GDC-0084 and Trastuzumab in Treating Patients with HER2 Positive Breast Cancer Brain Metastases

Status: Active

Description

This phase II trial studies how well PI3K inhibitor GDC-0084 (GDC-0084) in combination with trastuzumab works in treating patients with HER2 positive breast cancer that has spread to the brain. GDC-0084 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Trastuzumab is a form of “targeted therapy” because it works by attaching itself to specific molecules (receptors) on the surface of breast cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by body’s immune system. It is not yet known how a HER2-positive breast cancer that has spread to the brain responds to combination of GDC-0084 and trastuzumab.

Eligibility Criteria

Inclusion Criteria

  • COHORT A: At least one measurable CNS metastasis, defined as >= 10 mm in at least one dimension
  • COHORT A: Unequivocal evidence of new and/or progressive brain metastases, and at least one of the following scenarios: * Treated with stereotactic radiosurgery (SRS) or surgery with residual un-treated lesions remaining. Such participants are eligible for immediate enrollment on this study providing that at least one untreated lesion is measurable * Participants who have had prior whole brain radiotherapy (WBRT) and/or SRS and then whose lesions have subsequently progressed or who have new lesions 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 for symptom control * Participants who present with systemic stable/absent or progressive disease are eligible to this trial, as long as they fulfill one of the above criteria
  • COHORT B: New and/or progressive brain metastasis(es) with clinical indication for resection
  • Pathologically confirmed HER2-positive MBC by local laboratory with the following requirements: HER2 overexpressed or amplified (immunohistochemistry of 3+ or HER2 gene amplification by in situ hybridization with a ratio of HER2-gene signals to centromere 17 signals >= 2.0 or average HER2 copy number >= 6.0 signals/cells)
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
  • Stable or decreasing corticosteroid dose for at least 7 days prior to initiation of treatment
  • Concurrent administration of other anti-cancer therapy during the course of this study is not allowed. Note that concurrent use of supportive care medications (e.g. anti-resorptive agents, pain medications) is allowed
  • Absolute neutrophil count >= 1,000/ul
  • Platelets >= 75,000/ul
  • Hemoglobin >= 9 g/dL
  • Total bilirubin =< 1.5 mg/dL (upper limit of normal) except subject with documented Gilbert's syndrome (=< 5 x upper limit of normal [ULN]) or liver metastasis, who must have a baseline total bilirubin =< 3.0 mg/dL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN OR =< 5.0 x institutional ULN for patients with documented liver metastases
  • Serum creatinine =< 1.5 mg/dL (or glomerular filtration rate >= 30 ml/min as determined by the Cockcroft-Gault equation)
  • Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 8 days of initiating protocol therapy
  • The effects of GDC-0084 on the developing human fetus are unknown and radiotherapy has known teratogenic effects so women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 7 months after completion of trastuzumab administration per recommendations from the trastuzumab package insert
  • The subject is capable of understanding and complying with the protocol and has signed the informed consent document
  • Participant must be able to swallow and retain oral medication

Exclusion Criteria

  • Visceral crisis or impending visceral crisis at time of screening
  • CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt placement)
  • Known leptomeningeal metastases (defined as positive CSF cytology and/or unequivocal radiological evidence of clinically significant leptomeningeal involvement. CSF sampling is not required in the absence of suggestive symptoms to exclude leptomeningeal involvement)
  • Patients with known contraindication to magnetic resonance imaging (MRI) (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme obesity, hypersensitivity, etc.). However, head computed tomography (CT) with contrast may be used in place of MRI at baseline and throughout the trial if MRI is contraindicated and a participant’s brain metastases are clearly measurable by head CT
  • Chemotherapy or targeted therapy within 14 days prior to initiation of protocol therapy. No washout is required for trastuzumab
  • Has received prior therapy with a PI3K or mTOR inhibitor
  • No washout is required for endocrine therapy. If a patient has been on ovarian suppression for at least 28 days prior to initiation of study treatment, continuation of ovarian suppression is permitted on protocol. Starting a new endocrine therapy during protocol therapy is not permitted
  • Current use or history of receiving a non-approved, investigational treatment within 14 days prior to initiation of protocol therapy
  • Subjects with a history of hypersensitivity to compounds of similar biologic composition to GDC-0084 or any constituent of the product
  • The subject has an uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus (DM), gastric or duodenal ulceration diagnosed within the previous 6 months, chronic liver or renal disease, or severe malnutrition. If a participant has controlled DM but is unable to monitor blood sugars at home, they will be excluded from the trial
  • The subject is pregnant or breast-feeding
  • No active, second potentially life-threatening cancer
  • Has had major surgery within 21 days before initiation of protocol therapy
  • Active infection requiring IV antibiotics at the time of protocol therapy initiation
  • Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest
  • Known intolerance to trastuzumab
  • Corrected QT (QTc) interval time of >= 470 msec
  • Participants receiving any medications or substances that are strong inhibitors or strong inducers of CYP3A4 are ineligible. Should a participant be taking one of these agents and is able to discontinue the therapy or switch to a different agent, no washout will be required prior to starting study medication. Corticosteroids, which are weak CYP3A4 inducers are allowed. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians’ Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Jose Pablo Leone
Phone: 617-632-3800
Email: josep_leone@dfci.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Jose Pablo Leone
Phone: 617-632-3800
Email: JoseP_Leone@dfci.harvard.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of PI3K inhibitor GDC-0084 (GDC-0084) in combination with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC), as measured by objective response rate (ORR) in the CNS according to response assessment in neuro-oncology-brain metastases (RANO-BM) criteria. (Cohort A)

