STRONG: An Open-Label, Multi-Centre, Study to Assess the Safety of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies.

• Sponsor: AstraZeneca (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03084471
• Collaborator: (none)
• Enrollment: 867
• Locations: 79
• Arms: 2
• Anticipated Duration (Months): 62.9
• Patients Per Site: 11
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

To evaluate the safety, tolerability, and anti-tumor activity of the combination of durvalumab + tremelimumab or durvalumab alone in different solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Malignancies	Biological: MEDI4736 (Durvalumab); Biological: MEDI4736 (Durvalumab) + Tremelimumab	Phase 3

Detailed Description

This is an open-label, multi-center, study to determine the short and long term safety of fixed doses of durvalumab 1500 mg + tremelimumab 75 mg combination therapy or durvalumab 1500 mg monotherapy in patients with advanced solid malignancies. This study is modular in design, one or more of the modules will be opened in a given country / region based on local patient population prevalence, and results of feasibility studies. The total number of patients to be enrolled overall and in each module will depend on the types and number of tumor modules added to the main study and country-specific ancillary studies. The number of patients and sites to be involved in individual countries will be dependent on each module or ancillary study. This study consisted of a screening period, a treatment period, a 90 day safety follow-up period and a survival follow-up period. Patients will receive the investigation product (IP) via intravenous (IV) infusion once every 4 weeks (Q4W) in combination therapy or monotherapy as mentioned below - Combination therapy: Durvalumab 1,500 mg + tremelimumab 75 mg on Week 0, for up to a maximum of 4 doses (or cycles) followed by durvalumab 1,500 mg starting 4 weeks after the last infusion of the combination or discontinuation of tremelimumab.

Monotherapy: Durvalumab 1,500 mg on week 0.

Patients will attend a safety follow-up visit 90 days after study treatment discontinuation. Thereafter, patients will be contacted by phone or electronic communication every 3 months for survival status up to 5 years following date of first patient treatment initiation. All patients will be followed for a minimum of 6 months following enrolment of last patient. It is anticipated that the total enrolment period for the overall study will be approximately 2 to 3 years, with an overall duration of approximately 5 years

Study Design

• Study Type: Interventional
• Actual Enrollment: 867 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Centre, Safety Study of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies.
• Actual Study Start Date: Jun 5, 2017
• Actual Primary Completion Date: Mar 31, 2020
• Anticipated Study Completion Date: Aug 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination therapy Combination therapy (durvalumab + tremelimumab) : Patients will receive the combination therapy followed by monotherapy via intravenous (IV) infusion once Q4W: Durvalumab 1,500 mg + tremelimumab 75 mg on Week 0, for up to a maximum of 4 doses (or cycles) and Durvalumab 1,500 mg starting 4 weeks after the last infusion of the combination or discontinuation of tremelimumab.	Biological: MEDI4736 (Durvalumab); A human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells and CD80 (B7.1) on immune cells (IC).; Biological: MEDI4736 (Durvalumab) + Tremelimumab; Durvalumab: A human mAb of IgG 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells and CD80 (B7.1) on IC. Tremelimumab: A human Ig G2 mAb that completely blocks the interaction of human CTLA-4 (cluster of differentiation [CD]152) with CD80 and CD86 and increase release of cytokines (interleukin [IL]-2 and interferon [IFN]-γ) from human T cells, peripheral blood mononuclear cells and whole blood.
Experimental: Monotherapy Monotherapy (Durvalumab 1,500 mg): Patients will receive durvalumab 1,500 mg via IV infusion Q4W on Week 0.	Biological: MEDI4736 (Durvalumab); A human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells and CD80 (B7.1) on immune cells (IC).

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events of Special Interest (AESIs) [From screening to safety follow up visit (90 days after last dose), up to approximately 3 years.]

   Incidence, severity, nature, seriousness, intervention/treatment, outcome, and causality of AESIs were assessed. AESIs included events with a potential inflammatory or immune-mediated mechanism that required interventions such as steroids, immunosuppressants, and/or hormone replacement therapy.

Secondary Outcome Measures

1. Overall Survival [From screening to final data cutoff (maximum up to 4 years) following date of first patient treatment initiation.]

