Patient case: 61-year-old male with melanoma; genetic feature: BRAF amplification

Clinical trial: Adapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: My Own Specific Treatment

Summary: MOST is a phase II trial conducted in adult patients with an advanced solid tumor in progression after at least 1 prior treatment regimen. The study aims to assess whether a 12-week treatment with a targeted therapy selected based on the alteration(s) detected in the tumor is sufficient to stabilize the disease compared with a longer treatment, for all patients presenting this alteration, regardless of the primary disease site or cancer type. All the targeted therapies administered in MOST study already obtained a marketing authorization (MA) but will be evaluated in indications other than those defined in their MA.
  Each patient enrolled will receive the matching targeted therapy during 12 weeks (induction treatment). At the end of this period:
  -  patients with a tumor response will continue the targeted therapy,
  -  patients in progression will discontinue the targeted therapy and will be withdrawn from study and oriented towards standard treatments
  -  patients with a stable disease at 12 weeks will be randomized in order to determine if they continue or stop the targeted therapy.
  About 80 patients will be treated in each of the 5 treatment groups opened to enrollment, each group corresponding to an available targeted therapy.


Eligibility: Inclusion Criteria:
  I1. Male or female patient ≥ 18 years of age I2. Histologically or cytologically confirmed diagnosis of metastatic or locally advanced and unresectable solid tumor of any type, not amenable to curative treatment. Concerning primitive tumors of the central nervous system (CNS), all histological types of malignant tumors (including parenchymal and meningeal tumors) are eligible.
  I3. Documented disease progression at the time of study entry. I4. At least one prior systemic treatment regimen for locally advanced or metastatic disease. Patients who are candidates for a validated second line treatment regimen are not eligible for the study. For patients with a primitive CNS tumor, the absence of other therapeutic options must be validated by the reference committee for the patient's pathology before inclusion. As there is no prior systemic treatment regimen available for locally advanced or metastatic PEComa, these tumors are eligible for a MTT treatment in first line of their advanced or metastatic disease I5. Patient with measurable disease, defined as at least one lesion that can be accurately measured on CT-scan or MRI according to RECIST 1.1 I6. A multidisciplinary molecular board must have recommended one of the investigational MTT available in the study after review of a tumor molecular profiling previously established from a biopsied lesion and/or primitive tumor.
  I7. The MTT recommended by the multidisciplinary molecular board after the review of tumor molecular profile is not approved and reimbursed in France for the disease affecting the patient.
  I8. ECOG performance status 0, 1 or 2
  I9. Adequate organ system function as assessed by the following minimal laboratory requirements :
  -  ANC ≥ 1 x 109/L (for pazopanib: ≥ 1.5 x 109/L)
  -  Platelets ≥ 100 x 109/L
  -  Hemoglobin ≥ 9 g/dL. Transfusion is not allowed within 7 days of screening assessment.
  -  For pazopanib: aPTT ≤ 1.2x ULN and PT or INR ≤ 1.2x ULN; Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation.
  -  AST and ALT ≤ 3x ULN in the absence of liver metastases (≤ 5x ULN for patients with liver involvement of their cancer) and total bilirubin ≤ 1.5x ULN. (for pazopanib: AST and ALT ≤ 2.5x ULN; concomitant elevations in bilirubin and AST or ALT above 1x ULN are not permitted).
  -  Serum creatinine ≤ 1.5x ULN or creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula, or MDRD formula for patients older than 65 years) (for pazopanib: creatinine clearance ≥ 30 mL/min)
  -  For pazopanib: Urine Protein to Creatinine ratio (UPC) <1; if UPC ≥1, 24-hour urine protein must be <1g (use of urine dipstick for renal function assessment is not acceptable).
  -  Corrected QT interval ≤ 450 msecs (≤ 480 msecs if recommended MTT has no known effect on QT interval) on screening ECG, within 14 days prior to C1D1 I10. Life expectancy of at least 4 months I11. Specific toxicities related to any prior anti-cancer therapy must have resolved to grade ≤1 except for alopecia and fatigue. Grade 2 neutropenia or anemia is accepted.
  I12. Women of childbearing potential must have a negative pregnancy test performed within 3 days prior to study treatment start. A positive urine test must be confirmed by a serum pregnancy test.
  I13. Women of childbearing potential (entering the study after a confirmed menstrual period and who have a negative pregnancy test) and men of reproductive potential must agree, if sexually active, to use two methods of medically acceptable forms of contraception during the study and for at least 8 weeks following the last treatment intake.
