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Toripalimab, Endostar Combined With Radiotherapy and Chemotherapy for Nasopharyngeal Carcinoma

Primary Purpose

Nasopharyngeal Carcinoma

Status

Not yet recruiting

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Toripalimab, Endostar Combined With Radiotherapy and Chemotherapy

IC＋CCRT

About this trial

This is an interventional treatment trial for Nasopharyngeal Carcinoma

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

With ECOG score 0-1.
Subjective aged 18-65 years, male or non-pregnant female.
Pathologically diagnosed as nasopharyngeal non-keratinizing carcinoma (differentiated or undifferentiated, i.e., the WHO type II or III).
Stage IVa (8th AJCC/UICC stage) T4 and/or N3, untreated patients with nasopharyngeal carcinoma.
Agreeing to provide previously stored tumor tissue samples or perform biopsy to collect tumor tissues, which were sent to the central laboratory for the PD-L1 IHC test.
Hematology: white blood cells ≥ 4000 /μL; neutrophils ≥ 2000 /μL; hemoglobin ≥ 9 g/dL; and platelets ≥ 100000 /μL.
Liver function: ALT and AST lower than the 1.5 times (1.5 × ) the upper limits of normal (ULN); and total bilirubin < 1.5 × ULN.
Renal function: serum creatinine < 1.5 × ULN.
Patients signing the informed consents, and willing and able to follow the study plan (visit and treatment plan), laboratory tests, and other research procedures.

Exclusion criteria:

Patients with nasopharyngeal carcinoma with recurrence and distant metastasis.
Pathologically diagnosed as keratinizing squamous cell carcinoma (WHO classification type I).
Patients who had undergone radiotherapy or systemic chemotherapy.
Pregnant or breastfeeding females, or females in fertility period while with no effective contraceptive measures.
Positive for HIV.
Having suffered from other malignant tumors (except for the cured basal cell carcinoma or cervical carcinoma in situ).
Having been treated with inhibitors of immune regulatory points (i.e., CTLA-4, PD-1, PD-L1, etc.).
With complications needing long-term application of immunosuppressive drugs, or systemic or local application of corticosteroids with immunosuppressive doses of comorbidities.
Patients with immunodeficiency diseases, or a history of organ transplantation (including but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, nephritis, hyperthyroidism, hypothyroidism; patients suffering from vitiligo, or asthma in childhood completely relieved, with no need of any intervention after adulthood could be included; and patients with asthma requiring bronchodilators for medical intervention could not be included).
With excessive usage of glucocorticoids within 4 weeks.
Whose laboratory examination values that did not meet the relevant standards within 7 days before participating in the research.
Patients with markedly reduced heart, liver, lung, kidney and/or bone marrow functions.
With serious and uncontrolled medical diseases and infections.
Using other test drugs or in other clinical trials.
Refusing or failing to sign the informed consent to participate in the trial.
With other treatment contraindications.
With personality or mental illness, with no or limited civil capacity.
Positive for hepatitis B surface antigen (HBsAg), and peripheral blood hepatitis B virus deoxyribonucleic acid (HBV DNA) ≥ 1000 cps/mL.
Patients positive for the HCV antibody test could only be included in this study with the negative results from the HCV RNA polymerase chain reaction test.
Unable to cooperate with regular follow-up due to psychological, social, family and geographical reasons.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

IC＋CCRT＋Toripalimab＋Endostar

IC＋CCRT

Arm Description

Three cycles of induction chemotherapy with GP regimen (Q3W): Gem 1000 mg/m2 d1,8; DDP 80mg/m2 d1, Q3W; IMRT (6-7 weeks, 5 times each week) combined with cisplatin for 2-3 cycles (Q3W): DDP 100 mg/m2, Q3W, 2-3 cycles; IMRT: GTVnx 70-74Gy/30-33f, 5d/w, 6-7 w; Toripalimab: 240 mg, Q3W, starting on D1, for totally 12 cycles; Endostar: 7.5 mg/m2/d, continuous intravenous pumping for 10 days, Q3W, starting on D1, for totally 5 cycles.

Outcomes

Primary Outcome Measures

progression-free survival, PFS

calculated from the date of randomisation to the date of the documented local or regional relapse, distant metastasis, or death from any cause, whichever occurred first. distant failure, or death from any cause, whichever occurred first.

Secondary Outcome Measures

Overall Survival，OS

the time from random assignment to death from any cause or censored at the date of last follow-up.

locoregional relapse-free Survival, LRFS

the time from random assignment to local or regional relapse.