   Overall survival was defined as the time from the first date of treatment until death due to any cause.

2. Number of Participants With Adverse Events [From screening to safety follow up visit (90 days after last dose), maximum up to 4 years.]

   Incidence, severity, nature, seriousness, intervention/treatment, outcome, and causality of treatment-emergent AEs (including SAEs) will be assessed

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Must have a life expectancy of at least 12 weeks.

2. Age ≥18 years at the time of screening. For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative

3. 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. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. For patients aged <20 years and enrolling in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.

4. Disease not amenable to curative surgery

5. Eastern Cooperative Oncology Group (ECOG) performance status as defined in the specific module.

6. Body weight >30 kg.

7. No prior exposure to anti-PD-1 or anti-PD-L1, including on another AstraZeneca study. Exposure to other investigational agents may be permitted after discussion with the Sponsor.

8. Adequate organ and marrow function as defined below

• Hemoglobin ≥9.0 g/dL

• Absolute neutrophil count ≥1.0 × 109 /L

• Platelet count ≥75 × 109/L

• Serum bilirubin ≤1.5 × the 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.

• ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN

• Measured creatinine clearance (CL) >40 mL/min or calculated creatinine clearance (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) x 0.85 (mL/min) 72 × serum creatinine (mg/dL)

1. Female patients of childbearing potential (ie, not surgically sterile or post menopausal) who are sexually active with a non sterilized male partner must use 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 last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy (see Section 3.8 and specifically Table 1).

2. Evidence of post-menopausal status or negative urinary or serum pregnancy test (per Section 4) 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:

3. Women <50 years of age would be considered post-menopausal if they have been 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).

Non sterilized male patients who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening through 180 days after receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days after receipt of the final dose of durvalumab monotherapy.

Exclusion criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

2. Previous IP assignment in the present study.

3. Concurrent enrollment in another clinical study, or another sub-study of this protocol, unless it is an observational (non-interventional) clinical study or during the follow up period of an interventional study.

4. Participation in another clinical study with an investigational product during the last 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment.

5. Any concurrent chemotherapy, investigational agent, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.

6. Local treatment of isolated lesions for palliative intent is acceptable (eg, local surgery or radiotherapy).

7. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment.

8. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug. Note: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable.

9. 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.

10. History of allogenic organ transplantation.

11. 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 GI 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

12. 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 investigational product (durvalumab + tremelimumab) 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

1. History of leptomeningeal carcinomatosis

2. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on baseline brain imaging (please refer to RECIST for details on the imaging modality) obtained during the screening period or identified prior to signing the ICF. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least 4 weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of ≤10 mg/day of prednisone or its equivalent and anti-convulsants for at least 14 days prior to the start of treatment. Brain metastases will not be recorded as RECIST Target Lesions at baseline.

3. History of active primary immunodeficiency.

4. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen (HBsAg) result), hepatitis C, 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 virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

5. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. 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

1. 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 may be included but only after consultation with the study physician

• Patients with celiac disease controlled by diet alone

1. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.

2. Known allergy or hypersensitivity to study drug(s) or compounds of similar biologic composition to the study drug(s), or any of the study drug excipients.

3. Any unresolved NCI CTCAE Grade ≥2 toxicities from prior anti cancer therapy with the exception of vitiligo, alopecia, and the laboratory values defined in the inclusion criteria.

• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.

• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician

1. For women only, currently pregnant (confirmed with positive pregnancy test) or breast feeding.

2. 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 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy.

3. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Santa Rosa	California	United States	95403
2	Research Site	Washington	District of Columbia	United States	20007
3	Research Site	Tinley Park	Illinois	United States	60487
4	Research Site	Omaha	Nebraska	United States	68130
5	Research Site	Hackensack	New Jersey	United States	07601
6	Research Site	East Setauket	New York	United States	11733
7	Research Site	Greenville	South Carolina	United States	29607
8	Research Site	Knoxville	Tennessee	United States	37920
9	Research Site	Blacksburg	Virginia	United States	24060
10	Research Site	Spokane	Washington	United States	99208
11	Research Site	Moncton	New Brunswick	Canada	E1C 6Z8
12	Research Site	Brampton	Ontario	Canada	L6R 3J7
13	Research Site	Hamilton	Ontario	Canada	L8V 5C2
14	Research Site	Kingston	Ontario	Canada	K7L 5P9
15	Research Site	London	Ontario	Canada	N6A 4L6
16	Research Site	Newmarket	Ontario	Canada	L3Y 2P9
17	Research Site	Toronto	Ontario	Canada	M4N 3M5
18	Research Site	Toronto	Ontario	Canada	M5G 2M9
19	Research Site	Greenfield Park	Quebec	Canada	J4V 2H1
20	Research Site	Quebec		Canada	G1R 2J6
21	Research Site	Besançon Cedex		France	25030
22	Research Site	Bordeaux Cedex		France	33075
23	Research Site	Bordeaux		France	33076
24	Research Site	Brest		France	29609
25	Research Site	Dijon		France	21034
26	Research Site	Lille		France	59000
27	Research Site	Lyon Cedex 08		France	69373
28	Research Site	Marseille		France	13005
29	Research Site	Montpellier		France	34298
30	Research Site	Nice		France	6189
31	Research Site	Nimes		France	30029
32	Research Site	Paris		France	75010
33	Research Site	Pierre Benite		France	69495
34	Research Site	Poitiers Cedex		France	86021
35	Research Site	Rouen		France	76031
36	Research Site	Saint Herblain Cedex		France	44805
37	Research Site	STRASBOURG Cedex		France	67065
38	Research Site	Toulouse		France	31059
39	Research Site	Tours CEDEX		France	37044
40	Research Site	Villejuif		France	94805
41	Research Site	Berlin		Germany	13585
42	Research Site	Bielefeld		Germany	33611
43	Research Site	Dresden		Germany	01307
44	Research Site	Duisburg		Germany	47179
45	Research Site	Erlangen		Germany	91054
46	Research Site	Essen		Germany	45136
47	Research Site	Guetersloh		Germany	33332
48	Research Site	Hamburg		Germany	20246
49	Research Site	Jena		Germany	07747
50	Research Site	Kiel		Germany	24116
51	Research Site	Münster		Germany	48149
52	Research Site	Stuttgart		Germany	70174
53	Research Site	Würzburg		Germany	97080
54	Research Site	Ancona		Italy	60126
55	Research Site	Arezzo		Italy	52100
56	Research Site	Avellino		Italy	83100
57	Research Site	Bari		Italy	70124
58	Research Site	Catania		Italy	95126
59	Research Site	Lecce		Italy	73100
60	Research Site	Meldola		Italy	47014
61	Research Site	Milano		Italy	20141
62	Research Site	Modena		Italy	41124
63	Research Site	Padova		Italy	35128
64	Research Site	Pisa		Italy	56126
65	Research Site	Ravenna		Italy	48100
66	Research Site	Roma		Italy	00128
67	Research Site	Roma		Italy	00152
68	Research Site	Rozzano		Italy	20089
69	Research Site	Udine		Italy	33100
70	Research Site	Busan		Korea, Republic of	49241
71	Research Site	Goyang-si		Korea, Republic of	10408
72	Research Site	Seoul		Korea, Republic of	03722
73	Research Site	Seoul		Korea, Republic of	05505
74	Research Site	Leiden		Netherlands	2333 ZA
75	Research Site	London		United Kingdom	EC1A 7BE
76	Research Site	London		United Kingdom	W1G 6AD
77	Research Site	London		United Kingdom	W6 8RF
78	Research Site	Newcastle		United Kingdom	NE7 7DN
79	Research Site	Sheffield		United Kingdom	S10 2SJ

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Dec 13, 2019
• Statistical Analysis Plan - Jul 21, 2020

More Information

Additional Information:

• redacted_CSP
• redacted_SAP

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03084471
• Other Study ID Numbers: D4191C00068
• First Posted: Mar 21, 2017
• Last Update Posted: Aug 19, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Programmed death ligand 1 (PD-L1); Cytotoxic T-lymphocyte antigen-4 (CTLA-4); Durvalumab in combination with tremelimumab
• Additional relevant MeSH terms: Neoplasms; Durvalumab; Tremelimumab; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	Participants who met all the inclusion and none of the exclusion criteria were randomized at 77 study centers across 8 countries (Canada, France, Germany, Italy, Republic of Korea, Netherlands, United Kingdom and United States of America).
Pre-assignment Detail	During the screening period (4 weeks), eligible participants signed the informed consent. All the study assessments were performed as per the schedule of assessment.