  I14. Signed and dated informed consent document indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrollment.
  I15. The patient must be affiliated to the French social security system.
  Exclusion Criteria:
  Patients eligible for this study must not meet any of the following criteria:
  E1. Previous treatment in advanced phase with a targeted therapy inhibiting the same target proteins as this recommended for the study.
  E2. Any contra-indication to receive the recommended MTT, including known or suspected hypersensitivity to compounds of similar chemical or biologic composition as the active substance, or to any of the excipients.
  E3. For nilotinib, sorafenib, pazopanib and lapatinib: Patient with hypokalemia or known history of congenital long QT syndrome (QT interval prolongation).
  E4. Prior malignancy or presence of any other active malignancy. Subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
  E5. Patient who have had major surgery or trauma within 28 days prior to first dose of investigational product.
  E6. Patient with symptomatic CNS metastatic involvement of his/her cancer, unless the patient have stable neurological function without evidence of CNS progression within 12 weeks prior to study entry and does not require treatment with enzyme-inducing anticonvulsants or steroids. Patients with a primitive tumor of the CNS are not eligible if one of the following conditions is fulfilled:
  -  Alteration of cognitive functions impeding the patient's comprehension of study and the provision of informed consent by the patient himself/herself.
  -  Need for supportive care treatment(s) interfering with study treatment. E7. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment: radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of study treatment OR immunotherapy within 28 days OR chemotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or 5 half-lives of a drug (whichever is longer). Palliative radiotherapy is authorized only if the irradiated field does not include target lesions.
  E8. Administration of any non-oncologic investigational agent within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment.
  E9. Patient with any condition that impairs their ability to swallow and retain tablets and may affect the absorption of the investigational product are excluded.
  E10. For pazopanib: Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
  -  Active peptic ulcer disease
  -  Known intraluminal metastatic lesion(s) with risk of bleeding
  -  Inflammatory bowel disease or other gastrointestinal conditions with increased risk of perforation
  -  History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
  E11. For pazopanib: Evidence of active bleeding or bleeding diathesis. E12. For pazopanib: Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage.
  -  Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is acceptable.
  -  Large protruding endobronchial lesions in the main or lobar bronchi are excluded; however, endobronchial lesions in the segmented bronchi are allowed.
  -  Lesions extensively infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in the wall of the bronchi are allowed.
  E13. For pazopanib: Recent hemoptysis.
  E14. Any clinically significant and/or uncontrolled medical disease that could compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results. These conditions include but are not limited to:
  -  Active clinically serious bacterial or fungal infection
  -  History of uncontrolled or significant cardiac disease within the past 6 months: LVEF < 50%, congestive cardiac failure, active ischemic heart disease, ventricular arrhythmia, myocardial infarction within 1 year, unstable angina pectoris, cardiac surgery.
  -  Patients with cerebrovascular accident (including transient ischemic attack), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months are not eligible for pazopanib treatment group
  -  Poorly controlled hypertension [for pazopanib: defined as systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥ 90mmHg]
  -  Severely impaired lung function
  -  Active gastrointestinal tract ulceration
  -  Acute or chronic uncontrolled liver disease, or severe renal disease
  -  Uncontrolled diabetes
  -  Known history of HIV infection, or active viral infection (HBV, HCV) at the time of study entry and/or requiring anti-viral therapy, or chronic hepatitis B or C. Detection of hepatitis C RNA must be performed before inclusion of patients with a history of HCV infection: patients with a positive result are excluded.
  -  History of organ allograft or patient taking immunosuppressive treatment E15. Patient unable or unwilling to discontinue use of prohibited medications for at least 14 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.
  E16. Pregnant or breastfeeding women. E17. Patients with any medical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule or evaluations of the study results.

Relevance to patient case: possibly relevant