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A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Solid Tumors

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ClinicalTrials.gov Identifier: NCT02403271
Recruitment Status : Completed
First Posted : March 31, 2015
Results First Posted : January 3, 2019
Last Update Posted : January 3, 2019
Sponsor:
Information provided by (Responsible Party):
Pharmacyclics LLC.

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Non-Small Cell Lung Cancer
Breast Cancer
Pancreatic Cancer
Interventions Drug: Ibrutinib
Drug: Durvalumab
Enrollment 124
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Phase 1b Phase 2
Hide Arm/Group Description In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 will be explored and will follow a 6 + 3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma). Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.
Period Title: Period 1
Started 7 [1] 0
Completed 6 0
Not Completed 1 0
Reason Not Completed
Other varied reasons             1             0
[1]
All Phase 1b participants went on to participate in Phase 2.
Period Title: Period 2
Started 0 124 [1]
Completed 0 0
Not Completed 0 124
Reason Not Completed
Withdrawal by Subject             0             14
Death             0             84
Lost to Follow-up             0             2
Study Terminated by Sponsor             0             14
Other varied reasons             0             10
[1]
Phase 2 includes all subjects who participated in Phase 1b.
Arm/Group Title Phase 1b/2
Hide Arm/Group Description All participants who received at least one dose of study treatment.
Overall Number of Baseline Participants 122
Hide Baseline Analysis Population Description
Baseline analysis population includes all patients that received at least one dose of study treatment.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 122 participants
<=18 years
0
   0.0%
Between 18 and 65 years
78
  63.9%
>=65 years
44
  36.1%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 122 participants
60.0  (12.03)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 122 participants
Female
75
  61.5%
Male
47
  38.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 122 participants
Hispanic or Latino
6
   4.9%
Not Hispanic or Latino
116
  95.1%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 122 participants
American Indian or Alaska Native
1
   0.8%
Asian
5
   4.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
11
   9.0%
White
104
  85.2%
More than one race
0
   0.0%
Unknown or Not Reported
1
   0.8%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 122 participants
122
 100.0%
1.Primary Outcome
Title Phase 1b: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Durvalumab (MEDI4736) and to Find the Recommended Phase II Dose.
Hide Description [Not Specified]
Time Frame From the date of first study treatment until DLT or disease progression per RECIST 1.1.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase 1b
Hide Arm/Group Description:
In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 will be explored and will follow a 6 + 3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma).
Overall Number of Participants Analyzed 6
Measure Type: Number
Unit of Measure: participants
6
2.Primary Outcome
Title Phase 2: Efficacy of Ibrutinib in Combination With Durvalumab (MEDI4736) in Participants With Relapsed or Refractory Solid Tumors by Assessing the ORR Per RECIST 1.1.
Hide Description [Not Specified]
Time Frame From the date of first study treatment until progressive disease per RECIST 1.1 or unacceptable toxicity.
Hide Outcome Measure Data
Hide Analysis Population Description
The Response-evaluable population was participants who received at least 1 dose of treatment (ibrutinib and durvalumab) and provided 1 post-baseline response assessment.
Arm/Group Title Phase 2
Hide Arm/Group Description:
Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.
Overall Number of Participants Analyzed 105
Measure Type: Count of Participants
Unit of Measure: Participants
2
   1.9%
3.Secondary Outcome
Title Phase 1b/2: Pharmacokinetics (Cmax) of Ibrutinib
Hide Description Cmax = the peak (maximum) plasma concentration of ibrutinib during the dosing interval on Cycle 3 Day 1.
Time Frame 0hr, 1hr, 2hr, and 4hr post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data. Data were analyzed together for Phase 1b and Phase 2 because the dose was the same.
Arm/Group Title Phase 1b/2 (Pharmacokinetic Population)
Hide Arm/Group Description:
All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Overall Number of Participants Analyzed 34
Mean (Standard Deviation)
Unit of Measure: ng/mL
218  (163)
4.Secondary Outcome
Title Phase 1b/2: Pharmacokinetics (AUC0-24h) of Ibrutinib
Hide Description AUC0-24 = the area under the plasma concentration-time curve of ibrutinib during the dosing interval on Cycle 3 Day 1
Time Frame 0hr, 1hr, 2hr, and 4hr post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data. Data were analyzed together for Phase 1b/2 because the dose was the same.
