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Clinical Trials List

Protocol NumberD4190C00006
NCT Number(ClinicalTrials.gov Identfier)NCT02000947

2016-01-31 - 2017-02-10

Phase I

Not yet recruiting1

Terminated7

ICD-10C34

Malignant neoplasm of bronchus and lung

ICD-9162.9

Malignant neoplasm of bronchus and lung, unspecified

A dose-escalation and dose-expansion study of MEDI4736 (a monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1)) will evaluate the safety, tolerability, PK, IM, and antitumor activity of MEDI4736 in adult patients with solid tumors. A dose exploration cohort will look at the safety profile of Q4W dosing of MEDI4736.

  • Trial Applicant

    ICON Clinical Research Pte Ltd

  • Sponsor

    MedImmune, LLC, a wholly owned subsidiary of AstraZeneca PLC

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2025/08/20

Investigators and Locations

Principal Investigator Inn-Wen Chong Division of Thoracic Medicine
Kaohsiung Municipal Gangshan Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Not yet recruiting

Audit

None

Principal Investigator Gee-chen Chang Division of Thoracic Medicine
Taichung Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Stop recruiting

Principal Investigator Yuh-Min Chen Division of Thoracic Medicine
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Stop recruiting

Audit

None

Principal Investigator Wu-Chou Su Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Stop recruiting

Audit

None

Principal Investigator Inn-Wen Chong Division of Thoracic Medicine
Kaohsiung Medical Univeristy Chung-Ho Memorial Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Stop recruiting

Principal Investigator
CHANGHUA CHRISTIAN HOSPITAL

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Stop recruiting

Principal Investigator HsingJin Eugene Liu Division of Hematology & Oncology
Taipei WanFang Hospital (Managed by Taipei Medical Univeristy)

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Stop recruiting

Principal Investigator James Chih-Hsin Yang Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Stop recruiting

Audit

None

Condition/Disease

NSCLC

Objectives

Primary Objectives (Dose-escalation phase): • To determine the maximum tolerated dose (MTD) or the highest protocol-defined dose for each agent in the absence of exceeding the MTD • To determine the safety profile of MEDI4736 in combination with tremelimumab in subjects with advanced NSCLC using every 2 weeks (Q2W) and every 4 weeks (Q4W) dosing schedules. Primary Objectives (Dose-expansion phase): • Cohort A: To determine the safety profile of MEDI4736 in combination with tremelimumab at the recommended dose using Q4W dosing schedule administered in subjects with treatment-naïve, nonepidermal growth factor receptor (EGFR) mutation positive/non-anaplastic lymphoma kinase (ALK) rearrangement positive, advanced NSCLC. • Cohort B (sequential administration): To determine antitumor activity of MEDI4736 in combination with tremelimumab at the recommended dose using Q4W dosing schedule in subjects who have received 1 prior line of treatment for immunotherapy naïve, non-EGFR mutation positive/ non-ALK rearrangement positive, PD-L1-negative advanced non-squamous NSCLC using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR). • Cohort B (co-administration): To determine the safety profile of MEDI4736 in combination with tremelimumab at the recommended dose using the Q4W dosing schedule co-administered in subjects previously treated with 1 or 2 prior lines of anticancer therapy for advanced NSCLC. • Cohort C: To determine the safety profile of MEDI4736 in combination with tremelimumab at the recommended dose using the Q4W dosing schedule administered to subjects with advanced NSCLC who have received up to 3 prior lines of systemic therapy (including immunotherapy) and failed PD-1/PD-L1 monotherapy. • Cohort C: To determine antitumor activity of MEDI4736 in combination with tremelimumab at the recommended dose using Q4W dosing schedule administered to subjects with advanced NSCLC who have received up to 3 prior lines of systemic therapy (including immunotherapy) and failed PD-1/PD-L1 monotherapy using RECIST v1.1 as determined by BICR. • Dose-expansion Cohorts: To evaluate the safety profile of MEDI4736 monotherapy in subjects who have experienced immune-related AEs after discontinuing MEDI4736 in combination with tremelimumab.