Arm/Group Title	Durvalumab
Arm/Group Description	All participants received fixed-dose of durvalumab 1500 mg every 4 weeks until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	867
COMPLETED	0
NOT COMPLETED	867

Baseline Characteristics

Arm/Group Title	Durvalumab
Arm/Group Description	All participants received fixed-dose of durvalumab 1500 mg every 4 weeks until disease progression or unacceptable toxicity.
Overall Participants	867
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.5 (9.36)
Sex: Female, Male (Count of Participants)
Female	173 20%
Male	694 80%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	65 7.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 0.2%
White	508 58.6%
More than one race	0 0%
Unknown or Not Reported	28 3.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events of Special Interest (AESIs)
Description	Incidence, severity, nature, seriousness, intervention/treatment, outcome, and causality of AESIs were assessed. AESIs included events with a potential inflammatory or immune-mediated mechanism that required interventions such as steroids, immunosuppressants, and/or hormone replacement therapy.
Time Frame	From screening to safety follow up visit (90 days after last dose), up to approximately 3 years.

Outcome Measure Data

Analysis Population Description

Safety analysis set: all enrolled participants who received at least one dose of durvalumab.

Arm/Group Title	AESI	AEPI	imAE
Arm/Group Description	AESIs are defined as AEs with a likely inflammatory or immune-mediated pathophysiological basis, resulting from the mechanism of action of durvalumab and/or tremelimumab and requiring more frequent monitoring and/or interventions, such as corticosteroids, immunosuppressants, and/or endocrine therapy.	AEPIs are defined as AEs that could have a potential inflammatory or immune-mediated pathophysiological basis, resulting from the mechanism of action of durvalumab but are more likely to have occurred due to other pathophysiological mechanisms, thus, the likelihood of the event being inflammatory or immune-mediated in nature is not high and/or is most often or usually explained by the other causes.	The imAEs that occurred during this study were determined by a programmatic algorithm that required specific treatment for AESIs to be considered imAEs; the same specific treatment was required for AEPIs as well.
Measure Participants	867	867	867
Any adverse event (AE)	265 30.6%	300 NaN	97 NaN
Any AE of common terminology criteria for AEs Grade 3 or 4	21 2.4%	49 NaN	17 NaN
Any serious adverse event (SAE) (including events with outcome = death)	19 2.2%	13 NaN	11 NaN
Any AE with outcome = death	1 0.1%	0 NaN	0 NaN
Any AE, causally related to treatment	191 22%	145 NaN	87 NaN
Any AE of common terminology criteria Grade 3 or 4, causally related to treatment	15 1.7%	20 NaN	16 NaN
Any SAE, causally related to treatment	14 1.6%	3 NaN	10 NaN
Any AE with outcome = death, causally related to treatment	1 0.1%	0 NaN	0 NaN
Any AE leading to discontinuation of study treatment	12 1.4%	7 NaN	10 NaN
Event outcome resolved	140 16.1%	119 NaN	32 NaN
Event outcome not resolved	124 14.3%	181 NaN	65 NaN

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from the first date of treatment until death due to any cause.
Time Frame	From screening to final data cutoff (maximum up to 4 years) following date of first patient treatment initiation.

Outcome Measure Data

Analysis Population Description

Safety analysis set: all enrolled participants who received at least 1 dose of durvalumab.

Arm/Group Title	Durvalumab
Arm/Group Description	All participants received fixed-dose of durvalumab 1500 mg every 4 weeks until disease progression or unacceptable toxicity.
Measure Participants	867
Median (95% Confidence Interval) [months]	7.0

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Incidence, severity, nature, seriousness, intervention/treatment, outcome, and causality of treatment-emergent AEs (including SAEs) will be assessed
Time Frame	From screening to safety follow up visit (90 days after last dose), maximum up to 4 years.

