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Interest of Intrathecal Chemotherapy With Liposomal Cytarabine (DepoCyte®) in Meningeal Metastasis of Breast Cancer (DEPOSEIN)

Primary Purpose

Breast Cancer, Leptomeningeal Metastases

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Liposomal Cytarabine
Sponsored by
Centre Oscar Lambret
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring Leptomeningeal metastasis, Intrathecal chemotherapy, Depocyte

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Centre Hospitalier Universitaire Groupe Sud
  • Centre Hospitalier Universitaire Lyon
  • Centre G.F. Leclerc
  • CHU de Grenoble
  • Centre Oscar Lambret
  • Centre Hospitalier Bretagne Sud
  • Centre Val d'Aurelle
  • Centre Hospitalier Universitaire de Nice
  • Centre Antoine Lacassagne
  • Hôpital Salpétrière

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Systemic treatment with Depocyte

Systemic treatment without Depocyte

Arm Description

Intrathecal injection of Liposomal Cytarabine (Depocyte®) every 14 ± 2 days for a total of 5 cycles and then every 28 ± 4 days until progression.

No intrathecal injection.

Outcomes

Primary Outcome Measures

Leptomeningeal disease-related neurological progression-free survival (LM-PFS)
time between randomization and date of first leptomeningeal progression (defined according to clinical-neurological or imaging criteria) or date of death (death from any cause) whatever occurs first. Patients alive without neurological progression at the time of the last follow-up will be censored at the date of the last visit.

Secondary Outcome Measures

Response of leptomeningeal metastases
Evaluated by clinical improvement, cytological improvement and MRI improvement. At 2 and 6 months, and best leptomeningeal disease response to treatment in response to treatment
Progression free survival (PFS)
PFS defined by the time between randomization and date of first progression: leptomeningeal, parenchymal, systemic (extra-CNS) or date of death (from any cause) if it occurs first. Patients alive and without progression at the time of the last follow-up will be censured at the date of the last visit. The different components of PFS will also be estimated considering the competing risk approach.
Overall survival
Time between the date of randomization in the study and the death of the patient (from any cause).
Tolerance to DepoCyte® according to NCI CTCAE V4.0
Safety and tolerability profile of DepoCyte® according to NCI-CTCAE v4.0. Adverse events will be considered as severe if the grade is more than 2. All AE will be taken into account except events unequivocally related to the underlying disease or its progression. SAE will be also reported.
Q-TWiST
Q-TWiSTanalysis defined by 3 health status: time with toxicity before progression (TOX), time after progression (PROG) considering progression at any site, and time without toxicity and without progression (TWiST).

Full Information

First Posted
July 16, 2012
Last Updated
June 11, 2019
Sponsor
Centre Oscar Lambret
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1. Study Identification

Unique Protocol Identification Number
NCT01645839
Brief Title
Interest of Intrathecal Chemotherapy With Liposomal Cytarabine (DepoCyte®) in Meningeal Metastasis of Breast Cancer
Acronym
DEPOSEIN
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

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Completed
Study Start Date
August 30, 2011 (Actual)
Primary Completion Date
August 2018 (Actual)
Study Completion Date
March 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre Oscar Lambret

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Leptomeningeal Metastases
Keywords
Leptomeningeal metastasis, Intrathecal chemotherapy, Depocyte

