Concurrent Intrathecal-pemetrexed and Involved-field Radiotherapy for Leptomeningeal Metastasis From Solid Tumors

Leptomeningeal Metastasis Clinical Trial

Official title:

Intrathecal-pemetrexed Combined With Concurrent Involved-field Radiotherapy for Leptomeningeal Metastasis From Solid Tumor: a Phase I/II Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03507244
• Other study ID #: IPLM
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 12, 2018
• Est. completion date: July 30, 2019

Study information

• Verified date: December 2019
• Source: First Hospital of Jilin University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Intrathecal chemotherapy is one of the most important treatment modalities for leptomeningeal metastasis of solid tumors. In the previous retrospective study, it has been proved that concurrent radiotherapy and intrathecal methotrexate for leptomeningeal metastasis from solid tumors with adverse prognostic factors showed great effectiveness and safety. The preliminary results of investigators' current prospective clinical study (Involved-field Radiotherapy Combined With Concurrent Intrathecal-methotrexate Versus Intrathecal-Ara-C for Leptomeningeal Metastases From Solid Tumor: A Randomized Phase II Clinical Trial. ClinicalTrials.gov identification number: NCT03082144) also showed that the regimen of concurrent intrathecal chemotherapy and radiotherapy may serve as an optimal therapeutic option for treatment of leptomeningeal metastases from solid tumors. Pemetrexed is a newer multitargeted antifolate which has shown activity in various tumors. In investigators' current study (Intrathecal Pemetrexed for Recurrent Leptomeningeal Metastasis From Non-small Cell Lung Cancer: A Prospective Pilot Clinical Trial. ClinicalTrials.gov identification number: NCT03101579), the regimen of intrathecal pemetrexed with folic acid and vitamin B12 supplementation may provide higher effectiveness and safety for recurrent leptomeningeal metastasis from non-small cell lung cancer. Therefore, the purpose of the study is to evaluate the tolerability, safety and effectiveness of intrathecal pemetrexed combined with involved-field radiotherapy as the first line treatment in patients with leptomeningeal metastases from malignant solid tumors.

Description:

This study is a single arm, open clinical trial. Consecutive patients with leptomeningeal metastases from malignant solid tumors are enrolled into this study. Concomitant regimen consisted of intrathecal chemotherapy (via lumbar puncture, pemetrexed 10 mg, plus dexamethasone 5 mg, once per week, 5 to 8 times, 4 to 7 weeks in total) and radiotherapy. Radiotherapy consisted of fractionated, conformal radiation given at a daily dose of 2 Gy. The planning volume consisted of sites of symptomatic disease, bulky disease observed on magnetic resonance imaging(MRI), including the whole brain and basis cranii received 40 Gy in 20 fractions, 4 weeks in total, and/or segment of spinal canal received 40-50 Gy. The RANO proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: July 30, 2019
• Est. primary completion date: January 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Patients who have been definitely diagnosed as leptomeningeal metastasis according to cerebrospinal fluid (CSF) cytology, or patients who got the clinical diagnosis by combining history of cancer, neuroimaging, clinical manifestation, and CSF examination, etc.

2. Patients who have been diagnosed as malignant solid tumor with definite pathologic type, excluding hematological malignancies (e.g., leukemia and lymphoma) or intracranial germ cell tumors;

3. No severe abnormal liver function; normal kidney function; WBC=4000/mm3, Plt=110000/mm3;

4. No other severe chronic diseases;

5. No severe dyscrasia.

Exclusion Criteria:

1. Patients with leptomeningeal metastasis from unknown primary tumor;

2. Patients who had received whole brain radiotherapy in the past 10 months;

3. Patients who had accepted systemic chemotherapy within two weeks, or molecular targeted therapy less than two weeks;

4. Patients with poor compliance, or for other reasons, the researchers considered unsuitable to participate in this clinical study.

Related Conditions & MeSH terms

• Leptomeningeal Metastasis
• Meningeal Carcinomatosis
• Neoplasm Metastasis
• Neoplasms, Second Primary

Intervention

Drug:
• Pemetrexed
Pemetrexed, 10 mg,intrathecal injection, plus dexamethasone 5 mg, once per week, 5 to 8 times, 4 to 7 weeks in total.
• Dexamethasone
Dexamethasone, 5 mg, intrathecal injection, simultaneously with pemetrexed, once per week, 5 to 8 times, 4 to 7 weeks in total.

