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Submitted by: Ranelle Lou Dorado 2018-06-01 00:00:00 Last Updated by: Ranelle Lou Dorado 2020-05-18 16:50:56


A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab Given Concurrently with Platinum-based Chemoradiation Therapy in Patients with Locally Advanced, Unresectable Non-small Cell Lung Cancer (Stage III)

PHRR180601-001840

D933KC00001

2018-CT0442

A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab Given Concurrently with Platinum-based Chemoradiation Therapy in Patients with Locally Advanced, Unresectable Non-small Cell Lung Cancer (Stage III) (PACIFIC 2)

This is a Phase III, randomized, double-blind, placebo-controlled, multi-center, international study assessing the efficacy and safety of durvalumab given concurrently with platinum-based CRT (durvalumab + standard of care [SoC] CRT) in patients with locally advanced, unresectable NSCLC (Stage III).
 
Approximately 390 patients with locally advanced, unresectable NSCLC (Stage III) will be recruited and 300 patients randomized in a 2:1 ratio to durvalumab + SoC CRT or placebo + SoC CRT. Patients will be stratified by age (
Other countries participating are Brazil, Hungary, India, Japan, South Korea, Mexico, Peru, Poland, Russia, Thailand, Turkey, Ukraine and Vietnam. For Philippines, target number of patients to be randomized is 9.

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug discovery and development
Start Date Duration in Months Target Completion Date Actual Completion Date
2018-06-30 48 2022-06-30 0000-00-00

Ongoing

Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR CDRR-NCR-S-17
Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR CDRR-NCR-S-17
Institution Region
AstraZeneca Pharmaceuticals (Philippines) Inc. NCR
Name E-Mail Institution and Institution Address
Samia T. Necesito samia.necesito@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name E-Mail Institution and Institution Address
Samia T. Necesito samia.necesito@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name Expertise Affiliation
Annielyn Beryl Ong-Cornel, MD Oncology Veterans Memorial Medical Center
Barbara M. Domingo, MD Oncology Makati Medical Center
Cherry Pink Villa, MD Oncology St. Paul's Hospital of Iloilo, Inc.
Jerry Tan Chun Bing, MD Oncology Cebu Doctors' University Hospital
Joseph Parra, MD Oncology St. Luke's Medical Center - Global City
Marie Grace Dawn T. Isidro, MD Oncology West Visayas State University Medical Center
Teresa T. Sy Ortin, MD Oncology University of Santo Tomas Hospital
Project Location Institutional Ethics Review Board
Veterans Memorial Medical Center Veterans Memorial Medical Center Ethics Review Committee
Makati Medical Center Makati Medical Center Institutional Review Board
St. Paul's Hospital of Iloilo, Inc. St. Paul’s Hospital Iloilo – Institutional Ethics Review Board
Cebu Doctors' University Hospital Cebu Doctors' University Hospital - Institutional Ethics Review Committee
St. Luke's Medical Center - Global City N/A
West Visayas State University Medical Center N/A
University of Santo Tomas Hospital University of Santo Tomas Hospital Institutional Review Board

Locally Advanced, Unresectable Non-small Cell Lung Cancer (Stage III)

PFS using BICR assessments according to RECIST 1.1

ORR using BICR assessments according to RECIST 1.1

OS and OS24

Rate of CR, DoR, DCR, and TTDM using BICR assessments according to RECIST 1.1

PFS2 as defined by local standard clinical practice

Concentration of durvalumab in blood (such as peak and trough concentration, as data allow; sparse sampling)

ADA (confirmatory results: positive or negative; titers [ADA neutralizing antibodies will also be assessed])

Presence of ADA for durvalumab (confirmatory results: positive or negative; titers)

EORTC QLQ-C30 and QLQ-LC13: Change in symptoms, functioning, and global health status/QoL

