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

Study Overview
=================
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.

Official Title
-----------------
A Multi-Center Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination With Durvalumab (MEDI4736), in Subjects With Relapsed or Refractory Solid Tumors

Conditions
-----------------
Non-Small Cell Lung Cancer, Breast Cancer, Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: Ibrutinib
* Drug: Durvalumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically confirmed: Non-small cell lung cancer (NSCLC, adenocarcinoma or squamous-cell carcinoma), Breast Cancer (HER2 positive or triple negative), Pancreatic Cancer (adenocarcinoma) 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. Measurable lesion by RECIST 1.1 Adequate hematologic function: ANC >1500 cells/mm3 Platelet count >100,000 cells/mm3 HGB >9.0 g/dL 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) PT/INR <1.5 x ULN and PTT/ aPTT <1.5 x ULN Exclusion Criteria: Mixed small cell and NSCLC histology 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. Anti-tumor therapy within 21 days of study Day 1 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. History of allogeneic organ transplant Treatment with a strong cytochrome P450 (CYP) 3A inhibitor

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b<br>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). | Drug: Ibrutinib<br>* BTK Inhibitor<br>* Other names: PCI-32765;Drug: Durvalumab<br>* Anti PDL-1<br>* Other names: MEDI4736;|
| Experimental: Phase 2<br>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. | Drug: Ibrutinib<br>* BTK Inhibitor<br>* Other names: PCI-32765;Drug: Durvalumab<br>* Anti PDL-1<br>* Other names: MEDI4736;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b/2: Pharmacokinetics (Cmax) of Ibrutinib | Cmax = the peak (maximum) plasma concentration of ibrutinib during the dosing interval on Cycle 3 Day 1. | 0hr, 1hr, 2hr, and 4hr post-dose | 
| 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 | 0hr, 1hr, 2hr, and 4hr post-dose | 
| Phase 1b/2: Pharmacokinetics (Cmax) of Durvalumab (MEDI4736) | Cmax = the peak (maximum) plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1. | 60 minutes post-dose (dose administered as an infusion over a 1 hour period) | 
| Phase 1b/2: Pharmacokinetics (Ctrough) of Durvalumab (MEDI4736) | Ctrough = the trough plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1 | Pre-dose | 
| Phase 1b: Pharmacodynamics | BTK occupancy | From the date of first study treatment until DLT or disease progression per RECIST 1.1. | 
| 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 | BTK binding site occupancy of ibrutinib was measured from peripheral blood samples collected from participants during Cycle 3 Day 1. | Pre-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Immunotherapy, Pharmacyclics, NSCLC, Squamous, Squamous NSCLC, Squamous Non-Small Cell Lung Cancer, IMBRUVICA®, Tumor Immunotherapy, Anti-PD-L1, Lung Cancer, Breast Cancer, Triple Negative, HER2 Positive, HER2 + Breast Cancer, Pancreatic Cancer, PCYC, Ibrutinib, Durvalumab (MEDI4736), Relapsed Refractory Solid Tumor, Non-Small Cell Lung Cancer