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

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ClinicalTrials.gov Identifier: NCT03084471
Recruitment Status : Active, not recruiting
First Posted : March 21, 2017
Results First Posted : June 15, 2021
Last Update Posted : July 30, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Advanced Solid Malignancies
Interventions Biological: MEDI4736 (Durvalumab)
Biological: MEDI4736 (Durvalumab) + Tremelimumab
Enrollment 867
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 Details 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
Hide 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
Reason Not Completed
Development of study specific discontinuation criteria             2
Condition under investigation worsened             84
Lack of therapeutic response             2
Protocol Violation             1
Adverse Event             73
Withdrawal by Subject             12
Disease relapse             181
Subjective disease progression             359
Other (as recorded)             33
Patients who were still on study treatment at Data Cutoff             120
Arm/Group Title Durvalumab
Hide Arm/Group Description All participants received fixed-dose of durvalumab 1500 mg every 4 weeks until disease progression or unacceptable toxicity.
Overall Number of Baseline Participants 867
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 867 participants
67.5  (9.36)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 867 participants
Female
173
  20.0%
Male
694
  80.0%
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 603 participants
American Indian or Alaska Native
0
   0.0%
Asian
65
  10.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
2
   0.3%
White
508
  84.2%
More than one race
0
   0.0%
Unknown or Not Reported
28
   4.6%
[1]
Measure Analysis Population Description: Race was not a mandatory variable to be collected in some sites due to data privacy reasons. Hence, the total number of participants analysed for race is lesser than Overall (Safety Analysis Set)
1.Primary Outcome
Title Number of Participants With Adverse Events of Special Interest (AESIs)
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set: all enrolled participants who received at least one dose of durvalumab.
Arm/Group Title AESI AEPI imAE
Hide 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.
Overall Number of Participants Analyzed 867 867 867
Measure Type: Number
Unit of Measure: participants
Any adverse event (AE) 265 300 97
Any AE of common terminology criteria for AEs Grade 3 or 4 21 49 17
Any serious adverse event (SAE) (including events with outcome = death) 19 13 11
Any AE with outcome = death 1 0 0
Any AE, causally related to treatment 191 145 87
Any AE of common terminology criteria Grade 3 or 4, causally related to treatment 15 20 16
Any SAE, causally related to treatment 14 3 10
Any AE with outcome = death, causally related to treatment 1 0 0
Any AE leading to discontinuation of study treatment 12 7 10
Event outcome resolved 140 119 32
Event outcome not resolved 124 181 65
2.Secondary Outcome
Title Overall Survival
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set: all enrolled participants who received at least 1 dose of durvalumab.
Arm/Group Title Durvalumab
Hide Arm/Group Description:
All participants received fixed-dose of durvalumab 1500 mg every 4 weeks until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 867
Median (95% Confidence Interval)
Unit of Measure: months
7.0
(6.44 to 8.18)
3.Secondary Outcome
Title Number of Participants With Adverse Events
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set: all enrolled participants who received at least one dose of durvalumab.
