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Phase I Trial of VS-6766 Alone and in Combination With Everolimus (RAF/MEK)

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ClinicalTrials.gov Identifier: NCT02407509
Recruitment Status : Recruiting
First Posted : April 3, 2015
Last Update Posted : May 2, 2022
Sponsor:
Collaborators:
Institute of Cancer Research, United Kingdom
Chugai Pharmaceutical
Verastem, Inc.
Information provided by (Responsible Party):
Royal Marsden NHS Foundation Trust

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.


Condition or disease Intervention/treatment Phase
Solid Tumours Multiple Myeloma Lung Cancer Drug: VS-6766 Drug: Everolimus Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 17, 2013
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : February 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma
Drug Information available for: Everolimus

Arm Intervention/treatment
Experimental: Part I - Twice weekly (COMPLETED)
VS-6766 will be administered twice weekly in 4 week cycles in patients with solid tumours.
Drug: VS-6766
Experimental: Part I - Three times weekly (COMPLETED)
VS-6766 will be administered three times weekly in 4 week cycles in patients with solid tumours.
Drug: VS-6766
Experimental: Part IIA (COMPLETED)
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
Experimental: Part IIB
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
Experimental: Part IIC (COMPLETED)
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
Experimental: Part IID - Once weekly dose confirmation (COMPLETED)
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
Experimental: Part IID - Twice weekly dose confirmation (COMPLETED)
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
Experimental: Part IID - Dose expansion
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



Primary Outcome Measures :
  1. Recommend a phase II dose and dosing schedule for VS-6766, as a single agent and also in combination with everolimus. [ Time Frame: In the first cycle of treatment (28-35 days). ]
    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.

  2. Assess the safety and toxicity profile of each schedule of administration of VS-6766 both as a single agent and in combination with everolimus. [ Time Frame: Throughout time on trial per patient, estimated to be 6 months. ]
    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.


Secondary Outcome Measures :
  1. Determining the pharmacokinetic profile of VS-6766 - Cmax [ Time Frame: In the first cycle of treatment (28-35 days). ]
    Determining Peak Plasma Concentration (Cmax) of VS-6766 given via intermittent dosing schedules in selected patients.

  2. Determining the pharmacokinetic profile of VS-6766 - AUC [ Time Frame: In the first cycle of treatment (28-35 days). ]
    Determining the Area under the plasma concentration versus time curve (AUC) of VS-6766 given via intermittent dosing schedules in selected patients.

  3. Determining the pharmacokinetic profile of VS-6766 - T½ [ Time Frame: In the first cycle of treatment (28-35 days). ]
    Determining the half-life (T½) of VS-6766 given via intermittent dosing schedules in selected patients.

  4. Determining the pharmacokinetic profile of VS-6766 - Accumulation index [ Time Frame: In the first cycle of treatment (28-35 days). ]
    Determining the accumulation index of VS-6766 given via intermittent dosing schedules in selected patients.

  5. Determining the pharmacodynamic profile of VS-6766 [ Time Frame: In the first cycle of treatment (28-35 days). ]
    Quantifying pERK levels in PBMCs in selected patients.

  6. Determining anti-tumour activity of VS-6766, as a single agent and also in combination with everolimus. [ Time Frame: Throughout time on trial per patient, estimated to be 6 months. ]
    Anti-tumour activity is any response (stable disease, partial response or complete response) in any of the patients as determined by the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.


Other Outcome Measures:
  1. Pharmacodynamic studies in optional pre- and post-treatment paired tumour biopsy samples in selected patients. [ Time Frame: In the first cycle of treatment (28-35 days). ]
    Quantifying downstream activation of signal transduction and cell death.

  2. Exploratory Functional Imaging Studies [ Time Frame: Throughout time on trial per patient, estimated to be 6 months. ]
    Review of diffusion-weighted (DW)-MRI, 1H-MRS (Magnetic Resonance Spectroscopy) and 18F-choline positron emission tomography (PET) imaging scans for exploration of predictive imaging biomarkers of response in selected patients.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  1. 18 years or over
  2. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
  3. 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
  4. Life expectancy of at least 12 weeks
  5. World Health Organisation (WHO) performance status of 0 or 1
  6. Measurable and/or evaluable disease according to RECIST 1.1 for patients with solid tumours or according to IMWG for multiple myeloma patients.
  7. 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.

    ADDITIONAL INCLUSION CRITERIA FOR Part II:

  8. 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.
  9. 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.
  10. Archival tumour sections available for patients with solid tumours, or diagnostic bone marrow samples available for patients with multiple myeloma.
  11. For patients with solid tumours only: presence of at least one measurable disease lesion according to RECIST 1.1.

EXCLUSION CRITERIA:

  1. 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.
  2. Ongoing toxic manifestations of previous treatments except Grade 1 toxicities which in the opinion of the Investigator should not exclude the patient.
  3. 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.
  4. 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.
  5. Major thoracic or abdominal surgery from which the patient has not yet recovered.
  6. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
  7. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
  8. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
  9. History of any bowel disease including abdominal fistula, gastro-intestinal perforation, and diverticulitis.
  10. 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.
  11. Concurrent ocular disorders:

    1. 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.
    2. 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.
    3. 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
  12. Patients exposed to CYP3A4 inhibitors within 7 days prior to the first dose.
  13. 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.
  14. Symptoms of COVID-19 and/or documented current COVID-19 infection (the patient can be reassessed for eligibility following a full recovery and negative COVID-19 test)
  15. 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 SPECIFIC EXCLUSIONS:

  16. 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.
  17. 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.
  18. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02407509


Contacts
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Contact: Tom Parker, BSc 02034376690 tom.parker@icr.ac.uk
Contact: Alison Turner, PhD 02087224303 alison.turner@icr.ac.uk

Locations
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United Kingdom
Royal Marsden NHS Foundation Trust Recruiting
Sutton, Surrey, United Kingdom, SM2 5PT
Contact: Udai Banerji, MBBS, PhD    020 3437 6078    DDU3808@icr.ac.uk   
Guy's and St Thomas' Hospital Recruiting
London, United Kingdom
Contact: James Spicer    020 7188 7188 ext 56079    adam.ovid@gstt.nhs.uk   
Principal Investigator: James Spicer         
Sponsors and Collaborators
Royal Marsden NHS Foundation Trust
Institute of Cancer Research, United Kingdom
Chugai Pharmaceutical
Verastem, Inc.
Investigators
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Principal Investigator: Udai Banerji, MBBS, PhD The Institute of Cancer Research, Royal Marsden NHS Foundation Trust
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Royal Marsden NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02407509    
Other Study ID Numbers: CCR3808
2012-001040-22 ( EudraCT Number )
First Posted: April 3, 2015    Key Record Dates
Last Update Posted: May 2, 2022
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Everolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs