Open-Label Study Evaluating the Safety and Tolerability of LJM716, BYL719 and Trastuzumab in Patients With Metastatic HER2+ Breast Cancer

NCT02167854 | Completed Phase 1

• 1 other identifier: 14-057
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 6

Brief Summary

This is a Phase I study. The purpose of this study is to determine what is the best dose of the study drug BYL719 in combination with the study drug LJM716 and traztuzumab (Herceptin®). The study will test the safety of the combination of these three drugs, and to find out the effects, good and/or bad, that these three drugs have on the patient and breast cancer.

Conditions

Breast Cancer

Keywords

LJM716; BYL719 [Alpelisib]; TRASTUZUMAB; HER2+; 14-057

Outcome Measures

Primary Outcomes (2)

• maximum tolerated dose (MTD) of BYL719

  1 year

• recommended dose for expansion (RDE)

  The MTD is defined as per the Continual Reassessment Method. The RDE will be determined by the Principal Investigator with input from other investigators and Novartis, and will be based on the MTD, review of required intra-patient dose de-escalations, pharmacodynamic evaluations, and consideration of toxicities occurring in cycles 2+.

  1 year

Secondary Outcomes (1)

• Toxicity will be assessed using the NCI Common Toxicity Criteria, version 4.0, unless otherwise specified. The type, severity, timing and relationship of each adverse event will be documented.

  2 years

Study Arms (1)

LJM716, BYL719 AND TRASTUZUMAB

EXPERIMENTAL

A treatment cycle will consist of 28 days. Treatment doses for trastuzumab and LJM716 will be fixed at trastuzumab 2mg/kg weekly, and LJM716 20mg/kg weekly. The exception to this is if dose de-escalation results in treatment of patients at dose level 1, where LJM will be dosed at 10mg/kg weekly. On Arm A, BYL719 was administered orally once daily continuously at one of 5 dosing levels, beginning with dose level 3, 250mg orally daily. On Arm B, BYL719 will be administered orally once daily during 4 of 7 days in a week, at one of 5 dosing levels, beginning with dose level 3, 250mg orally daily. This means BYL719 will be given to patients on Arm B during days 1-4, 8-11, 15-18, and 22-25 of each cycle. The dose-finding phase will follow a Continuous Reassessment Methods (CRM) phase I biostatistical design.

Drug: BYL719; Drug: LJM716; Drug: TRASTUZUMAB

Interventions

BYL719 DRUG

LJM716, BYL719 AND TRASTUZUMAB

LJM716 DRUG

LJM716, BYL719 AND TRASTUZUMAB

TRASTUZUMAB DRUG

LJM716, BYL719 AND TRASTUZUMAB

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- Age ≥ 18 years
• Willing and able to comply with scheduled visits, treatment plan and laboratory tests, including biopsies
• Patients with a histologically or cytologically confirmed diagnosis of breast cancer. Patients must have metastatic HER2+ disease.
• Documented HER2+ breast cancer defined as: 3+ by IHC or with amplification by in situ hybridization with ratio ≥ 2.0 ; results from the local lab are acceptable. Eligibility will not be affected by hormone receptor status.
• For the dose-escalation phase, a PIK3CA mutation is also required. MSKCC or outside documentation is acceptable.
• There is no upper limit on prior chemotherapy, targeted therapy, or endocrine therapy.
• \- HER2+ patients must have received pertuzumab and TDM-1 (ado-trastuzumab emtansine) prior to trial enrollment. unless deemed ineligible for these therapies, and with the exceptions listed below:
• Patients with metastatic breast cancer who have not received prior pertuzumab are eligible if: heavily pretreated prior to FDA approval of pertuzumab (6/8/2012) for first-line treatment of HER2+ MBC
• Patients with metastatic breast cancer who have not received ado-trastuzumab emtansine are eligible if: heavily pretreated prior to FDA approval of ado-trastuzumab emtansine (2/22/2013) for the treatment of patients with HER2+ MBC who previously received trastuzumab and a taxane separately or in combination - For the dose-escalation phase, measurable or non-measurable disease per RECIST criteria v1.1 is permitted. For the dose expansion phase, patients must have measurable disease by RECIST v1.1.
• Patients must have archived tumor specimens available unless pre-treatment biopsy is being performed. If pre-treatment biopsy is being performed, availability of archived specimen must still be assessed and collected if available.
• ECOG performance status 0-1
• Adequate organ function, as defined by all of the following:
• i. Hematologic parameters:
• Absolute neutrophil count (ANC) ≥ 1500/μl (without growth factor support)
• Platelets ≥ 100,000/μl (no platelet transfusion allowed within 2 weeks)

