Table 4.

Active Therapeutic Clinical Trials for Patients with Leptomeningeal Metastases

NCT	Phase	Primary Histology	Site, Sponsor	Drug	Primary Outcome(s)	Secondary Outcome(s)	Study Arms	Key Inclusion Criteria	Key Exclusion Criteria	Recruiting?
NCT02939300	II	Melanoma	Massachusetts General Hospital, Bristol-Myers Squibb	Nivolumab and ipilimumab	OS	IC/EC RR LM RR IC/EC PFS Toxicity	Single arm: combination of nivolumab with ipilimumab followed by nivolumab monotherapy	• Adults only • ECOG ≤2 or KPS ≥60 • Life expectancy ≥3 wks • LM confirmed by cytology	• Active, known, or suspected autoimmune disease • Condition requiring systemic corticosteroid treatment • Prior systemic treatment with anti-CTLA4 antibody • Known history of active TB	Yes
NCT01645839	III	Breast cancer	Multiple sites in France, Centre Oscar Lambret	Liposomal cytarabine	Neurological PFS	Neurological, physical, cognitive, cytological, radiological improvement PFS (radiological, clinical, cytological) OS Toxicity	A: Standard systemic treatment without liposomal cytarabine B: Standard systemic treatment with liposomal cytarabine	• Female adults only • ECOG ≤2 • Life expectancy ≥2 mo • New diagnosis of LM by cytology OR clinical signs and symptoms • Measurable CNS disease < 0.5 cm or > 0.5 cm if focused radiation therapy	• Symptomatic BM or BM requiring WBRT • Previous CSI or IT therapy • Previous systemic treatment with ARA-C or high-dose systemic methotrexate • Contraindication to LP and ventricular catheterization • VPS	Yes
NCT01325207	I/II	HER2+ breast cancer	Multiple US sites; Northwestern University	IT trastuzumab	Safety MTD	Response (radiological, cytological, clinical) CSF PK	Single arm, dose escalation: twice weekly for 2 wks, then weekly for 4 wks, then every 2 wks	• Adults only • HER2+ by IHC or FISH breast cancer • LM determined by MRI or cytology • Life expectancy ≥8 wks • KPS ≥50 • Willing to have Ommaya reservoir placed • May continue on IV trastuzumab, lapatinib or hormonal agents if controlling ECD and developed LM while on therapy	• Previously-treated BM • BM requiring active treatment • Systemic agents (chemotherapy) that have CNS penetration, unless LM developed while on these agents and ECD controlled	Ongoing, not recruiting
NCT01373710	I/II	HER2+ breast cancer	Multiple sites in France, Institut Curie	IT/IVent trastuzumab	MTD	CNS TTP QoL OS PFS PK Radiological, CSF response	Single arm, dose escalation: 1 injection/wk during 8 wks by lumbar puncture or Ommaya Reservoir, 4 dose levels expected from 30 mg to 150 mg	• Adults only • Life expectancy ≥2 mo • HER2+ by IHC and/or FISH • LM diagnosis by cytology and/or clinical signs and symptoms of LM with abnormal MRI	• Symptomatic untreated BM • Symptomatic BM, unless surgery and/or RT were performed ≥3 wks before treatment initiation and lesion(s) accessible to IT or IVent treatment • Obstructive hydrocephalus • On lapatinib, unless wash out >2 wks before first dose of IT study drug • VPS or atrial shunt, unless can be turned off during treatment	Yes
NCT02650752	I	HER2+ breast cancer	3 US sites, Memorial Sloan Kettering Cancer Center	High-dose lapatinib + capecitabine	MTD	Not specified	Single arm: weekly treatment cycle consisting of lapatinib 3 d on/11 d off + capecitabine 7 d on/7 d off. Both drugs administered orally with dose escalation.	• Female adults only • HER2+ by IHC or FISH • Life expectancy ≥12 wks • ECOG ≤2 • Non-escalating corticosteroid dose (≤16 mg dexamethasone daily) for ≥ 5 d • Radiological evidence of new and/or progressive BM/LM or CSF cytological evidence of LM	• Prior capecitabine therapy allowed if ≥6 mo since last dose • Everolimus therapy • Craniotomy, other major surgery, open biopsy, or significant traumatic injury ≤4 wks of enrollment • HIV infection or chronic hepatitis B or C • Concurrent chemotherapy, hormonal therapy, radiation therapy, surgery, immunotherapy, tumor embolization, or biologic therapy, except for trastuzumab or hormonal therapy	Yes
NCT02422641	II	Breast cancer	Wake Forest University and Sidney Kimmel Comprehensive Cancer Center, Wake Forest University Health Sciences	High-dose methotrexate	3 mo OS	1 yr OS PFS Tolerability Cost Cytologic sterilization	Single arm: high dose methotrexate (8 gm/m2 IV every 2 wks)	• Adults only • ECOG 0–1 • Triple negative, HER2+, or HR+ hormone refractory breast cancer • Cytologic or radiographic confirmation of LM with/without BM	• Chemotherapy or SRS within 2 wks, WBRT within 6 mo • Heart failure (>NYHA Class 3) • Prior treatment with any methotrexate-containing systemic regimen within 1 yr (excluding IT methotrexate) • Concurrent or planned systemic chemotherapy, radiotherapy, or new hormonal/anti-HER2 directed therapy	Yes
