Patient case: 64-year-old male with cholangiocarcinoma; genetic feature: BRAF (V600E)

Clinical trial: Phase I Trial of RO5126766 Alone and in Combination With Everolimus

Summary: 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).

Detailed description: 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.

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 or Multiple Myeloma 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) for patients with solid tumours or according to IMWG (appendix 4) for multiple myeloma patients.
  7. Haematological and biochemical indices within the ranges shown in the protocol. These measurements must be performed within one week (Day -7 to Day 1) before the patient is entered into the trial.
  ADDITIONAL INCLUSION CRITERIA FOR Part II:
  8. Documented presence of RAS-RAF-MEK pathway mutations including BRAF, KRAS and NRAS. In Part IIC at least three patients should have KRAS mutant lung cancer. In Part IID expansion, all 10 patients should have RAS mutant cancer.
  9. Patients with multiple myeloma refractory to conventional treatment. Haematological indices as in section 4.1.1 above except ANC ≥ 1.0 x 109/L, platelet count ≥ 50 x 109/L and serum creatinine ≤ 1.5 x (ULN). Patients can be deemed as eligible based on serum creatinine alone if creatinine clearance/isotope clearance is deranged.
  10. Archival tumour sections available for patients with solid tumours, or diagnostic bone marrow samples available for patients with multiple myeloma.
  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), with the exception of Dexamethasone for patients with multiple myeloma (see section 5.6). 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 an 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] - refer to Appendix 5), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive pulmonary disease.
  12. Concurrent ocular disorders:
  1. 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.
  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
  13. Patients exposed to CYP3A4 inhibitors within 7 days prior to the first dose.
  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. Has received a live vaccine within 30 days of planned start of study therapy. Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.
  16. Clinically significant abnormalities of glucose metabolism as defined by any of the following:
  -  Diagnosis of diabetes mellitus types I or II (irrespective of management).
  -  Glycosylated haemoglobin (HbA1C) ≥7.0% at screening
  -  Fasting Plasma Glucose ≥ 8.3mmol/L at screening. Fasting is defined as no caloric intake for at least 8 hours.
  17. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial. Examples of which include: hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption; hypersensitivity to RO5126766 and/or Everolimus, to other rapamycin derivatives or to any of the excipients; pre-existing infections.

Relevance to patient case: possibly relevant