Solid TumoursPhase 1RAF/MEKNCT02407509
Phase I Trial of VS-6766 Alone and in Combination With Everolimus
A Phase 1 study testing VS-6766 and Everolimus in people with Solid Tumours and Multiple Myeloma, run by Royal Marsden NHS Foundation Trust at 3 sites in United Kingdom.
Trial summary
This study is a multi-centre, investigator-initiated, Phase I clinical trial evaluating different dosing schedules of VS-6766, given either alone or in combination with everolimus, in patients with advanced solid tumours or multiple myeloma. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Tumours, Multiple Myeloma, Lung Cancer
- What is being tested?
- VS-6766 and Everolimus
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 104 participants
- Where
- 3 sitesUnited Kingdom
- Study dates
- 17 Jun 2013to 15 Oct 2025
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 years or over
- Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
- Histologically or cytologically proven solid tumours or Multiple Myeloma refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient
- Life expectancy of at least 12 weeks
- World Health Organisation (WHO) performance status of 0 or 1
- Measurable and/or evaluable disease according to RECIST 1.1 for patients with solid tumours or according to IMWG for multiple myeloma patients.
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- Haematological and biochemical indices within the ranges shown in the protocol. These measurements must be performed within two weeks (Day -14 to Day 1) before the patient is entered into the trial:
- Laboratory Test Value required 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) ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible Aspartate aminotransferase (AST) ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible
- Either:
- Calculated creatinine clearance per the Cockroft -Gault formula
- ≥ 50 mL/min (uncorrected value)
- Or:
- Isotope clearance measurement
- ≥ 50mL/min (corrected) INR and PTT ≤ 1.5 x ULN
- ADDITIONAL INCLUSION CRITERIA FOR Part II:
- Patients with multiple myeloma refractory to conventional treatment. Haematological indices as in section 4.1.1 above except ANC ≥ 1.0 x 109/L, platelet count ≥ 50 x 109/L and serum creatinine ≤ 1.5 x (ULN). Patients can be deemed as eligible based on serum creatinine alone if creatinine clearance/isotope clearance is deranged.
- Archival tumour sections available for patients with solid tumours, or diagnostic bone marrow samples available for patients with multiple myeloma.
- For patients with solid tumours only: presence of at least one measurable disease lesion according to RECIST 1.1.
- Additional inclusion criteria for Part IIA, Part IIB, Part IIC, Part IID and Part IIE:
- Documented presence of RAS-RAF-MEK pathway mutations including BRAF, KRAS and NRAS. In Part IIC at least three patients should have KRAS mutant lung cancer. In Part IID expansion, all 20 patients should have KRAS mutant lung cancer. In Part IIE, all 6 evaluable patients should have any RAS or RAF mutant solid tumours.
- Additional inclusion criteria for Part IIE:
- Patients must have disease that is amenable to biopsy and must be willing to undergo tumour biopsies (collected pre- and post-treatment). Patients must be willing to have blood draws for PK analysis (collected pre- and post-treatment).
- Additional inclusion criteria for Part IIF:
- Patients must have low-grade serous ovarian cancer (LGSOC) which has previously displayed anti-tumour activity on the combination treatment of VS-6766 and defactinib, where anti-tumour activity is defined as one of the following:
- A best response of confirmed complete response (CR) or partial response (PR), according to RECIST 1.1.
- OR
- A best response of stable disease (SD), according to RECIST 1.1, AND received VS-6766 and defactinib combination treatment for a minimum of 12 months.
- Patients must have received the combination treatment of VS-6766 and defactinib within 24 months of the first dose of either study drug.
Who cannot join
- Prior chemotherapy, radiotherapy (other than a short cycle of palliative radiotherapy for bone pain), or immunotherapy within 28 days of first receipt of study drug (within 6 weeks for nitrosoureas and mitomycin C), with the exception of Dexamethasone for patients with multiple myeloma (see section 5.6). Hormone therapy within 14 days of first receipt of study drug, with exception of prostate cancer if indicated. In patients with brains metastases, previous radiotherapy should have finished at least 28 days prior and limited steroid management is required. Steroid management should not exceed 4mg dexamethasone, or equivalent, per day.
- Ongoing toxic manifestations of previous treatments, except for:
- Grade 1 toxicities which in the opinion of the Investigator should not exclude the patient, and/or;
- Grade 2 or above alopecia or any toxicity which is Grade 2 or above because of ongoing anticoagulation therapy due to prior thromboembolic episodes.