Outcome Measure Data

Analysis Population Description

Safety analysis set: all enrolled participants who received at least one dose of durvalumab.

Arm/Group Title	Durvalumab
Arm/Group Description	All participants received fixed-dose of durvalumab 1500 mg every 4 weeks until disease progression or unacceptable toxicity.
Measure Participants	867
Any AE	787 90.8%
Any AE causally related to any study treatment	407 46.9%
Any AE of common terminology criteria grade 3 or higher	365 42.1%
Any AE of common terminology criteria grade 3 or higher, causally related to study treatment	78 9%
Any AE with outcome = death	42 4.8%
Any AE with outcome = death causally related to study treatment	9 1%
Any SAE (including events with outcome = death)	254 29.3%
Any SAE (including events with outcome = death) causally related to study treatment	41 4.7%
Any AE leading to discontinuation of study treatment	77 8.9%
Any AE leading to discontinuation of study treatment causally related to study treatment	33 3.8%

Adverse Events

Time Frame	From screening to safety follow up visit (90 days after last dose), maximum up to 4 years.
Adverse Event Reporting Description	MedDRA version 23.0
Arm/Group Title	Durvalumab
Arm/Group Description	All participants received fixed-dose of durvalumab 1500 mg every 4 weeks until disease progression or unacceptable toxicity.
All Cause Mortality
	Durvalumab
	Affected / at Risk (%)	# Events
Total	600/867 (69.2%)
Serious Adverse Events
	Durvalumab
	Affected / at Risk (%)	# Events
Total	254/867 (29.3%)
Blood and lymphatic system disorders
Anaemia	6/867 (0.7%)
Febrile neutropenia	4/867 (0.5%)
Pancytopenia	1/867 (0.1%)
Cardiac disorders
Cardiac failure	4/867 (0.5%)
Pericardial effusion	2/867 (0.2%)
Acute myocardial infarction	1/867 (0.1%)
Angina pectoris	1/867 (0.1%)
Arrhythmia	1/867 (0.1%)
Cardiac arrest	1/867 (0.1%)
Coronary artery occlusion	1/867 (0.1%)
Left ventricular dysfunction	1/867 (0.1%)
Endocrine disorders
Hyperthyroidism	1/867 (0.1%)
Hypophysitis	1/867 (0.1%)
Gastrointestinal disorders
Diarrhoea	7/867 (0.8%)
Abdominal pain	5/867 (0.6%)
Constipation	5/867 (0.6%)
Colitis	4/867 (0.5%)
Gastrointestinal haemorrhage	2/867 (0.2%)
Intestinal obstruction	2/867 (0.2%)
Subileus	2/867 (0.2%)
Anal fistula	1/867 (0.1%)
Autoimmune colitis	1/867 (0.1%)
Colitis ischaemic	1/867 (0.1%)
Duodenal ulcer	1/867 (0.1%)
Duodenitis haemorrhagic	1/867 (0.1%)
Enterocolitis	1/867 (0.1%)
Enterovesical fistula	1/867 (0.1%)
Ileus	1/867 (0.1%)
Ileus paralytic	1/867 (0.1%)
Intestinal atony	1/867 (0.1%)
Intestinal ischaemia	1/867 (0.1%)
Intestinal pseudo-obstruction	1/867 (0.1%)
Large intestine perforation	1/867 (0.1%)
Nausea	1/867 (0.1%)
Rectal haemorrhage	1/867 (0.1%)
Small intestinal obstruction	1/867 (0.1%)
Stomatitis	1/867 (0.1%)
Upper gastrointestinal haemorrhage	1/867 (0.1%)
General disorders
General physical health deterioration	7/867 (0.8%)
Death	5/867 (0.6%)
Pyrexia	3/867 (0.3%)
Asthenia	2/867 (0.2%)
Chest pain	1/867 (0.1%)
