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Phase I Trial of VS-6063 and RO5126766. (FRAME)

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ClinicalTrials.gov Identifier: NCT03875820
Recruitment Status : Recruiting
First Posted : March 15, 2019
Last Update Posted : September 11, 2020
Sponsor:
Collaborators:
Verastem, Inc.
Chugai Pharmaceutical
Information provided by (Responsible Party):
Institute of Cancer Research, United Kingdom

Tracking Information
First Submitted Date  ICMJE November 15, 2018
First Posted Date  ICMJE March 15, 2019
Last Update Posted Date September 11, 2020
Actual Study Start Date  ICMJE December 12, 2017
Estimated Primary Completion Date July 12, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 12, 2019)
  • To establish a dose for Phase II evaluation from the maximum tolerated dose of the combination of RO5126766 and VS-6063. [ Time Frame: 12 months ]
    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.
  • Measure Adverse Events according to CTCAE v4.0 [ Time Frame: 6 months ]
    To assess the safety and toxicity profile of RO5126766 and VS-6063. 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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2019)
  • To characterise the pharmacokinetic profile of RO5126766 in combination with VS-6063. [ Time Frame: 12 months ]
    Determination of the PK parameter Cmax of RO5126766 and VS-6063 when dosed together
  • To characterise the pharmacokinetic profile of RO5126766 in combination with VS-6063 [ Time Frame: 12 months ]
    Determination of the PK parameter terminal half-life of RO5126766 and VS-6063 when dosed together
  • To characterise the pharmacokinetic profile of RO5126766 in combination with VS-6063 [ Time Frame: 12 months ]
    Determination of the PK parameter area under the curve of RO5126766 and VS-6063 when dosed together
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: March 12, 2019)
  • To document any possible anti-tumour activity in patients. [ Time Frame: 24 months ]
    Determination of disease response by RECIST criteria version 1.1 and collection of data related to progression free survival.
  • To study the pharmacodynamic profile of RO5126766 alone and in combination with VS-6063 in pre-treatment and post-treatment biopsies and PBMC's. [ Time Frame: 24 months ]
    Quantification of biomarkers such as p-MEK, p-ERK and p-FAK, E-cadherin and vimentin and enumeration of T cell populations which express CD8, CD4 and CD25.
  • To assess putative predictive biomarkers of response and resistance to the combination of RO5126766 and VS-6063. [ Time Frame: 24 months ]
    Correlation of antitumour activity of the combination of RO5126766 and VS-6063 with the detection of putative predictive biomarkers of response and resistance in archival tumours and plasma DNA.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Phase I Trial of VS-6063 and RO5126766.
Official Title  ICMJE FRAME: A Phase I Trial of the Combination of VS-6063 (FAK Inhibitor) and RO5126766 (CH5126776) (a Dual RAF/MEK Inhibitor) in Patients With Advanced Solid Tumours
Brief Summary

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

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, VS-6063, and the dual RAF/MEK inhibitor, RO5126766 in patients with advanced solid tumours. RO5126766 is the same compound to 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). Up to 24 patients with solid tumours will be treated in the dose escalation phase of this study.

This will be followed by a dose expansion phase of 56 patients to further characterise the safety and tolerability and to assess the pharmacodynamic activity of the combination.

The dose expansion phase will be made up of 4 cohorts: 20 patients with KRAS mutant non-small-cell lung cancer (NSCLC); 6 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) and 10 patients with colorectal cancer (CRC) that have consented.

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

RO5126766 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 RO5126766 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.

VS-6063 will be administered orally twice a day immediately after a meal. The starting dose of VS-6063 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 (RO5126766 and VS-6063) 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 RO5126766 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
The dose escalation phase will enrol patients with advanced RAS mutant solid tumours. In the dose expansion phase, patients are assigned to the KRAS mutant NSCLC cohort, LGSOC cohort, RAS mutant CRC cohort or advanced RAS mutant solid tumour cohort based on their diagnosis. Patients in the advanced RAS mutant solid tumour dose expansion cohort must have biopsiable disease, be willing and has consented to undergo biopsies at three time-points.
Masking: None (Open Label)
Masking Description:
Non-randomised: Participants are expressly assigned by phase of study and diagnosis.
Primary Purpose: Health Services Research
Condition  ICMJE
  • NSCLC
  • Solid Tumor
  • Low Grade Serous Ovarian Cancer
  • Colorectal Cancer
Intervention  ICMJE
  • Drug: RO5126766

    RO5126766 will be supplied as 0.8mg hypromellose (HPMC) capsules for oral administration. The capsule fill consists of RO5126766 and the inactive ingredients mannitol and magnesium stearate.

    RO5126766 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).

    Other Name: CH5126766
  • Drug: VS-6063

    VS-6063 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 VS-6063, formulation components include microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, and magnesium stearate.

    Patients will receive VS-6063 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).

    Other Name: Defactinib
Study Arms  ICMJE
  • Experimental: Dose Escalation Phase

    Escalating doses of RO5126766 and VS-6063 will be evaluated in patients with advanced solid tumours to establish the recommended phase II dose. Dose escalation will follow a 3+3 design with a maximum of four patient cohorts.

    This arm is now complete.

    Interventions:
    • Drug: RO5126766
    • Drug: VS-6063
  • Experimental: Dose Expansion KRAS mutant NSCLC Cohort
    The dose expansion phase will evaluate the recommended phase II dose of the combination of RO5126766 and VS-6063, as decided in the dose escalation phase in patients with KRAS mutant NSCLC (20 patients).
    Interventions:
    • Drug: RO5126766
    • Drug: VS-6063
  • Experimental: Dose Expansion biopsy cohort

    The dose expansion phase will evaluate the recommended phase II dose of the combination of RO5126766 and 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.

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

    The dose expansion phase will evaluate the recommended phase II dose of the combination of RO5126766 and VS-6063, as decided in the dose escalation phase in patients with CRC (10 patients).

    This arm is now complete.

    Interventions:
    • Drug: RO5126766
    • Drug: VS-6063
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 15, 2019)
80
Original Estimated Enrollment  ICMJE
 (submitted: March 12, 2019)
50
Estimated Study Completion Date  ICMJE July 12, 2021
Estimated Primary Completion Date July 12, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).

  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 > 21 mm 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 RO5126766 in combination with VS-6063. Participation in an observational trial would be acceptable.
  17. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03875820
Other Study ID Numbers  ICMJE CCR4642
2017-001035-39 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Institute of Cancer Research, United Kingdom
Study Sponsor  ICMJE Institute of Cancer Research, United Kingdom
Collaborators  ICMJE
  • Verastem, Inc.
  • Chugai Pharmaceutical
Investigators  ICMJE
Principal Investigator: Udai Banerji, FRCP, PhD Institute of Cancer Research, United Kingdom
PRS Account Institute of Cancer Research, United Kingdom
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP