Clinical Trials List
Protocol NumberONO-4538-66/CA2099TM
NCT Number(ClinicalTrials.gov Identfier)NCT03349710
2018-03-01 - 2022-12-13
Phase III
Not yet recruiting1
Terminated3
ICD-10C44.42
Squamous cell carcinoma of skin of scalp and neck
A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Nivolumab or Nivolumab plus Cisplatin, in Combination with Radiotherapy in Participants with Cisplatin Ineligible and Cisplatin Eligible Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN).
-
Trial Applicant
PPD DEVELOPMENT (HK) LIMITED
-
Sponsor
ONO Pharmaceutical Co., Ltd.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 吳沅樺 Division of Radiation Therapy
- Shang-Yin Wu Division of Hematology & Oncology
- 蔡牧宏 Division of Radiation Therapy
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Co-Principal Investigator
- Ming-Hung Tsai Division of Hematology & Oncology
- Yao-Ching Wang Division of Hematology & Oncology
- Shih-Neng Yang Division of Hematology & Oncology
- Ming-Yu Lien Division of Hematology & Oncology
- Chi-Ching Chen Division of Hematology & Oncology
- Ying-Chun Lin Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
Audit
None
Audit
None
Linkou Chang Gung Medical Foundation
Taiwan National PI
王宏銘
Co-Principal Investigator
Audit
None
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Not yet recruiting
Audit
None
Condition/Disease
Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Objectives
Primary
Cohort 1: cisplatin-ineligible participants
To compare the event free survival (EFS) of nivolumab in
combination with radiotherapy (RT) to that of cetuximab in
combination with RT in participants with locally advanced
squamous cell carcinoma of the head and neck (SCCHN) who are
ineligible for cisplatin based chemoradiotherapy (CRT)
Cohort 2: cisplatin-eligible participants
To compare the EFS of nivolumab plus cisplatin in combination with
RT to that of cisplatin alone in combination with RT, in participants
with locally advanced SCCHN who are eligible for cisplatin based
CRT
Test Drug
Nivolumab
Active Ingredient
Nivolumab
Dosage Form
Solution for Injection
Dosage
100 mg/Vial (10 mg/mL)
Endpoints
The primary endpoint in both cohorts is EFS. EFS is defined as the time from randomization to radiographic progression, as
determined by a Blinded Independent Central Review (BICR) using RECIST 1.1 (Appendix 10) or, for participants who do not have radiographic progression, the time from randomization to death. (See Section 10.3, Endpoints, for details.);
determined by a Blinded Independent Central Review (BICR) using RECIST 1.1 (Appendix 10) or, for participants who do not have radiographic progression, the time from randomization to death. (See Section 10.3, Endpoints, for details.);
Inclution Criteria
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be obtained
before the performance of any protocol related procedures that are not part of normal
participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule,
and laboratory testing.
2) Type of Participant and Target Disease Characteristics
a) Histologically proven squamous cell carcinoma of the head and neck (SCCHN) from one
of the following primary sites: oral cavity, oropharynx, hypopharynx, and larynx
b) Locally advanced disease which is unresectable, or resectable but suitable for an organ
sparing approach
c) No previous radiotherapy or systemic treatment for SCCHN
d) Eastern cooperative oncology group (ECOG) score of 0-1 (Appendix 7)
e) Measurable disease by RECIST1.1 (Appendix 10) criteria, and tumor assessment
performed prior to randomization
f) Sufficient sample of fresh or archival (< 3 months from informed consent date) formalinfixed, paraffin-embedded (FFPE) tissue block, or unstained tumor tissue sections, with an
associated pathology report, must be submitted for biomarker evaluation for PD-L1 status.
Central lab must provide Interactive Response Technology (IRT) with confirmation of
receipt of evaluable tumor tissue prior to randomization. Biopsy should be excisional,
incisional or core needle. Fine needle or aspiration is unacceptable for submission. PD-L1
status must be available prior to randomization.
g) HPV p16 test result available (performed locally or centrally) for participants with
oropharyngeal disease
h) Patients must be of intermediate or high risk categories*:
i) High risk:
(1) Oral cavity, hypopharynx, larynx, oropharynx (p16 negative): Stage III/IV
(2) Oropharynx (p16 positive): Stage III (T4 any N or T1-3 N3) - irrespective of
smoking status.
ii) Intermediate risk:
(1) Oropharynx (p16 positive): T3 N0-2 or T1-3 N2 disease if smoking > 20 pack year
history
*TNM clinical staging according to AJCC version 8 (Appendix 6).
