Breast Cancer, Non-Small Cell Lung Cancer, Pancreatic Cancer
Conditions
Keywords
Pharmacyclics, PCYC, Ibrutinib, Durvalumab (MEDI4736), Relapsed Refractory Solid Tumor, Non-Small Cell Lung Cancer, NSCLC, Squamous, Squamous NSCLC, Squamous Non-Small Cell Lung Cancer, Immunotherapy, IMBRUVICA®, Tumor Immunotherapy, Anti-PD-L1, Lung Cancer, Breast Cancer, Triple Negative, HER2 Positive, HER2 + Breast Cancer, Pancreatic Cancer
Brief summary
This is a Phase 1b/2, multi-center study to assess the safety and efficacy of ibrutinib in combination with durvalumab (MEDI4736) in participants with relapsed or refractory solid tumors.
Interventions
DRUGIbrutinib
BTK Inhibitor
DRUGDurvalumab
Anti PDL-1
Sponsors
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Pathologically confirmed: Non-small cell lung cancer (NSCLC, adenocarcinoma or squamous-cell carcinoma), Breast Cancer (HER2 positive or triple negative), Pancreatic Cancer (adenocarcinoma) 2. Relapsed or refractory disease (Stage III or IV): NSCLC or pancreatic cancer must have failed at least 1 prior treatment. Breast cancer must have failed at least 2 prior treatments. 3. Measurable lesion by RECIST 1.1 4. Adequate hematologic function: * ANC \>1500 cells/mm3 * Platelet count \>100,000 cells/mm3 * HGB \>9.0 g/dL 5. Adequate hepatic and renal function: * AST and ALT ≤2.5 x ULN for subjects without liver metastases and ≤3.5 x ULN for subjects with liver metastases * Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) * Creatinine ≤2.0 x ULN and Creatinine Clearance ≥40 mL/min (Cockcroft-Gault or 24-hour creatinine clearance collection) 6. PT/INR \<1.5 x ULN and PTT/ aPTT \<1.5 x ULN
Exclusion criteria
1. Mixed small cell and NSCLC histology 2. A history of CNS involvement except as follows: Subjects with previously treated CNS metastases that are adequately treated with whole brain radiotherapy, that are neurologically stable, and do not require corticosteroids for symptomatic management for at least 14 days prior to first dose of study drug. There must be no clear evidence of radiographically active disease for at least 90 days prior to enrollment. 3. Anti-tumor therapy within 21 days of study Day 1 4. Prior treatment with ibrutinib or other BTK inhibitor anti-CD137 or CTLA-4 antibody. The following are exceptions to this criterion: Subjects previously treated with an anti-PD1, anti-PD-L1, or anti-PD-L2 antibody. 5. History of allogeneic organ transplant 6. Treatment with a strong cytochrome P450 (CYP) 3A inhibitor
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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. | From the date of first study treatment until DLT or disease progression per RECIST 1.1. |
| 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. | From the date of first study treatment until progressive disease per RECIST 1.1 or unacceptable toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b/2: Pharmacokinetics (Cmax) of Durvalumab (MEDI4736) | 60 minutes post-dose (dose administered as an infusion over a 1 hour period) | Cmax = the peak (maximum) plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1. |
| Phase 1b/2: Pharmacokinetics (Ctrough) of Durvalumab (MEDI4736) | Pre-dose | Ctrough = the trough plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1 |
| Phase 1b/2: Pharmacokinetics (Cmax) of Ibrutinib | 0hr, 1hr, 2hr, and 4hr post-dose | Cmax = the peak (maximum) plasma concentration of ibrutinib during the dosing interval on Cycle 3 Day 1. |
| Phase 2: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Durvalumab (MEDI4736) | From the date of first study treatment until DLT or disease progression per RECIST 1.1. | — |
| Phase 2: Pharmacodynamics | Pre-dose | BTK binding site occupancy of ibrutinib was measured from peripheral blood samples collected from participants during Cycle 3 Day 1. |
| Phase 1b: Pharmacodynamics | From the date of first study treatment until DLT or disease progression per RECIST 1.1. | BTK occupancy |
| Phase 1b/2: Pharmacokinetics (AUC0-24h) of Ibrutinib | 0hr, 1hr, 2hr, and 4hr post-dose | AUC0-24 = the area under the plasma concentration-time curve of ibrutinib during the dosing interval on Cycle 3 Day 1 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b/2 All participants who received at least one dose of study treatment. | 122 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Other varied reasons | 1 | 0 |
| Period 2 | Death | 0 | 84 |
| Period 2 | Lost to Follow-up | 0 | 2 |
| Period 2 | Other varied reasons | 0 | 10 |
| Period 2 | Study Terminated by Sponsor | 0 | 14 |
| Period 2 | Withdrawal by Subject | 0 | 14 |
Baseline characteristics
| Characteristic | Phase 1b/2 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 44 Participants |
| Age, Categorical Between 18 and 65 years | 78 Participants |
| Age, Continuous | 60.0 years STANDARD_DEVIATION 12.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 116 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 104 Participants |
| Region of Enrollment United States | 122 Participants |
| Sex: Female, Male Female | 75 Participants |
| Sex: Female, Male Male | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 96 / 122 |
| other Total, other adverse events | 122 / 122 |
| serious Total, serious adverse events | 77 / 122 |
Outcome results
Primary
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.
Time frame: From the date of first study treatment until DLT or disease progression per RECIST 1.1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b | 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. | 6 participants |
Primary
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.
Time frame: From the date of first study treatment until progressive disease per RECIST 1.1 or unacceptable toxicity.
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b | 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. | 2 Participants |
Secondary
Phase 1b/2: Pharmacokinetics (AUC0-24h) of Ibrutinib
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b | Phase 1b/2: Pharmacokinetics (AUC0-24h) of Ibrutinib | 2126 h.ng/mL | Standard Deviation 1315 |
Secondary
Phase 1b/2: Pharmacokinetics (Cmax) of Durvalumab (MEDI4736)
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)
Population: All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b | Phase 1b/2: Pharmacokinetics (Cmax) of Durvalumab (MEDI4736) | 386 μg/mL | Geometric Coefficient of Variation 19.5 |
Secondary
Phase 1b/2: Pharmacokinetics (Cmax) of Ibrutinib
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b | Phase 1b/2: Pharmacokinetics (Cmax) of Ibrutinib | 218 ng/mL | Standard Deviation 163 |
Secondary
Phase 1b/2: Pharmacokinetics (Ctrough) of Durvalumab (MEDI4736)
Ctrough = the trough plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1
Time frame: Pre-dose
Population: All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b | Phase 1b/2: Pharmacokinetics (Ctrough) of Durvalumab (MEDI4736) | 168 μg/mL | Geometric Coefficient of Variation 19.6 |
Secondary
Phase 1b: Pharmacodynamics
BTK occupancy
Time frame: From the date of first study treatment until DLT or disease progression per RECIST 1.1.
Population: Data not collected
Secondary
Phase 2: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Durvalumab (MEDI4736)
Time frame: From the date of first study treatment until DLT or disease progression per RECIST 1.1.
Population: Participants who enrolled and received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b | Phase 2: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Durvalumab (MEDI4736) | 122 Participants |
Secondary
Phase 2: Pharmacodynamics
BTK binding site occupancy of ibrutinib was measured from peripheral blood samples collected from participants during Cycle 3 Day 1.
Time frame: Pre-dose
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b | Phase 2: Pharmacodynamics | 87.8 percentage of BTK binding site occupancy | Standard Error 4.2 |