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

Phase 1

Recruiting

• Conditions: MEK Mutation; Solid Tumor, Adult; RAF Gene Mutation; NSCLC; Oncology; Ras (KRAS or NRAS) Gene Mutation; MAPK Pathway Gene Mutation; Melanoma; Glioma
• Interventions: Drug: NST-628

• Registration Number: NCT06326411
• Lead Sponsor: Nested Therapeutics, Inc

Brief Summary

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.

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 Timeline

• Study First Submitted: 2024-03-15
• Study First Submitted QC: 2024-03-21
• Study First Posted: 2024-03-22
• Study Start: 2024-04-09
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-15
• Last Update Posted: 2025-04-18
• Primary Completion: 2028-11
• Study Completion: 2029-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 230

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part A Dose Escalation and Part B Dose Expansion	NST-628	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

Primary Outcome Measures

Name	Time	Method
Part A and B: Evaluate the safety of NST-628 in patients with advanced solid tumors	Through study completion, an average of 1 year	Adverse effects
Part A: Determine the recommended dose for expansion of NST-628	The first 28 days of treatment (DLTs)	Dose limiting toxicities (DLTs)
Part B: Evaluate objective tumor response rate	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.

Secondary Outcome Measures

Name	Time	Method
Part A: Evaluate objective tumor response rate	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.
Part A and B: Evaluate progression free survival (PFS)	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
Part A and B: Characterize the pharmacokinetics of NST-628	Through study completion, an average of 1 year	NST-628 concentrations in plasma
Part A and B: Evaluate overall survival (OS)	Through study completion, an average of 2 years	Overall survival (OS) defined as the time to death

Trial Locations

Locations (21)

Laura & Isaac Perlmutter Cancer Center at NYU Langone Health; 🇺🇸 New York, New York, United States

Sarah Cannon Research Institute at Health ONE; 🇺🇸 Denver, Colorado, United States

UPMC Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

SCRI Oncology Partners; 🇺🇸 Nashville, Tennessee, United States

UCSF Helen Diller Family Comprehensive Cancer Center; 🇺🇸 San Francisco, California, United States

UCLA Hematology/Oncology; 🇺🇸 Westwood, California, United States

Yale Cancer Center; 🇺🇸 New Haven, Connecticut, United States

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

Roswell Park; 🇺🇸 Buffalo, New York, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

Memorial Slone Kettering Cancer Center; 🇺🇸 New York, New York, United States

NEXT Oncology - Austin; 🇺🇸 Austin, Texas, United States

NEXT Oncology - Dallas; 🇺🇸 Dallas, Texas, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

START Moutain Region; 🇺🇸 West Valley City, Utah, United States

NEXT Oncology - Virginia; 🇺🇸 Fairfax, Virginia, United States

The Kinghorn Cancer Center, St. Vincent's Health Network; 🇦🇺 Darlinghurst, New South Wales, Australia

Scientia Clinical Research, Ltd; 🇦🇺 Randwick, New South Wales, Australia

Gallipoli Medical Research Centre- Greenslopes Private Hospital; 🇦🇺 Greenslopes, Queensland, Australia

Southern Oncology Research Unit; 🇦🇺 Adelaide, South Australia, Australia

Cabrini Hospital; 🇦🇺 Malvern, Victoria, Australia