You may not qualify if:

• Patients with untreated or symptomatic metastatic central nervous system (CNS) disease. However patients with CNS involvement may participate if:
• i. Clinically stable with respect to the CNS tumor at the time of screening and \>4 weeks from prior therapy completion (including radiation and/or surgery) to the start of study treatment ii. Not receiving steroid therapy iii. Not receiving enzyme inducing anti-epileptic medications that were started for brain metastases (these include carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, topiramate, and vigabatrin)
• Patients who have received chemotherapy within 3 weeks prior to the initiation of study treatment, or endocrine therapy within 2 weeks prior to the initiation of study treatment.
• Current grade ≥ 1 toxicity (except alopecia) from prior therapy
• History of prior grade 3 or 4 hypersensitivity or any toxicity to trastuzumab that warranted permanent cessation of this antibody
• Patients who have received radiotherapy ≤ 2 weeks prior to starting study treatment and/or from whom ≥ 30% of the bone marrow was irradiated as determined by the Investigator
• Patients who have undergone major surgery ≤ 4 weeks prior to starting study treatment, who have not recovered from side effects of such procedure
• Patient with diabetes mellitus that is suboptimally controlled (fasting plasma glucose ≥ 140, glycosylated hemoglobin \>7.0) despite oral medication, insulin-dependent diabetes, or documented steroid-induced diabetes mellitus
• Current need for chronic corticosteroid therapy or other immunosuppressive agents (≥10mg of prednisone daily or an equivalent dose of other corticosteroid), or patients who have received systemic corticosteroids ≤ 2 weeks prior to starting study drug
• Current therapeutic anticoagulation with warfarin (or coumarin derivatives) Prior treatment with a PI3K or AKT inhibitor. Patients previously treated with an mTOR inhibitor are eligible.
• Clinically significant cardiac disease or impaired cardiac function, such as:
• i. Baseline LVEF \< 50% on baseline echocardiogram or MUGA ii. Congestive heart failure requiring treatment (e.g., New York Heart Association Class II, III or IV) within 6 months prior to screening iii. Acute coronary syndromes \< 3 months prior to screening (including myocardial infarction, unstable angina, coronary artery bypass graft, coronary angioplasty, or stenting) iv. Uncontrolled arterial hypertension defined by blood pressure \> 140/100 mm Hg at rest (average of 3 consecutive readings) v. History or current evidence of unstable, clinically significant cardiac arrhythmias vi. Patients that require medications with a narrow therapeutic window vii. Clinically significant conduction abnormality, e.g. congenital long QT syndrome, high-Grade/complete AV-blockage viii. Corrected QT interval (QTc) \> 480 msec on screening ECG
• Patients who are currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment
• Impaired gastrointestinal function or poorly controlled gastrointestinal disease that may significantly alter the absorption of oral BYL719 (e.g. Crohn's disease, ulcerative colitis, malabsorption syndrome, small bowel resection, uncontrolled nausea or vomiting, or grade ≥ 3 diarrhea of any etiology) based on treating physician assessment
• Patients may not have a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse.

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Novartis: collaborator

Study Sites (6)

Memorial Sloan Kettering at Basking Ridge

Basking Ridge, New Jersey, 07920, United States

Location

Memorial Sloan Kettering Monmouth

Middletown, New Jersey, 07748, United States

Location

Memorial Sloan Kettering Commack

Commack, New York, 11725, United States

Location

Memoral Sloan Kettering Westchester

Harrison, New York, 10604, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Memorial Sloan Kettering Rockville Centre

Rockville Centre, New York, 11570, United States

Location

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Alpelisib; elgemtumab; Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Shanu Modi, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2014
• First Posted: June 19, 2014
• Study Start: June 16, 2014
• Primary Completion: July 7, 2021
• Study Completion: July 7, 2021
• Last Updated: July 9, 2021

Record last verified: 2021-07

Locations

US (6)