Clinical Trials /

Phase I Trial of VS-6063 and RO5126766.

NCT03875820

Description:

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, VS-6063, and the dual RAF/MEK inhibitor, RO5126766 in patients with advanced solid tumours. RO5126766 is the same compound to 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.

Related Conditions:
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Trial of VS-6063 and RO5126766.
  • Official Title: FRAME: A Phase I Trial of the Combination of VS-6063 (FAK Inhibitor) and RO5126766 (CH5126776) (a Dual RAF/MEK Inhibitor) in Patients With Advanced Solid Tumours

Clinical Trial IDs

  • ORG STUDY ID: CCR4642
  • SECONDARY ID: 2017-001035-39
  • NCT ID: NCT03875820

Conditions

  • NSCLC
  • Solid Tumor

Interventions

DrugSynonymsArms
RO5126766CH5126766Dose Escalation Phase
VS-6063DefactinibDose Escalation Phase

Purpose

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, VS-6063, and the dual RAF/MEK inhibitor, RO5126766 in patients with advanced solid tumours. RO5126766 is the same compound to 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.

Detailed Description

      This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the
      combination of the FAK inhibitor, VS-6063, and the dual RAF/MEK inhibitor, RO5126766 in
      patients with advanced solid tumours. RO5126766 is the same compound to 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). Up to 24 patients with
      solid tumours will be treated in the dose escalation phase of this study.

      This will be followed by a dose expansion phase of 26 patients to further characterise the
      safety and tolerability and to assess the pharmacodynamic activity of the combination.

      The dose expansion phase will be made up of 2 cohorts: 20 patients with KRAS mutant
      non-small-cell lung cancer (NSCLC) and 6 patients with solid tumours (enriched for those with
      RAS mutations) that have consented and are willing to undergo biopsies at three time points
      throughout the study.

      Patients will take the two investigational medicinal products (IMPs) as follows:

      RO5126766 will be administered orally twice a week on Monday/Thursday or Tuesday/Friday at
      least one hour prior or two hours after a meal. The starting dose of RO5126766 will be 3.2mg
      once a day, twice a week and can be escalated to a maximum of 4mg once a day, twice a week.

      VS-6063 will be administered orally twice a day immediately after a meal. The starting dose
      of VS-6063 will be 200mg twice daily and can be escalated to a maximum of 400mg twice daily.

      A cycle length is 4 weeks (28 days). Combination dosing (RO5126766 and VS-6063) will commence
      on Cycle 1 Day 1 for 3 weeks followed by one week without either drug in week 4 (i.e. 3 weeks
      on, 1 week off).

      For patients consenting to optional biopsies, a run-in dose of RO5126766 will be administered
      on a single day anywhere between Days -7 to Day -3 in order to facilitate pharmacodynamic
      (PD) biomarker analysis. Therefore, for patients undergoing biopsies the first cycle will be
      5 weeks long and subsequent cycles will consist of 4 weeks.

      If this schedule is not tolerated, alternative schedules may be explored following discussion
      by the Safety Review Committee.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation PhaseExperimentalEscalating doses of RO5126766 and VS-6063 will be evaluated in patients with advanced solid tumours to establish the recommended phase II dose. Dose escalation will follow a 3+3 design with a maximum of four patient cohorts.
  • RO5126766
  • VS-6063
Dose Expansion KRAS mutant NSCLC CohortExperimentalThe dose expansion phase will evaluate the recommended phase II dose of the combination of RO5126766 and VS-6063, as decided in the dose escalation phase in patients with KRAS mutant NSCLC (20 patients).
  • RO5126766
  • VS-6063
Dose Expansion biopsy cohortExperimentalThe dose expansion phase will evaluate the recommended phase II dose of the combination of RO5126766 and VS-6063, as decided in the dose escalation phase in patients advanced RAS mutant solid tumours with biopsiable disease (6 patients).
  • RO5126766
  • VS-6063

Eligibility Criteria

        Inclusion Criteria:

          1. 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 solid tumours, refractory to conventional
             treatment, or for which no conventional therapy exists or is declined by the patient.
             Patient population enriched with RAS mutant solid tumours. Patient must have
             biopsiable disease, be willing and has consented to undergo biopsies at three
             time-points (6 patients).

          2. Predicted life expectancy of at least 12 weeks

          3. World Health Organisation (WHO) performance status of 0 or 1 (Appendix 1)

          4. 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

             Either:

             Calculated creatinine clearance ≥ 50 mL/min (uncorrected value)

             Or:

             Serum creatinine ≤ 1.5 x ULN

          5. Men and women aged 18 years or over.

          6. Written (signed and dated) informed consent and be capable of co-operating with
             treatment and follow-up.

          7. Absence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule.

          8. Dose escalation: Measurable disease according to RECIST 1.1 or evaluable disease. All
             radiology studies must be performed within 28 days prior to registration.

             Dose expansion: Measurable disease according to RECIST 1.1, all radiology studies must
             be performed within 28 days prior to registration.

          9. Corrected QT interval (QTc) < 470 ms (as calculated by the Fridericia correction
             formula, averaged over 3 ECGs).

         10. Agrees to the use of archival paraffin embedded tissue and has archival tumour tissue
             available.

        Exclusion Criteria:

          1. 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.

          2. 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.

          3. 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.

          4. 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.

          5. 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.

          6. 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.

          7. Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to LMWH.

          8. Known history of Gilbert's Syndrome.

          9. Acute or chronic pancreatitis.

         10. At high medical risk because of non-malignant systemic disease including active
             uncontrolled infection.

         11. Known to be serologically positive for hepatitis B, hepatitis C or human
             immunodeficiency virus (HIV).

         12. Patients with the inability to swallow oral medications or impaired gastrointestinal
             absorption due to gastrectomy or active inflammatory bowel disease.

         13. Concurrent ocular disorders:

               1. Patients with history of glaucoma, history of retinal vein occlusion (RVO),
                  predisposing factors for RVO, including uncontrolled hypertension, uncontrolled
                  diabetes

               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.

         14. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease
             (New York Heart Association [NYHA] - refer to Appendix 4), myocardial infarction
             within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive
             pulmonary disease.

         15. Patients exposed to strong CYP3A4 and strong CYP2C9 inhibitors within 7 days prior to
             the first dose.

             N.B. Because the lists of these agents are constantly changing, it is important to
             regularly consult a frequently-updated list such as
             http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as
             the Physicians' Desk Reference may also provide this information.

         16. Is a participant or plans to participate in another interventional clinical trial,
             whilst taking part in this Phase I study of RO5126766 in combination with VS-6063.
             Participation in an observational trial would be acceptable.

         17. Any other condition which in the Investigator's opinion would not make the patient a
             good candidate for the clinical trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To establish a dose for Phase II evaluation from the maximum tolerated dose of the combination of RO5126766 and VS-6063.
Time Frame:12 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:To characterise the pharmacokinetic profile of RO5126766 in combination with VS-6063.
Time Frame:12 months
Safety Issue:
Description:Determination of the PK parameter Cmax of RO5126766 and VS-6063 when dosed together
Measure:To characterise the pharmacokinetic profile of RO5126766 in combination with VS-6063
Time Frame:12 months
Safety Issue:
Description:Determination of the PK parameter terminal half-life of RO5126766 and VS-6063 when dosed together
Measure:To characterise the pharmacokinetic profile of RO5126766 in combination with VS-6063
Time Frame:12 months
Safety Issue:
Description:Determination of the PK parameter area under the curve of RO5126766 and VS-6063 when dosed together

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Institute of Cancer Research, United Kingdom

Trial Keywords

  • KRAS
  • RAS mutant

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