Clinical trial NCT06578624: Safety and Preliminary Efficacy of SA53-OS in Patients With Locally Advanced or Metastatic Solid Tumors
Official title: A Phase 1/2a, Open-Label Study of Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SA53-OS, an MDM2 Inhibitor, in Patients With Locally Advanced or Metastatic p53 Wild-Type Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Solid Tumor
Keywords: p53 wild-type tumor
liposarcoma
MDM2 inhibitor
solid tumors
dedifferentiated liposarcoma (DD LPS)
p53
Advanced or metastatic solid tumors
Lead sponsor: Lamassu Bio Inc
Sponsor class: INDUSTRY
First posted: 2024-08-29
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Phase 1 of the study will start with dose escalation by 2-fold (i.e., 2x preceding dose level) in cohorts of a single participant until Grade 2 or greater toxicity is observed. When a single Grade 2 or higher toxicity is observed, 3+3 multi-participant cohorts will be treated at the dose in which the Grade 2 or higher toxicity was observed by enrolling another 2 participants at this dose. The 3+3 multi-participant cohorts will follow the standard 3+3 paradigm based on occurrence of any DLT with 50% dose escalation until the MTD is identified. In phase 2 of the study, the MTD will be administered to 2 cohorts of 20 participants each: Cohort A) with known MDM2 amplified DD LPS; Cohort B) p53 wild-type solid tumors.
Primary purpose: TREATMENT

Brief summary: The objective of this study is to assess the safety, efficacy, and pharmacokinetics of SA53-OS in adult participants with refractory solid tumors.

The study is comprised of 2 parts: Part 1 called dose escalation, and Part 2a called dose expansion. This study starts with Part 1 where participants who are diagnosed with advanced or metastatic solid tumor cancers receive different doses of SA53-OS (starting with the lowest dose) to find the maximum tolerated dose (MTD) of SA53-OS. Once the MTD of SA53-OS is known, the study continues to Part 2a where participants who are diagnosed with dedifferentiated liposarcoma (DD LPS) or other solid tumor cancers will receive SA53-OS at the MTD.

The study drug, SA53-OS, will be administered for 3 consecutive days every 3 weeks as an oral solution for up to 2 years.

Detailed description: This is a phase 1/2a, open-label, dose escalation study conducted in adult participants with p53 wild-type refractory solid tumors. The study will assess the safety, efficacy, and pharmacokinetics of SA53-OS a novel MDM2 inhibitor capable of selective activation of p53. This enables the p53 tumor suppressor protein to selectively facilitate tumor cell death and growth inhibition.

The study drug, SA53-OS, will be administered for 3 consecutive days every 3 weeks as an oral solution. Phase 1 will consist of a dose escalation study to establish a candidate recommended phase 2 dose (RP2D). Phase 2a will enroll 2 expansion cohorts to establish any preliminary efficacy of SA53-OS in participants with dedifferentiated liposarcoma (DD LPS) with MDM2 amplifications and other p53 wild-type solid tumors as a single agent.

Phase 1 dose escalation:

Escalating doses of SA53-OS will be provided to participants with p53 wild-type refractory solid tumors to determine the RP2D. The MTD is the highest dose of a drug or treatment that does not cause unacceptable side effects in the first cycle. The RP2D considers all available safety, pharmacokinetics, and efficacy data including, the frequency, severity, and manageability of toxicities occurring after Cycle 1.

Phase 1 of the study will start with dose escalation by 2-fold (i.e., 2x preceding dose level) in cohorts of a single participant until Grade 2 or greater toxicity is observed.

When a single Grade 2 or higher toxicity is observed, 3+3 multi-participant cohorts will be treated at the dose in which the Grade 2 or higher toxicity was observed by enrolling another 2 participants at this dose. The 3+3 multi-participant cohorts will follow the standard 3+3 paradigm based on occurrence of any DLT with 50% dose escalation until the MTD is identified.

Phase 2a dose expansion:

The purpose of Phase 2a of the study is to describe any preliminary evidence of efficacy from SA53-OS monotherapy in participants with DD LPS or other p53 wild-type or MDM2 amplified solid tumors. Phase 2a will also be used to confirm the safety and tolerability of the candidate RP2D of SA53-OS determined in Phase 1 of the study, to further describe the toxicity and pharmacokinetics profiles of SA53-OS, and to assess potential biomarkers of sensitivity resistance, and toxicity.

