NCT03875820

Brief Summary

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.

Trial Health

75
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
87

participants targeted

Target at P75+ for phase_1

Timeline
6mo left

Started Dec 2017

Longer than P75 for phase_1

Geographic Reach
1 country

5 active sites

Status
active not recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress95%
Dec 2017Oct 2026

Study Start

First participant enrolled

December 12, 2017

Completed
11 months until next milestone

First Submitted

Initial submission to the registry

November 15, 2018

Completed
4 months until next milestone

First Posted

Study publicly available on registry

March 15, 2019

Completed
4.1 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 30, 2023

Completed
3.5 years until next milestone

Study Completion

Last participant's last visit for all outcomes

October 31, 2026

Expected
Last Updated

March 10, 2026

Status Verified

March 1, 2026

Enrollment Period

5.4 years

First QC Date

November 15, 2018

Last Update Submit

March 8, 2026

Conditions

NSCLCLow Grade Serous Ovarian CancerEndometrioid CarcinomaPancreatic Cancer

Keywords

KRAS G12VRASRAF

Outcome Measures

Primary Outcomes (2)

  • To establish a dose for Phase II evaluation from the maximum tolerated dose of the combination of VS-6766 and Defactinib.

    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.

    12 months

  • Measure Adverse Events according to CTCAE v4.0.

    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.

    6 months

Secondary Outcomes (3)

  • To characterise the pharmacokinetic profile of VS-6766 in combination with Defactinib.

    12 months

  • To characterise the pharmacokinetic profile of VS-6766 in combination with Defactinib.

    12 months

  • To characterise the pharmacokinetic profile of VS-6766 in combination with Defactinib.

    12 months

Other Outcomes (3)

  • To document any possible anti-tumour activity in patients.

    24 months

  • To study the pharmacodynamic profile of VS-6766 alone and in combination with Defactinib in pre-treatment and post-treatment biopsies and PBMCs.

    24 months

  • To assess putative predictive biomarkers of response and resistance to the combination of VS-6766 and Defactinib.

    24 months

Study Arms (8)

Dose Escalation Phase

EXPERIMENTAL

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.

Drug: VS-6766Drug: Defactinib

Dose Expansion KRAS mutant NSCLC Cohort

EXPERIMENTAL

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.

Drug: VS-6766Drug: Defactinib

Dose Expansion biopsy cohort

EXPERIMENTAL

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.

Drug: VS-6766Drug: Defactinib

Dose Expansion LGSOC cohort

EXPERIMENTAL

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).

Drug: VS-6766Drug: Defactinib

Dose Expansion CRC cohort

EXPERIMENTAL

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.

Drug: VS-6766Drug: Defactinib

Dose Expansion KRAS G12V mutant NSCLC cohort

EXPERIMENTAL

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).

Drug: VS-6766Drug: Defactinib

Dose Expansion RAS/RAF mutant endometrioid cancer cohort

EXPERIMENTAL

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).

Drug: VS-6766Drug: Defactinib

Dose Expansion pancreatic cancer

EXPERIMENTAL

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).

Drug: VS-6766Drug: Defactinib

Interventions

VS-6766DRUG

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).

Also known as: RO5126766, CH5126766
Dose Escalation PhaseDose Expansion CRC cohortDose Expansion KRAS G12V mutant NSCLC cohortDose Expansion KRAS mutant NSCLC CohortDose Expansion LGSOC cohortDose Expansion RAS/RAF mutant endometrioid cancer cohortDose Expansion biopsy cohortDose Expansion pancreatic cancer
DefactinibDRUG

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).

Also known as: VS-6063
Dose Escalation PhaseDose Expansion CRC cohortDose Expansion KRAS G12V mutant NSCLC cohortDose Expansion KRAS mutant NSCLC CohortDose Expansion LGSOC cohortDose Expansion RAS/RAF mutant endometrioid cancer cohortDose Expansion biopsy cohortDose Expansion pancreatic cancer

