ARRY-380 + Trastuzuamab for Breast w/ Brain Mets

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ClinicalTrials.gov Identifier: NCT01921335

Recruitment Status : Active, not recruiting

First Posted : August 13, 2013

Last Update Posted : August 16, 2022

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborators:

Array BioPharma

Breast Cancer Research Foundation

Information provided by (Responsible Party):

Nancy Lin, MD, Dana-Farber Cancer Institute

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Brain Metastases From HER2 and Breast Cancer Advanced HER2-positive Breast Cancer	Drug: ARRY-380 Twice Daily Dosage Drug: ARRY-380 Once Daily Drug: Trastuzumab	Phase 1

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Detailed Description:

If a patient participates in this research study, the patient will receive ARRY-380 and a drug-dosing diary to record when the patient took ARRY-380 for each study treatment cycle. Each study treatment cycle will last for 3 weeks (21 days) during which time the patient will be taking ARRY-380 by mouth every day. At the time the patient enters the study, the patient will be assigned to either Arm A or Arm B. The difference between the two study arms includes ARRY-380 administered twice-daily (morning and evenings - Arm A) or once-daily (morning - Arm B). The patient will also be given Trastuzumab by intravenous infusion (by vein) on day 1 of each cycle (same dose and schedule for both study arms).

The dose of trastuzumab will be the same for everyone on study, and will be the standard approved dose for this medication. In the first portion of the study, the investigators will examine the effects of different dose of ARRY-380 when given in combination with trastuzumab. Initially, 3 participants will be treated with a low dose of the ARRY-380 in combination with standard dose of trastuzumab. If this dose does not cause intolerable side effects, more participants may receive the drug combination at the same dose. The patient will be informed of the assigned dose when the patient enters the study. The patient will be asked to take ARRY-380 for as long as the study treatment is of possible benefit to the patient. After the patient is finished taking ARRY-380, the study doctor will ask the patient to visit the office for follow-up exams for at least one more visit within 4 weeks of the patient's last study treatment.

At the start of each cycle the patient will have:

A medical history, which includes questions about health, current medications, and any allergies.
Performance status, which evaluates the ability to carry on with usual activities.
Physical examination, the doctor will examine the patient body, including measuring height, weight, and vital signs (blood pressure, body temperature, pulse rate and breathing rate).
A neurological examination to asses any neurological symptoms(for example, difficulties with balance)
Blood tests will be drawn at the beginning of each study treatment cycle for tests to monitor the function of liver and kidneys and to check blood cell counts. In addition, blood tests will be drawn on days 4, 8, and 15 of the first cycle of study treatment to monitor liver function.

Periodically the patient will undergo:

The patient will have a brain MRI every two cycles. If the brain scans are stable or improved after the patient has been on the study for 6 months or longer, the frequency of your body scans will be decreased to once every 4 cycles. The patient will also have CT or MRI scans of the body at the end of cycle 2, cycle 4 and every 4 cycles thereafter. The research doctor may ask the patient to have a bone scan at the same time points if this is clinically indicated.
Electrocardiogram (EKG), which shows the electrical activity of the heart. It will be performed on Day 1 of cycle 2.
Echocardiogram (ECHO) (ultrasound of the heart) or MUGA scan (test of heart function using a small amount of a radioactive substance). This will be performed every 3-4 months.

Additional research procedures to be performed:

On Cycle 1, Day 15 blood for ("PK") pharmacokinetic (what the body does to the drug) sampling will be drawn before the morning dose of ARRY-380, after 2 hours and after six hours.
Blood tests for research, which will include about 2 tablespoons of blood collected before cycle 1 and after coming off study treatment. In general terms, scientists will study the genes, the RNA, and the proteins that are found in the blood samples. Scientists will also measure and characterize circulating tumor cells in the blood, if they are present. In addition, these specimens may be tested with new types of tests, as they become available. Results of the research tests on blood will not be reported back to the patient.
Archival Tumor Tissue Sample: A sample (or samples) of the patient's tumor tissue (from a past surgery and/or biopsy) will be collected and used to learn more about the development of metastatic breast cancer. In general terms, scientists will study the genes, the RNA, and the proteins that are found both in breast tumors and in normal tissue. In addition, these specimens may be tested with new types of tests, as they become available. Laboratory-based investigators conducting this research will not have access to patient identification information such as name or medical record number. Results of the research tests on tissue will not be reported back to the patient.