- 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 highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, 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 highly effective 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
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- Major thoracic or abdominal surgery from which the patient has not yet recovered.
- 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.
- History of any bowel disease including abdominal fistula, gastro-intestinal perforation, and diverticulitis.
- Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA] - refer to Appendix 5), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive pulmonary disease.
- Concurrent ocular disorders:
- Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, uncontrolled hypercholesterolemia, hyperviscosity syndromes, medically significant history of vasculitis, inflammatory, atherosclerotic or thrombophilic conditions and coagulopathy.
- Patient with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO.
- Patients with a history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions
- Patients exposed to potent CYP3A4 inhibitors or inducers within 7 days prior to the first dose
- Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I study of VS-6766 and/or everolimus. Participation in an observational trial would be acceptable.
- Symptoms of COVID-19 and/or documented current COVID-19 infection (the patient can be reassessed for eligibility once they have recovered and it is deemed safe for them to enter the trial by the Investigator, in line with government guidelines).
- Any other condition which in the Investigator's opinion would not make the patient a good candidate for a clinical trial with VS-6766 e.g. hypersensitivity to VS-6766.
- Part IID, Part IIE and Part IIF specific exclusions:
- Has received a live vaccine within 30 days of planned start of study therapy. Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.
- Clinically significant abnormalities of glucose metabolism as defined by any of the following:
- Diagnosis of diabetes mellitus types I or II (irrespective of management).
- Glycosylated haemoglobin (HbA1C) ≥7.0% at screening
- Fasting Plasma Glucose ≥ 8.3mmol/L at screening. Fasting is defined as no caloric intake for at least 8 hours.
- Any other condition which in the Investigator's opinion would not make the patient a good candidate for a clinical trial with Everolimus. Examples of which include: hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption; hypersensitivity to Everolimus, to other rapamycin derivatives or to any of the excipients; pre-existing infections.
- Additional exclusion criteria for Part IIF:
- Patients that have previously discontinued treatment of VS-6766 and/or defactinib for reasons of toxicity.
Trial locations and contacts
3 sites in 1 country.
United Kingdom3 sites
Guy's and St Thomas' Hospital
London
Gynaecological Unit - Royal Marsden NHS Foundation Trust
London
Royal Marsden NHS Foundation Trust
Sutton, Surrey, SM2 5PT
About this study
Official title: A Phase I Trial of VS-6766 (RO5126766) (a Dual RAF/MEK Inhibitor) Exploring Intermittent, Oral Dosing Regimens in Patients With Solid Tumours or Multiple Myeloma, With an Expansion to Explore Intermittent Dosing in Combination With Everolimus
This study is a multi-centre, investigator-initiated, Phase I clinical trial evaluating different dosing schedules of VS-6766, given either alone or in combination with everolimus, in patients with advanced solid tumours or multiple myeloma.
The study will investigate whether combining VS-6766 with everolimus can improve the treatment's effectiveness by blocking two important pathways that help cancer cells grow and survive. By targeting both pathways, researchers hope to reduce the likelihood of the cancer becoming resistant to treatment.
Read more
In Part I of the study, participants will receive VS-6766 on different intermittent dosing schedules to identify the safest and most effective way to administer the drug. The treatment will be given by mouth either two or three times per week in four-week treatment cycles. If significant side effects are observed, the dose may be reduced.
The dosing schedule identified as optimal in Part I will be taken forward into Part II. This phase will enrol patients whose cancers have specific genetic changes in the RAS/RAF/MEK pathway, including KRAS, NRAS, or BRAF mutations. Participants will receive either VS-6766 alone or VS-6766 in combination with everolimus.
The study will assess the safety and tolerability of the treatment, how the body processes the drugs, and whether the treatment shows signs of benefiting patients. Particular focus will be placed on cancers driven by RAS/RAF pathway mutations, including KRAS-mutant lung cancer.
Read the detailed description
This is a two centre Phase I trial evaluating two intermittent dosing schedules of VS-6766 alone and then in combination with everolimus.
Part I (COMPLETED): Patients will be given VS-6766 (4mg) twice weekly or three times per week in treatment cycles of 4 weeks to investigate a safe and tolerable dose of the drug. Up to six patients will be enrolled to each dosing schedule and once they have completed 1 cycle of treatment the Safety Review Committee (SRC) will review their safety data, PK and PD data and define the optimal schedule to be taken forward into Part II.
