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.
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 56 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 4 cohorts: 20 patients with KRAS mutant
non-small-cell lung cancer (NSCLC); 6 patients with solid tumours (enriched for those with
RAS mutations) willing to undergo biopsies at three time points throughout the study; 20
patients with low grade serous ovarian cancer (LGSOC) and 10 patients with colorectal cancer
(CRC) that have consented.
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.
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 advanced low grade serous ovarian cancer
(LGSOC), refractory to conventional treatment, or for which no conventional therapy
exists or is declined by the patient (20 patients).
OR Histologically or cytologically proven advanced colorectal cancer (CRC) with a
documented RAS mutation, refractory to conventional treatment, or for which no
conventional therapy exists or is declined by the patient (10 patients).
OR Histologically or cytologically proven RAS mutant solid tumours, refractory to
conventional treatment, or for which no conventional therapy exists or is declined by
the patient. 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.
