Phase I Trial of RO5126766 Alone and in Combination With Everolimus (DDU RAF/MEK)
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|ClinicalTrials.gov Identifier: NCT02407509|
Recruitment Status : Recruiting
First Posted : April 3, 2015
Last Update Posted : November 1, 2018
In Part I of the study RO5126766 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 (Part IIA&C), 10 patients with Multiple Myeloma (Part IIB) and upto 34 patients with solid tumours who will take RO5126766 in combination with everolimus (Part IID).
|Condition or disease||Intervention/treatment||Phase|
|Solid Tumours Multiple Myeloma||Drug: RO5126766 Drug: Everolimus||Phase 1|
This is a two centre Phase I trial evaluating two intermittent dosing schedules of RO5126766 alone and then in combination with everolimus.
Part I: Patients will be given RO5126766 (4mg) twice weekly or three times per week in treatment cycles of 4 weeks to investigate a safe and tolerable dose of the drug. Upto 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) 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 - 20 patients with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS or BRAF).
Part IIB - 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 - 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 34 patients with documented RAS-RAF-MEK pathway mutant solid tumours (including KRAS, NRAS and/or BRAF) will be administered with the combination of R05126766 and everolimus.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||94 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Trial of 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|
|Study Start Date :||May 2013|
|Estimated Primary Completion Date :||June 2020|
|Estimated Study Completion Date :||June 2021|
Experimental: Twice weekly
RO5126766 will be administered twice weekly in 4 week cycles.
Experimental: Three times weekly
RO5126766 will be administered three times weekly in 4 week cycles.
Experimental: RO5126766 & Everolimus
RO5126766 and Everolimus will be given in combination once or twice weekly for 3 weeks of a 4 week cycle.
- Safety & Toxicity Profile (adverse event and grading severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.) [ Time Frame: 1 cycle (28 days) ]
The schedule at which no more than one patient out of six patients experience a highly probable or probable drug-related dose limiting toxicity.
Causality of each adverse event to RO5126766 and grading severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
- Pharmacokinetic Profile (Cmax/ AUC/ T½ and accumulation index) [ Time Frame: duration of study (18 months) ]Cmax/ AUC/ T½ and accumulation index of RO5126766 given via intermittent dosing schedules
- Pharmacodynamic Profile (The relationship between RO5126766 plasma concentration and pERK levels in PBMCs) [ Time Frame: duration of study (18 months) ]The relationship between RO5126766 plasma concentration and pERK levels in PBMCs
- Anti-tumour Activity ( Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) [ Time Frame: duration of study (18 months) ]Any response (stable disease, partial response or complete response) in any of the patients as determined by the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1).
- Pharmacodynamics Studies in optional pre- and post-treatment paired tumour biopsy samples [ Time Frame: duration of study (18 months) ]Pharmacodynamic studies in optional pre- and post-treatment paired tumour biopsy samples.
- Exploratory Functional Imaging Studies [ Time Frame: duration of study (18 months) ]Exploratory functional imaging studies with diffusion-weighted (DW)-MRI, 1H-MRS (Magnetic Resonance Spectroscopy) and 18F-choline positron emission tomography (PET) for predictive imaging biomarkers of response.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02407509
|Contact: Alison Turner, PhD||+44(0)20 8661 firstname.lastname@example.org|
|Contact: Joanna Dawes, PhD||+44(0)20 8722 4779||DDU3808@icr.ac.uk|
|Royal Marsden NHS Foundation Trust||Recruiting|
|Sutton, Surrey, United Kingdom, SM2 5PT|
|Contact: Udai Banerji, MBBS, PhD|
|Guy's and St Thomas' Hospital||Not yet recruiting|
|London, United Kingdom|
|Contact: Alison Turner, PhD email@example.com|
|Contact: Joanna Dawes, PhD DDU3808@icr.ac.uk|
|Principal Investigator:||Udai Banerji, MBBS, PhD||he Institute of Cancer Research, Royal Marsden NHS Foundation Trust|