On the basis of the previous Phase I trial, dose limiting toxicities (DLTs) are not expected at a dose of 4 mg but in the event of ≥ 2 DLT's occurring in (a) the 2 x weekly arm, then no further patients will recruited into that arm and the schedule will not be taken forward to Part II, or (b) the 3 x weekly arm, a single dose reduction to 3.2mg on the same dosing schedule will be implemented and 6 patients enrolled at the reduced dose. If 4 mg given 3 x weekly is considered non-tolerable, then the SRC may decide to enrol patients to the 3.2 mg dose level in the absence of dose limiting toxicity.
- If both the 2 x weekly (Mon \& Thurs / Tues \& Fri) and 3 x weekly (Mon, Wed \& Fri) schedule are tolerated at 4 mg i.e. < 2 DLT's out of a 6 patients in each schedule, then the 3 x weekly schedule will be selected.
- If the 3 x weekly schedule requires a dose reduction to 3.2 mg and the 2 x weekly schedule is tolerated at 4 mg, then PD data will be evaluated relative to AUC to aid the selection.
- If ≥2 DLT's occur out of 6 patients in both schedules (despite the 3 x weekly arm being dose reduced), Part II will not be initiated and the study will be terminated.
Selection of the optimum schedule from Part I will be made by the Safety Review Committee and will be the schedule that delivers the highest, tolerable, cumulative weekly dose.
Part II: Once the optimal dosing schedule has been established in Part I, the following groups of patients will be enrolled:
Part IIA (COMPLETED) - 20 patients with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS or BRAF).
Part IIB (CLOSED) - 10 patients with documented KRAS, NRAS or BRAF multiple myeloma.
NB: In order to accommodate steroid use for patients with multiple myeloma, the optimal dosing schedule as determined in Part I will be administered for 3 weeks followed by a week interruption.
Part IIC (COMPLETED) - An additional 6 patients with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) will be enrolled at the MTD determined in Part I however, upon occurrence of Grade 2 drug-related skin rash, CPK elevation or diarrhoea the dosing intensity will be reduced to 3 weeks followed by a week interruption. Of the six patients in Part IIC, at least three patients should have KRAS mutant lung cancer.
Part IID - a maximum of 44 patients with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS and/or BRAF) will be administered with the combination of VS-6766 and everolimus for 3 weeks followed by a week interruption. Part IID will be split into two arms, dose confirmation and dose expansion:
- Part IID dose confirmation (COMPLETED) - Up to 24 patients will be treated at Schedule A (once-weekly dosing) or Schedule B (twice-weekly dosing). Each dose comprises 4mg VS-6766 + 5mg everolimus in combination. If Schedule A is tolerable, patients will be dosed at Schedule B. Should either of these schedules not be tolerable, the dose of VS-6766 can be reduced to 3.2mg.
- Part IID dose expansion (COMPLETED)- 20 patients will be treated at the optimal dosing schedule identified in Part IID dose confirmation. All patients will have KRAS-mutant lung cancer.
- Part IIE Biopsy Cohort - 6 patients will be treated at the optimal dosing schedule identified in Part IID dose expansion. Pharmacodynamic studies in pre- and post-treatment paired tumour biopsy samples will be investigated in this cohort, in addition to the plasma concentration of VS-6766 and everolimus at the time of on-treatment biopsies through pharmacokinetic analysis. Biopsies and blood draws for pharmacodynamic and pharmacokinetic assays will be mandatory.
- Part IIF LGSOC Cohort - 10 patients with LGSOC will be treated with the optimal dosing schedule identified in Part IID dose expansion. All patients in Part IIF will have been previously been treated with the combination of VS-6766 and defactinib within 24 months of trial entry.
