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Induction Versus Adjuvant Gemcitabine/Cisplatin in Locally Advanced Non-metastatic Nasopharyngeal Carcinoma

Primary Purpose

Nasopharyngeal Carcinoma

Status
Recruiting
Phase
Phase 3
Locations
Kuwait
Study Type
Interventional
Intervention
Gemcitabin/cisplatin
Sponsored by
Kuwait Cancer Control Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Nasopharyngeal Carcinoma focused on measuring Induction chemotherapy, neoadjuvant, adjuvant, non-metastatic, Nasopharyngeal Carcinoma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with newly histologically confirmed Nasopharyngeal carcinoma (according to World Health Organization (WHO) 2. The patient has stage III except T3N0 or IVA disease (according to 8th American Joint Committee on Cancer staging system) 3. WHO performance status 0-1 . 4. The patient must have achieved lawful age to provide informed consent according to local or national law .

    5. Laboratory values performed within 14 days prior to concurrent chemotherapy should be as follows: i) Absolute neutrophil count (ANC) ≥ 1500/mm ii) Platelet count ≥ 100.000/mm iii) Hemoglobin ≥ 8g/dl iv) Urea and serum creatinine ≤ 1.5 mg/dl. (for cisplatin) v) Creatinine clearance ≥ 60 ml/min. (for cisplatin) vi) SGOT and SGPT ≤ 2 × upper limit of laboratory normal 6. Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy

Exclusion Criteria:

  1. Age ≥70 or <18
  2. The patient has evidence of distant metastatic disease.
  3. The patient has received prior systemic chemotherapy within the last three years.
  4. The patient has undergone previous surgery for the tumor, other than biopsy.
  5. The patient has received prior radiation therapy to the head or neck
  6. The patient is pregnant or breast feeding.
  7. The patient has a medical (e.g. renal impairment) or psychological condition that would not permit the patient to complete the trial or sign informed consent.
  8. Has known history of Human Immunodeficiency Virus (HIV)
  9. Has history of a diagnosed and/or treated hematologic or primary solid tumor malignancy,
  10. Has a history of severe hypersensitivity reaction to Cisplatin, Gemcitabine or radiotherapy or their analogs
  11. Unstable cardiac disease requiring treatment.

Sites / Locations

  • Kuwait Cancer Control CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Induction Arm

Adjuvant Arm

Arm Description

patients will receive three cycles of IC Gemcitabin/Cisplatin followed by radical CRT

Patients will receive radical CRT followed by three cycles of AC Gemcitabin/Cisplatin

Outcomes

Primary Outcome Measures

Acute and late toxicity assessment
Incidence of acute toxicity is calculated for each adverse event respectively, and severity evaluated on based of common terminology criteria for adverse event (CTCAE)
Late radiation toxicity
assessed using the radiation therapy oncology group and Europe organization for research and treatment of cancer late radiation morbidity scoring scheme
Loco regional control rates (LCR)
Defined as the time from the date of randomization to 1st failure in nasopharynx or neck lymph nodes
Progression free survival (PFS)
Defined as the time from the date of randomization to 1st failure locally or systemically

Secondary Outcome Measures

Overall Survival (OS)
Defined as the time from the date of randomization to death from any cause
Distance Metastasis free survival (DMFS)
It is evaluated and calculated from the date of random assignment until date of first distance metastasis or until the date of last follow-up visit

Full Information

First Posted
May 13, 2021
Last Updated
August 16, 2022
Sponsor
Kuwait Cancer Control Center
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1. Study Identification

