Adapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatment

NCT02029001 | Recruiting Phase 2 DMC

• 2 other identifiers: ET12-0812012-004510-34
• Study Type: interventional
• Target: 900
• Locations: 1 country
• Sites: 7

Brief Summary

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• patients in progression will discontinue the targeted therapy and will be withdrawn from study and oriented towards standard treatments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.

Conditions

Malignant Solid Neoplasms

Keywords

Solid tumor; Recurrent/metastatic; Personalized medicine; Genomic alteration; Targeted therapy; Nilotinib; Everolimus; Sorafenib; Lapatinib; Pazopanib; Olaparib; Immunotherapy; Durvalumab; Tremelimumab

Outcome Measures

Primary Outcomes (2)

• 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).

  12 weeks for MTT or 52 weeks for IT after initiation of study treatment

• 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.

  16 weeks after randomisation date

Secondary Outcomes (4)

• Objective Response Rate (ORR)

  Over the induction period

• Overall survival (OS)

  from the date of randomization to the date of death from any cause

• Patient's quality of life score (QLQ-C30) in both arms after randomization

  At randomization (week 12 for MTT or week 52 for IT), 16 weeks after randomisation (week 28 for MTT or week 68 for IT) and end of study for patient (week 136 for MTT or until up to 130 months after treatment start for IT)

• Safety assessment

  Over the whole study

Other Outcomes (4)

• Duration of response (exploratory outcome)

  Over the whole study

• Medico-economic evaluation: cost analysis and cost-effectiveness analysis

  From randomization until patient's end of study

• Progression Free Survival (exploratory outcome)

  Through study completion, an average of 1 year

Study Arms (2)

Arm A: Maintenance treatment

EXPERIMENTAL

Patients will continue targeted treatment matching the molecular alterations identified in their tumor * for a maximum of 136 weeks starting from the date of patient's first study drug intake following inclusion or a discontinuation criteria (unacceptable toxicity, interruption of study drug more than 28 days, documented on-treatment disease progression, patient decision, investigator decision, pregnancy) is met for nilotinib, everolimus, sorafenib, lapatinib, pazopanib, olaparib. * until loss of clinical benefit, or until a permanent study drug discontinuation criteria is met (unacceptable toxicity, interruption of study drug more than 28 days, documented on-treatment disease progression, patient decision, investigator decision, pregnancy) or for up to 2 years duration for patients with CR/PR/SD with the possibility of rechallenge in case of PD after IT cessation for durvalumab + tremelimumab

Drug: Nilotinib (400 mg BID); Drug: Everolimus (10 mg QD); Drug: Sorafenib (400 mg BID); Drug: Lapatinib (1500 mg QD); Drug: Pazopanib (800 mg QD); Drug: Olaparib (300 mg BID); Combination Product: Durvalumab + Tremelimumab

Arm B:Interruption of targeted treatment

NO INTERVENTION

Targeted treatment received during induction period will be discontinued until a first documented off-treatment disease progression occurs. At progression, treatment reintroduction may be proposed to the patient (left at the investigator's appreciation, and upon patient approval). Treatment may be continued until on-treatment disease progression, unacceptable toxicity or for a maximum of 136 weeks from the date of patient's first study drug intake following inclusion for nilotinib, everolimus, sorafenib, lapatinib, pazopanib, olaparib or until loss of clinical benefit, or until a permanent study drug discontinuation criteria is met for durvalumab + tremelimumab. If the investigator considers that the treatment cannot be safely reintroduced (regarding patient's condition and/or laboratory results), the patient will be withdrawn from study.

Interventions

Nilotinib (400 mg BID) DRUG

Patient 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.

Also known as: Open cohort

Arm A: Maintenance treatment

Everolimus (10 mg QD) DRUG

Patients 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).

Also known as: Closed cohort

Arm A: Maintenance treatment

Sorafenib (400 mg BID) DRUG

Patients 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.

Also known as: Closed cohort

Arm A: Maintenance treatment

Lapatinib (1500 mg QD) DRUG

Patients whose tumor harbors mutations or amplifications of HER2

Also known as: Closed cohort

Arm A: Maintenance treatment

Pazopanib (800 mg QD) DRUG

Patients whose tumor harbors mutations of VEGFR1-3, PDGFRA, PDGFRB or KIT\* or amplification /translocation of the genes and/or of the ligands.

Also known as: Closed cohort

Arm A: Maintenance treatment

Olaparib (300 mg BID) DRUG

ATM, 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

Also known as: Open cohort

Arm A: Maintenance treatment

Durvalumab + Tremelimumab COMBINATION_PRODUCT

Any 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.

Also known as: Open cohort

Arm A: Maintenance treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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 )

You may not qualify if:

• 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. Patient already treated with with immune checkpoint inhibitors (anti-PD1/PDL1, anti-CTLA4, anti-LAG3 etc.) are excluded.
• 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

Sponsors & Collaborators

• Centre Leon Berard: lead
• National Cancer Institute, France: collaborator

Study Sites (7)

Institut Bergonié

Bordeaux, 33076, France

RECRUITING

Centre Leon Berard

Lyon, 69373, France

RECRUITING

Centre Hospitalier Lyon Sud

Lyon, 69495, France

RECRUITING

Institut Paoli Calmettes

Marseille, 13273, France

RECRUITING

Institut Curie

Paris, 75248, France

RECRUITING

Institut de Cancerologie de Strasbourg Europe

Strasbourg, 67033, France

RECRUITING

Institut Claudius Regaud

Toulouse, 31059, France

RECRUITING

Related Publications (1)

• Tredan O, Toulmonde M, Le Tourneau C, Montane L, Italiano A, Ray-Coquard I, De La Fouchardiere C, Bertucci F, Goncalves A, Gomez-Roca C, You B, Attignon V, Boyault S, Cassier PA, Dufresne A, Tabone-Eglinger S, Viari A, Sohier E, Kamal M, Garin G, Blay JY, Perol D. Sorafenib in Molecularly Selected Cancer Patients: Final Analysis of the MOST-Plus Sorafenib Cohort. Cancers (Basel). 2023 Jun 30;15(13):3441. doi: 10.3390/cancers15133441.

  PMID: 37444551 DERIVED

Related Links

• MOST study is part of the LyRICAN project, click here to access LyRICAN website

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

nilotinib; BID protein, human; Everolimus; Cohort Studies; Sorafenib; Lapatinib; pazopanib; olaparib; durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Epidemiologic Studies; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Jean-Yves BLAY, MD

  Centre Leon Berard

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jean-Yves BLAY, MD

CONTACT

+33478785126; jean-yves.blay@lyon.unicancer.fr

Olivier TREDAN, MD

CONTACT

+33478782828; olivier.tredan@lyon.unicancer.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2014
• First Posted: January 7, 2014
• Study Start: March 1, 2014
• Primary Completion: January 1, 2026
• Study Completion (Estimated): October 1, 2027
• Last Updated: August 7, 2025

Record last verified: 2025-08

Locations

FR (7)