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
74 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Systemic treatment with Depocyte
Arm Type
Experimental
Arm Description
Intrathecal injection of Liposomal Cytarabine (Depocyte®) every 14 ± 2 days for a total of 5 cycles and then every 28 ± 4 days until progression.
Arm Title
Systemic treatment without Depocyte
Arm Type
No Intervention
Arm Description
No intrathecal injection.
Intervention Type
Drug
Intervention Name(s)
Liposomal Cytarabine
Other Intervention Name(s)
Depocyte, Aracytine
Intervention Description
50mg (5 mL) by slow intrathecal injection (1-5 minutes) directly into the cerebrospinal fluid (CSF) via a ventricular catheter directly into the lumbar sac during a lumbar puncture.
Primary Outcome Measure Information:
Title
Leptomeningeal disease-related neurological progression-free survival (LM-PFS)
Description
time between randomization and date of first leptomeningeal progression (defined according to clinical-neurological or imaging criteria) or date of death (death from any cause) whatever occurs first. Patients alive without neurological progression at the time of the last follow-up will be censored at the date of the last visit.
Time Frame
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 Outcome Measure Information:
Title
Response of leptomeningeal metastases
Description
Evaluated by clinical improvement, cytological improvement and MRI improvement. At 2 and 6 months, and best leptomeningeal disease response to treatment in response to treatment
Time Frame
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)
Title
Progression free survival (PFS)
Description
PFS defined by the time between randomization and date of first progression: leptomeningeal, parenchymal, systemic (extra-CNS) or date of death (from any cause) if it occurs first. Patients alive and without progression at the time of the last follow-up will be censured at the date of the last visit. The different components of PFS will also be estimated considering the competing risk approach.
Time Frame
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)
Title
Overall survival
Description
Time between the date of randomization in the study and the death of the patient (from any cause).
Time Frame
Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.
Title
Tolerance to DepoCyte® according to NCI CTCAE V4.0
Description
Safety and tolerability profile of DepoCyte® according to NCI-CTCAE v4.0. Adverse events will be considered as severe if the grade is more than 2. All AE will be taken into account except events unequivocally related to the underlying disease or its progression. SAE will be also reported.
Time Frame
Up to 30 days after the last administration of the study treatment
Title
Q-TWiST
Description
Q-TWiSTanalysis defined by 3 health status: time with toxicity before progression (TOX), time after progression (PROG) considering progression at any site, and time without toxicity and without progression (TWiST).
Time Frame
Calculated at the end of study
Other Pre-specified Outcome Measures:
Title
Quality of life (questionnaire QLQ C30, BN20 and C15)
Description
Quality of life data will be described and compared between the 2 groups of treatment by estimating the impact of DepoCyte® in terms of time to definitive deterioration of quality of life will be also compared. A deterioration of quality of life is defined as by a decrease of 10 points of the quality of life score or an increase of 10 points for quality of life symptoms.
Time Frame
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)
Title
Autonomy in daily life (questionnaire Instrumental Activities in Daily Living)
Description
IADL scale which evaluates the repercussions of the patients difficulties in the different activities of daily life.
Time Frame
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)
Title
Emotional state of the patient assessed by the psychological distress score
Description
Emotional Distress Profile (EDP) scale and Patient Global Impression of Change (PGI-C) scale.
Time Frame
At baseline
Title
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
Description
60 samples analysed at the diagnostic and monitoring of tumor meningitis moments, by VERIDEX technique: the presence of tumours cells is affirmed if there is no more than 1 cell in 7.5 mL.
Time Frame
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)
Title
Leptomeningeal response according to RANO criteria combining clinical, CSF cytological and imaging response
Description
Leptomeningeal response according to RANO criteria combining clinical, CSF cytological and imaging response
Time Frame
Done at the end of study

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Emilie LERHUN, MD
Organizational Affiliation
Centre Oscar Lambret
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centre Hospitalier Universitaire Groupe Sud
City
Amiens
ZIP/Postal Code
80054
Country
France
Facility Name
Centre Hospitalier Universitaire Lyon
City
Bron
ZIP/Postal Code
69677
Country
France
Facility Name
Centre G.F. Leclerc
City
Dijon
ZIP/Postal Code
21079
Country
France
Facility Name
CHU de Grenoble
City
Grenoble
ZIP/Postal Code
38042
Country
France
Facility Name
Centre Oscar Lambret
City
Lille
ZIP/Postal Code
59020
Country
France
Facility Name
Centre Hospitalier Bretagne Sud
City
Lorient
ZIP/Postal Code
56100
Country
France
Facility Name
Centre Val d'Aurelle
City
Montpellier
ZIP/Postal Code
34298
Country
France
Facility Name
Centre Hospitalier Universitaire de Nice
City
Nice
ZIP/Postal Code
06002
Country
France
Facility Name
Centre Antoine Lacassagne
City
Nice
ZIP/Postal Code
06189
Country
France
Facility Name
Hôpital Salpétrière
City
Paris
ZIP/Postal Code
75013
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31637444
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.
Results Reference
derived

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Interest of Intrathecal Chemotherapy With Liposomal Cytarabine (DepoCyte®) in Meningeal Metastasis of Breast Cancer

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