Arm/Group Title Phase 1b/2 (Pharmacokinetic Population)
Hide Arm/Group Description:
All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Overall Number of Participants Analyzed 34
Mean (Standard Deviation)
Unit of Measure: h.ng/mL
2126  (1315)
5.Secondary Outcome
Title Phase 1b/2: Pharmacokinetics (Cmax) of Durvalumab (MEDI4736)
Hide Description Cmax = the peak (maximum) plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1.
Time Frame 60 minutes post-dose (dose administered as an infusion over a 1 hour period)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Arm/Group Title Phase 1b/2 (Pharmacokinetic Population)
Hide Arm/Group Description:
All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Overall Number of Participants Analyzed 8
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg/mL
386
(19.5%)
6.Secondary Outcome
Title Phase 1b/2: Pharmacokinetics (Ctrough) of Durvalumab (MEDI4736)
Hide Description Ctrough = the trough plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1
Time Frame Pre-dose
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Arm/Group Title Phase 1b/2 (Pharmacokinetic Population)
Hide Arm/Group Description:
All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Overall Number of Participants Analyzed 10
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg/mL
168
(19.6%)
7.Secondary Outcome
Title Phase 1b: Pharmacodynamics
Hide Description BTK occupancy
Time Frame From the date of first study treatment until DLT or disease progression per RECIST 1.1.
Hide Outcome Measure Data
Hide Analysis Population Description
Data not collected
Arm/Group Title Phase 1b
Hide Arm/Group Description:
In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 will be explored and will follow a 6 + 3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma).
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
8.Secondary Outcome
Title Phase 2: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Durvalumab (MEDI4736)
Hide Description [Not Specified]
Time Frame From the date of first study treatment until DLT or disease progression per RECIST 1.1.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled and received at least 1 dose of study treatment.
Arm/Group Title Phase 2
Hide Arm/Group Description:
Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.
Overall Number of Participants Analyzed 122
Measure Type: Count of Participants
Unit of Measure: Participants
122
 100.0%
9.Secondary Outcome
Title Phase 2: Pharmacodynamics
Hide Description BTK binding site occupancy of ibrutinib was measured from peripheral blood samples collected from participants during Cycle 3 Day 1.
Time Frame Pre-dose
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who received at least one dose of ibrutinib and who had at least one evaluable BTK occupancy assay result at Cycle 3 Day 1.
Arm/Group Title Phase 2
Hide Arm/Group Description:
Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.
Overall Number of Participants Analyzed 30
Mean (Standard Error)
Unit of Measure: percentage of BTK binding site occupancy
87.8  (4.2)
Time Frame 2 years, 5 months
Adverse Event Reporting Description Adverse events were not collected by phase (Arm) because the treatments between Phase 1b and Phase 2 were not appreciably different.
 
Arm/Group Title Phase 1b/2
Hide Arm/Group Description All subjects who received at least one dose of study treatment.
