Patient case: 63-year-old female with melanoma; genetic feature: NRAS (Q61R)

Clinical trial: Phase I Trial of RO5126766

Summary: RO5126766 will be administered initially as a single daily dose of 4mg using either a twice weekly dosing schedule (Monday-Thursday) or a 3 times per week dosing schedule (Monday-Wednesday-Friday). The daily dose will be given orally according to the dosing schedule. A cycle of treatment will comprise 28 days. In Part I of the study both the twice weekly and the three times per week schedules will be assessed. In the absence of dose limiting toxicities 6 patients will be recruited to each dosing schedule cohort. In the event of a DLT being observed in Part I of the study, a single dose reduction to 3.2 mg will then be instigated and up to 6 patients will be recruited to that dosing schedule at the lower dose. The optimal dosing schedule determined in Part I will be taken forward to Part II and 20 patients with tumours harbouring BRAF, KRAS and NRAS mutations will be enrolled.

Detailed description: This is a single centre Phase I trial evaluating two intermittent dosing schedules.
  Part I: A total of six patients will be enrolled to each dosing schedule and based on assessment of toxicity, PK and PD data the optimal schedule will be taken forward into Part II (see below).
  Patients will be treated on a 4-weekly cycle with a single daily dose of 4 mg of RO5126766 on either the twice weekly (Monday & Thursday) or three times weekly (Monday, Wednesday and Friday) schedule. Six patients will be enrolled per arm and after all patients have received at least one cycle of treatment, safety data and available PK/PD data will be reviewed by the Safety Review Committee (SRC). 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.
  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. Therefore selection will be as follows:
  -  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.
  Part II: Once the optimal dosing schedule has been established 20 patients with either solid tumours or multiple myeloma with documented KRAS, NRAS or BRAF mutations will be enrolled.

Eligibility: Inclusion Criteria:
  1. 18 years or over
  2. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
  3. Histologically or cytologically proven solid tumours refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient
  4. Life expectancy of at least 12 weeks
  5. World Health Organisation (WHO) performance status of 0 or 1 (Appendix 1)
  6. Measurable and/or evaluable disease according to RECIST 1.1 (appendix 3) except for patients with multiple myeloma. Patients with solid tumours for enrolment into Part II only should have at least one measurable disease lesion.
  7. Haematological and biochemical indices within the ranges shown below. These measurements must be:
  Haemoglobin (Hb) ≥ 9.0 g/dL; Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; Platelet count ≥ 100 x 10^9/L; Serum bilirubin ≤ 1.5 x upper limit of normal (ULN); Alanine aminotransferase (ALT) and 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: Isotope clearance measurement ≥ 50mL/min (corrected); Serum calcium (corrected for albumin levels) ≤ 1.0 x ULN; INR and PTT ≤ 1.5 x ULN
  Additional inclusion criteria for Part II:
  8. Patients with multiple myeloma refractory to conventional treatment. Haematological indices as in section 4.1.1 above except ANC ≥ 1.0 x 10^9/L and platelet count ≥ 50 x 10^9/L.
  9. Archival tumour sections available for patients with solid tumours, or diagnostic bone marrow samples available for patients with multiple myeloma.
  10. Documented presence of BRAF, KRAS or NRAS mutations in tumour cells.
  11. For patients with solid tumours only: presence of at least one measurable disease lesion according to RECIST 1.1
  Exclusion Criteria:
  1. Prior chemotherapy, radiotherapy (other than a short cycle of palliative radiotherapy for bone pain), or immunotherapy within 28 days of first receipt of study drug (within 6 weeks for nitrosoureas and mitomycin C). Hormone therapy within 14 days of first receipt of study drug, with exception of prostate cancer if indicated.
  2. Ongoing toxic manifestations of previous treatments except Grade 1 toxicities which in the opinion of the Investigator should not exclude the patient.
  3. Brain metastases.
  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 highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have a intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, 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 highly effective 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 thoracic or abdominal surgery from which the patient has not yet recovered.
  7. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
  8. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
  9. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
  10. History of any bowel disease including abdominal fistula, gastro-intestinal perforation, and diverticulitis.
  11. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA], myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive pulmonary disease.
  12. Concurrent ocular disorders:
  -  Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, uncontrolled hypercholesterolemia, hyperviscosity syndromes, medically significant history of vasculitis, inflammatory, atherosclerotic or thrombophilic conditions and coagulopathy.
  -  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.
  -  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
  13. Patients exposed to CYP3A4 inhibitors within 7 days prior to the first dose and CYP3A4 inducers 7 days prior to the first dose (see Appendix 6 table for CYP3A4 inducers and inhibitors).
  14. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I study of RO5126766. Participation in an observational trial would be acceptable.
  15. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.

Relevance to patient case: possibly relevant