Radiation:
• Radiotherapy
The sites of symptomatic disease, bulky disease observed on MRI, including the whole brain and basis cranii, 40 Gy in 20 fractions;and/or segment of spinal canal received 40-50 Gy in 20-25 fractions.

Locations

Country	Name	City	State
China	The First Hospital of Jilin University	Changchun	Jilin

Sponsors (1)

Lead Sponsor	Collaborator
First Hospital of Jilin University

Country where clinical trial is conducted

China, 

References & Publications (10)

Adjei AA. Pharmacology and mechanism of action of pemetrexed. Clin Lung Cancer. 2004 Apr;5 Suppl 2:S51-5. Review. — View Citation

Chattopadhyay S, Moran RG, Goldman ID. Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther. 2007 Feb;6(2):404-17. Review. — View Citation

Kumthekar P, Grimm SA, Avram MJ, Kaklamani V, Helenowski I, Rademaker A, Cianfrocca M, Gradishar W, Patel J, Mulcahy M, McCarthy K, Raizer JJ. Pharmacokinetics and efficacy of pemetrexed in patients with brain or leptomeningeal metastases. J Neurooncol. 2 — View Citation

McDonald AC, Vasey PA, Adams L, Walling J, Woodworth JR, Abrahams T, McCarthy S, Bailey NP, Siddiqui N, Lind MJ, Calvert AH, Twelves CJ, Cassidy J, Kaye SB. A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res. 19 — View Citation

Mita AC, Sweeney CJ, Baker SD, Goetz A, Hammond LA, Patnaik A, Tolcher AW, Villalona-Calero M, Sandler A, Chaudhuri T, Molpus K, Latz JE, Simms L, Chaudhary AK, Johnson RD, Rowinsky EK, Takimoto CH. Phase I and pharmacokinetic study of pemetrexed administ — View Citation

Pan Z, Yang G, He H, Zhao G, Yuan T, Li Y, Shi W, Gao P, Dong L, Li Y. Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: A prospective and single-arm study. Int J — View Citation

Rinaldi DA, Kuhn JG, Burris HA, Dorr FA, Rodriguez G, Eckhardt SG, Jones S, Woodworth JR, Baker S, Langley C, Mascorro D, Abrahams T, Von Hoff DD. A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the — View Citation

Sørensen JB. Pharmacokinetic evaluation of pemetrexed. Expert Opin Drug Metab Toxicol. 2011 Jul;7(7):919-28. doi: 10.1517/17425255.2011.587411. Epub 2011 May 21. Review. — View Citation

Stapleton SL, Reid JM, Thompson PA, Ames MM, McGovern RM, McGuffey L, Nuchtern J, Dauser R, Blaney SM. Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. Cancer Chemother Pharmacol. 2007 M — View Citation

Stoop MP, Visser S, van Dijk E, Aerts JGJV, Stricker BH, Luider TM. A new quantification method for assessing plasma concentrations of pemetrexed and its polyglutamate metabolites. J Pharm Biomed Anal. 2016 Sep 5;128:1-8. doi: 10.1016/j.jpba.2016.04.036. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of treatment-related adverse events	The incidence of treatment-related adverse events were measured for determing tolerability and safety. Adverse events (AEs) are evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03). Events of grade 3-5 are defined as moderate and severe adverse events.	The evaluation was performed at 3 months after the end of treatment or when patient died.
Secondary	Clinical response rate	The RANO proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.	The evaluation was performed at 3 months after the end of treatment or when patient died.
Secondary	Overall survival	Survival time was recorded since the date of patient enrollment. All patients were followed up until death or the end of the study.	The evaluation was performed at least 7 months after leptomeningeal metastasis diagnosis or until death.
Secondary	Neurological progression-free survival (NPFS)	NPFS was defined as time from the start of treatment until neurological progression or death. The neurological progression was determined based on the RANO proposal evaluation criteria which have been established and published on Neuro Oncol.	All patients were followed up at least 6 months, and the evaluation of NPFS was performed from the beginning of treatment until the date of first documented neurological progression or date of death from any cause, whichever came first.