Overview
The MOST Plus study is a two-period phase II clinical trial, conducted in patients with all types of progressive solid tumors after at least 1 prior systemic treatment regimen for advanced disease (in the absence of a validated second line therapy).
The main goal of this study is to evaluate for these patients the clinical benefit of a maintenance treatment in patients with stable disease (SD) after induction treatment with a selected therapy (Molecular Targeted Therapy (MTT) or with SD, partial response (PR) or complete reponse (CR) with Immunotherapy (IT)).
For MTT, the first period of this trial (induction period) will enable to establish whether the identification of genomic alterations in genes encoding for "actionable" targets in the tumor cells, regardless of the histological subtype, can be used to select efficient treatment targeting the pathway activated by the mutation.
For Immunotherapy, induction period with durvalumab + tremelimumab is expected to be an innovative therapy for an efficient tumor control and may allow to identify types of cancer or molecular types of cancer that are more receptive to immunotherapy.
For all treatments, the second period (maintenance period) will use a randomized design to evaluate the clinical benefit of a maintenance treatment with the targeted therapy or immunotherapy selected based on tumor molecular profile in patients treated by MTT with SD and in patients treated by IT with SD, PR or CR.
Each patient enrolled will receive the matching targeted therapy during 12 weeks (MTT) or 52 weeks (IT). At the end of this induction period:
MTT cohorts :
- patients with a tumor response (CR: complete response or PR: partial 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- patients in progression will discontinue the targeted therapy and will be withdrawn from study and oriented towards standard treatments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 therapy.
IT cohort :
- patients with SD, PR or CR at 52 weeks will be randomized in order to determine if they continue or stop the therapy.
For each MTT treatment group: ~80 patients treated in the first step (induction period), 50 patients randomized in the second step (maintenance period, 25 patients per arm).
For IT treatment group: ~125 patients treated in the first step (induction period), 50 patients randomized in the second step (maintenance period, 25 patients per arm).
In total (for 7 treatment groups): ~ 900 patients treated in the induction period and 350 patients randomized in maintenance period.
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, except for Nilotinib cohort: only pigmented
villonodular synovitis are eligible, 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 (except for IT).
I3. Documented disease progression at the time of study entry.
I4. At least one prior systemic treatment regimen for locally advanced or metastatic
disease - except for Nilotinib cohort : patients can be treated with Nilotinib in first
line systemic treatment.
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. No previous treatment by immunotherapy is allowed for IT
group.
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 (or blood for pazopanib, olaparib and
immunotherapy cohorts) molecular profiling previously established from a biopsied lesion
and/or primitive tumor, and/or from a liquid biopsy, respectively (for pazopanib, olaparib
and immunotherapy cohorts).
I7. The MTT recommended by the multidisciplinary molecular board after the review of tumor
or blood molecular profile is not approved and reimbursed in France for the disease
affecting the patient in the same label.
I8. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
I9. Adequate organ system function as assessed by the following minimal laboratory
requirements :
- Absolute neutrophil count (ANC) ≥ 1 x 109/L (for pazopanib and olaparib: ≥ 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 olaparib: Hemoglobin ≥ 10 g/dL. Transfusion is not allowed within 28 days of
screening assessment, no features suggestive of myelodysplastic syndrome (MDS)/Acute
myeloid leukemia (AML) on peripheral blood smear within the 28 days)
- For pazopanib: activated partial thromboplastin time (aPTT) ≤ 1.2x Upper limit of
normal (ULN) and prothrombin time (PT) or international normalized ratio (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.
- Aspartate Aminotransferase (AST) and alanine transaminase (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; for
olaparib and IT: AST and ALT ≤ 2.5x ULN in the absence of liver metastases (≤ 5x ULN
for patients with liver involvement of their cancer) and total bilirubin ≤ 1.5x ULN.).
