Phase I Trial of Defactinib and VS-6766.

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, Defactinib (VS-6063), and the dual RAF/MEK inhibitor, VS-6766 (RO5126766) in patients with advanced solid tumours. VS-6766 (RO5126766) is the same compound as 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, Defactinib, and the dual RAF/MEK inhibitor, VS-6766 in patients with advanced solid tumours.

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 were enrolled to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Up to 24 patients with solid tumours were treated in the dose escalation phase of this study.

The dose escalation phase is now closed to recruitment.

This will be followed by a dose expansion phase of 86 patients to further characterise the safety and tolerability and to assess the pharmacodynamic activity of the combination.

The dose expansion phase is made up of 7 cohorts:

* 20 patients with KRAS mutant non-small-cell lung cancer (NSCLC);
* 7 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);
* 10 patients with colorectal cancer (CRC);
* 10 patients with KRAS G12V mutant NSCLC;
* 10 patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis related) and
* 10 patients with pancreatic cancer.

The following cohorts are still open to recruitment:

* Patients with low grade serous ovarian cancer (LGSOC);
* Patients with KRAS G12V mutant NSCLC;
* Patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis-related) and
* Patients with pancreatic cancer.

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

VS-6766 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 VS-6766 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.

Defactinib will be administered orally twice a day immediately after a meal. The starting dose of Defactinib 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 (VS-6766 and Defactinib) 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 VS-6766 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.

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 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).

   OR Histologically or cytologically proven advanced pancreatic cancer or metastatic pancreatic cancer, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient (10 patients).

   OR Endometroid subtype of gynaecological cancers (ovarian, endometrial, endometriosis related) with a documented RAS or RAF 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 advanced non-small-cell lung cancer (NSCLC) with a documented KRAS G12V specific mutation, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient (10 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 \> 21mm 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 VS-6766 in combination with Defactinib. Participation in an observational trial would be acceptable.
17. 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).
18. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.