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

  • STATUS
    Recruiting
  • End date
    Oct 11, 2024
  • participants needed
    560
  • sponsor
    Centre Leon Berard
Updated on 11 February 2021

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 after induction treatment with a selected therapy (Molecular Targeted Therapy (MTT) or 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 this targeted therapy selected based on tumor molecular profile in patients with stable disease.

Each patient enrolled will receive the matching targeted therapy during 12 weeks (MTT) or 24 weeks (IT). At the end of this induction period:

  • 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  • patients in progression will discontinue the targeted therapy and will be withdrawn from study and oriented towards standard treatments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 (MTT) or 24 weeks (IT) 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): ~ 600 patients treated in the induction period and 350 patients randomized in maintenance period.

Details
Condition Malignant Solid Neoplasms
Treatment Nilotinib (400 mg BID), Everolimus (10 mg QD), Sorafenib (400 mg BID), Lapatinib (1500 mg QD), Pazopanib (800 mg QD), durvalumab + tremelimumab, Olaparib (300 mg BID)
Clinical Study IdentifierNCT02029001
SponsorCentre Leon Berard
Last Modified on11 February 2021

Eligibility

Yes No Not Sure

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. 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 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. 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 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
weeks following the last treatment intake. (for olaparib : during the study
and for at least 1 month 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)
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
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 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
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
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: monotherapy for the maintenance treatment of adult patients with platinum sensitive relapsed BRCA mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum based chemotherapy
Patients with the following cancers: breast or prostate or stomach or ovarian or small cell lung cancers
Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable)
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