- Serum creatinine ≤ 1.5x ULN or creatinine clearance ≥ 50 mL/min (calculated by
Cockcroft-Gault formula, or modification of diet in renal disease (MDRD) formula for
patients older than 65 years) (for pazopanib: creatinine clearance ≥ 30 mL/min; for
olaparib : creatinine clearance ≥ 51 mL/min; for IT : creatinine clearance ≥ 40 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 (QTc) interval ≤ 450 msecs (≤ 480 msecs if recommended MTT has no known
effect on QT interval) on screening ECG, within 14 days prior to C1D1 (for olaparib :
QTc < 470 msec on 2 or more time points within a 24 hour period on screening ECG,
within 7 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 (defined by the NCI-CTCAE v4.03) except for alopecia, vitiligo 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. (for olaparib :
during the study and for at least 6 months for women and 3 months for men following the
last treatment intake; for IT : during the study and for at least 3 months following the
last treatment intake). Refrain from breastfeeding (for nilotinib cohort : not breast-feed
for at least two weeks after the last dose of nilotinib) and egg cell donation. Males
should not donate sperm during or for 3 months after treatment 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.
I16. The recommended study treatment must have been approved by the medical staff of the
Steering committee.
I17. Patient should be able and willing to comply with study visits and procedures as per
protocol.
I18. Patient must fulfill ALL following conditions (criteria only applicable for Durvalumab
+ Tremelimumab cohort):
- Availability of a pre-treatment sample of primary tumor (only formalin-fixed
paraffin-embedded (FFPE) block with sufficient material) and presence of at least one
biopsiable tumor lesion for on-treatment biopsy,
- Weight > 50 Kg,
- Patient with a maximum of 2 prior lines of treatment at time of C1D1 for their
metastatic or locally advanced.
Exclusion Criteria:
Patients eligible for this study must not meet any of the following criteria:
E1. Previous treatment in advanced phase with an investigational 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, lapatinib and olaparib: Patient with hypokalemia
(< Lower Limit of Normal) 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. Patient must have recovered from any effects of any major surgery.
E6. Patient with symptomatic or uncontrolled 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 to
IT and 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 (for olaparib : within 3 weeks or 5 half-lives of a drug
whichever is longer), surgery or tumor embolization within 14 days prior to the first dose
of study treatment OR immunotherapy within 28 days (except for IT : patient already treated
with an immunotherapy are excluded) OR chemotherapy (for olaparib : within 3 weeks or 5
half-lives of a drug whichever is longer), 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. For oral treatment : 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 and IT: 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: left
ventricular ejection fraction (LVEF) < 50%, congestive cardiac failure, active
ischemic heart disease, ventricular arrhythmia, myocardial infarction within 1 year,
unstable angina pectoris, cardiac surgery. (except for Nilotinib, all patients with
uncontrolled or significant cardiac disease are excluded)
- 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) ≥ 90 mmHg]
- Severely impaired lung function
- Active gastrointestinal tract ulceration
- Acute or chronic uncontrolled liver disease, or severe renal disease
- Uncontrolled diabetes
- Known history of human immunodeficiency virus (HIV) infection, or active viral
infection (hepatitis B virus (HBV), hepatitis C virus (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.
E18. Patient currently treated with drugs that could interfere with study drugs metabolism
E19. Patients filling at least one of these criteria are excluded. (Specific to olaparib)
- Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
suggestive of MDS/AML.
- Patients considered a poor medical risk due to a serious, uncontrolled seizures,
uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled
infection. Examples include, but are not limited to, uncontrolled ventricular
arrhythmia, recent myocardial infarction, unstable spinal cord compression , superior
vena cava syndrome, extensive bilateral lung disease on High-resolution computed
tomography (HRCT) scan.
- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation and whole blood transfusions in the last 120 days prior to entry to
the study (packed red blood cells and platelet transfusions are acceptable) are not
allowed.
- Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors. The
required washout period prior to starting olaparib is 2 weeks.
- Concomitant use of known strong or moderate CYP3A inducers. The required washout
period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
weeks for other agents.
- Patients eligible for olaparib (Lynparza®) in its approved indication in France E20.
For IT: Patients filling at least one of these criteria are excluded.
- Patients with lung or urothelial or head and neck cancers or CNS tumors or patients
who fulfill conditions to receive one of the investigational therapy of the study
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of Durvalumab or Tremelimumab, with the exceptions of intranasal and inhaled
corticosteroids or systemic corticosteroids at physiological doses, which are not to
exceed 10mg/day of prednisone, or an equivalent corticosteroid.