Arm/Group Title Durvalumab
Hide Arm/Group Description:
All participants received fixed-dose of durvalumab 1500 mg every 4 weeks until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 867
Measure Type: Number
Unit of Measure: participants
Any AE 787
Any AE causally related to any study treatment 407
Any AE of common terminology criteria grade 3 or higher 365
Any AE of common terminology criteria grade 3 or higher, causally related to study treatment 78
Any AE with outcome = death 42
Any AE with outcome = death causally related to study treatment 9
Any SAE (including events with outcome = death) 254
Any SAE (including events with outcome = death) causally related to study treatment 41
Any AE leading to discontinuation of study treatment 77
Any AE leading to discontinuation of study treatment causally related to study treatment 33
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
Hide 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 (%)
Total   600/867 (69.20%) 
Hide Serious Adverse Events
Durvalumab
Affected / at Risk (%)
Total   254/867 (29.30%) 
Blood and lymphatic system disorders   
Anaemia *  6/867 (0.69%) 
Febrile neutropenia *  4/867 (0.46%) 
Pancytopenia *  1/867 (0.12%) 
Cardiac disorders   
Cardiac failure *  4/867 (0.46%) 
Pericardial effusion *  2/867 (0.23%) 
Acute myocardial infarction *  1/867 (0.12%) 
Angina pectoris *  1/867 (0.12%) 
Arrhythmia *  1/867 (0.12%) 
Cardiac arrest *  1/867 (0.12%) 
Coronary artery occlusion *  1/867 (0.12%) 
Left ventricular dysfunction *  1/867 (0.12%) 
Endocrine disorders   
Hyperthyroidism *  1/867 (0.12%) 
Hypophysitis *  1/867 (0.12%) 
Gastrointestinal disorders   
Diarrhoea *  7/867 (0.81%) 
Abdominal pain *  5/867 (0.58%) 
Constipation *  5/867 (0.58%) 
Colitis *  4/867 (0.46%) 
Gastrointestinal haemorrhage *  2/867 (0.23%) 
Intestinal obstruction *  2/867 (0.23%) 
Subileus *  2/867 (0.23%) 
Anal fistula *  1/867 (0.12%) 
Autoimmune colitis *  1/867 (0.12%) 
Colitis ischaemic *  1/867 (0.12%) 
Duodenal ulcer *  1/867 (0.12%) 
Duodenitis haemorrhagic *  1/867 (0.12%) 
Enterocolitis *  1/867 (0.12%) 
Enterovesical fistula *  1/867 (0.12%) 
Ileus *  1/867 (0.12%) 
Ileus paralytic *  1/867 (0.12%) 
Intestinal atony *  1/867 (0.12%) 
Intestinal ischaemia *  1/867 (0.12%) 
Intestinal pseudo-obstruction *  1/867 (0.12%) 
Large intestine perforation *  1/867 (0.12%) 
Nausea *  1/867 (0.12%) 
Rectal haemorrhage *  1/867 (0.12%) 
Small intestinal obstruction *  1/867 (0.12%) 
Stomatitis *  1/867 (0.12%) 
Upper gastrointestinal haemorrhage *  1/867 (0.12%) 
General disorders   
General physical health deterioration *  7/867 (0.81%) 
Death *  5/867 (0.58%) 
Pyrexia *  3/867 (0.35%) 
Asthenia *  2/867 (0.23%) 
Chest pain *  1/867 (0.12%) 
Drug intolerance *  1/867 (0.12%) 
Generalised oedema *  1/867 (0.12%) 
Hyperthermia *  1/867 (0.12%) 
Hyperthermia malignant *  1/867 (0.12%) 
Performance status decreased *  1/867 (0.12%) 
Vascular stent thrombosis *  1/867 (0.12%) 
Hepatobiliary disorders   
Hepatitis *  2/867 (0.23%) 
Hepatocellular injury *  1/867 (0.12%) 
Hyperbilirubinaemia *  1/867 (0.12%) 
Portal vein thrombosis *  1/867 (0.12%) 
Immune system disorders   
Haemophagocytic lymphohistiocytosis *  1/867 (0.12%) 
Infections and infestations   
Sepsis *  18/867 (2.08%) 
Urinary tract infection *  17/867 (1.96%) 
Pyelonephritis *  8/867 (0.92%) 
