Ignite Creation Date:
2024-05-06 @ 3:53 AM
Last Modification Date:
2024-10-26 @ 11:41 AM
Study NCT ID:
NCT02407509
Status:
RECRUITING
Last Update Posted:
2024-03-21
First Post:
2015-02-09
Brief Title:
Phase I Trial of VS-6766 Alone and in Combination With Everolimus
Sponsor:
Royal Marsden NHS Foundation Trust
Organization:
Royal Marsden NHS Foundation Trust
Study Overview
Official Title:
A Phase I Trial of VS-6766 RO5126766 a Dual RAFMEK 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
Status Verified Date:
2023-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
RAFMEK
Brief 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 andor 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 andor 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
Once the optimal dosing schedule is defined the following patients with BRAF KRAS andor 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 andor 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
Detailed 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 DLTs 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 32mg 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 32 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 ie 2 DLTs 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 32 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 DLTs 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 andor 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 32mg
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
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 DLTs 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 32mg 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 32 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 ie 2 DLTs 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 32 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 DLTs 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 andor 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 32mg
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2012-001040-22 | EUDRACT_NUMBER | None | None |