Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Trastuzumab

Ibrutinib

Antineoplastic Agents, Immunological

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

In Phase I, starting dose of Ibrutinib will be 560 mg orally per day. 3 patients will be enrolled first. If none of these have DLTs, 3 new patients will be enrolled at the next higher Ibrutinib dose level (840 mg orally per day). If 1 of these 3 patients have a DLT, expand this arm to 6 patients. If 2 or more of these 6 patients have a DLT, enroll 3 patients in lower dose lever (420 mg).

If no patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this higher dose is tolerated.

If 2 or more patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this lower dose is tolerated.

Maximum tolerated dose from Phase I will be used here in Phase II.

8 mg/kg loading dose (first dose), followed by 6 mg/kg every 3 weeks, administered intravenously (IV)

Ibrutinib 560 mg

Ibrutinib 840 mg

Ibrutinib 420 mg

Joyce O'Shaughnessy, MD

This is a Phase I/II, open-label dose-escalation study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting side effects of ibrutinib (560 or 840 or 420 mg daily oral dose), given in combination with trastuzumab administered through the vein, in patients with HER2-amplified Metastatic Breast Cancer that has gotten worse after prior therapy with ado-trastuzumab emtansine (T-DM1).

Ado-trastuzumab emtansine (T-DM1) is approved by the FDA for patients with HER2-positive metastatic breast cancer (MBC) previously treated with a taxane and trastuzumab, and is currently listed as the preferred second-line therapy in the NCCN guidelines (NCCN 2014). While the benefit of continued HER2 inhibition has been conclusively established for disease that has progressed on a trastuzumab-containing regimen, there are currently no data regarding the efficacy of HER2- targeted therapies following progression on T-DM1.

With the population of T-DM1-treated patients steadily growing, clinical trials are needed to investigate novel therapies in this setting,to meet the medical need for effective, evidence-based therapies for these patients.

The oral small-molecule Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib has also demonstrated the ability to inhibit erythroblastosis virus oncogene B (ErbB)/HER receptor family kinases in preclinical studies at clinically relevant concentrations, with an equivalent or greater potency than other HER2-directed tyrosine kinase inhibitors (TKIs) with demonstrated activity in HER2-positive MBC, including lapatinib, neratinib, and afatinib. Of note, in preclinical HER2-positive cell model systems the growth inhibitory ability of ibrutinib was substantially greater in HER2-amplified breast cancer cells versus those that simply overexpressed the HER2 protein.

Ibrutinib is currently approved for use in patients with Chronic lymphocytic leukemia (CLL) or Mantle cell lymphoma (MCL), and has an established safety record from clinical trials in these patient populations. Thus there is a reasonable rationale to investigate ibrutinib in patients with HER2- amplified MBC, in the setting of T-DM1-pretreated disease. Previous studies have demonstrated that combined targeting of HER2 with multiple HER2-directed agents is more effective that single agent therapy and therefore this study will explore the safety and efficacy of ibrutinib in combination with trastuzumab.

This is a Phase I/II, open-label, unblinded, nonrandomized, standard 3+3 dose-escalation study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of ibrutinib (560 or 840 or 420 mg QD) given orally in combination with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg q3w) administered intravenously (IV) in patients with HER2-amplified MBC that has progressed on prior therapy with ado-trastuzumab emtansine.

Once the recommended phase II dose of ibrutinib plus trastuzumab has been determined (no more than 1 of 6 patients with dose-limiting toxicity) in the required 6 to 18 patients over the 3 possible dose levels, additional patients will be enrolled on the phase II part of the study at the recommended phase II dose of ibrutinib plus trastuzumab, for a maximum of 51 patients total.

This is a Phase I/II, open-label, unblinded, nonrandomized, standard 3+3 dose-escalation study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of ibrutinib (560 or 840 or 420 mg QD) given orally in combination with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg q3w) administered intravenously (IV) in patients with HER2-amplified MBC.

Once the recommended phase II dose of ibrutinib plus trastuzumab has been determined (no more than 1 of 6 patients with dose-limiting toxicity) in the required 6 to 18 patients over the 3 possible dose levels, additional patients will be enrolled on the phase II part of the study at the recommended phase II dose of ibrutinib plus trastuzumab, for a maximum of 51 patients total.

Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer

Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer

Changes in Th1- and Th2-related cytokine gene expression in whole blood, from Baseline to Week 12 to End of Treatment with ibrutinib plus trastuzumab, using NanoString human immunology gene panel.

Highest dose of ibrutinib from Phase 1 (420, 560, or 840 mg by mouth daily) that had fewer than two dose-limiting toxicities in its respective cohort

To define the clinical benefit rate (CBR = CR \[complete response\] + PR \[partial response\] + SD \[stable disease\] \> 6 months) of ibrutinib plus trastuzumab in patients with HER2-amplified, T-DM1-pretreated MBC

To determine the objective response rate (ORR = CR + PR) associated with ibrutinib plus trastuzumab.

To assess median overall survival (OS) associated with ibrutinib plus trastuzumab.

To assess median progression-free survival (PFS) associated with ibrutinib plus trastuzumab

Number of Adverse Events and Serious Adverse Events from informed consent signature to 30 days after last dose of study drug, using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.03: June 14, 2010)

maximum (or peak) serum concentration that Ibrutinib achieves in Cycle 1 at indicated time points, and on Day 1 of cycle 3 for pharmacokinetic analysis

Area Under the Curve of Ibrutinib in 24 hours

AbbVie

Pharmacyclics LLC.

US Oncology Research

Blood and Lymph Conditions

Immune System Diseases

Symptoms and General Pathology

Rare Diseases

Lymphoma

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoma, Mantle-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Lymphoma, Non-Hodgkin

Lymphosarcoma

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Mantle Cell Lymphoma

Chromosome 17p Deletion

Participants will receive ibrutinib 420 milligram (mg) (three 140 mg capsules) as a single daily dose for chronic lymphocytic leukemia (CLL) and 560 mg (four 140 mg capsules) as a single daily dose for mantle cell lymphoma (MCL) for up to 12 months or till disease progression, whichever is earlier.

Ibrutinib capsule administered orally at a dose of 420 mg for CLL participants.

Ibrutinib capsule administered orally at a dose of 560 mg for MCL participants.

Johnson & Johnson Private Limited Clinical Trial

The primary purpose of this study is to evaluate the post-marketing safety of ImbruvicaTM (ibrutinib capsule 140 milligram \[mg\]) under actual conditions of use, and to understand the incidence of adverse events (AEs) (serious and non-serious AEs).

A Study to Assess Safety of ImbruvicaTM in Indian Participants With Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy or Chronic Lymphocytic Leukemia With 17p Deletion

A Prospective, Multicenter, Open Label Single Arm Phase IV Clinical Trial to Assess Safety of ImbruvicaTM (Ibrutinib Capsules 140 mg) in Indian Patients With Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy or Chronic Lymphocytic Leukemia With 17p Deletion

An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Any AE occurred at or after the initial administration of study drug up to maximum of 30 days after last dose was considered as treatment emergent.

An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was an AE which resulted in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Any AE occurred at or after the initial administration of study drug up to maximum of 30 days after last dose was considered as treatment emergent.

Johnson & Johnson Private Limited

Safety analysis set included all participants who had signed the ICF and received at least one dose of ibrutinib.

Enrolled participants were prescribed ibrutinib as per locally approved prescribing information: a single daily dose of ibrutinib 420 mg (3 capsules of 140 mg) for participants with CLL and ibrutinib 560 mg (4 capsules of 140 mg) for participants with MCL, for up to 12 months or till disease progression, whichever was earlier.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

India

Region of Enrollment

Sr. Medical Advisor

Safety analysis set included all participants who had signed the informed consent form (ICF) and received at least one dose of ibrutinib.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer	NCT03379428	Breast Neoplasm... Malignant Neopl...	Trastuzumab Ibrutinib 560 m... Ibrutinib 840 m... Ibrutinib 420 m...	18 Years -	US Oncology Research
A Study to Assess Safety of ImbruvicaTM in Indian Participants With Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy or Chronic Lymphocytic Leukemia With 17p Deletion	NCT03190330	Leukemia, Lymph... Lymphoma, Mantl...	Ibrutinib 420 m... Ibrutinib 560 m...	18 Years -	Johnson & Johnson Private Limited

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