3) Cohort 1 (cisplatin ineligible) Specific Inclusion Criteria (Arms A and Arm B)
a) Physician assesses participant to be non-eligible for treatment with platinum based
combined CRT. This must be for one or more of the following reasons:
i) Age ≥ 70 years at enrolment
ii) Creatinine clearance < 60mL/min and > 30mL/min (using the Cockcroft and Gault
formula– see below**)
iii) Severe hearing loss (minimal hearing threshold of 80 dB or more in either ear)
4) Cohort 2 (cisplatin eligible) Specific Inclusion Criteria (Arm C and Arm D)
a) Adequate renal function within 28 days prior to randomization as follows:
i) Creatinine clearance ≥ 60 mL/min. as determined by 24 hour collection or estimated
by Cockcroft-Gault formula:
Creatinine Clearance = [(140 - age) x (wt in kg)
Serum Cr mg/dL x 72**
**Participants aged ≥ 70 years may enter either Cohort 1 or 2 dependent on whether the physician’s assessment is that
the participant is eligible for cisplatin (Cohort 2) or ineligible for cisplatin (Cohort 1) based on their age. It is
anticipated that in the majority of cases, patients aged ≥ 70 years will be considered ineligible for cisplatin and enter
cohort 1.
5) Age and Reproductive Status
a) Males and Females > ages 18 or age of majority
b) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours
prior to the start of study treatment.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for
method(s) of contraception for the duration of study treatment with nivolumab and
5 months after the last dose of study treatment {i.e., 30 days (duration of ovulatory cycle)
plus the time required for the investigational drug to undergo approximately five halflives.}
e) Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of study treatment with nivolumab and
7 months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover)
plus the time required for the investigational drug to undergo approximately five halflives.}.
f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are
continuously not heterosexually active are also exempt from contraceptive requirements,
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP,
on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise on the use of highly effective methods of contraception (Appendix 4)
which have a failure rate of < 1% when used consistently and correctly.
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be obtained
before the performance of any protocol related procedures that are not part of normal
participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule,
and laboratory testing.
2) Type of Participant and Target Disease Characteristics
a) Histologically proven squamous cell carcinoma of the head and neck (SCCHN) from one
of the following primary sites: oral cavity, oropharynx, hypopharynx, and larynx
b) Locally advanced disease which is unresectable, or resectable but suitable for an organ
sparing approach
c) No previous radiotherapy or systemic treatment for SCCHN
d) Eastern cooperative oncology group (ECOG) score of 0-1 (Appendix 7)
e) Measurable disease by RECIST1.1 (Appendix 10) criteria, and tumor assessment
performed prior to randomization
f) Sufficient sample of fresh or archival (< 3 months from informed consent date) formalinfixed, paraffin-embedded (FFPE) tissue block, or unstained tumor tissue sections, with an
associated pathology report, must be submitted for biomarker evaluation for PD-L1 status.
Central lab must provide Interactive Response Technology (IRT) with confirmation of
receipt of evaluable tumor tissue prior to randomization. Biopsy should be excisional,
incisional or core needle. Fine needle or aspiration is unacceptable for submission. PD-L1
status must be available prior to randomization.
g) HPV p16 test result available (performed locally or centrally) for participants with
oropharyngeal disease
h) Patients must be of intermediate or high risk categories*:
i) High risk:
(1) Oral cavity, hypopharynx, larynx, oropharynx (p16 negative): Stage III/IV
(2) Oropharynx (p16 positive): Stage III (T4 any N or T1-3 N3) - irrespective of
smoking status.
ii) Intermediate risk:
(1) Oropharynx (p16 positive): T3 N0-2 or T1-3 N2 disease if smoking > 20 pack year
history
*TNM clinical staging according to AJCC version 8 (Appendix 6).
3) Cohort 1 (cisplatin ineligible) Specific Inclusion Criteria (Arms A and Arm B)
a) Physician assesses participant to be non-eligible for treatment with platinum based
combined CRT. This must be for one or more of the following reasons:
i) Age ≥ 70 years at enrolment
ii) Creatinine clearance < 60mL/min and > 30mL/min (using the Cockcroft and Gault
formula– see below**)
iii) Severe hearing loss (minimal hearing threshold of 80 dB or more in either ear)
4) Cohort 2 (cisplatin eligible) Specific Inclusion Criteria (Arm C and Arm D)
a) Adequate renal function within 28 days prior to randomization as follows:
i) Creatinine clearance ≥ 60 mL/min. as determined by 24 hour collection or estimated
by Cockcroft-Gault formula:
Creatinine Clearance = [(140 - age) x (wt in kg)
Serum Cr mg/dL x 72**
**Participants aged ≥ 70 years may enter either Cohort 1 or 2 dependent on whether the physician’s assessment is that
the participant is eligible for cisplatin (Cohort 2) or ineligible for cisplatin (Cohort 1) based on their age. It is
anticipated that in the majority of cases, patients aged ≥ 70 years will be considered ineligible for cisplatin and enter
cohort 1.