Distant metastasis-free survival,DMFS

calculated from date of randomisation to the first distant failure

Overall response rate (ORR)

complete response (CR) + partial response (PR)

adverse events (AEs) and severe adverse events (SAE)

graded according to NCI CTCAE 5.0

Full Information

NCT ID

NCT04447326

First Posted

June 23, 2020

Last Updated

June 24, 2020

Sponsor

First Affiliated Hospital of Guangxi Medical University

Collaborators

Shandong Cancer Hospital and Institute, Wuhan Union Hospital, China, The Affiliated Hospital Of Guizhou Medical University, Xiangya Hospital of Central South University, Jiangxi Provincial Cancer Hospital, Zhejiang Cancer Hospital, Fourth Affiliated Hospital of Guangxi Medical University, LiuZhou People's Hospital, Guilin Medical College, Afﬁliated Hospital of North Sichuan Medical College

1. Study Identification

Unique Protocol Identification Number

NCT04447326

Brief Title

Toripalimab, Endostar Combined With Radiotherapy and Chemotherapy for Nasopharyngeal Carcinoma

Official Title

Randomized Controlled, Multicenter Phase II Clinical Research of Toripalimab (PD-1 Inhibitor) and Endostar Combined With Radiotherapy and Chemotherapy in the Treatment of High-risk Locally Advanced Nasopharyngeal Carcinoma

Study Type

Interventional

2. Study Status

Record Verification Date

June 2020

Overall Recruitment Status

Not yet recruiting

Study Start Date

June 2020 (Anticipated)

Primary Completion Date

June 2024 (Anticipated)

Study Completion Date

June 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

First Affiliated Hospital of Guangxi Medical University

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

5. Study Description

Brief Summary

This study is to investigate the efficacy and safety of the induction chemotherapy + concurrent chemoradiotherapy（CCRT）combined with toripalimab and endostar treatment, in comparison with the induction chemotherapy + concurrent chemoradiotherapy（CCRT）, in treating locally advanced high-risk nasopharyngeal carcinoma

Detailed Description

GP-induced chemotherapy combined with concurrent chemoradiotherapy is the standard treatment for the locally advanced nasopharyngeal carcinoma recommended by the guidelines. However, the prognosis for T4 and/or N3 nasopharyngeal carcinoma is still poor, with the 3-year PFS of about 70%. Therefore, it is of great importance to improve the prognosis of patients with locally advanced high-risk nasopharyngeal carcinoma. Immunotherapy has been an emerging treatment method for tumors in recent years. Compared with the chemotherapy, immunotherapy has less adverse reactions, and the effects could last longer, significantly improving the prognosis and patients' quality of life. Endostar, as a VEGFR inhibitor, has good safety in treating nasopharyngeal carcinoma. Related data have shown that PD-1 and Endostar exert synergistic antitumor effects in a mouse model of lung cancer. A Phase II multi-center clinical study from our center has shown that, for patients with locally advanced low-risk nasopharyngeal carcinoma, all the 3-year OS, PFS, and DMFS for the radiotherapy combined with Endostar group were superior to the concurrent chemoradiotherapy group, and the combination of radiotherapy and Endostar lead to significantly reduced adverse effects. In clinical studies concerning other solid tumors, it has also been observed that the PD-1 inhibitors combined with VEGFR inhibitors could significantly improve the efficacy, and achieve synergistic effects. Therefore, A Phase II，randomized, prospective, multicentric clinical trail was conducted to compare the efficacy and safety of induction chemotherapy and the concurrent chemoradiotherapy plus Endostar and PD-1, followed by PD-1 treatment for half a year compared with the induction chemotherapy and the concurrent chemoradiotherapy for the T4 and/or N3 nasopharyngeal carcinoma.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Nasopharyngeal Carcinoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

106 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

IC＋CCRT＋Toripalimab＋Endostar

Arm Type

Experimental

Arm Description

Arm Title

IC＋CCRT

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Toripalimab, Endostar Combined With Radiotherapy and Chemotherapy

Other Intervention Name(s)

JS001

Intervention Description

Toripalimab: 240 mg, Q3W, starting on D1, for totally 12 cycles Endostar: 7.5 mg/m2/d, continuous intravenous pumping for 10 days, Q3W, starting on D1, for totally 5 cycles

Intervention Type

Drug

Intervention Name(s)

IC＋CCRT

Intervention Description

IC＋CCRT

Primary Outcome Measure Information:

Title

progression-free survival, PFS

Description

Time Frame

3 years

Secondary Outcome Measure Information:

Title

Overall Survival，OS

Description

the time from random assignment to death from any cause or censored at the date of last follow-up.

Time Frame

3 years

Title

locoregional relapse-free Survival, LRFS

Description

the time from random assignment to local or regional relapse.

Time Frame

3 years

Title

Distant metastasis-free survival,DMFS

Description

calculated from date of randomisation to the first distant failure

Time Frame

3 years

Title

Overall response rate (ORR)

Description

complete response (CR) + partial response (PR)

Time Frame

3 months

Title

adverse events (AEs) and severe adverse events (SAE)