- Conditions
- Solid Tumours, Multiple Myeloma, Lung Cancer, Ovarian Cancer
- Being tested
- VS-6766, Everolimus
- Medical subject headings
- Multiple Myeloma, Lung Neoplasms, Ovarian Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VS-6766Drug
EverolimusDrug
| Study group | Role | What they receive |
|---|---|---|
| Escalation cohort (Part I): Twice weekly 4.0 mg | Experimental | Participants with advanced solid tumors received 4.0 mg of VS-6766 twice weekly (Monday \& Thursday or Tuesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent Receives: Drug: VS-6766 |
| Escalation cohort (Part I): 3x weekly 4.0 mg | Experimental | Participants with advanced solid tumors received 4.0 mg of VS-6766 three times a week (Monday, Wednesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent Receives: Drug: VS-6766 |
| Escalation cohort (Part I): 3x weekly 3.2 mg | Experimental | Participants with advanced solid tumours received 3.2 mg of VS-6766 three times a week (Monday, Wednesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. Receives: Drug: VS-6766 |
| Part IIA (Solid Tumours) | Experimental | Participants with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS or BRAF) received 4.0 mg of VS-6766 twice weekly (Monday \& Thursday or Tuesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent Receives: Drug: VS-6766 |
| Part IIB (Multiple Myeloma) | Experimental | Participants with documented KRAS, NRAS or BRAF multiple myeloma received 4.0 mg of VS-6766 twice a week (Monday \& Thursday or Tuesday \& Friday) for three weeks (with one week off) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent
Dosing schedule was reduced to 3 weeks followed by a week interruption (three weeks on, one week off) to accommodate steroid use for these patients. Receives: Drug: VS-6766 |
| Part IIC (Toxicity Management) | Experimental | Participants with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) received 4.0 mg of VS-6766 twice weekly (Monday \& Thursday or Tuesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. At least three patients had KRAS mutant lung cancer.
In the event of Grade 2 drug-related skin rash, CPK elevation or diarrhoea the dosing intensity could be reduced to 3 weeks followed by a week interruption (three weeks on, one week off). Receives: Drug: VS-6766 |
| Part IID confirmation | Experimental | Participants with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) were treated with 4.0 mg VS-6766 once weekly and 5.0 mg Everolimus daily for three weeks on and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent.
Participants with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) were treated with 4.0 mg VS-6766 twice weekly and 5.0 mg Everolimus daily for three weeks on and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent.
Participants with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) were treated with 3.2 mg VS-6766 5.0 mg Everolimus twice-weekly for three weeks on and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. Receives: Drug: VS-6766; Drug: Everolimus |
| Part IID expansion | Experimental | Participants with KRAS mutant lung cancer were treated with 3.2 mg VS-6766 and 5.0 mg Everolimus twice-weekly for three weeks and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. Receives: Drug: VS-6766; Drug: Everolimus |
| Part IIE | Experimental | Participants with RAS- or RAF-mutant solid tumours were treated with 3.2 mg VS-6766 and 5.0 mg Everolimus twice-weekly for three weeks and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. Receives: Drug: VS-6766; Drug: Everolimus |
| Part IIF (LGSOC) | Experimental | Participants with Low-Grade Serous Ovarian Cancer (LGSOC) were treated with 3.2 mg VS-6766 and 5.0 mg Everolimus twice-weekly for three weeks and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. Receives: Drug: VS-6766; Drug: Everolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recommended Phase 2 Dose (RP2D) of VS-6766
The RP2D of VS-6766 is the optimum dosing schedule that is the highest, tolerable, cumulative weekly dose to be taken forward as a single agent to Part II (Dose Expansion)
Measured: Up to 28 days
Recommended Phase 2 Dose (RP2D) of VS-6766 and Everolimus
The RP2D of VS-6766 and Everolimus is the optimum dosing schedule that is the highest, tolerable, cumulative weekly dose to be taken forward as a combination to Part IID expansion arm
Measured: Up to 28 days
Number of treatment emergent advese events (TEAEs)
A TEAE is any undesirable medical event that appears or worsens after the first dose of VS-6766 and/or Everolimus are given, regardless of whether it is actually caused by the study drug(s). TEAEs were graded according to CTCAE v4.03. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; G4: life-threatening and G5: death. Higher grade indicates greater severity and increase in grade was defined relative to baseline grade
Measured: Throughout time on trial per patient, estimated to be 6 months.
Number of treatment related adverse events (TRAEs)
A TRAE is any undesirable medical event that the clinical investigator judges to be highly probably, probably, or possibly related to VS-6766 and/or Everolimus. TRAEs were graded according to CTCA v4.03. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; G4: life-threathening and G5: death. Higher grade indicates greater severity and increase in grade was defined relative to baseline grade
Measured: Throughout time on trial per patient, estimated to be 6 months.
Secondary outcomes (6)
Peak Plasma Concentration (Cmax) of VS-6766
Blood samples were obtained and plasma concentrations were determined in whole blood using a validated Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method
Measured: On Days 1 and 15 of Cycle 1 at the following time points: pre-dose then post-dose 30 mins, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs.
