mg every 3 weeks of pembrolizumab. Patients will be treated every week with ST-067 and every three weeks with pembrolizumab. The MTD will be determined based on the mTPI design.

Outcomes

Primary Outcome Measures

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
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.
Number of Participants With Treatment-Related Adverse Events
AE assessed by CTCAE 5.0
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

Secondary Outcome Measures

PK
Peak Plasma Concentration (Cmax)
ADA
Incidence of ADA to ST-067

Full Information

First Posted
February 16, 2021
Last Updated
July 30, 2023
Sponsor
Simcha IL-18, Inc.
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT04787042
Brief Title
Phase 1a and Phase 2 Study for Safety, Preliminary Efficacy, PK and PD of ST-067
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 6, 2021 (Actual)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
January 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Simcha IL-18, Inc.
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cancer, Solid Tumor, Melanoma, Renal Cell Carcinoma, Triple-negative Breast Cancer, Non Small Cell Lung Cancer, Squamous Cell Carcinoma of the Head and Neck, Carcinoma, MSI-High

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Model Description
Dose escalation and expansion
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
316 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase 1a, Dose Escalation
Arm Type
Experimental
Arm Description
In the Phase 1a monotherapy study, the starting dose of ST-067 will be 30 μg/kg, with a total of 7 dose level cohorts planned. The starting dose for the IV infusion monotherapy dosing will be 60 µg/kg. Patients will be treated every week with ST-067 in all cohorts. The DLT period is 28 days after the initial dose of ST-067. According to the mTPI schema initially there will be 3 patients per cohort until the first DLT is observed at which point cohorts will be expanded according to the predetermined mTPI design. Up to 12 patients will be treated at the RP2D.
Arm Title
Phase 2, Expansion
Arm Type
Experimental
Arm Description
Phase 2 will enroll patients aged 18 years or older diagnosed with the following solid tumors: melanoma, renal cell carcinoma (RCC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and microsatellite instability-high (MSI-Hi) tumors at the RP2D.
Arm Title
Phase 1a, Dose Escalation, ST-067 SC + Obinutuzumab Pre-treatment
Arm Type
Experimental
Arm Description
Patients will be treated every week with ST-067 in all cohorts. The DLT period is 28 days after the initial dose of ST-067. According to the mTPI schema initially there will be 3 patients per cohort until the first DLT is observed at which point cohorts will be expanded according to the predetermined mTPI design. The starting dose for ST-067 with obinutuzumab pre-treatment will be 120µg/kg. Obinutuzumab will be administered at 1000 mg daily via IV infusion on 2 consecutive days, with the first dose given at least 7 days prior to first dose of SC ST-067.
Arm Title
Phase 1 combination therapy
Arm Type
Experimental
Arm Description
Phase 1 dose escalation in combination with pembrolizumab will start at a dose of 30 µg/kg of ST-067 and 200 mg every 3 weeks of pembrolizumab. Patients will be treated every week with ST-067 and every three weeks with pembrolizumab. The MTD will be determined based on the mTPI design.
Intervention Type
Biological
Intervention Name(s)
ST-067
Intervention Description
ST-067 is an engineered variant of human interleukin-18.
Intervention Type
Biological
Intervention Name(s)
Obinutuzumab 25 MG/1 ML Intravenous Solution [GAZYVA]
Other Intervention Name(s)
GAZYVA
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
pembrolizumab
Other Intervention Name(s)
KEYTRUDA
Intervention Description
Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody.
Primary Outcome Measure Information:
Title
Determine the maximum tolerated dose of ST-067 in phase 1a monotherapy
Description
Patients will be enrolled at a dose level that is predicted to be the MTD
Time Frame
Day 29
Title
Evaluate the overall safety and tolerability of ST-067 in combination with pembrolizumab
Description
In patients experiencing insufficient response to a checkpoint inhibitor (PD-1) therapy administered alone or in combination.
Time Frame
Day 29
Title
Number of Participants With Treatment-Related Adverse Events
Description
AE assessed by CTCAE 5.0
Time Frame
Day 29
Title
Initial assessment of efficacy in phase 2
Description
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
Time Frame
At 8 weeks
Secondary Outcome Measure Information:
Title
PK
Description
Peak Plasma Concentration (Cmax)
Time Frame
Day 29
Title
ADA
Description
Incidence of ADA to ST-067
Time Frame
Day 29

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 1. Male and female patients aged ≥18 years Must provide written informed consent and any authorizations required by local law Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 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. For patients who have developed disease progression through standard therapy, or 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 Has at least 1 measurable lesion per RECIST 1.1 criteria which has not been biopsied or received prior irradiation Has an accessible tumor for biopsy pre- and on-treatment (mandatory). Exclusion Criteria: History of another malignancy Known symptomatic brain metastases requiring >10 mg/day of prednisolone or equivalent 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 Any degree of respiratory compromise (from either malignant or non-malignant disease) Evidence of an ongoing systemic bacterial, fungal, or viral infection Has received a live vaccine within 30 days Major surgery within 4 weeks Prior solid organ or bone marrow progenitor cell transplantation Prior high dose chemotherapy requiring stem cell rescue History of active autoimmune disorders Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids. Treatment with an approved, systemic anticancer therapy or an investigational agent within 4 weeks of Day 1 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 Subjects with adrenal insufficiency Subjects with any chemistry or hematology laboratory values that are ≥Grade 2 Additional exclusion criteria for Phase 1 combination therapy only: 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. Prior radiotherapy within 2 weeks of start of study treatment or history of radiation pneumonitis. 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. 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 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 History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease NSCLC subjects that have received radiation therapy to the lung that is >30Gy within 6 months of the first dose of study treatment
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Beatrice McQueen, Ph.D.
Phone
805-300-3912
Email
beatrice@simchatherapeutics.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeremy Barton, MD
Organizational Affiliation
Simcha IL-18, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
HonorHealth Research Institute
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85258
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Justin Moser, MD
Facility Name
Sarah Cannon Research Institute at HealthONE
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gerald Falchook, MD, MS
Facility Name
Yale Cancer Center
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06519
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Harriet Kluger, MD
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ahmad Tarhini, MD
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ryan Sullivan, MD
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Igor Puzanov, MD
Facility Name
Providence Cancer Institute Franz Clinic
City
Portland
State/Province
Oregon
ZIP/Postal Code
97213
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew Taylor, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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

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