Drug intolerance	1/867 (0.1%)
Generalised oedema	1/867 (0.1%)
Hyperthermia	1/867 (0.1%)
Hyperthermia malignant	1/867 (0.1%)
Performance status decreased	1/867 (0.1%)
Vascular stent thrombosis	1/867 (0.1%)
Hepatobiliary disorders
Hepatitis	2/867 (0.2%)
Hepatocellular injury	1/867 (0.1%)
Hyperbilirubinaemia	1/867 (0.1%)
Portal vein thrombosis	1/867 (0.1%)
Immune system disorders
Haemophagocytic lymphohistiocytosis	1/867 (0.1%)
Infections and infestations
Sepsis	18/867 (2.1%)
Urinary tract infection	17/867 (2%)
Pyelonephritis	8/867 (0.9%)
Device related infection	7/867 (0.8%)
Pneumonia	6/867 (0.7%)
Urosepsis	5/867 (0.6%)
Pyelonephritis acute	4/867 (0.5%)
Bacterial infection	3/867 (0.3%)
Cellulitis	2/867 (0.2%)
Septic shock	2/867 (0.2%)
Atypical pneumonia	1/867 (0.1%)
Bacteraemia	1/867 (0.1%)
COVID-19	1/867 (0.1%)
Clostridium colitis	1/867 (0.1%)
Cystitis	1/867 (0.1%)
Diverticulitis	1/867 (0.1%)
Enterobacter infection	1/867 (0.1%)
Enterobacter sepsis	1/867 (0.1%)
Escherichia infection	1/867 (0.1%)
Escherichia urinary tract infection	1/867 (0.1%)
Fournier's gangrene	1/867 (0.1%)
Hepatitis E	1/867 (0.1%)
Infection	1/867 (0.1%)
Pneumocystis jirovecii infection	1/867 (0.1%)
Spinal cord infection	1/867 (0.1%)
Staphylococcal infection	1/867 (0.1%)
Staphylococcal sepsis	1/867 (0.1%)
Streptococcal infection	1/867 (0.1%)
Tracheitis	1/867 (0.1%)
Upper respiratory tract infection	1/867 (0.1%)
Urinary tract infection enterococcal	1/867 (0.1%)
Injury, poisoning and procedural complications
Fall	4/867 (0.5%)
Femoral neck fracture	2/867 (0.2%)
Femur fracture	1/867 (0.1%)
Forearm fracture	1/867 (0.1%)
Fracture	1/867 (0.1%)
Hip fracture	1/867 (0.1%)
Infusion related reaction	1/867 (0.1%)
Overdose	1/867 (0.1%)
Postoperative ileus	1/867 (0.1%)
Stomal hernia	1/867 (0.1%)
Urinary tract stoma complication	1/867 (0.1%)
Investigations
Blood creatinine increased	5/867 (0.6%)
Aspartate aminotransferase increased	2/867 (0.2%)
Ejection fraction decreased	1/867 (0.1%)
Troponin increased	1/867 (0.1%)
Metabolism and nutrition disorders
Decreased appetite	1/867 (0.1%)
Dehydration	1/867 (0.1%)
Diabetic ketoacidosis	1/867 (0.1%)
Hypercalcaemia	1/867 (0.1%)
Hyperglycaemia	1/867 (0.1%)
Hyperkalaemia	1/867 (0.1%)
Hyponatraemia	1/867 (0.1%)
Ketoacidosis	1/867 (0.1%)
Musculoskeletal and connective tissue disorders
Pain in extremity	3/867 (0.3%)
Back pain	2/867 (0.2%)
Musculoskeletal chest pain	2/867 (0.2%)
Arthralgia	1/867 (0.1%)
Flank pain	1/867 (0.1%)
Lumbar spinal stenosis	1/867 (0.1%)
Muscular weakness	1/867 (0.1%)
Neck pain	1/867 (0.1%)
Rotator cuff syndrome	1/867 (0.1%)
Spinal pain	1/867 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour hyperprogression	11/867 (1.3%)
Basal cell carcinoma	2/867 (0.2%)
Tumour associated fever	2/867 (0.2%)
Bladder cancer recurrent	1/867 (0.1%)
Bladder neoplasm	1/867 (0.1%)
Bronchial carcinoma	1/867 (0.1%)
Cancer pain	1/867 (0.1%)
Gastric cancer	1/867 (0.1%)
Infected neoplasm	1/867 (0.1%)
Lymphangiosis carcinomatosa	1/867 (0.1%)