All-Cause Mortality
Phase 1b/2
Affected / at Risk (%)
Total   96/122 (78.69%) 
Show Serious Adverse Events Hide Serious Adverse Events
Phase 1b/2
Affected / at Risk (%)
Total   77/122 (63.11%) 
Blood and lymphatic system disorders   
Anaemia  1  1/122 (0.82%) 
Thrombocytopenia  1  1/122 (0.82%) 
Cardiac disorders   
Pericardial effusion  1  3/122 (2.46%) 
Supraventricular tachycardia  1  2/122 (1.64%) 
Acute myocardial infarction  1  1/122 (0.82%) 
Atrial fibrillation  1  1/122 (0.82%) 
Sinus tachycardia  1  1/122 (0.82%) 
Ventricular tachycardia  1  1/122 (0.82%) 
Endocrine disorders   
Hypothyroidism  1  1/122 (0.82%) 
Gastrointestinal disorders   
Abdominal pain  1  4/122 (3.28%) 
Diarrhoea  1  3/122 (2.46%) 
Vomiting  1  3/122 (2.46%) 
Constipation  1  2/122 (1.64%) 
Nausea  1  2/122 (1.64%) 
Ascites  1  1/122 (0.82%) 
Gastrointestinal haemorrhage  1  1/122 (0.82%) 
Intestinal obstruction  1  1/122 (0.82%) 
Obstruction gastric  1  1/122 (0.82%) 
Small intestinal obstruction  1  1/122 (0.82%) 
Intestinal perforation  1  1/122 (0.82%) 
General disorders   
Pyrexia  1  6/122 (4.92%) 
Death  1  3/122 (2.46%) 
Multiple organ dysfunction syndrome  1  2/122 (1.64%) 
Asthenia  1  1/122 (0.82%) 
Malaise  1  1/122 (0.82%) 
Oedema peripheral  1  1/122 (0.82%) 
Hepatobiliary disorders   
Cholangitis  1  1/122 (0.82%) 
Hepatic failure  1  1/122 (0.82%) 
Hepatic function abnormal  1  1/122 (0.82%) 
Pneumonia  1  8/122 (6.56%) 
Infections and infestations   
Sepsis  1  4/122 (3.28%) 
Cellulitis  1  2/122 (1.64%) 
Pneumonia bacterial  1  2/122 (1.64%) 
Urinary tract infection  1  2/122 (1.64%) 
Diverticulitis  1  1/122 (0.82%) 
Escherichia sepsis  1  1/122 (0.82%) 
Gastroenteritis  1  1/122 (0.82%) 
Pyelonephritis  1  1/122 (0.82%) 
Serratia bacteraemia  1  1/122 (0.82%) 
Staphylococcal bacteraemia  1  1/122 (0.82%) 
Staphylococcal sepsis  1  1/122 (0.82%) 
Pneumonia  1  8/122 (6.56%) 
Stenotrophomonas sepsis  1  1/122 (0.82%) 
Injury, poisoning and procedural complications   
Compression fracture  1  1/122 (0.82%) 
Metabolism and nutrition disorders   
Dehydration  1  6/122 (4.92%) 
Hyponatraemia  1  4/122 (3.28%) 
Electrolyte imbalance  1  1/122 (0.82%) 
Failure to thrive  1  1/122 (0.82%) 
Hypercalcaemia  1  1/122 (0.82%) 
Hyperkalaemia  1  1/122 (0.82%) 
Hypoglycaemia  1  1/122 (0.82%) 
Hypokalaemia  1  1/122 (0.82%) 
Musculoskeletal and connective tissue disorders   
Muscular weakness  1  1/122 (0.82%) 
Myalgia  1  1/122 (0.82%) 
Rhabdomyolysis  1  1/122 (0.82%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Pancreatic carcinoma  1  14/122 (11.48%) 
Breast cancer  1  6/122 (4.92%) 
Metastases to central nervous system  1  2/122 (1.64%) 
Pancreatic carcinoma metastatic  1  2/122 (1.64%) 
Breast cancer metastatic  1  1/122 (0.82%) 
Cancer pain  1  1/122 (0.82%) 
Lung neoplasm malignant  1  1/122 (0.82%) 
Metastases to meninges  1  1/122 (0.82%) 
Non-small cell lung cancer  1  1/122 (0.82%) 
Tumour pain  1  1/122 (0.82%) 
Nervous system disorders   
Cerebrovascular accident  1  3/122 (2.46%) 
Embolic stroke  1  1/122 (0.82%) 
Metabolic encephalopathy  1  1/122 (0.82%) 
Seizure  1  1/122 (0.82%) 
Psychiatric disorders   
Mental status changes  1  4/122 (3.28%) 
Renal and urinary disorders   
Acute kidney injury  1  3/122 (2.46%) 
Urinary retention  1  2/122 (1.64%) 
Haematuria  1  1/122 (0.82%) 
Obstructive uropathy  1  1/122 (0.82%) 
Renal failure  1  1/122 (0.82%) 
Reproductive system and breast disorders   
Breast mass  1  1/122 (0.82%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1  5/122 (4.10%) 
