Phase I Trial of VS-6766 Alone and in Combination With Everolimus

NCT02407509 | Completed Phase 1

• 2 other identifiers: CCR38082012-001040-22
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 3

Brief Summary

In Part I of the study VS-6766 will be given twice weekly or three times per week in treatment cycles of 4 weeks to investigate a safe and tolerable dose of the drug. Once the optimal dosing schedule is defined, the following patients with BRAF, KRAS and/or NRAS mutations will be enrolled: 26 patients with solid tumours (Parts IIA \& IIC) and 10 patients with Multiple Myeloma (Part IIB). Up to 44 patients with solid tumours containing BRAF, KRAS and/or NRAS mutations will take VS-6766 in combination with everolimus (Part IID). Of these, 20 patients will comprise the Part IID dose expansion and will all have KRAS-mutant lung cancer.

Conditions

Solid Tumours; Multiple Myeloma; Lung Cancer; Ovarian Cancer

Outcome Measures

Primary Outcomes (2)

• Recommend a phase II dose and dosing schedule for VS-6766, as a single agent and also in combination with everolimus.

  Determining the schedule at which no more than one patient out of six patients experience a highly probable or probable drug-related dose limiting toxicity.

  In the first cycle of treatment (28-35 days).

• Assess the safety and toxicity profile of each schedule of administration of VS-6766 both as a single agent and in combination with everolimus.

  Determining causality of each adverse event to VS-6766 and everolimus, grading severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

  Throughout time on trial per patient, estimated to be 6 months.

Secondary Outcomes (6)

• Determining the pharmacokinetic profile of VS-6766 - Cmax

  In the first cycle of treatment (28-35 days).

• Determining the pharmacokinetic profile of VS-6766 - AUC

  In the first cycle of treatment (28-35 days).

• Determining the pharmacokinetic profile of VS-6766 - T½

  In the first cycle of treatment (28-35 days).

• Determining the pharmacokinetic profile of VS-6766 - Accumulation index

  In the first cycle of treatment (28-35 days).

• Determining the pharmacodynamic profile of VS-6766

  In the first cycle of treatment (28-35 days).

Other Outcomes (2)

• Pharmacodynamic studies in optional pre- and post-treatment paired tumour biopsy samples in selected patients.

  In the first cycle of treatment (28-35 days).

• Exploratory Functional Imaging Studies

  Throughout time on trial per patient, estimated to be 6 months.

Study Arms (10)

Part I - Twice weekly (COMPLETED)

EXPERIMENTAL

VS-6766 will be administered twice weekly in 4 week cycles in patients with solid tumours.

Drug: VS-6766

Part I - Three times weekly (COMPLETED)

EXPERIMENTAL

VS-6766 will be administered three times weekly in 4 week cycles in patients with solid tumours.

Drug: VS-6766

Part IIA (COMPLETED)

EXPERIMENTAL

VS-6766 will be administered twice weekly in 4 week cycles in patients with solid tumours with a mutation in the RAS-RAF-MEK pathway.

Drug: VS-6766

Part IIB (CLOSED)

EXPERIMENTAL

VS-6766 will be administered twice weekly in 4 week cycles in patients with multiple myeloma with a mutation in KRAS, NRAS or BRAF. In order to accommodate steroid use for patients with multiple myeloma, patients will be administered for 3 weeks followed by a week interruption.

Drug: VS-6766

Part IIC (COMPLETED)

EXPERIMENTAL

VS-6766 will be administered twice weekly in 4 week cycles in patients with solid tumours with a mutation in the RAS-RAF-MEK pathway. Upon occurrence of specified G2 toxicity, dosing intensity will be reduced to 3 weeks followed by a week interruption in a 4 week cycle.

Drug: VS-6766

Part IID - Once weekly dose confirmation (COMPLETED)

EXPERIMENTAL

VS-6766 and everolimus will be administered once weekly in 4 week cycles in patients with solid tumours with a mutation in the RAS-RAF-MEK pathway. All patients will dose for 3 weeks followed by a week interruption in a 4 week cycle.

