Clinical trial NCT01645839: Interest of Intrathecal Chemotherapy With Liposomal Cytarabine (DepoCyte®) in Meningeal Metastasis of Breast Cancer
Official title: Role of Intrathecal Chemotherapy With Liposomal Cytarabine (DepoCyte®) in Patients Wih Leptomeningeal Metastasis of Breast Cancer. A Randomized Phase III Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Leptomeningeal Metastases
Keywords: Leptomeningeal metastasis
Intrathecal chemotherapy
Depocyte
Lead sponsor: Centre Oscar Lambret
Sponsor class: OTHER
First posted: 2012-07-20
Enrollment: 74
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the impact of Depocyte® IT combined with the systemic standard treatment in terms of clinical and/or radiological neuromeningeal progression free survival (SSPN)

Detailed description: After the signature of the consent form and validation of the eligibility inclusion criteria, patients will be randomized. Treatment will start within a maximum of 10 days after randomization.

Arm A: Systemic standard treatment without DepoCyte® Arm B: Systemic standard treatment with DepoCyte® DepoCyte® will be slowly administered by injection (1 to 5 minutes) of 50 mg (5 mL) into the CSF via a lumbar puncture or a ventricular device

* every 14 +/- 2 days for a total of 5 cycles (induction treatment)
* then every 28 +/-4 days until progression (maintenance treatment) Standard systemic treatment by chemotherapy, targeted therapy or hormonal therapy is at the discretion of the investigator taking into account the breast cancer sub-type and previous treatments. The systemic treatment will be determined before randomization. It can be modified at any time according to the treating oncologist. Focal radiotherapy to symptomatic sites is allowed. The usual follow-up of patients treated by IT DepoCyte® of every 14 days for the first two months and then monthly is not modified in patients of Arm B. Evaluation in Arm A will be matched to Arm B, and are thus more frequent than routinely done because such patients are usually seen every 3 weeks. The follow-up for systemic disease is left at the discretion of the treating oncologist.

Translational research Only Oscar Lambret Center will participate in this exploratory analysis. For patients who accept to participate, a 10 mL CSF sample will be collected at enrollment and once per month, just before treatment.

* Arm A: at monthly visit
* Arm B: at a IT injection, once per month, just before DepoCyte® injection Samples will be sent to the analysis center as soon as possible and will be destroyed at the end of all study-related procedures.

Eligibility criteria: Inclusion Criteria:

* Histologically proven invasive breast cancer
* New diagnosis of leptomeningeal metastasis confirmed by CSF cytology, or by the combination of typical clinical symptoms or signs with typical MRI abnormalities
* Cerebrospinal MRI criteria: no visible lesion, or meningeal metastases \<0.5 cm, or \>0.5 cm largest diameter if focal radiotherapy planned
* Indication for systemic treatment (chemotherapy and/or targeted therapy and/or hormonal therapy) at the time of enrollment. Systemic treatment is at the discretion of the investigator (in collaboration with the treating oncologist if different) according to cancer characteristics, previous treatments, and clinical and biological disease characteristics. Focal radiotherapy is permitted.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Patients unable to walk due to a palsy but able to use a wheelchair are considered as ambulatory patients
* Expected survival of at least 2 months. Patients with rapidly progressive systemic disease are not eligible for this trial
* Co-existing asymptomatic brain metastases are permitted
* In case of suspicion of CSF flow block, or after focal radiotherapy for the treatment of a CSF flow block, a CSF flow study will be performed (isotopic method) to confirm the absence of CSF block
* Patients must have recovered from acute adverse events of other anticancer treatments previously administered
* Adequate bone marrow, renal, and hepatic function with the following range: bilirubin ≤ 3 x upper limit of normal (ULN), ASAT ≤ 2.5 x ULN or ≤ 5 x ULN in presence of liver metastases
* Adequate contraception (CPMP/ICH/286/95) for patients of reproductive potential (e.g., barrier method, vasectomy of partner, abstinence) (hormonal contraception not permitted)
* Patient affiliated to the French Social Security
* Able to understand the requirements of the study, date and sign written informed consent

Exclusion Criteria:

* Leptomeningeal metastasis related to other primary tumors than breast cancer
* History of other cancer (\<5 years) except adequately treated cervical cancer, or basocellular or spinocellular skin cancer
* Contra-indication to MRI (including claustrophobia)
* MRI criteria: CSF flow obstruction (hydrocephalus on brain MRI or obstacle on spinal MRI)
* Contra-indication to lumbar puncture and to implantation of a ventricular device
* Progressive brain metastases thought to require whole brain radiotherapy
* Prior cranio-spinal irradiation (prior brain focal radiotherapy or whole brain radiotherapy for brain metastases permitted)
* Prior intrathecal chemotherapy or targeted therapy
* Prior systemic cytarabine treatment or prior systemic high-dose methotrexate treatment
* Concomitant systemic high-dose methotrexate treatment
* Ventriculo-peritoneal shunt
* Active infection (systemic or CNS)
* Hypersensitivity to cytarabine or DepoCyte
* Patient presenting with other severe non-controlled disease which could compromise the participation in the study (infection, cardio-vascular disease, gastro-intestinal disease, renal disease, pulmonary disease)
* Enrollment into another study evaluating a drug within 30 days before the screening visit
* Breast feeding woman or pregnancy. Nursing is not permitted for 6 months after the study
* Impossibility to adhere to the requirements of the study for geographic, social or psychological reasons

Primary outcomes:
measure: Leptomeningeal disease-related neurological progression-free survival (LM-PFS)
timeFrame: At baseline, then every 2 weeks for 2 months, after 2 months from baseline once a month until progression (up to 6 months) and at the end of the study (up to 6 months)
Secondary outcomes:
measure: Response of leptomeningeal metastases
timeFrame: At baseline, then every 2 weeks for 2 months, after 2 months from baseline once a month until progression (up to 6 months) and at the end of the study (up to 6 months)
measure: Progression free survival (PFS)
timeFrame: At baseline, then every 2 weeks for 2 months, after 2 months from baseline once a month until progression (up to 6 months) and at the end of the study (up to 6 months)
measure: Overall survival
timeFrame: Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.
measure: Tolerance to DepoCyte® according to NCI CTCAE V4.0
timeFrame: Up to 30 days after the last administration of the study treatment
measure: Q-TWiST
timeFrame: Calculated at the end of study
Other outcomes:
measure: Quality of life (questionnaire QLQ C30, BN20 and C15)
timeFrame: At baseline, then every 2 weeks for 2 months, after 2 months from baseline once a month until progression (up to 6 months) and at the end of the study (up to 6 months)
measure: Autonomy in daily life (questionnaire Instrumental Activities in Daily Living)
timeFrame: At baseline, then every 2 weeks for 2 months, after 2 months from baseline once a month until progression (up to 6 months) and at the end of the study (up to 6 months)
measure: Emotional state of the patient assessed by the psychological distress score
timeFrame: At baseline
measure: Identification and quantification of tumor cells in the CSF by the Veridex technique for the diagnosis and the follow-up of breast cancer leptomeningeal metastases
timeFrame: At baseline, then every 2 weeks for 2 months, after 2 months from baseline once a month until progression (up to 6 months) and at the end of the study (up to 6 months)
measure: Leptomeningeal response according to RANO criteria combining clinical, CSF cytological and imaging response
timeFrame: Done at the end of study
Locations:
city: Amiens
country: France
facility: Centre Hospitalier Universitaire Groupe Sud
city: Bron
country: France
facility: Centre Hospitalier Universitaire Lyon
city: Dijon
country: France
facility: Centre G.F. Leclerc
city: Grenoble
country: France
facility: CHU de Grenoble
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lorient
country: France
facility: Centre Hospitalier Bretagne Sud
city: Montpellier
country: France
facility: Centre Val d'Aurelle
city: Nice
country: France
facility: Centre Hospitalier Universitaire de Nice
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hôpital Salpétrière
Study officials:
affiliation: Centre Oscar Lambret
name: Emilie LERHUN, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Le Rhun E, Wallet J, Mailliez A, Le Deley MC, Rodrigues I, Boulanger T, Lorgis V, Barriere J, Robin YM, Weller M, Bonneterre J. Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer. Neuro Oncol. 2020 Apr 15;22(4):524-538. doi: 10.1093/neuonc/noz201.