Test Drug

MEDI4736 & Tremelimumab

Active Ingredient

MEDI4736
Tremelimumab

Dosage Form

vial

Dosage

500 mg/vial
400 mg/vial

Endpoints

Primary Endpoints:
• Dose-escalation phase: MTD, which is the highest dose where no more than 1 of 6 subjects within a cohort
experience dose-limiting toxicities (DLTs) or the highest protocol-defined dose for each agent in the
absence of exceeding the MTD.
• Dose-escalation, Cohort A, Cohort B (co-administration) and Cohort C: The endpoints for safety will
include adverse events (AEs), serious adverse events (SAEs), laboratory evaluations, vital signs, physical
examinations, and electrocardiogram (ECG) results.
• Cohort B (sequential administration) and Cohort C: Objective response (OR) as determined by BICR based
on RECIST v1.1.

Inclution Criteria

Inclusion Criteria
Subjects must meet all of the following criteria:
1. Age ≥ 18 years at the time of screening
2. Histologically confirmed locally advanced or metastatic NSCLC (squamous and nonsquamous; according to International Association for the Study of Lung Cancer [IASLC]
Staging Manual in Thoracic Oncology v7; IASLC Staging Manual in Thoracic Oncology,
2010)
3. For the dose-escalation phase and expansion Cohorts A and B, subjects must have no
prior exposure to immunotherapy (prior exposure to immunotherapy, including, but not
limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1 MAbs, cell-based therapies, or
cancer vaccines)
4. Eastern Cooperative Oncology Group performance status of 0 or 1
5. Subjects must have at least 1 measurable lesion according to RECIST v1.1. For Cohort B,
the presence of measurable disease must have been confirmed by BICR prior to dosing
(sequential dosing subjects only). A previously irradiated lesion can be considered a
target lesion if the lesion is well defined, measurable per RECIST v1.1, and there is
objective evidence of interval increase in size.
6. Dose escalation: Able and willing to give valid written consent for available archival
tumor samples (fresh tumor biopsies if archival tumor biopsy is not available). Subjects
in any given dose-escalation cohort who are enrolled beyond the initial 6 subjects will be
required to have fresh tumor biopsies (see Section 4.3.2.2). Biopsies should be obtained
preferentially from safely accessible sites (as determined by the investigator) using
low-risk procedures and should not be target lesions, unless there are no other lesions
suitable for biopsy. Fine-needle aspirate specimens are not acceptable.
NOTE: Subjects who require a fresh tumor biopsy must provide the biopsy during
screening or provide an available tumor sample taken ≤ 3 months prior to screening.
Tumor lesions used for fresh biopsies should not be target lesions, unless there are no
other lesions suitable for biopsy. Fine needle aspirate specimens are not acceptable.
7. Dose expansion: All subjects must consent to and have at least 1 lesion amenable to
biopsy at screening. Biopsies should be obtained from safely accessible sites (as
determined by the investigator) using low-risk procedures. Tumor lesions used for biopsy
should not be lesions used as target lesions as determined by RECIST v1.1.
8. Dose escalation: Subjects in the dose-escalation phase must have either failed to respond
to or relapsed after, declined, were unable to tolerate, or were not eligible for standard
treatment. Subjects cannot have had more than 3 prior lines of therapy in metastatic
NSCLC. The 3 prior lines included standard and investigational agents.
9. Dose-expansion phase: Subjects must meet eligibility for any of the cohorts below:
a. Cohort A: be treatment-naïve with non-EGFR mutation or non-ALK rearrangement
positive tumors
i. PD-L1 expression status (positive or negative) must be established during
screening prior to dosing. Subjects with undetermined status will not be permitted
to initiate study therapy until PD-L1 expression status has been established by a
repeat assay on available tissue or by another biopsy. To ensure enrollment of
20 PD-L1-positive and 20 PD-L1-negative subjects, subjects may be excluded
based on PD-L1 status.
NOTE: Prior platinum-containing adjuvant, neoadjuvant, or definitive
chemoradiation therapy given for locally advanced disease is considered first-line
therapy only if recurrent (local or metastatic) disease developed within 6 months
of completing therapy.
b. For Cohort B:
i. Subjects must have at least 1 measurable lesion according to RECIST v1.1 that
has been confirmed by BICR prior to dosing.
ii. Subjects must have non-squamous NSCLC and have documented radiographic
progression after one prior line of platinum-based therapy in the metastatic setting
and be immunotherapy naïve. Subjects with EGFR-activating mutations and
subjects with ALK rearrangement positive tumors are excluded. Patients with
known sensitizing EGFR-mutation or ALK-rearrangement are excluded. All
subjects must be tested for wild-type for EGFR Exon 19 deletions and Exon 21
L858R mutation (by IHC or sequencing) and ALK (by IHC, fluorescence in-situ
hybridization [FISH], or sequencing) in a Clinical Laboratory Improvement
Amendments (CLIA) certified lab in the USA. Countries outside the USA must
use one of the methods mentioned for EGFR mutation and ALK rearrangement
testing that has regulatory approval in the country the subject is being enrolled.
iii. PD-L1 expression status (positive or negative) must be established during
screening prior to dosing. Subjects with undetermined status will not be permitted
to initiate study therapy until PD-L1 expression status has been established by a
repeat assay on available tissue or by another biopsy.
c. Cohort C: Must be either refractory or relapsed while receiving anti-PD-1 or
anti-PD-L1 monotherapy, meet discontinuation criteria due to PD, and meet all of the
criteria below:
i. Refractory: Subjects must have documented radiographic disease progression
≤ 16 weeks from the start of treatment with no evidence of clinical benefit