Unique Protocol Identification Number
NCT04898374
Brief Title
Induction Versus Adjuvant Gemcitabine/Cisplatin in Locally Advanced Non-metastatic Nasopharyngeal Carcinoma
Official Title
Induction Versus Adjuvant Gemcitabine/Cisplatin in Locally Advanced Non-metastatic Nasopharyngeal Carcinoma: A Randomized Phase III Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 1, 2021 (Actual)
Primary Completion Date
April 30, 2025 (Anticipated)
Study Completion Date
April 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Kuwait Cancer Control Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The standard of care for locally advanced nasopharyngeal carcinoma is radical chemoradiation(CRT).Recent advances in radiation techniques and supportive measures resulted in improvemnent of locoregional control and quality of life.However distant failure is still the main challenging reason of poor survival Addition of systemic therapy to concurrent CRT is widely used and accepted as an option to reduce these failures ,however selection of chemotherapy regimen and timing in relation to CRT is controversial. Doublet and triplet chemotherapy regimens using cisplatin and 5FU are throughly investigated in this setting.Inspite of significant improvement in disease free survival and overall survival they were poorly tolerated.Hence,minority of patients in the daily practice could tolerate those studied regimens as propsed. Recently, in multicenter randomized trial, Zhang and his group investigated gemcitabine and cisplatin as induction chemotherapy (ICT) added to CRT.It showed improvement in recurrence free survival and overall survival.More importantly 96.7% of the experimental arm completed the treatment protocol. This was further confirmed by an updated network of meta analysis by Bongiovanni et al.Again the question of "when" is still valid.Our proposal is to compare tolerable regimen in induction versus adjuvant settings.
Detailed Description
Background Nasopharyngeal carcinoma (NPC) is one of the cancers which shows significant geographic prevalence variation. Worldwide, there were 130,000 new cases in 2018.As a non-endemic region, only 35 new cases were diagnosed in Kuwait in the same year. Nevertheless, it accounts for 1.3% of cancer related mortality in Kuwait. Radical radiotherapy (RT) is the mainstay treatment of NPC for decades. A high cure rate can be achieved for patients with early-stage. The breakthrough in the management of NPC came with the intergroup study 009 which showed significant improved progression free survival with adding chemotherapy (CTH) to the radiation. As compared to RT alone, concurrent chemoradiation (CRT), showed significant improvement in 10-year overall survival and progression free survival in meta-analysis of nasopharyngeal carcinoma (MAC-NPC) collaborative group. Addition of systemic therapy to concurrent CRT was the proposed solution to treatment failures; whether in the induction (ICT) or adjuvant (ACT) settings. However, ICT or ACT in NPC remains controversial; largely due to inconsistent results of several prospective randomized trials. The above-mentioned MAC-NPC group reviewed six clinical trials in which CRT followed by ACT was compared with RT alone (administrated without concurrent or adjuvant chemotherapy). Overall survival (OS) was significantly improved compared with RT alone (10-year overall survival 57% versus 43.1%, HR 0.65, 95% CI 0.56-0.76), as well as 10-year progression-free survival; PFS (53.2% versus 38.5%). However, this was not consistent in endemic areas with high prevalence of Epstein-Barr virus (EBV); which is known causative for NPC. Chen et al reported in a Chinese phase III trial 508 patients with advanced NPC randomized to ACT (cisplatin plus fluorouracil) vs observation following CRT with weekly cisplatin. There was no improvement in the five-year failure-free rate with ACT compared with CRT alone (five-year rate 75% versus 71%, HR 0.88, 95% CI 0.64-1.22) Later, from the same endemic region, Sun Yat-sen university conducted a multi center phase III clinical trial in which 480 patients, stage III to IVB, node-positive NPC were randomly assigned to ICT followed by CRT versus CRT alone. This study showed improvement of recurrence-free survival (RFS) and distant RFS. Another reason for reluctancy to adopt ICT or ACT in the management of advanced NPC, is the morbidity of current chemotherapy regimens. The high toxicity profile with some of these regimens was the real obstacle toward the use of them. In previous studies, the back bone for adjuvant or induction chemotherapy in NPC has been platinum and 5-fluoruracil, with or without a taxane. This regimen was poorly tolerated, with only 40-60 % of patients could complete their preplanned course of treatment in many trials. Recently, in multicenter randomized trial, Zhang and his group compared gemcitabine and cisplatin as ICT plus CRT with CRT alone. The 3-year RFS was 85.3% in the induction group and 76.5% in the standard-therapy group (HR 0.51; 95% CI, 0.34 to 0.77; P=0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (HR 0.43; 95% CI, 0.24 to 0.77). What is more important is that 96.7% of the experimental arm completed 3 cycles of ICT. On behalf of the Nasopharyngeal Cancer Portal Group of Investigators, Bossi colleagues from Europe, Kuwait, Jordan, Turkey and USA, assessed the impact of treatment intensity within a large retrospective multicenter cohort, nasopharyngeal cancer in non-endemic areas. Our group shared in this pooled analysis and the data showed a higher rate of death and recurrence with non-intensive treatment, (defined as no "added" systemic treatment to CRT). Ongoing Phase 3 Trials exploring ICT or ACT in NPC: There are multiple phase 3 trials ongoing to refine the ICT or ACT approach. Sun Yat-sen University is conducting a study comparing TPF with PF as ICT regimen in stage IVa-b NPC (NCT02940925). They also explore the effect of triple combination of ICT, CRT and ACT in high risk NPC (NCT02621970). Another comparison between induction TPF vs adjuvant PF is recruiting (NCT03306121). Fudan University also from China exploring maintenance gemcitabine after radical treatment in N3 disease (NCT03403829). Jiangxi Provincial Cancer Hospital testing adding neoadjuvant and adjuvant PD-1 inhibitor to ICT-CRT (NCT04557020) Another promising strategy to control the distant failures in locally advanced NPC, is to employ immunotherapy in the primary treatment. There are many ongoing trials exploring this strategy, mainly in China. However, the validity in endemic vs non-endemic regions should be taken with caution. Aim of the study In our proposal we are trying to compare the efficacy and tolerability of ICT followed by CRT with CRT followed ACT in locally advanced NPC