Device related infection *  7/867 (0.81%) 
Pneumonia *  6/867 (0.69%) 
Urosepsis *  5/867 (0.58%) 
Pyelonephritis acute *  4/867 (0.46%) 
Bacterial infection *  3/867 (0.35%) 
Cellulitis *  2/867 (0.23%) 
Septic shock *  2/867 (0.23%) 
Atypical pneumonia *  1/867 (0.12%) 
Bacteraemia *  1/867 (0.12%) 
COVID-19 *  1/867 (0.12%) 
Clostridium colitis *  1/867 (0.12%) 
Cystitis *  1/867 (0.12%) 
Diverticulitis *  1/867 (0.12%) 
Enterobacter infection *  1/867 (0.12%) 
Enterobacter sepsis *  1/867 (0.12%) 
Escherichia infection *  1/867 (0.12%) 
Escherichia urinary tract infection *  1/867 (0.12%) 
Fournier's gangrene *  1/867 (0.12%) 
Hepatitis E *  1/867 (0.12%) 
Infection *  1/867 (0.12%) 
Pneumocystis jirovecii infection *  1/867 (0.12%) 
Spinal cord infection *  1/867 (0.12%) 
Staphylococcal infection *  1/867 (0.12%) 
Staphylococcal sepsis *  1/867 (0.12%) 
Streptococcal infection *  1/867 (0.12%) 
Tracheitis *  1/867 (0.12%) 
Upper respiratory tract infection *  1/867 (0.12%) 
Urinary tract infection enterococcal *  1/867 (0.12%) 
Injury, poisoning and procedural complications   
Fall *  4/867 (0.46%) 
Femoral neck fracture *  2/867 (0.23%) 
Femur fracture *  1/867 (0.12%) 
Forearm fracture *  1/867 (0.12%) 
Fracture *  1/867 (0.12%) 
Hip fracture *  1/867 (0.12%) 
Infusion related reaction *  1/867 (0.12%) 
Overdose *  1/867 (0.12%) 
Postoperative ileus *  1/867 (0.12%) 
Stomal hernia *  1/867 (0.12%) 
Urinary tract stoma complication *  1/867 (0.12%) 
Investigations   
Blood creatinine increased *  5/867 (0.58%) 
Aspartate aminotransferase increased *  2/867 (0.23%) 
Ejection fraction decreased *  1/867 (0.12%) 
Troponin increased *  1/867 (0.12%) 
Metabolism and nutrition disorders   
Decreased appetite *  1/867 (0.12%) 
Dehydration *  1/867 (0.12%) 
Diabetic ketoacidosis *  1/867 (0.12%) 
Hypercalcaemia *  1/867 (0.12%) 
Hyperglycaemia *  1/867 (0.12%) 
Hyperkalaemia *  1/867 (0.12%) 
Hyponatraemia *  1/867 (0.12%) 
Ketoacidosis *  1/867 (0.12%) 
Musculoskeletal and connective tissue disorders   
Pain in extremity *  3/867 (0.35%) 
Back pain *  2/867 (0.23%) 
Musculoskeletal chest pain *  2/867 (0.23%) 
Arthralgia *  1/867 (0.12%) 
Flank pain *  1/867 (0.12%) 
Lumbar spinal stenosis *  1/867 (0.12%) 
Muscular weakness *  1/867 (0.12%) 
Neck pain *  1/867 (0.12%) 
Rotator cuff syndrome *  1/867 (0.12%) 
Spinal pain *  1/867 (0.12%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Tumour hyperprogression *  11/867 (1.27%) 
Basal cell carcinoma *  2/867 (0.23%) 
Tumour associated fever *  2/867 (0.23%) 
Bladder cancer recurrent *  1/867 (0.12%) 
Bladder neoplasm *  1/867 (0.12%) 
Bronchial carcinoma *  1/867 (0.12%) 
Cancer pain *  1/867 (0.12%) 
Gastric cancer *  1/867 (0.12%) 
Infected neoplasm *  1/867 (0.12%) 
Lymphangiosis carcinomatosa *  1/867 (0.12%) 
Neuroendocrine tumour *  1/867 (0.12%) 
Pelvic neoplasm *  1/867 (0.12%) 
Prostate cancer *  1/867 (0.12%) 
Rectal cancer *  1/867 (0.12%) 
Tumour pain *  1/867 (0.12%) 
Nervous system disorders   
Ischaemic stroke *  2/867 (0.23%) 
Basilar artery occlusion *  1/867 (0.12%) 
Embolic stroke *  1/867 (0.12%) 
Frontal lobe epilepsy *  1/867 (0.12%) 
IIIrd nerve paralysis *  1/867 (0.12%) 
Peroneal nerve palsy *  1/867 (0.12%) 
Somnolence *  1/867 (0.12%) 
Syncope *  1/867 (0.12%) 
VIth nerve disorder *  1/867 (0.12%) 