Neuroendocrine tumour	1/867 (0.1%)
Pelvic neoplasm	1/867 (0.1%)
Prostate cancer	1/867 (0.1%)
Rectal cancer	1/867 (0.1%)
Tumour pain	1/867 (0.1%)
Nervous system disorders
Ischaemic stroke	2/867 (0.2%)
Basilar artery occlusion	1/867 (0.1%)
Embolic stroke	1/867 (0.1%)
Frontal lobe epilepsy	1/867 (0.1%)
IIIrd nerve paralysis	1/867 (0.1%)
Peroneal nerve palsy	1/867 (0.1%)
Somnolence	1/867 (0.1%)
Syncope	1/867 (0.1%)
VIth nerve disorder	1/867 (0.1%)
Product Issues
Device occlusion	2/867 (0.2%)
Device dislocation	1/867 (0.1%)
Stent malfunction	1/867 (0.1%)
Psychiatric disorders
Confusional state	1/867 (0.1%)
Delirium	1/867 (0.1%)
Mental status changes	1/867 (0.1%)
Renal and urinary disorders
Acute kidney injury	8/867 (0.9%)
Haematuria	7/867 (0.8%)
Renal failure	4/867 (0.5%)
Hydronephrosis	3/867 (0.3%)
Urinary tract obstruction	3/867 (0.3%)
Urinary tract inflammation	2/867 (0.2%)
Renal impairment	1/867 (0.1%)
Ureteric stenosis	1/867 (0.1%)
Urinary retention	1/867 (0.1%)
Urine abnormality	1/867 (0.1%)
Reproductive system and breast disorders
Pelvic pain	1/867 (0.1%)
Scrotal mass	1/867 (0.1%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	7/867 (0.8%)
Dyspnoea	4/867 (0.5%)
Pleural effusion	4/867 (0.5%)
Lung disorder	3/867 (0.3%)
Hypoxia	2/867 (0.2%)
Pneumonitis	2/867 (0.2%)
Acute respiratory distress syndrome	1/867 (0.1%)
Bronchiectasis	1/867 (0.1%)
Chronic obstructive pulmonary disease	1/867 (0.1%)
Epistaxis	1/867 (0.1%)
Haemoptysis	1/867 (0.1%)
Interstitial lung disease	1/867 (0.1%)
Pleural thickening	1/867 (0.1%)
Respiratory failure	1/867 (0.1%)
Vascular disorders
Deep vein thrombosis	2/867 (0.2%)
Haemorrhage	1/867 (0.1%)
Lymphoedema	1/867 (0.1%)
Peripheral ischaemia	1/867 (0.1%)
Shock haemorrhagic	1/867 (0.1%)
Thrombosis	1/867 (0.1%)
Other (Not Including Serious) Adverse Events
	Durvalumab
	Affected / at Risk (%)	# Events
Total	669/867 (77.2%)
Blood and lymphatic system disorders
Anaemia	172/867 (19.8%)
Endocrine disorders
Hypothyroidism	57/867 (6.6%)
Gastrointestinal disorders
Constipation	171/867 (19.7%)
Diarrhoea	136/867 (15.7%)
Nausea	126/867 (14.5%)
Vomiting	76/867 (8.8%)
Abdominal pain	64/867 (7.4%)
General disorders
Asthenia	228/867 (26.3%)
Fatigue	83/867 (9.6%)
Pyrexia	79/867 (9.1%)
Oedema peripheral	75/867 (8.7%)
Infections and infestations
Urinary tract infection	84/867 (9.7%)
Investigations
Blood creatinine increased	48/867 (5.5%)
Weight decreased	46/867 (5.3%)
Metabolism and nutrition disorders
Decreased appetite	149/867 (17.2%)
Musculoskeletal and connective tissue disorders
Back pain	82/867 (9.5%)
Arthralgia	65/867 (7.5%)
Renal and urinary disorders
Haematuria	64/867 (7.4%)
Respiratory, thoracic and mediastinal disorders
Cough	84/867 (9.7%)
Dyspnoea	74/867 (8.5%)
Skin and subcutaneous tissue disorders
Pruritus	109/867 (12.6%)

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

Disclosure of study information is prohibited without providing advance notice to AstraZeneca and opportunity to object.