NCT02616393	II	EGFR-mutant NSCLC	Multiple US sites, Kadmon Corp. LLC	Tesevatinib	Clinical activity using RECIST 1.1 (Cohorts A, C), symptom resolution (Cohort B)	QoL Median PFS CNS TTP Median OS PK	Dosing the same among all arms: 300 mg orally once daily A: NSCLC who have progressed with BM B: NSCLC who have progressed with LM C: NSCLC with BM at initial presentation	• Adults only • EGFR mutation that has clinical response to erlotinib, afatinib, or gefitinib • BM occurrence or progression while receiving erlotinib, afatinib, or gefitinib • Measurable BM (≥10 mm) • ECOG ≤2 • No clinically significant progression outside of the CNS on most recent EGFR inhibitor therapy	• First day of dosing with tesevatinib • <2 wks from the last treatment of cytotoxic chemotherapy, biological therapy, or immunotherapy, • <6 wks for nitrosoureas and mitomycin C • <2 wks since surgical procedure • <4 wks since last CNS-direct RT • <3 d since discontinuing erlotinib, afatinib, or TKI • Any concurrent BM (Cohorts A and C), LM (Cohort B) therapy other than study treatment	Yes
NCT02336451	II	NSCLC with ALK rearrangement	Multiple US and international sites, Novartis	Ceritinib	ORR	TTIR and TTR IC/EC DOR IC/EC ORR IC/EC DCR PFS Safety PK	Dosing the same among all arms: 750 mg orally once daily • ALK+ NSCLC with BM, without LM, with previous exposure to crizotinib • ALK+ NSCLC with BM, without LM, without previous exposure to crizotinib • ALK+ NSCLC with LM, with or without previous exposure to crizotinib	• ≥1 measurable EC lesion • ECOG ≤2 • Life expectancy ≥6 wks	• Prior ALK inhibitor other than crizotinib • BM requiring WBRT • Previously-treated BM, unless progressive or new since WBRT • Unstable or increasing dosage of corticosteroids • Planning to receive local treatment to BM (e.g. surgery, SRS, WBRT, IT chemotherapy)	Yes
NCT00445965	II	GD2-positive LMD (primarily neuroblastoma, primary CNS tumors)	Memorial Sloan Kettering Cancer Center, Same	IVent 131-I-labeled monoclonal antibody 3F8	6mo OS RR (alive at 6 mo)	Toxicity	Single arm: 10 mCi injected IT weekly for up to 4 courses as tolerated	• Children and adults • Histologically-confirmed diagnosis of a malignancy known to express GD2	• Rapidly progressing or deteriorating neurologic examination • Obstructive or symptomatic communicating hydrocephalus • CSI or systemic chemotherapy <3 wks prior to start of protocol • >45 Gy CSI or >72 Gy focal brain radiation	Ongoing, not recruiting
NCT00089245	I	Malignancy known to be 8H9 reactive, confirmed by IHC or bone marrow IF	Memorial Sloan Kettering Cancer Center, Same	131-I-labeled 8H9	MTD over 2 yrs	Not specified	Single arm, dose escalation with patients entering in cohorts of: 3 patients at each dose level from 10–60 mCi 6 patients at each dose level from 70–100 mCi	• Children and adults• LMD refractory to conventional therapies or recurrent brain tumors with predilection for LM dissemination (medulloblastoma, PNET, rhabdoid tumors)	• Rapidly progressing or deteriorating neurologic examination • Obstructive or symptomatic communicating hydrocephalus • CSI or systemic chemotherapy <3 wks prior to start of protocol	Yes
NCT02308020	II	HR+ breast cancer, NSCLC, or melanoma	Multiple US sites, Eli Lilly and Co.	Abemaciclib	IC ORR	BOIR IC DOR DCR IC DCR ICBR OS OR PFS PK at 3 mo	Same treatment for all arms, UOS: 200mg study drug Q 12 hr, days 1–21 of each 21 d cycle • A: HER2+ breast cancer • B: HER2- breast cancer • C: Surgical resection indicated for intracranial lesions, drug days 5–14 prior to surgical resection and resumed dosing after wound healing • D: NSCLC, 150 mg drug if receiving concurrent gemcitabine or pemetrexed • E: Melanoma • F: HR+ Breast cancer, NSCLC, or melanoma	• Adults only • KPS ≥70 • Life expectancy ≥12 wks • Completed local therapy (surgical resection, WBRT, or SRS) ≥14 d prior to initiating study drug	• Require immediate local therapy (including WBRT, SRS, surgical resection) • Concurrent EIAED use • Evidence of symptomatic intracranial hemorrhage • ≥2 seizures within 4 wks prior to study initiation	Yes
NCT02886585	II	Multiple histologies	Massachusetts General Hospital, Merck Sharp & Dohme Corp.	Pembrolizumab	ORR OS EC ORR	Toxicity OS rate IC/EC RR EC PFS	Same treatment for all arms, UOS: study drug Q 3 wks • A: previously untreated BM • B: progressive BM after prior local CNS-directed therapy (e.g. WBRT, SRS, or surgery) • C: LM with positive CSF cytology • D: 1–4 BM from histologically-confirmed melanoma with clinical indication for SRS, cycles 1 and 2 of study drug administered 3 wks apart with SRS between	• Adults only • Progressive systemic disease from any histologically or cytologically confirmed solid tumor • Measurable CNS disease (≥10 mm), except for Arm C • ECOG ≤2 or KPS ≥60 • Life expectancy ≥6 wks • Stable dose of dexamethasone ≤2 mg for ≥7 d prior to treatment initiation	• Arm A: excludes HER2+ breast cancer, SCLC,; NSCLC with targetable genomic tumor aberrations (e.g. EGFR, ALK) • Known history of active TB • Immunodeficient HIV-positive participants on combination antiretroviral therapy • Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent	Yes