II. To evaluate the correlation between inhibition of phosphorylated (p)-4EBP1 in resected brain tumor tissue of human subjects, with the intracranial response in mouse bearing the corresponding patient-derived xenograft (PDX) models of breast cancer brain metastases (BCBM) and treated with GDC-0084 in combination with trastuzumab. (Cohort B)

SECONDARY OBJECTIVES:

I. To evaluate clinical benefit rate at 18 and 24 weeks, defined as the proportion of participants with stable or responsive disease in both CNS and non-CNS at 18 and 24 weeks per RANO-BM criteria. (Cohort A only)

II. To evaluate pharmacodynamic biomarkers associated with exposure to GDC-0084 in resected brain tumor tissue. (Cohort B only)

SAFETY OBJECTIVES:

I. To evaluate the safety, and tolerability of the combination of GDC-0084 and trastuzumab.

EFFICACY OBJECTIVES:

I. To evaluate the duration of response (DOR) in the CNS. (Cohort A only)

II. To evaluate the efficacy of the study combination, as defined by bi-compartmental progression-free survival (PFS) according to RANO-BM criteria.

III. To evaluate the extracranial ORR according Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

IV. To evaluate PFS according to the RECIST 1.1 single-compartmental model.

V. To describe the site of first progression (CNS versus [vs] extracranial vs both).

VI. To evaluate the overall survival (OS) among patients included in this trial.

PATIENT-REPORTED OUTCOME OBJECTIVES:

I. To evaluate the impact of the experimental treatment on patient-reported outcomes (PROs), as measured by the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) assessment.

INVESTIGATOR-ASSESSED NEUROLOGICAL EVALUATION:

I. To evaluate the impact of the study treatment, for these same patients, on investigator-assessed neurological evaluation, as measured by the Neurological Assessment in Neuro-Oncology (NANO) scale.

EuroQol (EQ)-5 Dimensional (5D) EVALUATION

I. To evaluate the impact of the study treatment, for these same patients, on general health status assessed by the EQ-5D questionnaire.

CORRELATIVE OBJECTIVES:

I. To describe the landscape of somatic mutations and copy number alterations that occur in matched primary tumors, extracranial metastases, and brain metastases, and to trace clonal evolution over time.

II. To describe a range of tissue-based biomarkers using tissue-based cyclic immunofluorescence (t-CyCIF) for high-dimensional assessment of phosphorylated (p)Akt, pS6RP, p4EBP1, Ki-67 and cleaved caspase-3, and the immune microenvironment (a variety of 6 color panels will be assessed each incorporating pan-cytokeratin and 4′,6-diamidino-2-phenylindole [DAPI] [PD-L1, PD-L2, CD3, CD20; CD4, CD8, PD-1, FoxP3; CD4, CD8, TIM-3, LAG3; CD33, CD11b, CD68, granzyme B]) to quantitate cytotoxic and regulatory T cell populations, T cell activation, checkpoint expression and macrophage populations.

III. To explore the correlation between Akt/mTOR signature with CNS ORR, PFS, and OS.

IV. To explore whether the number and/or type of somatic mutations (e.g. PIK3CA, AKT1, etc), detected either in archival tumor specimens, fresh tumor specimens, plasma cell-free deoxyribonucleic acid (cfDNA), or cerebral spinal fluid (CSF) cfDNA are correlated with patient outcomes (PFS, CNS ORR, clinical benefit rate [CBR], and OS).

V. To explore whether tumor mutational burden is associated with patient outcomes (PFS, CNS ORR, CBR, and OS).

VI. To collect blood and CSF to study cell-free DNA for quantification of tumor DNA content, copy number variation, targeted sequencing, and/or whole exome sequencing.

VII. To explore whether cfDNA tumor fraction, derived from plasma or CSF, and assessed using ultra low pass whole genome sequencing (ULP-WGS), is associated with patient outcomes (PFS, CNS ORR, CBR, and OS).

VIII. To characterize and compare mutations and copy number variation between cfDNA in blood and CSF versus tumor tissue specimens.

IX. To compare mutations, copy number variation, and tumor mutational burden between cfDNA in blood and CSF in baseline versus time-of-progression samples.

X. To explore the correlation between baseline mutational load (as assessed in cfDNA) with CNS ORR, bi-compartmental PFS, and OS.

XI. To characterize changes in cfDNA tumor fraction in blood and CSF at baseline, on treatment and at time of progression.

XII. To explore whether cfDNA fraction in blood or CSF at baseline is associated with clinical outcomes (PFS, CNS ORR, CBR, and OS).

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive PI3K inhibitor GDC-0084 orally (PO) once daily (QD) and trastuzumab intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive PI3K inhibitor GDC-0084 PO QD and trastuzumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Within 3-9 days of cycle 1, patients undergo surgical brain resection.

After completion of study treatment, patients are followed up within 30 days and then every 6 months for up to 3 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Jose Pablo Leone

Trial IDs

Primary ID 18-516
Secondary IDs NCI-2019-01756
Clinicaltrials.gov ID NCT03765983