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Mannitol

Escalating doses of VS-6766 (RO5126766) and Defactinib (VS-6063) were evaluated in patients with advanced solid tumours to establish the recommended phase II dose. Dose escalation followed a 3+3 design with a maximum of four patient cohorts.

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS mutant NSCLC (20 patients).

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients advanced RAS mutant solid tumours with biopsiable disease (6 patients).

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with LGSOC (20 patients).

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with CRC (10 patients).

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS G12V mutant NSCLC (10 patients).

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis-related) (10 patients).

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with pancreatic cancer (10 patients).

VS-6766 will be supplied as 0.8mg hypromellose (HPMC) capsules for oral administration. The capsule fill consists of VS-6766 and the inactive ingredients mannitol and magnesium stearate.

VS-6766 will be administered on a twice weekly (Monday and Thursday or Tuesday and Friday) schedule for 3 weeks followed by 1 week off in every 4 week cycle, under fasting conditions (approximately 1 hour prior or 2 hours after a meal). The starting dose, based on the previous Phase I trial will be 3.2 mg given orally as a single daily dose. This can be escalated to a maximum of 4mg (as per dose escalation rules in the protocol).

VS-6766

Defactinib is formulated as a white to off-white oval tablet for oral administration and supplied in single unit dose strength of 200 mg in 120 cc (HDPE) bottles. In addition to Defactinib, formulation components include microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, and magnesium stearate.

Patients will receive Defactinib orally immediately after a meal twice daily (approximately every 12 hours) for 3 weeks followed by 1 week off in every 4 week cycle. The starting dose will be 200mg. This can be escalated to a maximum of 400mg (as per dose escalation rules in the protocol).

Defactinib

Udai Banerji, FRCP, PhD

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, Defactinib (VS-6063), and the dual RAF/MEK inhibitor, VS-6766 (RO5126766) in patients with advanced solid tumours. VS-6766 (RO5126766) is the same compound as CH5126766.

There are two parts to this study, the dose escalation phase and the dose expansion phase. In the dose escalation phase, cohorts of 3 to 6 patients will be enrolled to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). This will be followed by a dose expansion phase to further characterise the safety and tolerability and to assess the pharmacodynamic activity of the combination.

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, Defactinib, and the dual RAF/MEK inhibitor, VS-6766 in patients with advanced solid tumours.

There are two parts to this study, the dose escalation phase and the dose expansion phase. In the dose escalation phase, cohorts of 3 to 6 patients were enrolled to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Up to 24 patients with solid tumours were treated in the dose escalation phase of this study.

The dose escalation phase is now closed to recruitment.

This will be followed by a dose expansion phase of 86 patients to further characterise the safety and tolerability and to assess the pharmacodynamic activity of the combination.

The dose expansion phase is made up of 7 cohorts:

* 20 patients with KRAS mutant non-small-cell lung cancer (NSCLC);
* 7 patients with solid tumours (enriched for those with RAS mutations) willing to undergo biopsies at three time points throughout the study;
* 20 patients with low grade serous ovarian cancer (LGSOC);
* 10 patients with colorectal cancer (CRC);
* 10 patients with KRAS G12V mutant NSCLC;
* 10 patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis related) and
* 10 patients with pancreatic cancer.

The following cohorts are still open to recruitment:

* Patients with low grade serous ovarian cancer (LGSOC);
* Patients with KRAS G12V mutant NSCLC;
* Patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis-related) and
* Patients with pancreatic cancer.

Patients will take the two investigational medicinal products (IMPs) as follows:

VS-6766 will be administered orally twice a week on Monday/Thursday or Tuesday/Friday at least one hour prior or two hours after a meal. The starting dose of VS-6766 will be 3.2mg once a day, twice a week and can be escalated to a maximum of 4mg once a day, twice a week.

Defactinib will be administered orally twice a day immediately after a meal. The starting dose of Defactinib will be 200mg twice daily and can be escalated to a maximum of 400mg twice daily.

