Study to Demonstrate the Safety of WBR Administered at the Same Time as Intrathecal Liposomal Cytarabine (DepoCyte®) Versus Intrathecal Liposomal Cytarabine (DepoCyte®) Administered After WBR for the Treatment of Solid Tumour Neoplastic Meningitis in Patients With or Without Brain Metastasis.

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate the safety of giving Whole Brain Radiotherapy (WBRT) together with intrathecal liposomal cytarabine (DepoCyte®) for patients with leptomeningeal metastases. The study will compare the safety of giving DepoCyte at the same time as WBRT with giving the drug after WBRT is complete.

Official Title
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Phase I Randomised Multi-centre Study to Demonstrate the Safety of WBRT Concomitant to Intrathecal Liposomal Cytarabine (DepoCyte®) Versus WBRT & Sequential Intrathecal Liposomal Cytarabine (DepoCyte®) for Treatment of STNM With or Without Brain Metastasis.

Conditions
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Solid Tumour Neoplastic Meningitis, Brain Metastases

Intervention / Treatment
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* Drug: Whole Brain Radio Therapy (WBRT) with sequential Depocyte
* Drug: Whole brain radiotherapy (WBRT) with concomitant Depocyte


Participation Criteria
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Eligibility Criteria
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Indication and Criteria for Inclusion/Exclusion: Subjects who are to be included in the study have to meet all of the following criteria: Informed consent Male and female, age over 18 years Solid tumour neoplastic meningitis as demonstrated by a positive lumbar CSF cytology (obtained within 21 days prior to treatment initiation) OR Characteristic signs and symptoms of neoplastic meningitis PLUS an MRI indicating the presence of meningeal tumour (diagnosis to be made by neuro-oncologist and confirmed / signed within the CRF). All MRIs will be forwarded for central review and confirmation of diagnosis. In case of discrepancy the central review overrides the assessment of the investigator. CSF flow abnormality excluded by either an MRI scan or a 99Tc-DTPA or 111In-DTPA flow study. (If a flow abnormality is initially demonstrated but the flow block is subsequently documented by another flow study or MRI scan to be relieved following limited field radiation therapy, the subject may then be eligible) If brain metastasis confirmed (including subjects who have had previous stereotactical radiosurgery or solitary lesion brain surgery) the lesion should be less than 3cm diameter Mini Mental State Examination (MMSE) score more than 24 ECOG performance status 0-2 Laboratory values as follows: Platelet count more than or equal to 80,000/mm3 ANC more than or equal to 1,000/mm3 Serum creatinine less than or equal to 2 x upper limit of normal Total bilirubin less than or equal to 3 x upper limit of normal SGOT (AST) less than or equal to 3 x upper limit of normal LDH less than or equal to 3 x upper limit of normal Females of child-bearing potential must have a negative (urine or serum) pregnancy test within 21 days prior to the start of study treatment. Females of childbearing potential must be willing to use an effective method of contraception to prevent pregnancy for the duration of the study (e.g. implants, combined oral contraceptives, intrauterine devices (IUDs), sexual abstinence or vasectomised partner). Males must be willing to use an effective method of contraception with their partner to prevent pregnancy for the duration of the study (e.g. implants, combined oral contraceptives, intrauterine devices (IUDs), sexual abstinence or vasectomy). Exclusion Criteria: Previous WBRT Brain metastases more than 3 cm diameter Previous IT treatment Uncontrolled infection including HIV infection Any present condition that is regarded as contraindication for WBRT and intrathecal chemotherapy Prior treatment with systemic ARA-C Anticipated hypersensitivity to DepoCyte or ARA-C Clinically manifest encephalopathy On anticoagulant therapy Ventricular peritoneal CSF drain in situ Subjects unable to comply with study procedures Pregnancy and lactation Any other investigational drug administered within 21 days prior to study entry

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Whole brain radiotherapy (WBRT) with concomitant Depocyte<br>Subjects will receive a total of 38.4 Gray (Gy) WBRT given over 4 weeks. Subjects will receive 3 GyWBRT on Days 1 and 2 and then 1.8 Gy on the third fourth and fifth days of WBRT treatment during Week 1. Subjects will then receive 1.8 Gy WBRT per day; 5 days out of seven, each week for the next 3 weeks. A total of 4 doses of DepoCyte (50 mg of liposomal ARA-C) will be administered intrathecally. The first dose will be administered on Day 3 (or Day 4 or 5) of Week 1, i.e. the third day of radiotherapy treatment when the dosage is reduced to 1.8 Gy. The second dose will be administered on Day 17(+2 days); the third dose will be administered on Day 31 (+2 days); the fourth dose will be administered on Day 45 (+2 days) to complete the induction phase of the protocol. Subjects will continue to receive an additional 6 doses of DepoCyte one dose every 28 days (+2 days) during the maintenance period. The first dose will be given 28 days after the last dose in the induction phase. | Drug: Whole brain radiotherapy (WBRT) with concomitant Depocyte<br> <br> |
| Active Comparator: Whole Brain Radio Therapy (WBRT) with sequential Depocyte<br>Subjects will receive a total of 38.4 Gy WBRT given over 4 weeks. Subjects will receive 3 Gy (WBRT on Day 1 and Day 2) and then 1.8 Gy on the third fourth and fifth days of WBRT treatment during Week 1. Subjects will then receive 1.8 Gy WBRT per day; 5 days out of seven, each week for the next 3 weeks. A total of 4 doses of DepoCyte (50 mg of liposomal ARA-C) will be administered intrathecally. The first dose will be administered on Day 29 (+2 days); the second dose will be administered on Day 43(+2 days); the third dose will be administered on Day 57 (+2 days); the fourth dose will be administered on Day 71 (+2 days) to complete the induction phase of the protocol. DepoCyte should never be administered more frequently than every 14th day. Subjects will continue to receive an additional 6 doses of DepoCyte one dose every 28 days (+2 days) during the maintenance period. The first dose will be given 28 days after the last dose in the induction phase. | Drug: Whole Brain Radio Therapy (WBRT) with sequential Depocyte<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate that WBRT concomitant to DepoCyte is as safe as WBRT & sequential DepoCyte in treating solid tumour neoplastic meningitis with/without brain metastasis. |  | Safety is reviewed at every visit & for 3 months after last Depocyte administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) |  | Safety is reviewed at every visit & for 3 months after last Depocyte administration | 
| Progression free survival (PFS) |  | Safety is reviewed at every visit & for 3 months after last Depocyte administration | 
| Time to neurologial progression (TNP) |  | Safety is reviewed at every visit & for 3 months after last Depocyte administration | 
| Overall survival (OS) |  | Safety is reviewed at every visit & for 3 months after last Depocyte administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumour neoplastic meningitis, STNM, leptomeningeal metastases, DepoCyte, WBRT, Whole Brain Radiotherapy, Liposomal cytarabine intrathecal, Solid Tumour Neoplastic Meningitis with or without brain metastasis