(ie, CR, PR or SD on any scan) while receiving monotherapy treatment with an
anti-PD-1 or anti-PD-L1 antibody
or
Relapsed: Following initial clinical benefit (ie, CR, PR or SD on any scan),
subjects must have documented radiographic disease progression while receiving
monotherapy treatment with an anti-PD-1 or anti-PD-L1 antibody.
ii. Subjects must not have received more than 3 prior lines of therapy in the
metastatic setting including anti-PD-1 or anti-PD-L1 monotherapy. The 3 prior
lines include standard and investigational agents. Subjects who are EGFR
mutation and ALK rearrangement positive must have failed a platinum based
regimen. Subjects with EGFR sensitizing mutations must have received an EGFR
tyrosine kinase inhibitor (TKI) and subjects with ALK rearrangement positive
tumors must have received an ALK TKI. The subject must not have had
symptomatic progression (clinical deterioration) that led to treatment
discontinuation (only applicable to the prior PD-1/PD-L1 therapy).
iii. Must not have had intervening systemic therapy between prior anti-PD-1 or
anti-PD-L1 treatment and start of study treatment.
iv. The interval between the last dose of anti-PD1 or anti-PD-L1 therapy and the first
dose of the study regimen should be at least 14 days.
v. Must not have experienced a toxicity that led to permanent discontinuation of
prior immunotherapy.
vi. All AEs while receiving prior immunotherapy must have completely resolved or
resolved to baseline prior to screening for this study.
vii. Must not have experienced a ≥ Grade 3 AE or a neurologic or ocular AE of any
grade while receiving prior immunotherapy.
NOTE: Subjects with endocrine AE of ≤ Grade 2 are permitted to enroll if they
are stably maintained on appropriate replacement therapy and are asymptomatic.
viii. Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of
an AE if re-challenged, and not currently require maintenance doses of > 10 mg
prednisone or equivalent per day.
10. Adequate organ and marrow function (subjects must not have received transfusions or
growth factor support within 28 days prior to first dose), as defined below:
a. Hemoglobin ≥ 9 g/dL
b. Absolute neutrophil count ≥ 1,500/mm3
c. Platelet count ≥ 100,000/mm3
d. Total bilirubin ≤ 1.5 × ULN except subjects with documented Gilbert’s syndrome
(> 3 × ULN) or liver metastasis, who must have a baseline total bilirubin ≤ 3.0 mg/dL
e. Alanine aminotransferase and AST ≤ 2.5 × ULN; for subjects with hepatic
metastases, ALT and AST ≤ 5 × ULN
f. Serum creatinine ≤ 2.0 mg/dL
11. At the time of Day 1 of the study, subjects with central nervous system (CNS) metastases
must have been treated and must be asymptomatic and meet the following:
a. No concurrent treatment, inclusive of but not limited to surgery, radiation, and/or
corticosteroids
b. Neurologic stability (lack of signs or symptoms greater than baseline prior to XRT)
until the time of dosing of MEDI4736 and tremelimumab
c. For radiation treatment:
i. At least 14 days between last day of stereotactic radiosurgery or gamma-knife
treatment and Day 1 of protocol treatment
At least 28 days between last day of whole brain radiation therapy and Day 1 of
protocol treatment
d. At least 14 days since last dose of corticosteroids and Day 1 of protocol treatment
e. Note: Subjects with leptomeningeal disease or cord compression are excluded from
the study.
12. Written informed consent and any locally required authorization (eg, Health Insurance
Portability and Accountability Act in the USA or Data Privacy Directive in the European
Union obtained from the subject/legal representative prior to performing any protocolrelated procedures, including screening evaluations). However, if evaluations performed
for other purposes prior to obtaining informed consent are considered standard of care,
are suitable for screening and occurred within 7 days prior to starting treatment (or for
scans, within 28 days prior to starting treatment), those evaluations do not need to be
repeated if the subject consents to their use.
13. Females of childbearing potential who are sexually active with a non-sterilized male
partner must have used at least one highly effective method of contraception from the
time of screening, and must agree to continue using such precautions for 180 days after
the final dose of investigational product. It is strongly recommended for the male partner
of a female subject to also use male condom plus spermicide throughout this period.
Cessation of contraception after this point should be discussed with a responsible
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not
acceptable methods of contraception. They must also refrain from egg cell donation for
180 days after the final dose of investigational product;
a. Females of childbearing potential are defined as those who are not surgically sterile
(ie, surgical sterilization includes bilateral tubal ligation, bilateral oophorectomy, or
complete hysterectomy) or those who are not postmenopausal (defined as 12 months
with no menses with postmenopausal gonadotropin levels, luteinizing hormone and
follicle-stimulating hormone, or postmenopausal estradiol levels within the
postmenopausal range according to local guidelines without an alternative medical
cause).
b. A highly effective method of contraception is defined as one that results in a low
failure rate (ie, less than 1% per year) when used consistently and correctly. The
acceptable methods of contraception are described in Table 4.1.2-1.
14. Non-sterilized male subjects who are sexually active with a female partner of
childbearing potential must use male condom with spermicide from Day 1 through
180 days after receipt of the final dose of investigational product. It is strongly
recommended for the female partner of a male subject to also use a highly effective
method of contraception throughout this period, as described in Table 4.1.2-1. In
addition, they must refrain from sperm donation for 180 days after the final dose of
investigational product.