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nasopharyngeal Carcinoma
Keywords
Induction chemotherapy, neoadjuvant, adjuvant, non-metastatic, Nasopharyngeal Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Randomised controlled non-blinded
Masking
None (Open Label)
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Induction Arm
Arm Type
Experimental
Arm Description
patients will receive three cycles of IC Gemcitabin/Cisplatin followed by radical CRT
Arm Title
Adjuvant Arm
Arm Type
Active Comparator
Arm Description
Patients will receive radical CRT followed by three cycles of AC Gemcitabin/Cisplatin
Intervention Type
Drug
Intervention Name(s)
Gemcitabin/cisplatin
Intervention Description
chemotherapy combination
Primary Outcome Measure Information:
Title
Acute and late toxicity assessment
Description
Incidence of acute toxicity is calculated for each adverse event respectively, and severity evaluated on based of common terminology criteria for adverse event (CTCAE)
Time Frame
3-5 years
Title
Late radiation toxicity
Description
assessed using the radiation therapy oncology group and Europe organization for research and treatment of cancer late radiation morbidity scoring scheme
Time Frame
5-7 years
Title
Loco regional control rates (LCR)
Description
Defined as the time from the date of randomization to 1st failure in nasopharynx or neck lymph nodes
Time Frame
3-5 years
Title
Progression free survival (PFS)
Description
Defined as the time from the date of randomization to 1st failure locally or systemically
Time Frame
3-5 Years
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
Description
Defined as the time from the date of randomization to death from any cause
Time Frame
5 years
Title
Distance Metastasis free survival (DMFS)
Description
It is evaluated and calculated from the date of random assignment until date of first distance metastasis or until the date of last follow-up visit
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with newly histologically confirmed Nasopharyngeal carcinoma (according to World Health Organization (WHO) 2. The patient has stage III except T3N0 or IVA disease (according to 8th American Joint Committee on Cancer staging system) 3. WHO performance status 0-1 . 4. The patient must have achieved lawful age to provide informed consent according to local or national law . 5. Laboratory values performed within 14 days prior to concurrent chemotherapy should be as follows: i) Absolute neutrophil count (ANC) ≥ 1500/mm ii) Platelet count ≥ 100.000/mm iii) Hemoglobin ≥ 8g/dl iv) Urea and serum creatinine ≤ 1.5 mg/dl. (for cisplatin) v) Creatinine clearance ≥ 60 ml/min. (for cisplatin) vi) SGOT and SGPT ≤ 2 × upper limit of laboratory normal 6. Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy Exclusion Criteria: Age ≥70 or <18 The patient has evidence of distant metastatic disease. The patient has received prior systemic chemotherapy within the last three years. The patient has undergone previous surgery for the tumor, other than biopsy. The patient has received prior radiation therapy to the head or neck The patient is pregnant or breast feeding. The patient has a medical (e.g. renal impairment) or psychological condition that would not permit the patient to complete the trial or sign informed consent. Has known history of Human Immunodeficiency Virus (HIV) Has history of a diagnosed and/or treated hematologic or primary solid tumor malignancy, Has a history of severe hypersensitivity reaction to Cisplatin, Gemcitabine or radiotherapy or their analogs Unstable cardiac disease requiring treatment.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mustafa Alsherify, MD
Phone
55466285
Email
Mustafashawki@yahoo.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shereen Issa, MD
Organizational Affiliation
KCCC
Official's Role
Principal Investigator
Facility Information:
Facility Name
Kuwait Cancer Control Center
City
Kuwait
ZIP/Postal Code
11911
Country
Kuwait
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shereen Issa, MD
Phone
51167336
Email
shereenissa@gmail.com
First Name & Middle Initial & Last Name & Degree
Mustafa Elsherify, MD
Phone
55466285
Email
mustafashawki@yahoo.com
First Name & Middle Initial & Last Name & Degree
Mohamed Ashour, MD
First Name & Middle Initial & Last Name & Degree
Mustafa Elsherify, MD
First Name & Middle Initial & Last Name & Degree
Khaled Alsaleh, MD
First Name & Middle Initial & Last Name & Degree
Hamdy Sakr, MD
First Name & Middle Initial & Last Name & Degree
Amany Beshir, MD
First Name & Middle Initial & Last Name & Degree
Sudhan Rajan, MD
First Name & Middle Initial & Last Name & Degree
Eman Almoghazy, MD
First Name & Middle Initial & Last Name & Degree
Jitendra Shete, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30207593
Citation
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Results Reference
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Citation
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Citation
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Links:
URL
https://gco.iarc.fr/
Description
Globocan.fr. Accessed January 2020.
URL
http://www.bccancer.bc.ca/health-professionals/clinical-resources/cancer-drug-manual/drug-index
Description
chemotherapy protocols

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Induction Versus Adjuvant Gemcitabine/Cisplatin in Locally Advanced Non-metastatic Nasopharyngeal Carcinoma

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