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Dose escalation:
  • Histologically or cytologically proven solid tumours, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient enriching for patients with RAS mutant solid tumours.
  • Dose expansion:
  • Histologically or cytologically proven advanced non-small-cell lung cancer (NSCLC) with a documented KRAS mutation, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient (20 patients).
  • OR Histologically or cytologically proven advanced low grade serous ovarian cancer (LGSOC), refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient (20 patients).
  • OR Histologically or cytologically proven advanced colorectal cancer (CRC) with a documented RAS mutation, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient (10 patients).
  • OR Histologically or cytologically proven RAS mutant solid tumours, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient. Patient must have biopsiable disease, be willing and has consented to undergo biopsies at three time-points (6 patients).
  • OR Histologically or cytologically proven advanced pancreatic cancer or metastatic pancreatic cancer, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient (10 patients).
  • OR Endometroid subtype of gynaecological cancers (ovarian, endometrial, endometriosis related) with a documented RAS or RAF mutation, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient (10 patients).
  • OR Histologically or cytologically proven advanced non-small-cell lung cancer (NSCLC) with a documented KRAS G12V specific mutation, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient (10 patients).
  • Predicted life expectancy of at least 12 weeks
  • World Health Organisation (WHO) performance status of 0 or 1 (Appendix 1)
  • Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.
  • Haemoglobin (Hb) ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)
  • ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible
  • +11 more criteria

You may not qualify if:

  • Radiotherapy (except for palliative reasons), endocrine therapy, biological therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) before treatment.
  • Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the DDU should not exclude the patient.
  • Known untreated or active central nervous system (CNS) metastases (progressing or requiring corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:
  • Evaluable or measurable disease outside the CNS is present.
  • Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the baseline disease assessment for at least 28 days.
  • Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two medically approved forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) from time of consent, during the trial and for six months afterwards are considered eligible.
  • Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of medically approved contraception \[condom plus spermicide\] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
  • Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study and from which the patient has not yet recovered.
  • Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to LMWH.
  • Known history of Gilbert's Syndrome.
  • Acute or chronic pancreatitis.
  • At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
  • Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
  • Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
  • Concurrent ocular disorders:
  • +9 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (5)

The Christie NHS Foundation Trust

Manchester, Greater Manchester, M20 4BX, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

Sutton, Surrey, SM2 5PT, United Kingdom

Location

The Royal Marsden NHS Foundation Trust - Gynecology Unit

London, SW3 6JJ, United Kingdom

Location

The Newcastle Upon Tyne Hospitals NHS Foundation Trust - Freeman Hospital

Newcastle, NE7 7DN, United Kingdom

Location

The Royal Marsden NHS Foundation Trust - Gynecology Unit

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (2)

  • Banerjee S, Krebs MG, Greystoke A, Garces AI, Perez VS, Terbuch A, Shinde R, Caldwell R, Grochot R, Rouhifard M, Ruddle R, Gurel B, Swales K, Tunariu N, Prout T, Parmar M, Symeonides S, Rekowski J, Yap C, Sharp A, Paschalis A, Lopez J, Minchom A, de Bono JS, Banerji U. Defactinib with avutometinib in patients with solid tumors: the phase 1 FRAME trial. Nat Med. 2025 Sep;31(9):3074-3080. doi: 10.1038/s41591-025-03763-y. Epub 2025 Jun 27.

    PMID: 40579546DERIVED

  • Fard D, Giraudo E, Tamagnone L. Mind the (guidance) signals! Translational relevance of semaphorins, plexins, and neuropilins in pancreatic cancer. Trends Mol Med. 2023 Oct;29(10):817-829. doi: 10.1016/j.molmed.2023.07.009. Epub 2023 Aug 17.

    PMID: 37598000DERIVED

MeSH Terms

Conditions

Carcinoma, EndometrioidPancreatic Neoplasms

Interventions

RO5126766defactinib

Condition Hierarchy (Ancestors)

AdenocarcinomaCarcinomaNeoplasms, Glandular and EpithelialNeoplasms by Histologic TypeNeoplasmsEndometrial NeoplasmsUterine NeoplasmsGenital Neoplasms, FemaleUrogenital NeoplasmsNeoplasms by SiteOvarian NeoplasmsOvarian DiseasesAdnexal DiseasesGenital Diseases, FemaleFemale Urogenital DiseasesFemale Urogenital Diseases and Pregnancy ComplicationsUrogenital DiseasesGenital DiseasesGonadal DisordersEndocrine System DiseasesDigestive System NeoplasmsEndocrine Gland NeoplasmsDigestive System DiseasesPancreatic Diseases

Study Officials

  • Udai Banerji, FRCP, PhD

    Institute of Cancer Research, United Kingdom

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
NON RANDOMIZED
Masking
NONE
Masking Details
Non-randomised: Participants are expressly assigned by phase of study and diagnosis.
Purpose
HEALTH SERVICES RESEARCH
Intervention Model
PARALLEL
Model Details: 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
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

November 15, 2018

First Posted

March 15, 2019

Study Start

December 12, 2017

Primary Completion

April 30, 2023

Study Completion (Estimated)

October 31, 2026

Last Updated

March 10, 2026

Record last verified: 2026-03

Data Sharing

IPD Sharing
Will not share

Locations

GB(5)