Exclusion Criteria

Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. Concurrent enrollment in another clinical study, unless in a follow-up period or it is an
observational study
2. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for
diabetes and hormone replacement therapy) is acceptable.
(NOTE: Local treatment of isolated lesions for palliative intent is acceptable [eg, by local
surgery or radiotherapy])
3. Any investigational anticancer therapy received within 28 days prior to the first dose of
MEDI4736 and tremelimumab. Anti-PD-1 and anti-PD-L1 agents will be permitted for
Cohort C provided the interval between the last dose of anti-PD-1 or anti-PD-L1 therapy
and the first dose of the study regimen is at least 14 days.
4. Major surgical procedure (as defined by the investigator) within 28 days prior to the first
dose of MEDI4736 and tremelimumab or still recovering from prior surgery
5. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to
NCI CTCAE v4.03 Grade 0 or 1 with the exceptions of alopecia, laboratory values listed
per the inclusion criteria, and endocrine AEs that are stably maintained on appropriate
replacement therapy and are asymptomatic. Subjects with irreversible toxicity that is not
reasonably expected to be exacerbated by MEDI4736 and tremelimumab may be
included (eg, hearing loss) after consultation with the medical monitor
6. Current or prior use of immunosuppressive medication within 14 days before the first
dose of MEDI4736 and tremelimumab with the exceptions of intranasal and inhaled
corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day
of prednisone or equivalent
7. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac
disease, irritable bowel disease; Wegner syndrome) within the past 2 years. Subjects with
vitiligo, alopecia, Grave’s disease, or psoriasis not requiring systemic treatment (within
the past 3 years) are not excluded.
8. History of primary immunodeficiency or solid or allogeneic transplant
9. True positive test results for human immunodeficiency virus (HIV), or hepatitis B, or C
10. Receipt of live, attenuated vaccine within 30 days prior to the first dose of MEDI4736
and tremelimumab
11. Females who are pregnant, lactating, or intend to become pregnant during their
participation in the study
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection,
current pneumonitis, symptomatic congestive heart failure, uncontrolled hypertension,
unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric
illness/social situations that would limit compliance with study requirements or
compromise the ability of the subject to give written informed consent
13. Other invasive malignancies within 2 years. Noninvasive malignancies such as cervical
carcinoma in situ, non-melanomatous carcinoma of the skin, or ductal carcinoma in situ
of the breast that has/have been surgically cured are allowed
14. Known allergy or hypersensitivity to study drug formulations
15. Any condition that, in the opinion of the investigator or sponsor, would interfere with
evaluation of the investigational product or interpretation of subject safety or study
results

The Estimated Number of Participants

  • Taiwan

    12 participants

  • Global

    418 participants

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