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will continue the targeted therapy, * patients in progression will discontinue the targeted therapy and will be withdrawn from study and oriented towards standard treatments * patients with a stable disease at 12 weeks will be randomized in order to determine if they continue or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.
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.
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.
Active peptic ulcer disease
Known intraluminal metastatic lesion(s) with risk of bleeding
Parallel
Nilotinib (400 mg BID)
DrugPatient with advanced pigmented villonodular synovitis and tumors with mutations of ABL1, KIT, PDGFRA, PDGFRB, DDR1, DDR2, CSF1R, or amplification/translocation of the genes and/or of the ligands.
Everolimus (10 mg QD)
DrugPatients whose tumor harbors mutations or amplification of the PIK3CA, PIK3R1, AKT1, AKT2, mTOR, RICTOR, RAPTOR genes, or with TSC1, TSC2 or PTEN loss (defined as complete loss of both gene copies OR loss of one copy + mutation on the other copy or loss of one copy + loss of expression using immunohistochemistry).
Sorafenib (400 mg BID)
DrugPatients whose tumor harbors mutations of VEGFR1-3, PDGFRB, FLT3, BRAF (other than V600 mutations), CRAF, HRAS, KRAS or RET or amplification/translocation of the genes and/or of the ligands.
Lapatinib (1500 mg QD)
DrugPatients whose tumor harbors mutations or amplifications of HER2
Pazopanib (800 mg QD)
DrugPatients whose tumor harbors mutations of VEGFR1-3, PDGFRA, PDGFRB or KIT\* or amplification /translocation of the genes and/or of the ligands.
Olaparib (300 mg BID)
DrugATM, BAP1 et BRIP1 Mutation only if double hit documented; BRCA2, BRCA1, RAD51C, PALB2, RAD51D Mutation; BRCA1, BRCA2, ATM and BAP1 Loss; BRCA1, BRCA2, ATM and BAP 1 : mutation and heterozygote deletion. except for patients eligible to olaparib's available labels and reimbursements in France. NOTE : only prostate cancer with RECIST 1.1 evaluable disease are eligible until the French price and reimbursement
Durvalumab + Tremelimumab
Combination productAny molecular types of tumor (which are known to be immunogenic or with high mutation load), except lung, urothelial and head and neck or CNS tumors, or patients who fulfill conditions to receive any other MTT of the MOST Plus study.
Induction Progression-Free Rate after induction treatment
The proportion of patients without documented disease progression within induction period (the first 12 weeks of study treatment or 52 weeks for IT).
Progression-Free Survival (PFS) in both study arms after randomization
Measured from the date of randomization until the date of event defined as the first documented progression or death from any cause. Patients with no event at the time of the analysis will be censored at the date of the last available tumor assessment.
Objective Response Rate (ORR)
Proportion of patients with complete response (CR) or partial response (PR) as best overall response over the induction period.
Overall survival (OS)
Patient's quality of life score (QLQ-C30) in both arms after randomization
Safety assessment
Type, frequency, seriousness and causality of adverse events reported from treatment initiation based on the common toxicity criteria grade (NCI CTC-AE-V4.03)
Duration of response (exploratory outcome)
Measured from the time of first documented response (CR or PR) until the first documented disease progression or death due to underlying cancer, and censored at the date of the last available tumor assessment
Medico-economic evaluation: cost analysis and cost-effectiveness analysis
Incremental cost-effectiveness ratios (ICERs) will be expressed as: * the cost per life year gained; * the cost per progression-free year gained.
Progression Free Survival (exploratory outcome)
Measured from the date of the first administration of the treatment until the date of event defined as the first documented progression or death from any cause. Patients with no event at the time of the analysis will be censored at the date of the last available tumor assessment.
Molecular evolution of tumor at progression (for olaparib and durvalumab + tremelimumab groups)
ctDNA analysis
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Centre Leon Berard
Lead sponsor
National Cancer Institute, France
Collaborator