Recruiting

  • Brazil
  • Hungary
  • India
  • Japan
  • Mexico
  • Peru
  • Philippines
  • Poland
  • Russia
  • South Korea
  • Thailand
  • Ukraine
  • Vietnam

Clinical Trial

D933KC00001

20180220174513

2018-05-17

0000-00-00

9

11

Unspecified

30 Jun 2018

INCLUSION CRITERIA
Informed consent
1. Capable of giving signed informed consent, which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol.
2. Provision of signed and dated, written ICF prior to any mandatory study-specific
procedures, sampling, and analyses.
The ICF process is described in Appendix A, A 3.
Age
3. 18 years or older at the time of signing the ICF. In Japan, patients must be 20 years or
older at the time of signing the ICF.
Type of patient and disease characteristics
4. Histologically or cytologically documented NSCLC who present with locally
advanced, unresectable (Stage III) disease (according to Version 8 of the International
Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology
[IASLC Staging Manual in Thoracic Oncology 2016]).
 Except for overt cT4 disease, nodal status N2 or N3 should be proven by biopsy,
via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. Absent biopsy,
nodal status should be confirmed with whole body 18F-fluoro-deoxyglucose
positron emission tomography, plus contrast-enhanced computed tomography
(CT) in addition to or in combination with PET.
 Mandatory brain magnetic resonance imaging (MRI; preferred) or high-quality
brain CT with IV contrast at the time of staging.
5. World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG)
performance status (PS) of 0 or 1 at enrollment and randomization.
6. Patients with at least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1
Target Lesion (TL) at baseline. Tumor assessment by CT or MRI must be performed
within 28 days prior to randomization.
7. Tumor sample requirements:
 Mandatory provision of an archived tumor tissue block (or at least 15 newly cut
unstained slides) ≤3 years old (refer to Section 8.8 and the Laboratory Manual for
details). If an archival sample is not available, provision of a recent (≤3 months)
tumor biopsy is mandated.
 The provision of an additional recent (≤3 months) tumor biopsy is optional,
provided that a biopsy procedure is technically feasible and the procedure is not
associated with unacceptable clinical risk.
8. Must have a life expectancy of at least 12 weeks at randomization
9. Pre- or post-bronchodilator forced expiratory volume 1 of 1.0 L or >40% predicted
value and diffusing capacity of the lung for carbon monoxide >30% predicted value.
Pulmonary function testing results for up to 8 weeks prior to registration are permitted.
10. Adequate organ and marrow function at enrollment and randomization as defined
below:
 Hemoglobin ≥9.0 g/dL
 Absolute neutrophil count >1.5 × 109/L
 Platelet count >100 × 109/L
 Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to
patients with confirmed Gilbert’s syndrome, who will be allowed in consultation
with their physician.
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN.
 Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min as
determined by Cockcroft-Gault (using actual body weight)
Males:
Creatinine CL = Weight (kg) × (140 - Age)
(mL/min) 72 × serum creatinine (mg/dL)
Females:
Creatinine CL = Weight (kg) × (140 - Age) × 0.85
(mL/min) 72 × serum creatinine (mg/dL)
11. Genetics research study (optional)
For inclusion in the optional (DNA) genetics research study, patients must fulfil the
following criteria:
 - Provide informed consent for the genetic sampling and analyses.
If a patient declines to participate in the genetics research, there will be no penalty or
loss of benefit to the patient. A patient who declines genetics research participation
will not be excluded from any other aspect of the main study.
Weight
12. Body weight >30 kg at enrollment and randomization.
Sex
13. Male or female
Reproduction
14. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they
have been amenorrheic for 12 months without an alternative medical cause. The
following age-specific requirements apply:
 Women amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
 Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous
hormonal treatments, had radiation-induced menopause with last menses >1 year
ago, had chemotherapy-induced menopause with last menses >1 year ago, or
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy,
or hysterectomy).