Area under curve (AUC) of VS-6766
Blood samples were obtained and plasma concentrations were determined in whole blood using a validated Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method
Measured: On Days 1 and 15 of Cycle 1 at the following time points: pre-dose then post-dose 30 mins, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs.
Half-life (T½) of VS-6766
Blood samples were obtained and plasma concentrations were determined in whole blood using a validated Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method
Measured: On Days 1 and 15 of Cycle 1 at the following time points: pre-dose then post-dose 30 mins, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs.
Accumulation Index of VS-6766
Blood samples were obtained and plasma concentrations were determined in whole blood using a validated Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method
Measured: On Days 1 and 15 of Cycle 1 at the following time points: pre-dose then post-dose 30 mins, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs.
Single Plasma Concentration of both VS-6766 and Everolimus
Blood samples were obtained and plasma concentrations were determined in whole blood using a validated Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method
Measured: Within 1 hour prior to VS-6766 run-in dose and within 1-hour before or after the run-in biopsy; within 1 hour prior to Everolimus dose on C1D1 and within 1 hour before or after the combination biopsy on C1D8 or C1D15
Best Response
Defined in solid tumours using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Defined in multiple myeloma patients using International Myeloma Working Group (IMWG) response criteria.
Measured: Time from start of treatment until last tumour assessment. Tumour imaging was performed at baseline, then every 2 cycles (each cycle is 28 days) during trial treatment and off-study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Apr 2015 (estimated)
- Study start17 Jun 2013
- Primary completion15 Oct 2025
- Study completion15 Oct 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Solid TumoursStudies of the same condition, open and under way.
- More trials run by Royal Marsden NHS Foundation TrustThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 104 participants (actual)
Sponsor and investigators
- Lead sponsor
- Royal Marsden NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Institute of Cancer Research, United Kingdom, Chugai Pharmaceutical, Verastem, Inc., Guy's and St Thomas' NHS Foundation Trust
- Responsible party
- Sponsor
- Investigators
- Anna Minchom, MB BCh, FRCP, MD (Res), Principal investigator, The Institute of Cancer Research, Royal Marsden NHS Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02407509
- Sponsor's protocol ID
- CCR3808
- Other IDs
- 2012-001040-22
- Acronym
- RAF/MEK
- Status last verified
- Oct 2026
- First submitted
- 9 Feb 2015
- Last updated
- 27 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Guo C, Chenard-Poirier M, Roda D, de Miguel M, Harris SJ, Candilejo IM, Sriskandarajah P, Xu W, Scaranti M, Constantinidou A, King J, Parmar M, Turner AJ, Carreira S, Riisnaes R, Finneran L, Hall E, Ishikawa Y, Nakai K, Tunariu N, Basu B, Kaiser M, Lopez JS, Minchom A, de Bono JS, Banerji U. Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. Lancet Oncol. 2020 Nov;21(11):1478-1488. doi: 10.1016/S1470-2045(20)30464-2. Epub 2020 Oct 28.
PubMed 33128873
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Trial of VS-6766 (RO5126766) (a Dual RAF/MEK Inhibitor) Exploring Intermittent, Oral Dosing Regimens in Patients With Solid Tumours or Multiple Myeloma, With an Expansion to Explore Intermittent Dosing in Combination With Everolimus
- ClinicalTrials.gov ID
- NCT02407509
- Acronym / sponsor ID
- RAF/MEK / CCR3808
- Conditions
- Solid Tumours, Multiple Myeloma, Lung Cancer, Ovarian Cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 104 participants (actual)
- Lead sponsor
- Royal Marsden NHS Foundation TrustUniversity, hospital or other
- Collaborators
- Institute of Cancer Research, United Kingdom, Chugai Pharmaceutical, Verastem, Inc., Guy's and St Thomas' NHS Foundation Trust
- Study start
- 17 Jun 2013 (actual)
- Primary completion
- 15 Oct 2025 (actual)
- Study completion
- 15 Oct 2025 (actual)
- First posted
- 3 Apr 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study is a multi-centre, investigator-initiated, Phase I clinical trial evaluating different dosing schedules of VS-6766, given either alone or in combination with everolimus, in patients with advanced solid tumours or multiple myeloma.
The study will investigate whether combining VS-6766 with everolimus can improve the treatment's effectiveness by blocking two important pathways that help cancer cells grow and survive. By targeting both pathways, researchers hope to reduce the likelihood of the cancer becoming resistant to treatment.
