Phase I Trial of VS-6766 Alone and in Combination With Everolimus — RAF/MEK  

Lung Cancer Clinical Trial

Official title: A Phase I Trial of VS-6766 (RO5126766) (a Dual RAF/MEK Inhibitor) Exploring Intermittent, Oral Dosing Regimens in Patients With Solid Tumours or Multiple Myeloma, With an Expansion to Explore Intermittent Dosing in Combination With Everolimus

Status Recruiting

Clinical Trial Summary

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.

Clinical Trial Description

This is a two centre Phase I trial evaluating two intermittent dosing schedules of VS-6766 alone and then in combination with everolimus.

Part I (COMPLETED): Patients will be given VS-6766 (4mg) twice weekly or three times per week in treatment cycles of 4 weeks to investigate a safe and tolerable dose of the drug. Up to six patients will be enrolled to each dosing schedule and once they have completed 1 cycle of treatment the Safety Review Committee (SRC) will review their safety data, PK and PD data and define the optimal schedule to be taken forward into Part II.

On the basis of the previous Phase I trial, dose limiting toxicities (DLTs) are not expected at a dose of 4 mg but in the event of ≥ 2 DLT's occurring in (a) the 2 x weekly arm, then no further patients will recruited into that arm and the schedule will not be taken forward to Part II, or (b) the 3 x weekly arm, a single dose reduction to 3.2mg on the same dosing schedule will be implemented and 6 patients enrolled at the reduced dose. If 4 mg given 3 x weekly is considered non-tolerable, then the SRC may decide to enrol patients to the 3.2 mg dose level in the absence of dose limiting toxicity.

• If both the 2 x weekly (Mon & Thurs / Tues & Fri) and 3 x weekly (Mon, Wed & Fri) schedule are tolerated at 4 mg i.e. < 2 DLT's out of a 6 patients in each schedule, then the 3 x weekly schedule will be selected.

• If the 3 x weekly schedule requires a dose reduction to 3.2 mg and the 2 x weekly schedule is tolerated at 4 mg, then PD data will be evaluated relative to AUC to aid the selection.

• If ≥2 DLT's occur out of 6 patients in both schedules (despite the 3 x weekly arm being dose reduced), Part II will not be initiated and the study will be terminated.

Selection of the optimum schedule from Part I will be made by the Safety Review Committee and will be the schedule that delivers the highest, tolerable, cumulative weekly dose.

Part II: Once the optimal dosing schedule has been established in Part I, the following groups of patients will be enrolled:

Part IIA (COMPLETED) - 20 patients with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS or BRAF).

Part IIB (CLOSED) - 10 patients with documented KRAS, NRAS or BRAF multiple myeloma.

NB: In order to accommodate steroid use for patients with multiple myeloma, the optimal dosing schedule as determined in Part I will be administered for 3 weeks followed by a week interruption.

Part IIC (COMPLETED) - An additional 6 patients with RAS-RAF-MEK pathway mutant solid tumours (including but not exclusive to KRAS, NRAS or BRAF) will be enrolled at the MTD determined in Part I however, upon occurrence of Grade 2 drug-related skin rash, CPK elevation or diarrhoea the dosing intensity will be reduced to 3 weeks followed by a week interruption. Of the six patients in Part IIC, at least three patients should have KRAS mutant lung cancer.

Part IID - a maximum of 44 patients with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS and/or BRAF) will be administered with the combination of VS-6766 and everolimus for 3 weeks followed by a week interruption. Part IID will be split into two arms, dose confirmation and dose expansion:

• Part IID dose confirmation (COMPLETED) - Up to 24 patients will be treated at Schedule A (once-weekly dosing) or Schedule B (twice-weekly dosing). Each dose comprises 4mg VS-6766 + 5mg everolimus in combination. If Schedule A is tolerable, patients will be dosed at Schedule B. Should either of these schedules not be tolerable, the dose of VS-6766 can be reduced to 3.2mg.

• Part IID dose expansion (COMPLETED)- 20 patients will be treated at the optimal dosing schedule identified in Part IID dose confirmation. All patients will have KRAS-mutant lung cancer.

• Part IIE Biopsy Cohort - 6 patients will be treated at the optimal dosing schedule identified in Part IID dose expansion. Pharmacodynamic studies in pre- and post-treatment paired tumour biopsy samples will be investigated in this cohort, in addition to the plasma concentration of VS-6766 and everolimus at the time of on-treatment biopsies through pharmacokinetic analysis. Biopsies and blood draws for pharmacodynamic and pharmacokinetic assays will be mandatory.

• Part IIF LGSOC Cohort - 10 patients with LGSOC will be treated with the optimal dosing schedule identified in Part IID dose expansion. All patients in Part IIF will have been previously been treated with the combination of VS-6766 and defactinib within 24 months of trial entry. ;

Related Conditions & MeSH terms

• Lung Cancer
• Multiple Myeloma
• Neoplasms, Plasma Cell
• Ovarian Cancer
• Solid Tumours

• NCT number: NCT02407509
• Study type: Interventional
• Source: Royal Marsden NHS Foundation Trust
• Contact: Taleen Shakouri, PhD
• Phone: 02034376629
• Email: DDU3808@icr.ac.uk
• Status: Recruiting
• Phase: Phase 1
• Start date: June 17, 2013
• Completion date: May 2024