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

Melanoma Clinical Trial

— NST-628  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06326411
• Other study ID #: NST-628-001
• Status: Recruiting
• Phase: Phase 1
• Start date: April 9, 2024
• Est. completion date: November 2029

Study information

• Verified date: May 2024
• Source: Nested Therapeutics, Inc
• Contact: CMO
• Phone: 617-468-4292
• Email: info[@]nestedtx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 230
• Est. completion date: November 2029
• Est. primary completion date: November 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Glioma
• MEK Mutation
• Melanoma
• Neoplasms
• NSCLC
• Oncology
• Solid Tumor, Adult

Intervention

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.

Locations

Country	Name	City	State
Australia	Southern Oncology Research Unit	Adelaide
Australia	Gallipoli Medical Research Centre- Greenslopes Private Hospital	Greenslopes	Queensland
Australia	One Clinical Research, Pty Ltd	Nedlands	Western Australia
Australia	Scientia Clinical Research, Ltd	Rand	New South Wales
Australia	The Kinghorn Cancer Center, St. Vincent's Health Network	Sidney	New South Wales
United States	NEXT Oncology - Austin	Austin	Texas
United States	NEXT Oncology - Dallas	Dallas	Texas
United States	NEXT Oncology - Virginia	Fairfax	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Nested Therapeutics, Inc

Countries where clinical trial is conducted

United States,  Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A and B: Evaluate the safety of NST-628 in patients with advanced solid tumors	Adverse effects	Through study completion, an average of 1 year
Primary	Part A: Determine the recommended dose for expansion of NST-628	Dose limiting toxicities (DLTs)	The first 28 days of treatment (DLTs)
Primary	Part B: Evaluate objective tumor response rate	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	Part A: Evaluate objective tumor response rate	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	Part A and B: Evaluate progression free survival (PFS)	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
Secondary	Part A and B: Evaluate overall survival (OS)	Overall survival (OS) defined as the time to death	Through study completion, an average of 2 years
Secondary	Part A and B: Characterize the pharmacokinetics of NST-628	NST-628 concentrations in plasma	Through study completion, an average of 1 year