In Part I of the study, participants will receive VS-6766 on different intermittent dosing schedules to identify the safest and most effective way to administer the drug. The treatment will be given by mouth either two or three times per week in four-week treatment cycles. If significant side effects are observed, the dose may be reduced.
The dosing schedule identified as optimal in Part I will be taken forward into Part II. This phase will enrol patients whose cancers have specific genetic changes in the RAS/RAF/MEK pathway, including KRAS, NRAS, or BRAF mutations. Participants will receive either VS-6766 alone or VS-6766 in combination with everolimus.
The study will assess the safety and tolerability of the treatment, how the body processes the drugs, and whether the treatment shows signs of benefiting patients. Particular focus will be placed on cancers driven by RAS/RAF pathway mutations, including KRAS-mutant lung cancer.
Detailed description
This is a two centre Phase I trial evaluating two intermittent dosing schedules of VS-6766 alone and then in combination with everolimus.
Part I (COMPLETED): Patients will be given VS-6766 (4mg) twice weekly or three times per week in treatment cycles of 4 weeks to investigate a safe and tolerable dose of the drug. Up to six patients will be enrolled to each dosing schedule and once they have completed 1 cycle of treatment the Safety Review Committee (SRC) will review their safety data, PK and PD data and define the optimal schedule to be taken forward into Part II.
On the basis of the previous Phase I trial, dose limiting toxicities (DLTs) are not expected at a dose of 4 mg but in the event of ≥ 2 DLT's occurring in (a) the 2 x weekly arm, then no further patients will recruited into that arm and the schedule will not be taken forward to Part II, or (b) the 3 x weekly arm, a single dose reduction to 3.2mg on the same dosing schedule will be implemented and 6 patients enrolled at the reduced dose. If 4 mg given 3 x weekly is considered non-tolerable, then the SRC may decide to enrol patients to the 3.2 mg dose level in the absence of dose limiting toxicity.
- If both the 2 x weekly (Mon \& Thurs / Tues \& Fri) and 3 x weekly (Mon, Wed \& Fri) schedule are tolerated at 4 mg i.e. < 2 DLT's out of a 6 patients in each schedule, then the 3 x weekly schedule will be selected.
- If the 3 x weekly schedule requires a dose reduction to 3.2 mg and the 2 x weekly schedule is tolerated at 4 mg, then PD data will be evaluated relative to AUC to aid the selection.
- If ≥2 DLT's occur out of 6 patients in both schedules (despite the 3 x weekly arm being dose reduced), Part II will not be initiated and the study will be terminated.
Selection of the optimum schedule from Part I will be made by the Safety Review Committee and will be the schedule that delivers the highest, tolerable, cumulative weekly dose.
Part II: Once the optimal dosing schedule has been established in Part I, the following groups of patients will be enrolled:
Part IIA (COMPLETED) - 20 patients with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS or BRAF).
Part IIB (CLOSED) - 10 patients with documented KRAS, NRAS or BRAF multiple myeloma.
NB: In order to accommodate steroid use for patients with multiple myeloma, the optimal dosing schedule as determined in Part I will be administered for 3 weeks followed by a week interruption.
Part IIC (COMPLETED) - An additional 6 patients with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) will be enrolled at the MTD determined in Part I however, upon occurrence of Grade 2 drug-related skin rash, CPK elevation or diarrhoea the dosing intensity will be reduced to 3 weeks followed by a week interruption. Of the six patients in Part IIC, at least three patients should have KRAS mutant lung cancer.
Part IID - a maximum of 44 patients with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS and/or BRAF) will be administered with the combination of VS-6766 and everolimus for 3 weeks followed by a week interruption. Part IID will be split into two arms, dose confirmation and dose expansion:
- Part IID dose confirmation (COMPLETED) - Up to 24 patients will be treated at Schedule A (once-weekly dosing) or Schedule B (twice-weekly dosing). Each dose comprises 4mg VS-6766 + 5mg everolimus in combination. If Schedule A is tolerable, patients will be dosed at Schedule B. Should either of these schedules not be tolerable, the dose of VS-6766 can be reduced to 3.2mg.
- Part IID dose expansion (COMPLETED)- 20 patients will be treated at the optimal dosing schedule identified in Part IID dose confirmation. All patients will have KRAS-mutant lung cancer.
- Part IIE Biopsy Cohort - 6 patients will be treated at the optimal dosing schedule identified in Part IID dose expansion. Pharmacodynamic studies in pre- and post-treatment paired tumour biopsy samples will be investigated in this cohort, in addition to the plasma concentration of VS-6766 and everolimus at the time of on-treatment biopsies through pharmacokinetic analysis. Biopsies and blood draws for pharmacodynamic and pharmacokinetic assays will be mandatory.