Participants will continue to receive study treatment until either: 1) disease progression; 2) occurrence of unacceptable treatment-related toxicity as per participant or Investigator discretion; 3) the maximum of 2 years of treatment has been reached; or 4) other reason(s) for study treatment discontinuation. In the case of complete response, treatment should be continued for at least 6 months if no other stopping criteria are met, and further treatment can be recommended at the investigator's discretion.

Eligibility criteria: Inclusion Criteria:

* Tumor characteristics of participants in Phase 1

  1. Histologically and/or cytologically confirmed diagnosis of advanced or metastatic solid tumor and/or non-Hodgkin lymphoma excluding primary central nervous system malignancy for which no standard effective treatment exists or where that treatment was declined. Participants with non-Hodgkin lymphoma should have failed ≥ 2 prior lines of systemic therapy prior enrollment.
  2. Tumor p53 wild-type.
* Tumor characteristics of participants in Phase 2a

  1. Cohort A: Tumor p53 wild-type with histologically confirmed diagnosis of advanced or metastatic DD LPS (and MDM2 amplification); OR Cohort B: Tumor p53 wild-type in other solid tumor.
  2. Measurable disease by RECIST 1.1.
* 18 years old or older.
* Resolution of clinically relevant toxicity-related to prior anticancer therapies prior to receipt of study treatment to Grade 1 or less.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Participants of childbearing/reproductive potential must agree to use adequate birth control measures during the course of the trial and for at least 3 months after discontinuing study treatment.

Exclusion Criteria:

* Anticipated need for major surgery and/or localized palliative radiation within the next 6 weeks
* Active, untreated central nervous system metastases. Participants with brain metastases identified at Screening may be rescreened after the lesion(s) have been appropriately treated; participants with treated brain metastases should be neurologically stable for 4 weeks post-treatment and prior to study enrollment, and off corticosteroids for at least 2 weeks before start of study treatment, and treated lesions should demonstrate no new growth on the re-screening scan.
* Known HIV infection or active hepatitis B or C infection.
* Thrombotic event requiring active and ongoing anticoagulation within the last 6 months prior to study treatment.
* Myocardial infarction within the last 6 months prior to study treatment.
* Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, congestive heart failure New York Heart Association (NYHA) Class III or IV related to primary cardiac disease, uncontrolled ischemic or severe vascular heart disease.
* A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
* Known bleeding disorder (e.g., hemophilia, von Willebrand disease).
* Conditions that may predispose to major bleeding (e.g., active GI ulcers, upper or lower GI bleedings in the last 6 months, significant hemoptysis in the last 6 months, tumor invasion of major vessels, etc.). Conditions that have been treated may be allowed if resolution of the risk is documented.
* Use or indication for full dose anticoagulation or anti-platelet therapy including low dose aspirin.
* Women who are pregnant or lactating.

Primary outcomes:
measure: Phase 1: Incidence of DLT
timeFrame: 21 days
measure: Phase 1 and 2: Adverse events
timeFrame: Approximately 2 years
Secondary outcomes:
measure: Phase 1: Peak plasma concentration
timeFrame: Day 4
measure: Phase 1: Area under the plasma concentration versus time curve between 0 and 24 hours
timeFrame: Day 4
measure: Phase 1: Half-life
timeFrame: Day 4
measure: Phase 2: Objective response rate (ORR)
timeFrame: Approximately 2 years
measure: Phase 2: Progression free survival (PFS)
timeFrame: Approximately 2 years
measure: Phase 2: Overall survival
timeFrame: Approximately 2 years
measure: Phase 2: Duration of response
timeFrame: Approximately 2 years
measure: Phase 2: Complete response rate
timeFrame: Approximately 2 years
measure: Phase 2: Stable disease rate
timeFrame: Approximately 2 years
measure: Phase 2: Disease control rate
timeFrame: Approximately 2 years
Other outcomes:
Locations:
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Institute
state: Ohio
Study officials:
affiliation: Lamassu Bio
name: Gabi Hanna, MD
role: STUDY_DIRECTOR
References: