A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors (NST-628)

April 15, 2026 updated by: Nested Therapeutics, Inc

A Phase I, Open Label Single-arm Two-part Study to Investigate Safety, Pharmacokinetics, and Preliminary Efficacy of Pan-RAF/MEK Glue NST-628 Oral Tablets in Subject With Solid Tumors Harboring Genetic Alterations in the MAPK Pathway and With Other Solid Tumors

This is a two-part Phase 1, open label, multi-center, single arm, non-randomized, multiple dose, safety, pharmacokinetic (PK) and preliminary efficacy study of single agent NST-628 in adult patients with MAPK pathway mutated/dependent advanced solid tumors who have exhausted standard treatment options.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The study includes two parts, a dose escalation part (Part A) followed by a dose expansion part (Part B). Part A will estimate the maximum tolerated dose (MTD) in dose escalation cohorts in patients with advanced solid tumors for whom no standard therapy is available in order to establish the recommended dose for expansion (RDE). Successive cohorts of subjects will receive escalating doses of NST-628 orally once daily in 28-day cycles.

Bayesian Optimal Interval (BOIN) method will be used for dose escalation.

Once MTD is reached or dose escalation is stopped prior to reaching MTD and provisional RDE selected, the provisional RDE level will be expanded. If warranted by dose/toxicity/anti-tumor activity observations, additional, lower dose level(s) may also be expanded.

Part B of the study will include up to 6 cohorts of approximately up to 30 subjects each with select MAPK pathway mutant solid tumors enrolled at the RDE in order to explore benefit from treatment as suggested by preclinical findings and will better define the safety profile of NST-628 at the RDE. Additional safety information gathered in Part B may be used to modify the dose recommended for future studies.

The end of the study is the last visit of the last subject.

Study Type

Interventional

Enrollment (Estimated)

230

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Australia
    • New South Wales
      • Darlinghurst, New South Wales, Australia, 2010
        • Recruiting
        • The Kinghorn Cancer Center, St. Vincent's Health Network
        • Contact:
        • Principal Investigator:
          • Jia (Jenny) Liu, MD
      • Randwick, New South Wales, Australia, 2031
        • Completed
        • Scientia Clinical Research, Ltd
    • Queensland
      • Greenslopes, Queensland, Australia, 120
        • Recruiting
        • Gallipoli Medical Research Centre- Greenslopes Private Hospital
        • Contact:
        • Principal Investigator:
          • Victoria Atkinson, MD
    • South Australia
      • Adelaide, South Australia, Australia, 5042
        • Recruiting
        • Southern Oncology Research Unit
        • Contact:
        • Principal Investigator:
          • Ganessan Kichenadasse, MD
    • Victoria
      • Malvern, Victoria, Australia, 3144
      • Malvern, Victoria, Australia, 3144
  • United States
    • California
      • San Francisco, California, United States, 94158
        • Recruiting
        • UCSF Helen Diller Family Comprehensive Cancer Center
        • Contact:
          • Phu Lam Clinical Research Manager
          • Phone Number: 415-818-7994
          • Email: Phu.Lam@ucsf.com
        • Principal Investigator:
          • Virun Monga, MD
      • Westwood, Los Angeles, California, United States, 90024
        • Recruiting
        • UCLA Hematology/Oncology
        • Principal Investigator:
          • Bartosz Chmielowski, MD
        • Contact:
    • Colorado
      • Denver, Colorado, United States, 80218
        • Recruiting
        • Sarah Cannon Research Institute at Health ONE
        • Principal Investigator:
          • Gerald Falchook, MD, MS
        • Contact:
          • Phone Number: 844-482-4812
    • Connecticut
      • New Haven, Connecticut, United States, 06511
        • Completed
        • Yale Cancer Center
    • Florida
    • New York
      • Buffalo, New York, United States, 14263
        • Recruiting
        • Roswell Park
        • Principal Investigator:
          • Igor Puzanov, MD
        • Contact:
      • New York, New York, United States, 10016
        • Recruiting
        • Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
        • Principal Investigator:
          • Janice Mehnert, MD
      • New York, New York, United States, 10032
        • Recruiting
        • Columbia University Medical Center
        • Contact:
        • Principal Investigator:
          • Benjamin Herzberg, MD
      • New York, New York, United States, 10065
        • Recruiting
        • Memorial Slone Kettering Cancer Center
        • Principal Investigator:
          • Monica Chen, MD
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15232
        • Recruiting
        • UPMC Hillman Cancer Center
        • Principal Investigator:
          • Jason Luke, MD
        • Contact:
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Recruiting
        • Vanderbilt-Ingram Cancer Center
        • Contact:
        • Principal Investigator:
          • Jordan D Berlin, MD
      • Nashville, Tennessee, United States, 37203
        • Recruiting
        • SCRI Oncology Partners
        • Principal Investigator:
          • Meredith McKean, MD, MPH
        • Contact:
          • Phone Number: 844-482-4812
    • Texas
      • Austin, Texas, United States, 78758
        • Active, not recruiting
        • NEXT Oncology - Austin
      • Dallas, Texas, United States, 75039
        • Active, not recruiting
        • NEXT Oncology - Dallas
      • Houston, Texas, United States, 77030
        • Recruiting
        • MD Anderson Cancer Center
        • Contact:
        • Principal Investigator:
          • Sarina Piha-Paul, MD
    • Utah
      • West Valley City, Utah, United States, 84119
        • Completed
        • START Moutain Region
    • Virginia
      • Fairfax, Virginia, United States, 22031
        • Recruiting
        • NEXT Oncology - Virginia
        • Contact:
        • Principal Investigator:
          • Mohamad Salkeni, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Subjects are eligible to be included in the study only if all of the following criteria apply:

  1. Subjects must be ≥18 years old (or of legal age of consent in the country in which the study is taking place) at the time of signing the informed consent.

