Overview

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.

Eligibility

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.

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 (Appendix 3).
        OR
        • A best response of stable disease (SD), according to RECIST 1.1 (Appendix 3), 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.
        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, Part IIE and Part IIF specific exclusions:
          1. 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.
          2. 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.
          3. 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:
          4. Patients that have previously discontinued treatment of VS-6766 and/or defactinib for
             reasons of toxicity.