A cycle length is 4 weeks (28 days). Combination dosing (VS-6766 and Defactinib) will commence on Cycle 1 Day 1 for 3 weeks followed by one week without either drug in week 4 (i.e. 3 weeks on, 1 week off).

For patients consenting to optional biopsies, a run-in dose of VS-6766 will be administered on a single day anywhere between Days -7 to Day -3 in order to facilitate pharmacodynamic (PD) biomarker analysis. Therefore, for patients undergoing biopsies the first cycle will be 5 weeks long and subsequent cycles will consist of 4 weeks.

If this schedule is not tolerated, alternative schedules may be explored following discussion by the Safety Review Committee.

The dose escalation phase will enrol patients with advanced RAS mutant solid tumours.

In the dose expansion phase, patients are assigned to one of the following cohorts based on their diagnosis:

* KRAS mutant NSCLC cohort
* LGSOC cohort
* RAS mutant CRC cohort
* Advanced RAS mutant solid tumour cohort - patients in this cohort must have biopsiable disease, be willing and consent to undergo biopsies at three time-points.
* KRAS G12V mutant NSCLC cohort
* RAS/RAF mutant endometrioid cohort
* Pancreatic cohort

Non-randomised: Participants are expressly assigned by phase of study and diagnosis.

Phase I Trial of Defactinib and VS-6766.

FRAME: A Phase I Trial of the Combination of Defactinib (VS-6063) (FAK Inhibitor) and VS-6766 (RO5126766) (CH5126776) (a Dual RAF/MEK Inhibitor) in Patients With Advanced Solid Tumours

Determination of disease response by RECIST criteria version 1.1 and collection of data related to progression free survival.

Quantification of biomarkers such as p-MEK, p-ERK and p-FAK, E-cadherin and vimentin and enumeration of T cell populations which express CD8, CD4 and CD25.

Correlation of antitumour activity of the combination of VS-6766 and Defactinib with the detection of putative predictive biomarkers of response and resistance in archival tumours and plasma DNA.

To determine the maximum dose at which no more than 1 of 6 patients at the same dose level experience a drug related toxicity (DLT) as specified in the protocol.

To assess the safety and toxicity profile of VS-6766 and Defactinib. To determine causality and grading severity of each adverse event by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Determination of the PK parameter Cmax of VS-6766 and Defactinib when dosed together.

Determination of the PK parameter terminal half-life of VS-6766 and Defactinib when dosed together.

Determination of the PK parameter area under the curve of VS-6766 and Defactinib when dosed together.

Verastem, Inc.

Institute of Cancer Research, United Kingdom

Skin and Connective Tissue Diseases

Melanoma

Glioma

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

NST-628 is a small molecule non-covalent pan-RAF/MEK dual molecular glue targeting RAF and MEK nodes of MAPK pathway.

NST-628

Ann Marie Kennedy

Brianna Flores

Andrea Vandross, MD

Erica Torres

Naga Cheedella, MD

Blake Patterson

Mohamad Salkeni, MD

Shiena Lemin

Charlotte Lemech, MD

Jia (Jenny) Liu, MD

Sarah McLennan

Victoria Atkinson, MD

Scott McGregor

Omar Faruque, MD

Meggan O'Riley

Ganessan Kichenadasse, MD

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.

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.

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

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

Objective response per RECIST v. 1.1 or other response assessment tool standard for a given tumor type.

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

Overall survival (OS) defined as the time to death

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I Trial of Defactinib and VS-6766.	NCT03875820	NSCLC Low Grade Serou... Endometrioid Ca... Pancreatic Canc...	VS-6766 Defactinib	18 Years -	Institute of Cancer Research, United Kingdom
A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors	NCT06326411	Oncology MEK Mutation RAF Gene Mutati... Ras (KRAS or NR... Melanoma NSCLC Glioma Solid Tumor, Ad... MAPK Pathway Ge...	NST-628	18 Years -	Nested Therapeutics, Inc

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Spots Global Cancer Trial Database for raf

Every month we try and update this database with for raf cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for raf cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.