ARRY-380 + Trastuzuamab for Breast w/ Brain Mets

NCT01921335 | Completed Phase 1 DMC

• 2 other identifiers: 13-198ARRAY-380-104X
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to test the safety of different doses of ARRY-380 in combination with trastuzumab. Trastuzumab is an FDA approved drug for the treatment of HER2 metastatic breast cancer. However, the combination of ARRY-380 and trastuzumab has not yet been tested. Both agents block the HER2 receptor, which is thought to be overactive in HER2-positive breast cancer. It is thought that ARRY-380 and trastuzumab might work together because they attach to different parts of the HER2 receptor and prevent it from functioning. Because HER2 positive breast cancer contains high levels of HER2 receptor, but normal cells in your body generally do not, the drugs may be able to "target" the cancer cells. In addition, in laboratory studies, ARRY-380 appears to have some penetration into the brain.

Conditions

Brain Metastases From HER2 and Breast Cancer; Advanced HER2-positive Breast Cancer

Keywords

ARRY-380; Trastuzumab; Advanced HER2-positive breast cancer

Outcome Measures

Primary Outcomes (1)

• Determine Maximum-tolerated dose of ARRY-380 with Trastuzumab

  To determine the maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ARRY-380 in combination with trastuzumab in participants with HER2+ breast cancer and central nervous system (CNS metastasis)

  2 years

Secondary Outcomes (7)

• CNS objective response rate according to volumetric criteria

  2 Years

• Non-CNS objective response rate according to RECIST 1.1

  2 years

• Proportion of participants with stable or responsive disease in both CNS and non-CNS at 16 and 24 weeks.

  2 Years

• Progression-free survival

  2 Years

• Clinical benefit (CR, PR, or SD>/=24 weeks)

  2 Years

Study Arms (2)

ARRY-380 Twice Daily Dosage

ACTIVE COMPARATOR

ARRY-380 will be 450mg orally twice-daily. Trastuzumab will be given at the standard full dose with a loading dose of 8 mg/kg on Day 1, cycle 1, followed by 6 mg/kg in subsequent cycles. Participants who are within 5 weeks of a 6 mg/kg dose or within 2 weeks of a 2 mg/kg dose of trastuzumab at the time of initial study dosing will not be required to have a re-loading dose but will begin treatment at 6 mg/kg.ARRY-380 will be escalated until MTD is defined or the maximum planned dose has been evaluated. The dose for subsequent dose levels will be determined according to the treatment-related AE observed during the cycle 1 (21 days) in the previous dose level

Drug: ARRY-380 Twice Daily Dosage; Drug: Trastuzumab

ARRY-380 Once Daily

ACTIVE COMPARATOR

ARRY-380 will be 750mg orally once-daily. Trastuzumab will be given at the standard full dose with a loading dose of 8 mg/kg on Day 1, cycle 1, followed by 6 mg/kg in subsequent cycles. Participants who are within 5 weeks of a 6 mg/kg dose or within 2 weeks of a 2 mg/kg dose of trastuzumab at the time of initial study dosing will not be required to have a re-loading dose but will begin treatment at 6 mg/kg. ARRY-380 will be escalated until MTD is defined or the maximum planned dose has been evaluated. The dose for subsequent dose levels will be determined according to the treatment-related AE observed during the cycle 1 (21 days) in the previous dose level

Drug: ARRY-380 Once Daily; Drug: Trastuzumab

Interventions

ARRY-380 Twice Daily Dosage DRUG

ARRY-380 will be administered daily (either twice-daily along with concurrent administration of trastuzumab on Day 1. PK sampling of ARRY-380 is planned on Day 15. Blood samples will be collected at pre-dosing, 2 hours (± 1 hour), and 6 hours (± 2 hours). The same time points will be collected for BID and QD schedules. On the PK collection day participants should fast one hour before and one hour after taking ARRY-380.

ARRY-380 Twice Daily Dosage

ARRY-380 Once Daily DRUG

ARRY-380 will be administered daily once-daily) along with concurrent administration of trastuzumab on Day 1. PK sampling of ARRY-380 is planned on Day 15. Blood samples will be collected at pre-dosing, 2 hours (± 1 hour), and 6 hours (± 2 hours). The same time points will be collected for BID and QD schedules. On the PK collection day participants should fast one hour before and one hour after taking ARRY-380.