Description

graded according to NCI CTCAE 5.0

Time Frame

3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: With ECOG score 0-1. Subjective aged 18-65 years, male or non-pregnant female. Pathologically diagnosed as nasopharyngeal non-keratinizing carcinoma (differentiated or undifferentiated, i.e., the WHO type II or III). Stage IVa (8th AJCC/UICC stage) T4 and/or N3, untreated patients with nasopharyngeal carcinoma. Agreeing to provide previously stored tumor tissue samples or perform biopsy to collect tumor tissues, which were sent to the central laboratory for the PD-L1 IHC test. Hematology: white blood cells ≥ 4000 /μL; neutrophils ≥ 2000 /μL; hemoglobin ≥ 9 g/dL; and platelets ≥ 100000 /μL. Liver function: ALT and AST lower than the 1.5 times (1.5 × ) the upper limits of normal (ULN); and total bilirubin < 1.5 × ULN. Renal function: serum creatinine < 1.5 × ULN. Patients signing the informed consents, and willing and able to follow the study plan (visit and treatment plan), laboratory tests, and other research procedures. Exclusion criteria: Patients with nasopharyngeal carcinoma with recurrence and distant metastasis. Pathologically diagnosed as keratinizing squamous cell carcinoma (WHO classification type I). Patients who had undergone radiotherapy or systemic chemotherapy. Pregnant or breastfeeding females, or females in fertility period while with no effective contraceptive measures. Positive for HIV. Having suffered from other malignant tumors (except for the cured basal cell carcinoma or cervical carcinoma in situ). Having been treated with inhibitors of immune regulatory points (i.e., CTLA-4, PD-1, PD-L1, etc.). With complications needing long-term application of immunosuppressive drugs, or systemic or local application of corticosteroids with immunosuppressive doses of comorbidities. Patients with immunodeficiency diseases, or a history of organ transplantation (including but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, nephritis, hyperthyroidism, hypothyroidism; patients suffering from vitiligo, or asthma in childhood completely relieved, with no need of any intervention after adulthood could be included; and patients with asthma requiring bronchodilators for medical intervention could not be included). With excessive usage of glucocorticoids within 4 weeks. Whose laboratory examination values that did not meet the relevant standards within 7 days before participating in the research. Patients with markedly reduced heart, liver, lung, kidney and/or bone marrow functions. With serious and uncontrolled medical diseases and infections. Using other test drugs or in other clinical trials. Refusing or failing to sign the informed consent to participate in the trial. With other treatment contraindications. With personality or mental illness, with no or limited civil capacity. Positive for hepatitis B surface antigen (HBsAg), and peripheral blood hepatitis B virus deoxyribonucleic acid (HBV DNA) ≥ 1000 cps/mL. Patients positive for the HCV antibody test could only be included in this study with the negative results from the HCV RNA polymerase chain reaction test. Unable to cooperate with regular follow-up due to psychological, social, family and geographical reasons.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

rensheng wang, Ph.D

Phone

86-771-5356509

13807806008@163.com

First Name & Middle Initial & Last Name or Official Title & Degree

min kang, Ph.D

Phone

86-771-5356509

km1019@163.com

12. IPD Sharing Statement

Citations:

PubMed Identifier

30610791

Citation

Zhang S, Huang X, Zhou L, Wu G, Lin J, Yang S, Chen J, Lin S. An open-label, single-arm phase II clinical study of induction chemotherapy and sequential Nimotuzumab combined with concurrent chemoradiotherapy in N3M0 stage nasopharyngeal carcinoma. J BUON. 2018 Nov-Dec;23(6):1656-1661.

Results Reference

background

PubMed Identifier

28837405

Citation

Hsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, Mehnert JM, Algazi A, van Brummelen EMJ, Saraf S, Thanigaimani P, Cheng JD, Hansen AR. Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol. 2017 Dec 20;35(36):4050-4056. doi: 10.1200/JCO.2017.73.3675. Epub 2017 Aug 24.

Results Reference

background

PubMed Identifier

29584545

Citation

Ma BBY, Lim WT, Goh BC, Hui EP, Lo KW, Pettinger A, Foster NR, Riess JW, Agulnik M, Chang AYC, Chopra A, Kish JA, Chung CH, Adkins DR, Cullen KJ, Gitlitz BJ, Lim DW, To KF, Chan KCA, Lo YMD, King AD, Erlichman C, Yin J, Costello BA, Chan ATC. Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol. 2018 May 10;36(14):1412-1418. doi: 10.1200/JCO.2017.77.0388. Epub 2018 Mar 27. Erratum In: J Clin Oncol. 2018 Aug 1;36(22):2360.

Results Reference

background

PubMed Identifier

32035692

Citation

Li Y, Tian Y, Jin F, Wu W, Long J, Ouyang J, Zhou Y. A phase II multicenter randomized controlled trial to compare standard chemoradiation with or without recombinant human endostatin injection (Endostar) therapy for the treatment of locally advanced nasopharyngeal carcinoma: Long-term outcomes update. Curr Probl Cancer. 2020 Feb;44(1):100492. doi: 10.1016/j.currproblcancer.2019.06.007. Epub 2019 Jul 2.

Results Reference

background

PubMed Identifier

29924009

Citation

Kang M, Wang F, Liao X, Zhou P, Wang R. Intensity-modulated radiotherapy combined with endostar has similar efficacy but weaker acute adverse reactions than IMRT combined with chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma. Medicine (Baltimore). 2018 Jun;97(25):e11118. doi: 10.1097/MD.0000000000011118.

Results Reference

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Toripalimab, Endostar Combined With Radiotherapy and Chemotherapy for Nasopharyngeal Carcinoma

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