Drug: VS-6766; Drug: Everolimus

Part IID - Twice weekly dose confirmation (COMPLETED)

EXPERIMENTAL

VS-6766 and everolimus will be administered twice weekly in 4 week cycles in patients with solid tumours with a mutation in the RAS-RAF-MEK pathway. All patients will dose for 3 weeks followed by a week interruption in a 4 week cycle.

Drug: VS-6766; Drug: Everolimus

Part IID - Dose expansion

EXPERIMENTAL

VS-6766 and everolimus will be administered twice weekly in 4 week cycles in patients with KRAS-mutant lung cancer. All patients will dose for 3 weeks followed by a week interruption in a 4 week cycle.

Drug: VS-6766; Drug: Everolimus

Part IIE- Biopsy Cohort

EXPERIMENTAL

VS-6766 and everolimus will be administered twice weekly in 4 week cycles in patients with documented RAS or RAF mutant solid tumours All patients will dose for 3 weeks followed by a week interruption in a 4 week cycle.

Drug: VS-6766; Drug: Everolimus

Part IIF- LGSOC Cohort

EXPERIMENTAL

VS-6766 and everolimus will be administered twice weekly in 4 week cycles in patients with LGSOC who have previously been treated with the combination of VS-6766 and defactinib within 24 months of trial entry. Additionally, all patients must have displayed anti-tumour activity on the VS-6766 and defactinib combination, defined as follows: • Experienced a response - confirmed partial response (PR) or complete response (CR) - according to RECIST 1.1. Or • Experienced stable disease (SD) according to RECIST 1.1 (Appendix 3) AND patient received VS-6766 and defactinib treatment for a minimum of 12 months. All patients will dose for 3 weeks followed by a week interruption in a 4 week cycle.

Drug: VS-6766; Drug: Everolimus

Interventions

VS-6766 DRUG

Part I - Three times weekly (COMPLETED); Part I - Twice weekly (COMPLETED); Part IIA (COMPLETED); Part IIB (CLOSED); Part IIC (COMPLETED); Part IID - Dose expansion; Part IID - Once weekly dose confirmation (COMPLETED); Part IID - Twice weekly dose confirmation (COMPLETED); Part IIE- Biopsy Cohort; Part IIF- LGSOC Cohort

Everolimus DRUG

Part IID - Dose expansion; Part IID - Once weekly dose confirmation (COMPLETED); Part IID - Twice weekly dose confirmation (COMPLETED); Part IIE- Biopsy Cohort; Part IIF- LGSOC Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.
• Patients with multiple myeloma refractory to conventional treatment. Haematological indices as in section 4.1.1 above except ANC ≥ 1.0 x 10\^9/L, platelet count ≥ 50 x 10\^9/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.
• 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.
• 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).
• 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 (Appendix 3).

You may not qualify if:

• 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. Hormone therapy within 14 days of first receipt of study drug, with exception of prostate cancer if indicated. In patients with brain 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 Grade 1 toxicities which in the opinion of the Investigator should not exclude the patient.
• 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.
• 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 CYP3A4 inhibitors within 7 days prior to the first dose.

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Institute of Cancer Research, United Kingdom: collaborator
• Chugai Pharmaceutical: collaborator
• Verastem, Inc.: collaborator

Study Sites (3)

Royal Marsden NHS Foundation Trust

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Guy's and St Thomas' Hospital

London, United Kingdom

Location

Gynaecological Unit - Royal Marsden NHS Foundation Trust

London, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 33128873 DERIVED

MeSH Terms

Conditions

Multiple Myeloma; Lung Neoplasms; Ovarian Neoplasms

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Officials

• Udai Banerji, MBBS, PhD

  The Institute of Cancer Research, Royal Marsden NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 9, 2015
• First Posted: April 3, 2015
• Study Start: June 17, 2013
• Primary Completion: October 15, 2025
• Study Completion: October 15, 2025
• Last Updated: January 29, 2026

Record last verified: 2026-01

Locations

GB (3)