- Part IIF LGSOC Cohort - 10 patients with LGSOC will be treated with the optimal dosing schedule identified in Part IID dose expansion. All patients in Part IIF will have been previously been treated with the combination of VS-6766 and defactinib within 24 months of trial entry.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 10
| Arm | Type | Receives |
|---|---|---|
| Escalation cohort (Part I): Twice weekly 4.0 mg | Experimental | Drug: VS-6766Participants with advanced solid tumors received 4.0 mg of VS-6766 twice weekly (Monday \& Thursday or Tuesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent |
| Escalation cohort (Part I): 3x weekly 4.0 mg | Experimental | Drug: VS-6766Participants with advanced solid tumors received 4.0 mg of VS-6766 three times a week (Monday, Wednesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent |
| Escalation cohort (Part I): 3x weekly 3.2 mg | Experimental | Drug: VS-6766Participants with advanced solid tumours received 3.2 mg of VS-6766 three times a week (Monday, Wednesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. |
| Part IIA (Solid Tumours) | Experimental | Drug: VS-6766Participants with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS or BRAF) received 4.0 mg of VS-6766 twice weekly (Monday \& Thursday or Tuesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent |
| Part IIB (Multiple Myeloma) | Experimental | Drug: VS-6766Participants with documented KRAS, NRAS or BRAF multiple myeloma received 4.0 mg of VS-6766 twice a week (Monday \& Thursday or Tuesday \& Friday) for three weeks (with one week off) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent Dosing schedule was reduced to 3 weeks followed by a week interruption (three weeks on, one week off) to accommodate steroid use for these patients. |
| Part IIC (Toxicity Management) | Experimental | Drug: VS-6766Participants with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) received 4.0 mg of VS-6766 twice weekly (Monday \& Thursday or Tuesday \& Friday) of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. At least three patients had KRAS mutant lung cancer. In the event of Grade 2 drug-related skin rash, CPK elevation or diarrhoea the dosing intensity could be reduced to 3 weeks followed by a week interruption (three weeks on, one week off). |
| Part IID confirmation | Experimental | Drug: VS-6766, Drug: EverolimusParticipants with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) were treated with 4.0 mg VS-6766 once weekly and 5.0 mg Everolimus daily for three weeks on and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. Participants with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) were treated with 4.0 mg VS-6766 twice weekly and 5.0 mg Everolimus daily for three weeks on and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. Participants with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) were treated with 3.2 mg VS-6766 5.0 mg Everolimus twice-weekly for three weeks on and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. |
| Part IID expansion | Experimental | Drug: VS-6766, Drug: EverolimusParticipants with KRAS mutant lung cancer were treated with 3.2 mg VS-6766 and 5.0 mg Everolimus twice-weekly for three weeks and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. |
| Part IIE | Experimental | Drug: VS-6766, Drug: EverolimusParticipants with RAS- or RAF-mutant solid tumours were treated with 3.2 mg VS-6766 and 5.0 mg Everolimus twice-weekly for three weeks and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. |
| Part IIF (LGSOC) | Experimental | Drug: VS-6766, Drug: EverolimusParticipants with Low-Grade Serous Ovarian Cancer (LGSOC) were treated with 3.2 mg VS-6766 and 5.0 mg Everolimus twice-weekly for three weeks and one week off of each 28-day cycle up to until disease progression, unacceptable toxicity, or withdrawal of consent. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (28 listed)
- 18 years or over
- Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
- Histologically or cytologically proven solid tumours or Multiple Myeloma refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient
- Life expectancy of at least 12 weeks
- World Health Organisation (WHO) performance status of 0 or 1
Key exclusion criteria (29 listed)
- Prior chemotherapy, radiotherapy (other than a short cycle of palliative radiotherapy for bone pain), or immunotherapy within 28 days of first receipt of study drug (within 6 weeks for nitrosoureas and mitomycin C), with the exception of Dexamethasone for patients with multiple myeloma (see section 5.6). Hormone therapy within 14 days of first receipt of study drug, with exception of prostate cancer if indicated. In patients with brains metastases, previous radiotherapy should have finished at least 28 days prior and limited steroid management is required. Steroid management should not exceed 4mg dexamethasone, or equivalent, per day.