All information obtained from clinicaltrials.gov

Abbreviations:

ALK – anaplastic lymphoma kinase, BM – brain metastasis(es), BOIR – best overall intracranial response, CNS – central nervous system, CR – complete response, CSI – craniospinal irradiation, CTLA4 – Cytotoxic T-Lymphocyte Associated Protein 4, DCR – disease control rate, DOR – duration of response, EC – extracranial, ECD – extracranial disease, ECOG – Eastern Cooperative Oncology Group Performance Status, EGFR – epidermal growth factor receptor, EIAED – enzyme-inducing antiepileptic drugs, FISH – fluorescence in situ hybridization, HER2 – human epidermal growth factor receptor 2, HIV – human immunodeficiency virus, HR – hormone receptor, IC – intracranial, ICBR – intracranial clinical benefit rate, IF – immunofluorescence, IHC – immunohistochemistry, IT – intrathecal, IV – intravenous, IVent – intraventricular, KPS – Karnofsky Performance Status, LMD – leptomeningeal metastasis/disease, MTD – maximum tolerated dose, NSCLC – non-small cell lung cancer, NYHA – New York Heart Association, ORR – objective response rate, OS – overall survival, PD – progressive disease, PD/PD-L – Programmed Death/Programmed Death-Ligand, PFS – progression-free survival, PK – pharmacokinetics, QoL – quality of life, RR – response rate, RT – radiotherapy, SCLC – small cell lung cancer, SRS – stereotactic radiosurgery, TB – Bacillus Tuberculosis, TT(I)R – time to (intracranial) tumor response, TKI – tyrosine kinase inhibitor, TTP – time to progression, UOS – unless otherwise specified, VPS – ventriculoperitoneal shunt, WBRT – whole-brain radiation therapy