Cyclophosphamide for Nasopharyngeal Carcinoma

Metronomic Oral Cyclosphosphamide as Third-line Systemic Treatment or Beyond in Patients With Inoperable Locoregionally Advanced Recurrent or Metastatic Nasopharyngeal Carcinoma

There is no standard third-line systemic treatment for inoperable locoregionally advanced recurrent or metastatic nasopharyngeal carcinoma (NPC). We investigated the efficacy and safety of metronomic oral cyclophosphamide as third-line treatment or beyond.

Study Overview

• Status: Completed
• Conditions: Recurrent Nasopharyngeal Undifferentiated Carcinoma; Stage IV Nasopharyngeal Undifferentiated Carcinoma
• Intervention / Treatment: Drug: Cyclophosphamide

Detailed Description

NPC is endemic in Southern China including Hong Kong. Despite aggressive definitive chemoradiotherapy for locoregionally advanced disease, still about 30% develop relapse locoregionally or distally. Salvage or second-course radical radiotherapy with or without chemotherapy may achieve durable disease control for locoregionally advanced recurrent disease. However for those who had received 2 courses of radical radiotherapy or those with distant metastases, systemic chemotherapy would be the only drug of choice. Platinum-based doublet chemotherapy including cisplatin + 5-fluorouracil, capecitabine, gemcitabine or taxane is considered the standard first-line treatment. For second-line treatment, whether platinum-based chemotherapy was given previously is a consideration. Re-challenge with cisplatin and 5-fluorouracil can be considered in patients who enjoyed a good initial response to the same regimen with an intervening disease-free period of more than 1 year.However so far there has been no recognized standard third-line systemic treatment. Metronomic oral chemotherapy may provide an ideal choice patients treated in this setting by shifting the targets from tumor cells to tumor vasculature so as to reduce the chance of drug resistance as well as offering a relatively low toxicity profile to them who have been significantly jeopardized by the long-term complications brought prior courses of radiation therapy, surgery and chemotherapy.

In view of the above, we investigated metronomic open-label oral cyclophosphamide as third-line treatment or beyond in patients with inoperable locoregionally advanced recurrent or metastatic NPC who had failed at least 2 lines of prior systemic chemotherapy.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 76 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Inoperable locoregionally advanced recurrent NPC of undifferentiated type beyond curative surgical resection or second and subsequent courses of radical radiotherapy or metastatic disease who all had received at least 2 lines palliative systemic chemotherapy
• Adequate hematological function defined as absolute neutrophil count ≥1.5 × 10^9/l; hemoglobin ≥9.0 g/dl and platelet ≥100 × 10^9/l
• Adequate renal function defined as serum creatinine ≤1.5 × upper normal limit
• Adequate hepatic function defined as serum bilirubin ≤1.5 × upper normal limit; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × upper normal limit for patients without liver metastases or ≤5 × upper normal limit for those with liver metastases
• Measurable disease according to the RECIST criteria (version 1.1), for the evaluation of measurable disease

Exclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status 3 or above
• Known brain metastases or leptomeningeal metastases; Note: symptomatic, and/or if they require immunosuppressive doses of corticosteroids (e.g. > 10 mg/day prednisone or equivalents) for at least 2 weeks prior to study drug administration; patients with treated brain metastases who are deemed clinically stable and without radiological progression on positron emission tomography (PET), MRI or computed tomography (CT) scan performed =< 8 weeks of study entry, are not excluded; Note: primary nasopharyngeal cancers that directly invade the skull base and extend into the infratemporal fossa (e) are not regarded as brain metastases and are not excluded
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide
• History of severe hypersensitivity reaction to any monoclonal antibody
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Any of the following:
• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception Note: breastfeeding should be discontinued if the mother is treated with cyclophosphamide; women of childbearing potential and men must use two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; they must adhere to contraception for a period of 31 weeks after the last dose of cyclophosphamide
• For patients with unknown human immunodeficiency virus (HIV) status at the time of enrollment, HIV serology must be tested during screening; patients who are tested positive for HIV could be included if there is an adequate cluster of differentiation 4 (CD4) count (> 350/ul) on a stable regimen of highly active anti-retroviral therapy (HAART) with no detectable or minimal viral burden, and no active infections
• Those who cannot provide written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cyclophosphamide; Patients receive oral cyclophosphamide 50 to 150mg daily continuously in the absence of disease progression or unacceptable toxicity.	Drug: Cyclophosphamide; Patient receive oral cyclophosphamide 50 to 150mg daily continuously in the absence of disease progressive or unacceptable toxicity.; Other Names: Endoxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Interval between the date of commencement of cyclophosphamide to the date of radiologically confirmed progressive disease or death, whichever comes earlier.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	The percentage of patients who demonstrate complete response or partial response after study medication as assessed by RECIST 1.1	12 months
Disease control rate	The percentage of patients who demonstrate complete response, partial response or stable disease after study medication as assessed by RECIST 1.1	12 months
Number of participants with treatment-related adverse events as assessed by CTCAE version 4.0	All treatment-related adverse events as assessed by CTCAE version 4.0 will be recorded	12 months
Overall survival	Time interval between the date of commencement of cyclophosphamide to the date of death	36 months

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Investigators: Principal Investigator: Victor Lee, MD, Department of Clinical Oncology, The University of Hong Kong, Hong Kong

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: May 30, 2016
• First Submitted That Met QC Criteria: June 2, 2016
• First Posted (Estimate): June 8, 2016

Study Record Updates

• Last Update Posted (Actual): October 2, 2019
• Last Update Submitted That Met QC Criteria: September 29, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Nasopharyngeal undifferentiated carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Nasopharyngeal Neoplasms; Carcinoma; Nasopharyngeal Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: Cyclophosphamide

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is no plan for to make individual participant data available.