Pleural effusion  1  5/122 (4.10%) 
Acute respiratory failure  1  3/122 (2.46%) 
Pulmonary embolism  1  3/122 (2.46%) 
Chronic obstructive pulmonary disease  1  2/122 (1.64%) 
Pneumothorax  1  2/122 (1.64%) 
Acute respiratory distress syndrome  1  1/122 (0.82%) 
Alveolitis allergic  1  1/122 (0.82%) 
Dyspnoea exertional  1  1/122 (0.82%) 
Hypoxia  1  1/122 (0.82%) 
Pneumonitis  1  1/122 (0.82%) 
Respiratory failure  1  3/122 (2.46%) 
Skin and subcutaneous tissue disorders   
Rash maculo-papular  1  2/122 (1.64%) 
Purpura  1  1/122 (0.82%) 
Rash  1  1/122 (0.82%) 
Urticaria  1  1/122 (0.82%) 
Vascular disorders   
Hypotension  1  3/122 (2.46%) 
Deep vein thrombosis  1  2/122 (1.64%) 
1
Term from vocabulary, MedDRA (19.1)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase 1b/2
Affected / at Risk (%)
Total   122/122 (100.00%) 
Blood and lymphatic system disorders   
Anaemia  1  26/122 (21.31%) 
Gastrointestinal disorders   
Nausea  1  33/122 (27.05%) 
Diarrhoea  1  22/122 (18.03%) 
Abdominal pain  1  19/122 (15.57%) 
Constipation  1  21/122 (17.21%) 
Vomiting  1  19/122 (15.57%) 
Stomatitis  1  16/122 (13.11%) 
Dyspepsia  1  8/122 (6.56%) 
Gastrooesophageal reflux disease  1  7/122 (5.74%) 
General disorders   
Fatigue  1  53/122 (43.44%) 
Oedema peripheral  1  26/122 (21.31%) 
Pyrexia  1  19/122 (15.57%) 
Infections and infestations   
Urinary tract infection  1  8/122 (6.56%) 
Investigations   
Aspartate aminotransferase increase  1  15/122 (12.30%) 
Weight decreased  1  12/122 (9.84%) 
Alanine aminotransferase increased  1  11/122 (9.02%) 
Blood alkaline phosphatase increased  1  8/122 (6.56%) 
Metabolism and nutrition disorders   
Decreased appetite  1  32/122 (26.23%) 
Hypomagnesaemia  1  28/122 (22.95%) 
Hyponatraemia  1  15/122 (12.30%) 
Hypokalaemia  1  13/122 (10.66%) 
Dehydration  1  9/122 (7.38%) 
Hypoalbuminaemia  1  8/122 (6.56%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  12/122 (9.84%) 
Back pain  1  12/122 (9.84%) 
Myalgia  1  12/122 (9.84%) 
Muscle spasms  1  11/122 (9.02%) 
Muscular weakness  1  8/122 (6.56%) 
Pain in extremity  1  8/122 (6.56%) 
Nervous system disorders   
Dizziness  1  13/122 (10.66%) 
Headache  1  12/122 (9.84%) 
Psychiatric disorders   
Insomnia  1  8/122 (6.56%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1  21/122 (17.21%) 
Cough  1  17/122 (13.93%) 
Epistaxis  1  12/122 (9.84%) 
Skin and subcutaneous tissue disorders   
Rash maculo-papular  1  19/122 (15.57%) 
Pruritus  1  14/122 (11.48%) 
Rash erythematous  1  11/122 (9.02%) 
1
Term from vocabulary, MedDRA (19.1)
Indicates events were collected by 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.
  1. Institution/Investigator will not publish without Sponsor prior review and approval
  2. Institution/Investigator will not publish until the earlier of (i) results of study are submitted for publication (ii) notification that submission of the multicenter results are no longer planned (iii) 18 months after study termination
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Thorsten Graef
Organization: Pharmacyclics LLC, An AbbVie Company
Phone: (408) 215-3127
EMail: tgraef@pcyc.com
Layout table for additonal information
Responsible Party: Pharmacyclics LLC.
ClinicalTrials.gov Identifier: NCT02403271     History of Changes
Other Study ID Numbers: PCYC-1135-CA
First Submitted: February 27, 2015
First Posted: March 31, 2015
Results First Submitted: August 29, 2018
Results First Posted: January 3, 2019
Last Update Posted: January 3, 2019