5) Age and Reproductive Status
a) Males and Females > ages 18 or age of majority
b) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours
prior to the start of study treatment.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for
method(s) of contraception for the duration of study treatment with nivolumab and
5 months after the last dose of study treatment {i.e., 30 days (duration of ovulatory cycle)
plus the time required for the investigational drug to undergo approximately five halflives.}
e) Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of study treatment with nivolumab and
7 months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover)
plus the time required for the investigational drug to undergo approximately five halflives.}.
f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are
continuously not heterosexually active are also exempt from contraceptive requirements,
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP,
on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise on the use of highly effective methods of contraception (Appendix 4)
which have a failure rate of < 1% when used consistently and correctly.
Exclusion Criteria
Exclusion Criteria
1) Medical Conditions
a) Carcinoma originating in the nasopharynx or paranasal sinus, squamous cell carcinoma
that originated from the skin and salivary gland or non-squamous histology (e.g., mucosal
melanoma), squamous cell carcinoma of unknown primary
b) Clinical or radiological evidence of metastatic disease
c) Prior radiotherapy that overlaps with radiation fields
d) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may
increase the risk associated with study participation or study drug administration, impair
the ability of the participant to receive protocol therapy, or interfere with the interpretation
of study results
e) Active unstable angina and/or congestive heart failure
f) Myocardial infarction within 6 months prior to randomization
g) Participants who have a weight loss of > 10% of body weight between start of screening
period and randomization will be considered a screen failure
h) Participants with an active, known or suspected autoimmune disease. Participants with type
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not
expected to recur in the absence of an external trigger are permitted to enroll.
2) Prior/Concomitant Therapy
a) Participants with a condition requiring systemic treatment with either corticosteroids
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
autoimmune disease.
b) Treatment with botanical preparations (eg herbal supplements or traditional Chinese
medicines) intended for general health support or to treat the disease under study within 4
weeks prior to randomization/treatment.
3) Physical and Laboratory Test Findings
a) Screening laboratory values should be obtained within 14 days prior to first dose, the below
values are exclusionary:
i) Neutrophils < 1500/µL
ii) Platelets < 100 x103
/µL
iii) Hemoglobin < 9.0 g/dL
iv) AST/ALT: > 3.0 x ULN
v) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have
a total bilirubin level of < 3.0 x ULN)
b) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of
virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C
antibody (anti-HCV) positive (except if HCV-RNA negative).
c) Known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed
at sites where mandated locally.
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific
circumstances a person who has been imprisoned may be included as a participant. Strict
conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical
(e.g., infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study
participants and that the results of the study can be used. It is imperative that participants fully
meet all eligibility criteria.
1) Medical Conditions
a) Carcinoma originating in the nasopharynx or paranasal sinus, squamous cell carcinoma
that originated from the skin and salivary gland or non-squamous histology (e.g., mucosal
melanoma), squamous cell carcinoma of unknown primary
b) Clinical or radiological evidence of metastatic disease
c) Prior radiotherapy that overlaps with radiation fields
d) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may
increase the risk associated with study participation or study drug administration, impair
the ability of the participant to receive protocol therapy, or interfere with the interpretation
of study results
e) Active unstable angina and/or congestive heart failure
f) Myocardial infarction within 6 months prior to randomization
g) Participants who have a weight loss of > 10% of body weight between start of screening
period and randomization will be considered a screen failure
h) Participants with an active, known or suspected autoimmune disease. Participants with type
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not
expected to recur in the absence of an external trigger are permitted to enroll.
2) Prior/Concomitant Therapy
a) Participants with a condition requiring systemic treatment with either corticosteroids
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
autoimmune disease.
b) Treatment with botanical preparations (eg herbal supplements or traditional Chinese
medicines) intended for general health support or to treat the disease under study within 4
weeks prior to randomization/treatment.
3) Physical and Laboratory Test Findings
a) Screening laboratory values should be obtained within 14 days prior to first dose, the below
values are exclusionary:
i) Neutrophils < 1500/µL
ii) Platelets < 100 x103
/µL
iii) Hemoglobin < 9.0 g/dL
iv) AST/ALT: > 3.0 x ULN
v) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have
a total bilirubin level of < 3.0 x ULN)
b) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of
virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C
antibody (anti-HCV) positive (except if HCV-RNA negative).
c) Known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed
at sites where mandated locally.
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific
circumstances a person who has been imprisoned may be included as a participant. Strict
conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical
(e.g., infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study
participants and that the results of the study can be used. It is imperative that participants fully
meet all eligibility criteria.
The Estimated Number of Participants
-
Taiwan
26 participants
-
Global
1046 participants
