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Patients will be enrolled to receive 30Gy (RBE) in 3Gy (RBE) or 25Gy (RBE) in 2.5Gy (RBE) fractions course of proton CSI.

The first 3 patients will be enrolled at dose level 30Gy (RBE) in 3Gy(RBE) fractions. If 1 or fewer patients develop dose-limiting toxicity (DLT), 3 additional patients will be enrolled. If 1 or fewer of the 6 patients experiences a DLT, the trial will proceed to the dose expansion cohort at 30Gy (RBE) . In contrast, if 2 or more patients experience a treatment DLT, 3 patients will be enrolled at dose level 25Gy (RBE) in 2.5Gy(RBE) fractions. If 1 or fewer patients develop a DLT, an additional three patients will be enrolled. If 2 or more patients experience a DLT at 25Gy, the study will be stopped. If 1 or fewer patients develop a DLT in these 6 patients, the trial will proceed to the dose expansion cohort at 25Gy (RBE) and the 6 patients who were treated in Phase Ib will be included in full assessment of safety and efficacy.

Patients will be enrolled to receive 30Gy (RBE) in 3Gy (RBE) or 25Gy (RBE) in 2.5Gy (RBE) fractions course of proton CSI.

Proton craniospinal irradiation (CSI)

Daniel Higginson, MD

The purpose of this study is to find the safest and most effective dose for delivering proton beam to the space containing CSF, brain, and spinal cord, in treating leptomeningeal metastases. The researchers think that using proton beam radiation to treat the space containing CSF, brain, and spinal cord, instead of treating only the areas where the metastasized tumor cells are causing symptoms, would improve the treatment of this disease.

Single-arm, prospective trial with 3+3 dose de-escalation and dose expansion cohort.

Study of Proton Radiation to the Brain and Spinal Cord for Patients With Leptomeningeal Metastases

A Phase Ib Study With Dose Expansion Cohort of Proton Craniospinal Irradiation for Leptomeningeal Metastases From Solid Tumors

will be assessed by physician-graded CTCEAv4

Memorial Sloan Kettering Cancer Center

Proton CSI (30Gy \[RBE\] in 10 fractions) followed by standard of care systemic treatments for leptomeningeal metastases per physician choice.

Involved field photon RT including WBRT and/or focal spine RT (30Gy in 10 fractions) followed by standard of care systemic treatments for leptomeningeal metastases per physician choice.

(Exploratory arm) Patients with solid tumor malignancies other than NSCLC or breast cancer will be enrolled to the exploratory proton CSI arm (Arm C) and will not undergo randomization. Proton CSI (30Gy \[RBE\] in 10 fractions) followed by standard of care systemic treatments for leptomeningeal metastases per physician choice.

Involved field photon RT including WBRT and/or focal spine RT (30Gy in 10 fractions)

Involved-field Photon Radiation Therapy

Proton CSI (30Gy \[RBE\] in 10 fractions)

Proton Craniospinal Irradiation (CSI)

All patients at MSKCC will complete a neurocognitive test battery at study entry (prior to RT), and approximately 3, 6 and 12 months and post -RT. The neurocognitive tests consists of standardized, validated and reliable measures of attention, executive functions, and memory, for which age- and education-matched healthy control published data are available. Patients will also complete self-report mood and fatigue scales at each of the same time points. This testing will only be done at MSKCC. Non-English-speaking patients and pediatric patients are exempt from completing the neurocognitive assessments. Neurocognitive assessments will be performed in person at MSK-Manhattan; an option to perform follow up assessments via telehealth will be available only for patients who are not able to go to Manhattan for these visits.

Neurocognitive Assessment

Using MDASI-BT and MDASI-SP questionnaires before, weekly during, at 3 months (+/- 4 weeks), 6 months (+/- 4 weeks), 9 months (+/- 4 weeks), and 12 months (+/- 4 weeks) after group assignment, and at CNS disease progression. Only one set needs to be completed. Non-English-speaking patients and pediatric patients are exempt from completing the patient-reported outcomes unless translated PRO assessment forms are available. Questionnaires will be completed via mail, in-person, or online (MSK Engage).

MDASI-BT and MDASI-SP

Divya Yerramilli, MD

The investigators are doing this study to find out whether proton craniospinal radiation therapy (proton CSI) or partial photon radiation therapy is more effective at preventing leptomeningeal metastasis from worsening. The proton CSI targets the entire space containing the CSF, brain, and spinal fluid. The partial photon radiation therapy treats only areas where the patient is having symptoms, such as the entire brain or part of the spine. The investigators also want to find out if proton CSI improves the symptoms patients may be experiencing because of the leptomeningeal metastasis. In addition, the investigators will compare the side effects of proton CSI and partial photon therapy.

Patients undergoing proton beam RT will receive their treatment at the New York Proton Center in New York, NY. As part of the New York Proton Consortium, MSK has contracted for its faculty to treat patients at the New York Proton Center. If it is unfeasible for patients to get treated at NYPC, patients will have the decision to get treated at ProCure in Summerset, NJ.

This is a randomized (2:1) phase II multicenter trial in patients with leptomeningeal metastases from NSCLC and breast cancer.

Proton Craniospinal Radiation Therapy vs. Partial Photon Radiation Therapy for Leptomeningeal Metastasis From Solid Tumors

A Phase II Randomized Study Assessing the Efficacy of Proton Craniospinal Irradiation (CSI) vs Involved-field Photon Radiation Therapy for Leptomeningeal Metastases From Solid Tumor Malignancies

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

For Arm A and Arm B, which will be defined as the duration of time from the date of randomization to the time of progression of disease or death, whichever occurs first. The baseline imaging study will be the diagnostic imaging obtained at study entry.

will be included in an analysis of overall survival, defined as time from randomization to death.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Proton Radiation to the Brain and Spinal Cord for Patients With Leptomeningeal Metastases	NCT03520504	Leptomeningeal ...	Proton craniosp...	10 Years -	Memorial Sloan Kettering Cancer Center
Study of Proton Radiation to the Brain and Spinal Cord for Patients With Leptomeningeal Metastases	NCT03520504	Leptomeningeal ...	Proton craniosp...	10 Years -	Memorial Sloan Kettering Cancer Center
Proton Craniospinal Radiation Therapy vs. Partial Photon Radiation Therapy for Leptomeningeal Metastasis From Solid Tumors	NCT04343573	Leptomeningeal ...	Involved-field ... Proton Craniosp... Neurocognitive ... MDASI-BT and MD...	- 99 Years	Memorial Sloan Kettering Cancer Center
Study of Proton Radiation to the Brain and Spinal Cord for Patients With Leptomeningeal Metastases	NCT03520504	Leptomeningeal ...	Proton craniosp...	10 Years -	Memorial Sloan Kettering Cancer Center

Spots Global Cancer Trial Database for proton craniospinal irradiation (csi)