After the final dose of the study drug:

The patient will have a follow-up visit one month after coming off study treatment. During that visit, the patient will have a physical examination, functional assessment, assessment of any toxicities and current medications. If the patient continues to have ongoing side effects related to the study treatment, the investigators will continue to follow the patient until these side effects resolve. If the patient withdrew from the study for another reason other than tumor progression, the patient will continue to be followed until tumor progression.

Planned Follow-up:

The investigators would like to keep track of the patient's medical condition indefinitely. The investigators would like to do this either by seeing the patient in clinic or by contacting the patient and the patient's primary doctor periodically to see how the patient is doing. Keeping in touch with the patient and checking the patient's condition periodically helps the investigators look at the long-term effects of the research study.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	41 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase I Dose-escalation Trial of ARRY-380 in Combination With Trastuzumab in Participants With Brain Metastases From HER2+ Breast Cancer
Actual Study Start Date :	August 2013
Actual Primary Completion Date :	March 2018
Estimated Study Completion Date :	December 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Breast cancer

MedlinePlus related topics: Breast Cancer

Drug Information available for: Trastuzumab

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: ARRY-380 Twice Daily Dosage 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 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. Drug: Trastuzumab 6 mg/kg IV every 3 weeks Other Name: Herceptin
Active Comparator: ARRY-380 Once Daily 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 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. Drug: Trastuzumab 6 mg/kg IV every 3 weeks Other Name: Herceptin

Arm

Intervention/treatment

Active Comparator: ARRY-380 Twice Daily Dosage

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

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.

Drug: Trastuzumab

6 mg/kg IV every 3 weeks

Other Name: Herceptin

Active Comparator: ARRY-380 Once Daily

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

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.

Drug: Trastuzumab

6 mg/kg IV every 3 weeks

Other Name: Herceptin

Outcome Measures

Primary Outcome Measures :

Determine Maximum-tolerated dose of ARRY-380 with Trastuzumab [ Time Frame: 2 years ]
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)

Secondary Outcome Measures :

CNS objective response rate according to volumetric criteria [ Time Frame: 2 Years ]
CNS objective response rate according to volumetric criteria
Non-CNS objective response rate according to RECIST 1.1 [ Time Frame: 2 years ]
Non-CNS objective response rate according to RECIST 1.1
Proportion of participants with stable or responsive disease in both CNS and non-CNS at 16 and 24 weeks. [ Time Frame: 2 Years ]
Proportion of participants with stable or responsive disease in both CNS and non-CNS at 16 and 24 weeks.
Progression-free survival [ Time Frame: 2 Years ]
Progression-free survival
Clinical benefit (CR, PR, or SD>/=24 weeks) [ Time Frame: 2 Years ]
Clinical benefit (CR, PR, or SD>/=24 weeks)
Overall survival [ Time Frame: 2 Years ]
Overall survival
CNS Response according to modified RECIST 1.1 [ Time Frame: 2 years ]

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

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
AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal in participants without liver metastases and < 5 ULN in participants with documented liver metastases
Left ventricular ejection fraction ≥ 50%, as determined by RVG or echocardiogram within 60 days prior to initiation of protocol therapy
Prior therapy - Prior trastuzumab and/or lapatinib are allowed. There is no limit on the number of prior lines of therapy.
The effects of ARRY-380 on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial may be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01921335

Locations

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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215

Sponsors and Collaborators

Dana-Farber Cancer Institute

Array BioPharma

Breast Cancer Research Foundation

Investigators

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Principal Investigator:	Nancy Lin, MD	Dana-Farber Cancer Institute

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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Responsible Party:	Nancy Lin, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT01921335
Other Study ID Numbers:	13-198 ARRAY-380-104X ( Other Grant/Funding Number: Array BioPharma )
First Posted:	August 13, 2013 Key Record Dates
Last Update Posted:	August 16, 2022
Last Verified:	August 2022

Keywords provided by Nancy Lin, MD, Dana-Farber Cancer Institute:


ARRY-380 Trastuzumab Advanced HER2-positive breast cancer

Additional relevant MeSH terms:

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Breast Neoplasms Neoplasm Metastasis Brain Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Neoplastic Processes Pathologic Processes	Central Nervous System Neoplasms Nervous System Neoplasms Brain Diseases Central Nervous System Diseases Nervous System Diseases Trastuzumab Antineoplastic Agents, Immunological Antineoplastic Agents

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