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

Phase 1

Completed

• Conditions: Breast Cancer; Non-Small Cell Lung Cancer; Pancreatic Cancer
• Interventions: Drug: Ibrutinib; Drug: Durvalumab

• Registration Number: NCT02403271
• Lead Sponsor: Pharmacyclics LLC.

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-02-27
• Study Start: 2015-03
• Study First Submitted QC: 2015-03-25
• Study First Posted: 2015-03-31
• Primary Completion: 2017-08
• Study Completion: 2017-08
• Results First Submitted: 2018-08-29
• Status Verified: 2018-12
• Results First Submitted QC: 2018-12-07
• Last Update Submitted: 2018-12-07
• Results First Posted: 2019-01-03
• Last Update Posted: 2019-01-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 124

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 1b	Ibrutinib	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).
Phase 1b	Durvalumab	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).
Phase 2	Durvalumab	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.
Phase 2	Ibrutinib	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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 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 1b: Pharmacodynamics	From the date of first study treatment until DLT or disease progression per RECIST 1.1.	BTK occupancy
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 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
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.