  2. Subjects who have a histologically or cytologically documented metastatic or locally advanced solid tumor, for which standard of care (SoC) therapy does not exist, no longer provides benefit, or is not tolerated by the subject, or the subject has been assessed by the Investigator as not being suitable for SoC therapy.

    1. Part A: Subjects with any solid tumor with genetic alteration of or evidence of tumor dependence upon the RAS/MAPK pathway (subject to additional restrictions specified in the study protocol)
    2. Part B: Subjects must be diagnosed with one of the following solid tumors harboring specified genetic alterations based on a validated local test:

    i. Melanoma Cohorts:

    1. Activating NRAS mutations
    2. Select BRAF alterations

    ii. Non-Melanoma Cohorts:

    1. Solid tumors with NRAS activating mutations
    2. Solid tumors with KRAS activating mutations
    3. Solid tumors with select BRAF alterations
    4. Glioma with BRAF alterations
  3. Newly obtained or archived tumor tissue is required
  4. Part B: measurable disease as defined by RECIST Version 1.1 or by other disease assessment tool standard for a given tumor type (if RECIST v. 1.1 is not standard)

  5. Performance status

    1. Solid tumors other than glioma: ECOG 0 or 1
    2. Glioma: Karnofsky ≥ 70 and ECOG 0 or 1
  6. Have adequate organ function
  7. Understand and voluntarily sign an Institutional Review Board/Independent Ethics Committee-approved informed consent form prior to any study-specific evaluation.
  8. Life expectancy ≥ 12 weeks

Exclusion Criteria:

Subjects are excluded from the study if any of the following criteria apply:

  1. Conditions interfering with oral intake of NST-628
  2. Conditions interfering with intestinal absorption of an orally administered drug
  3. A history or current evidence of significant retinal pathology leading to increased risk of RVO
  4. A history or evidence of cardiovascular risk
  5. Current or history within 6 months of planned Cycle 1 Day 1 of pneumonitis or interstitial lung disease (ILD)
  6. Part B: prior treatment with any MEK or BRAF inhibitor
  7. Untreated or symptomatic central nervous system (CNS) metastases
  8. Chemotherapy, radiation, gene therapy, vaccine therapy, or anti-cancer antibodies / ADCs within 28 days of Cycle 1 Day 1
  9. Targeted small molecule agents within 14 days or 5 half-lives of Cycle 1 Day 1
  10. Females who are pregnant or breastfeeding.
  11. For fertile patients (female able to become pregnant or male able to father a child), refusal to use effective contraception during the period of the trial and for 6 months after the last dose of NST-628
  12. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Part A Dose Escalation and Part B Dose Expansion

Part A will evaluate the safety of NST-628 with advanced solid tumors and determine the recommended dose for expansion of NST-628.

Part B will evaluate the objective tumor response rate in subjects with advanced solid tumors harboring specified genetic alterations receiving NST-628 and evaluate the safety of NST-628 in subjects with advanced solid tumors in cohorts defined below:

i. Melanoma Cohorts

  1. Activating NRAS mutations
  2. Select BRAF alterations

ii. Non-Melanoma Cohorts:

  1. Solid tumors with NRAS activating mutations
  2. Solid tumors with KRAS activating mutations
  3. Solid tumors with select BRAF alterations
  4. Glioma with BRAF alterations
Drug: NST-628
NST-628 is a small molecule non-covalent pan-RAF/MEK dual molecular glue targeting RAF and MEK nodes of MAPK pathway.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Part A and B: Evaluate the safety of NST-628 in patients with advanced solid tumors
Time Frame: Through study completion, an average of 1 year
Adverse effects
Through study completion, an average of 1 year
Part A: Determine the recommended dose for expansion of NST-628
Time Frame: The first 28 days of treatment (DLTs)
Dose limiting toxicities (DLTs)
The first 28 days of treatment (DLTs)
Part B: Evaluate objective tumor response rate
Time Frame: Through study completion, an average of 1 year
Objective response per RECIST v. 1.1 or other response assessment tool standard for a given tumor type.
Through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Part A: Evaluate objective tumor response rate
Time Frame: Through study completion, an average of 1 year
Objective response per RECIST v. 1.1 or other response assessment tool standard for a given tumor type.
Through study completion, an average of 1 year
Part A and B: Evaluate progression free survival (PFS)
Time Frame: Through study completion, an average of 1 year
PFS defined as the time to first occurrence of disease progression per RECIST v1.1 (or other response assessment tool standard for a given tumor type) or death
Through study completion, an average of 1 year
Part A and B: Evaluate overall survival (OS)
Time Frame: Through study completion, an average of 2 years
Overall survival (OS) defined as the time to death
Through study completion, an average of 2 years
Part A and B: Characterize the pharmacokinetics of NST-628
Time Frame: Through study completion, an average of 1 year
NST-628 concentrations in plasma
Through study completion, an average of 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nested Therapeutics, Inc

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 9, 2024

Primary Completion (Estimated)

November 1, 2028

Study Completion (Estimated)

November 1, 2029

Study Registration Dates

First Submitted

March 15, 2024

First Submitted That Met QC Criteria

March 21, 2024

First Posted (Actual)

March 22, 2024

Study Record Updates

Last Update Posted (Actual)

April 20, 2026

Last Update Submitted That Met QC Criteria

April 15, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NST-628-001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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