- Ongoing toxic manifestations of previous treatments, except for:
- 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 highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, 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 highly effective 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 thoracic or abdominal surgery from which the patient has not yet recovered.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VS-6766 | Drug | Escalation cohort (Part I): 3x weekly 3.2 mg, Escalation cohort (Part I): 3x weekly 4.0 mg, Escalation cohort (Part I): Twice weekly 4.0 mg, Part IIA (Solid Tumours), Part IIB (Multiple Myeloma), Part IIC (Toxicity Management), Part IID confirmation, Part IID expansion, Part IIE, Part IIF (LGSOC) |
| Everolimus | Drug | Part IID confirmation, Part IID expansion, Part IIE, Part IIF (LGSOC) |
Primary outcome
Recommended Phase 2 Dose (RP2D) of VS-6766
Time frame: Up to 28 days
The RP2D of VS-6766 is the optimum dosing schedule that is the highest, tolerable, cumulative weekly dose to be taken forward as a single agent to Part II (Dose Expansion)
Recommended Phase 2 Dose (RP2D) of VS-6766 and Everolimus
Time frame: Up to 28 days
The RP2D of VS-6766 and Everolimus is the optimum dosing schedule that is the highest, tolerable, cumulative weekly dose to be taken forward as a combination to Part IID expansion arm
Number of treatment emergent advese events (TEAEs)
Time frame: Throughout time on trial per patient, estimated to be 6 months.
A TEAE is any undesirable medical event that appears or worsens after the first dose of VS-6766 and/or Everolimus are given, regardless of whether it is actually caused by the study drug(s). TEAEs were graded according to CTCAE v4.03. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; G4: life-threatening and G5: death. Higher grade indicates greater severity and increase in grade was defined relative to baseline grade
Number of treatment related adverse events (TRAEs)
Time frame: Throughout time on trial per patient, estimated to be 6 months.
A TRAE is any undesirable medical event that the clinical investigator judges to be highly probably, probably, or possibly related to VS-6766 and/or Everolimus. TRAEs were graded according to CTCA v4.03. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; G4: life-threathening and G5: death. Higher grade indicates greater severity and increase in grade was defined relative to baseline grade
6 secondary outcomes
Peak Plasma Concentration (Cmax) of VS-6766
Time frame: On Days 1 and 15 of Cycle 1 at the following time points: pre-dose then post-dose 30 mins, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs.
Area under curve (AUC) of VS-6766
Time frame: On Days 1 and 15 of Cycle 1 at the following time points: pre-dose then post-dose 30 mins, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs.
Half-life (T½) of VS-6766
Time frame: On Days 1 and 15 of Cycle 1 at the following time points: pre-dose then post-dose 30 mins, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs.
Accumulation Index of VS-6766
Time frame: On Days 1 and 15 of Cycle 1 at the following time points: pre-dose then post-dose 30 mins, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs.
Single Plasma Concentration of both VS-6766 and Everolimus
Time frame: Within 1 hour prior to VS-6766 run-in dose and within 1-hour before or after the run-in biopsy; within 1 hour prior to Everolimus dose on C1D1 and within 1 hour before or after the combination biopsy on C1D8 or C1D15
Best Response
Time frame: Time from start of treatment until last tumour assessment. Tumour imaging was performed at baseline, then every 2 cycles (each cycle is 28 days) during trial treatment and off-study
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Oct 2026.
- Derived from this study: PubMed 33128873Guo C, Chenard-Poirier M, Roda D, de Miguel M, Harris SJ, Candilejo IM, Sriskandarajah P, Xu W, Scaranti M, Constantinidou A, King J, Parmar M, Turner AJ, Carreira S, Riisnaes R, Finneran L, Hall E, Ishikawa Y, Nakai K, Tunariu N, Basu B, Kaiser M, Lopez JS, Minchom A, de Bono JS, Banerji U. Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. Lancet Oncol. 2020 Nov;21(11):1478-1488. doi: 10.1016/S1470-2045(20)30464-2. Epub 2020 Oct 28.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anna Minchom, MB BCh, FRCP, MD (Res) principal investigator
The Institute of Cancer Research, Royal Marsden NHS Foundation Trust
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing VS-6766 and Everolimus in people with Solid Tumours and Multiple Myeloma, run by Royal Marsden NHS Foundation Trust at 3 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 28 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recommended Phase 2 Dose (RP2D) of VS-6766 (time frame: Up to 28 days). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02407509, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2026.