Product Issues   
Device occlusion *  2/867 (0.23%) 
Device dislocation *  1/867 (0.12%) 
Stent malfunction *  1/867 (0.12%) 
Psychiatric disorders   
Confusional state *  1/867 (0.12%) 
Delirium *  1/867 (0.12%) 
Mental status changes *  1/867 (0.12%) 
Renal and urinary disorders   
Acute kidney injury *  8/867 (0.92%) 
Haematuria *  7/867 (0.81%) 
Renal failure *  4/867 (0.46%) 
Hydronephrosis *  3/867 (0.35%) 
Urinary tract obstruction *  3/867 (0.35%) 
Urinary tract inflammation *  2/867 (0.23%) 
Renal impairment *  1/867 (0.12%) 
Ureteric stenosis *  1/867 (0.12%) 
Urinary retention *  1/867 (0.12%) 
Urine abnormality *  1/867 (0.12%) 
Reproductive system and breast disorders   
Pelvic pain *  1/867 (0.12%) 
Scrotal mass *  1/867 (0.12%) 
Respiratory, thoracic and mediastinal disorders   
Pulmonary embolism *  7/867 (0.81%) 
Dyspnoea *  4/867 (0.46%) 
Pleural effusion *  4/867 (0.46%) 
Lung disorder *  3/867 (0.35%) 
Hypoxia *  2/867 (0.23%) 
Pneumonitis *  2/867 (0.23%) 
Acute respiratory distress syndrome *  1/867 (0.12%) 
Bronchiectasis *  1/867 (0.12%) 
Chronic obstructive pulmonary disease *  1/867 (0.12%) 
Epistaxis *  1/867 (0.12%) 
Haemoptysis *  1/867 (0.12%) 
Interstitial lung disease *  1/867 (0.12%) 
Pleural thickening *  1/867 (0.12%) 
Respiratory failure *  1/867 (0.12%) 
Vascular disorders   
Deep vein thrombosis *  2/867 (0.23%) 
Haemorrhage *  1/867 (0.12%) 
Lymphoedema *  1/867 (0.12%) 
Peripheral ischaemia *  1/867 (0.12%) 
Shock haemorrhagic *  1/867 (0.12%) 
Thrombosis *  1/867 (0.12%) 
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Durvalumab
Affected / at Risk (%)
Total   669/867 (77.16%) 
Blood and lymphatic system disorders   
Anaemia *  172/867 (19.84%) 
Endocrine disorders   
Hypothyroidism *  57/867 (6.57%) 
Gastrointestinal disorders   
Constipation *  171/867 (19.72%) 
Diarrhoea *  136/867 (15.69%) 
Nausea *  126/867 (14.53%) 
Vomiting *  76/867 (8.77%) 
Abdominal pain *  64/867 (7.38%) 
General disorders   
Asthenia *  228/867 (26.30%) 
Fatigue *  83/867 (9.57%) 
Pyrexia *  79/867 (9.11%) 
Oedema peripheral *  75/867 (8.65%) 
Infections and infestations   
Urinary tract infection *  84/867 (9.69%) 
Investigations   
Blood creatinine increased *  48/867 (5.54%) 
Weight decreased *  46/867 (5.31%) 
Metabolism and nutrition disorders   
Decreased appetite *  149/867 (17.19%) 
Musculoskeletal and connective tissue disorders   
Back pain *  82/867 (9.46%) 
Arthralgia *  65/867 (7.50%) 
Renal and urinary disorders   
Haematuria *  64/867 (7.38%) 
Respiratory, thoracic and mediastinal disorders   
Cough *  84/867 (9.69%) 
Dyspnoea *  74/867 (8.54%) 
Skin and subcutaneous tissue disorders   
Pruritus *  109/867 (12.57%) 
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Disclosure of study information is prohibited without providing advance notice to AstraZeneca and opportunity to object.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Global Clinical Lead
Organization: AstraZeneca Clinical study Information Center
Phone: 1-877-240-9479
EMail: information.center@astrazeneca.com
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03084471    
Other Study ID Numbers: D4191C00068
First Submitted: March 7, 2017
First Posted: March 21, 2017
Results First Submitted: March 22, 2021
Results First Posted: June 15, 2021
Last Update Posted: July 30, 2021