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

PHASE1RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

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.

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.

Newly obtained or archived tumor tissue is required

Have adequate organ function

Understand and voluntarily sign an Institutional Review Board/Independent Ethics Committee-approved informed consent form prior to any study-specific evaluation.

Life expectancy ≥ 12 weeks

Exclusion criteria

Conditions interfering with oral intake of NST-628

Conditions interfering with intestinal absorption of an orally administered drug

A history or current evidence of significant retinal pathology leading to increased risk of RVO

A history or evidence of cardiovascular risk

Current or history within 6 months of planned Cycle 1 Day 1 of pneumonitis or interstitial lung disease (ILD)

Untreated or symptomatic central nervous system (CNS) metastases

Chemotherapy, radiation, gene therapy, vaccine therapy, or anti-cancer antibodies / ADCs within 28 days of Cycle 1 Day 1

Targeted small molecule agents within 14 days or 5 half-lives of Cycle 1 Day 1

Females who are pregnant or breastfeeding.

Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-04-09

Primary completion: 2028-11-01

Study completion finish: 2029-11-01

Study type

TREATMENT

Phase

PHASE1

Trial ID

NCT06326411

Intervention or treatment

DRUG: NST-628

Conditions

• Melanoma
• NSCLC
• Glioma
• Solid Tumor, Adult
• Oncology
• MEK Mutation
• RAF Gene Mutation
• Ras (KRAS or NRAS) Gene Mutation
• MAPK Pathway Gene Mutation

Condition: Melanoma, NSCLC and more
DRUG: NST-628
Rand, New South Wales, Australia and more
Sponsor: Nested Therapeutics, Inc

You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

Are you running this trial? If you're a clinic or sponsor, you can claim this study. Claim or learn more.

Find a site

Closest Location:

Scientia Clinical Research, Ltd

Research sites nearby

Select from list below to view details:

Scientia Clinical Research, Ltd
Rand, New South Wales, Australia
The Kinghorn Cancer Center, St. Vincent's Health Network
Sidney, New South Wales, Australia
Gallipoli Medical Research Centre- Greenslopes Private Hospital
Greenslopes, Queensland, Australia
Southern Oncology Research Unit
Adelaide, Not Specified, Australia

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?

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.

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

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
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
Part A: Determine the recommended dose for expansion of NST-628	Dose limiting toxicities (DLTs)	The first 28 days of treatment (DLTs)
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 outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
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
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
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
Part A and B: Characterize the pharmacokinetics of NST-628	NST-628 concentrations in plasma	Through study completion, an average of 1 year

Frequently Asked Questions

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References

Clinical Trials Gov: A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects with Solid Tumors