Phase I Trial of Defactinib and VS-6766.

Brief summary public domain (ClinicalTrials.gov)

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.

Detailed description public domain (ClinicalTrials.gov)

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.

Intervention public domain (ClinicalTrials.gov)

Drug: VS-6766. VS-6766 will be supplied as 0.8mg hypromellose (HPMC) capsules for oral administration. The capsule fill consists of VS-6766 and the inactive ingredients mannitol and magnesium stearate. VS-6766 will be administered on a twice weekly (Monday and Thursday or Tuesday and Friday) schedule for 3 weeks followed by 1 week off in every 4 week cycle, under fasting conditions (approximately 1 hour prior or 2 hours after a meal). The starting dose, based on the previous Phase I trial will be 3.2 mg given orally as a single daily dose. This can be escalated to a maximum of 4mg (as per dose escalation rules in the protocol).

Intervention public domain (ClinicalTrials.gov)

Drug: Defactinib. Defactinib is formulated as a white to off-white oval tablet for oral administration and supplied in single unit dose strength of 200 mg in 120 cc (HDPE) bottles. In addition to Defactinib, formulation components include microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, and magnesium stearate. Patients will receive Defactinib orally immediately after a meal twice daily (approximately every 12 hours) for 3 weeks followed by 1 week off in every 4 week cycle. The starting dose will be 200mg. This can be escalated to a maximum of 400mg (as per dose escalation rules in the protocol).

Arm public domain (ClinicalTrials.gov)

Dose Escalation Phase (experimental): Escalating doses of VS-6766 (RO5126766) and Defactinib (VS-6063) were evaluated in patients with advanced solid tumours to establish the recommended phase II dose. Dose escalation followed a 3+3 design with a maximum of four patient cohorts. This arm is now complete.

Arm public domain (ClinicalTrials.gov)

Dose Expansion KRAS mutant NSCLC Cohort (experimental): The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS mutant NSCLC (20 patients). This arm is now complete.

Arm public domain (ClinicalTrials.gov)

Dose Expansion biopsy cohort (experimental): The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients advanced RAS mutant solid tumours with biopsiable disease (6 patients). This arm is now complete.

Arm public domain (ClinicalTrials.gov)

Dose Expansion LGSOC cohort (experimental): The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with LGSOC (20 patients).

Arm public domain (ClinicalTrials.gov)

Dose Expansion CRC cohort (experimental): The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with CRC (10 patients). This arm is now complete.

Arm public domain (ClinicalTrials.gov)

Dose Expansion KRAS G12V mutant NSCLC cohort (experimental): The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS G12V mutant NSCLC (10 patients).

Primary outcome public domain (ClinicalTrials.gov)

To establish a dose for Phase II evaluation from the maximum tolerated dose of the combination of VS-6766 and Defactinib.. 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. Time frame: 12 months.

Primary outcome public domain (ClinicalTrials.gov)

Measure Adverse Events according to CTCAE v4.0.. To assess the safety and toxicity profile of VS-6766 and Defactinib. To determine causality and grading severity of each adverse event by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Time frame: 6 months.

Secondary outcome public domain (ClinicalTrials.gov)

To characterise the pharmacokinetic profile of VS-6766 in combination with Defactinib.. Time frame: 12 months.

Secondary outcome public domain (ClinicalTrials.gov)

To characterise the pharmacokinetic profile of VS-6766 in combination with Defactinib.. Time frame: 12 months.

Secondary outcome public domain (ClinicalTrials.gov)

To characterise the pharmacokinetic profile of VS-6766 in combination with Defactinib.. Time frame: 12 months.

Eligibility public domain (ClinicalTrials.gov)

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 …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 87 participants (actual).