ARRY-380 Once Daily

Trastuzumab DRUG

6 mg/kg IV every 3 weeks

Also known as: Herceptin

ARRY-380 Once Daily; ARRY-380 Twice Daily Dosage

Eligibility Criteria

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

You may qualify if:

• Participants must meet the following criteria on screening examination to be eligible to participate in the study. Laboratory evaluations must have been performed within 14 days of study entry. Non-laboratory tests must have been performed within 30 days of study entry. Evaluation of LVEF must have been performed within 60 days of study entry:
• Participants must have histologically confirmed HER2+ (3+ by immunohistochemistry and/or FISH ratio \>/= 2.0) invasive breast cancer. Central confirmation of HER2 status is not required.
• Participants must have measurable CNS disease, defined as at least one parenchymal brain lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 10 mm by local radiology review (note: measurable non-CNS disease is NOT required for study participation). See section 10 for the evaluation of measureable disease.
• New or progressive CNS lesions, as assessed by the patient's treating physician.
• It is anticipated that some participants may have multiple progressive CNS lesions, one or several of which are treated with SRS or surgery with residual un-treated lesions remaining. Such participants are eligible for enrollment on this study providing that at least one untreated lesion is measurable, as defined in section 3.1.2. The location of the measurable lesion should be documented in the patient chart and case report form.
• Participants who have had prior cranial surgery are eligible, provided that there is evidence of measurable residual or progressive lesions. If a patient has surgical resection followed by WBRT, then there must be evidence of progressive CNS disease after the completion of WBRT.
• Participants who have had prior WBRT and/or SRS and then whose lesions have progressed thereafter are also eligible. In this case, lesions which have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression following SRS.
• Participants who have not previously been treated with cranial radiation (e.g. WBRT or SRS) are eligible to enter the study, but such participants must be asymptomatic from their CNS metastases and not requiring corticosteroids.
• No increase in corticosteroid dose in the week prior to the baseline brain MRI.
• Age ≥18 years
• ECOG performance status 0 to 2 (see Appendix A)
• Participants must have normal organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1,000/mcL
• Platelets ≥ 75,000/mcL
• Total bilirubin \< 2 X institutional upper limit of normal

You may not qualify if:

• Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.
• Participants who have had chemotherapy or radiotherapy within 14 days prior to entering the study (with the exception of trastuzumab) or those who have not recovered from adverse events to ≤ grade 1 due to agents administered more than 4 weeks earlier.
• Participants may not be receiving any other investigational agents. Concurrent treatment with bisphosphonates or denosumab is allowed
• History of grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition to ARRY-380 or trastuzumab
• Known contraindication to MRI with gadolinium contrast, such as cardiac pacemaker, shrapnel, or ocular foreign body
• Leptomeningeal carcinomatosis as the only site of CNS involvement
• More than 2 seizures over the last 4 weeks prior to study entry
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnancy (positive pregnancy test) or lactation
• Individuals with a history of a different active malignancy are ineligible. Participants with a history of other malignancies are eligible if they have been disease-free for at least 2 years, not on active treatment, and deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 2 years: cervical cancer in situ, basal cell or squamous cell carcinoma of the skin.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Array BioPharma: collaborator
• Breast Cancer Research Foundation: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Metzger Filho O, Leone JP, Li T, Tan-Wasielewski Z, Trippa L, Barry WT, Younger J, Lawler E, Walker L, Freedman RA, Tolaney SM, Krop I, Winer EP, Lin NU. Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases. Ann Oncol. 2020 Sep;31(9):1231-1239. doi: 10.1016/j.annonc.2020.05.014. Epub 2020 May 24.

  PMID: 32461105 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

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

• Nancy Lin, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 2, 2013
• First Posted: August 13, 2013
• Study Start: August 1, 2013
• Primary Completion: March 1, 2018
• Study Completion: December 31, 2023
• Last Updated: November 6, 2024

Record last verified: 2024-11

Locations

US (2)