EXCLUSION CRITERIA
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
Medical conditions
1. History of allogeneic organ transplantation.
2. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
 Patients with vitiligo or alopecia
 Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement
 Any chronic skin condition that does not require systemic therapy
 Patients without active disease in the last 5 years at randomization may be
included but only after consultation with the study physician
 Patients with celiac disease controlled by diet alone
3. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, ILD, serious chronic gastrointestinal conditions
associated with diarrhea, or psychiatric illness/social situations that would limit
compliance with study requirement, substantially increase risk of incurring AEs, or
compromise the ability of the patient to give written informed consent
4. History of another primary malignancy except for
 Malignancy treated with curative intent and with no known active disease
≥5 years before the first dose of IP and of low potential risk for recurrence
 Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease
 Adequately treated carcinoma in situ without evidence of disease
5. History of leptomeningeal carcinomatosis
6. History of active primary immunodeficiency.
7. Active infection including tuberculosis (TB) (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen [HBsAg] result),
hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2
antibodies). Patients with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients
positive for hepatitis C antibody are eligible only if polymerase chain reaction is
negative for HCV RNA.
8. Mixed small cell and NSCLC histology.
9. Known allergy or hypersensitivity to any of the IPs or any of the IP excipients.
10. Any medical contraindication to treatment with platinum-based doublet chemotherapy
as listed in the local labelling.
11. Patients whose radiation treatment plans are likely to encompass a volume of whole
lung receiving ≥20 Gy in total (V20) of more than 35% of lung volume. V20s up to
37% will be permitted and viewed as a minor deviation, provided that the treating
radiation oncologist believes this level of exposure is within patient tolerance.
12. Planned radiation cardiac dose V50 >25%.
13. Patients who have disease considered for surgical treatment as part of their care plan,
such as Pancoast or superior sulcus tumors.
Prior/concomitant therapy
14. Receipt of prior or current cancer treatment, including but not limited to, radiation
therapy, investigational agents, chemotherapy, and mAbs. Prior surgical resection
(ie, Stage I or II) is permitted.
15. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine while receiving IP and up to
30 days after the last dose of IP.
16. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable.
17. Prior exposure to immune-mediated therapy, including but not limited to, other
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding
therapeutic anticancer vaccines.
18. Current or prior use of immunosuppressive medication within 14 days before the first
dose of IP. The following are exceptions to this criterion:
 Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular
injection)
 Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
 Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication)
Prior/concurrent clinical study experience
19. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
20. Previous IP assignment in the present study
21. Concurrent enrollment in another clinical study, unless it is an observational
(noninterventional) clinical study or the follow-up period of an interventional study.
22. Participation in another clinical study with an IP during the 4 weeks prior to
randomization
23. Prior randomization or treatment in a previous durvalumab clinical study regardless of
treatment arm assignment.
Other exclusions
24. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of IP.
25. Judgment by the Investigator that the patient is unsuitable to participate in the study
and the patient is unlikely to comply with study procedures, restrictions, and
requirements.
26. Genetics research study (optional):
Exclusion criteria for participation in the optional (DNA) genetics research component
of the study include:
 Previous allogeneic bone marrow transplant.
 Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample
collection.

Interventional

Durvalumab (MEDI4736)

Durvalumab is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2 [PD-L2]) with PD-1 on T cells and CD80 (B7.1) on immune cells. It is being developed by AstraZeneca/MedImmune for use in the treatment of cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.) The proposed mechanism of action for durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the restored proliferation of interferon gamma (IFNγ) (Stewart et al 2015). In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent mechanism (Stewart et al 2015). Based on these data, durvalumab is expected to stimulate the patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward an antitumor response. Durvalumab has been engineered to reduce antibodydependent cellular cytotoxicity and complement-dependent cytotoxicity.

None

Randomized

Single Blind

None

Parallel

To assess the efficacy of durvalumab + SoC CRT compared with placebo + SoC CRT in terms of PFS and ORR

Phase III

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