Clinical Trials /

GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases

NCT03765983

Description:

This research study is studying a drug called GDC-0084 as a possible treatment for HER2-Positive Breast Cancer. The drugs involved in this study are: - GDC-0084 - Trastuzumab (Herceptin®)

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases
  • Official Title: Phase II Trial of GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: 18-516
  • NCT ID: NCT03765983

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
TrastuzumabCohort A: single-arm, two stage, phase II cohort
GDC-0084Cohort A: single-arm, two stage, phase II cohort

Purpose

This research study is studying a drug called GDC-0084 as a possible treatment for HER2-Positive Breast Cancer. The drugs involved in this study are: - GDC-0084 - Trastuzumab (Herceptin®)

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational intervention to learn whether the intervention works
      in treating a specific disease. "Investigational" means that the intervention is being
      studied.

      The FDA (the U.S. Food and Drug Administration) has not approved GDC-0084 as a treatment for
      any disease.

      Trastuzumab is a targeted therapy approved by the FDA to be used alone or in combination with
      a chemotherapy drug to treat HER2-positive metastatic breast cancer.

      GDC-0084 has been shown to stop the activity of a protein called PI3-kinase. This action
      blocks a pathway in the body that cancer cells commonly use to grow and divide.

      Trastuzumab is called a "targeted therapy" because it works by attaching itself to specific
      receptors on the surface of breast cancer cells, known as HER2 receptors. When targeted
      therapies attach to HER2 receptors, the signals that tell the cells to grow are blocked and
      the cancer cell may be marked for destruction by the immune system. This process allows
      trastuzumab to help slow or stop the growth of the breast cancer.

      In this research study, the investigators are looking to see how your cancer responds to the
      combination of GDC-0084 and Trastuzumab.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A: single-arm, two stage, phase II cohortExperimentalGDC-0084 45 mg administered orally once daily Trastuzumab administered at a dose of 8 mg/kg intravenously (IV) loading dose; followed by 6 mg/kg IV every 3 weeks thereafter
  • Trastuzumab
  • GDC-0084
Cohort B: a pre-surgical window cohortExperimentalGDC-0084 45 mg administered orally once daily Trastuzumab administered at a dose of 8 mg/kg intravenously (IV) loading dose; followed by 6 mg/kg IV every 3 weeks thereafter Surgical brain metastasis resection
  • Trastuzumab
  • GDC-0084

Eligibility Criteria

        Inclusion Criteria:

        Cohort A:

          -  At least one measurable CNS metastasis, defined as ≥ 10 mm in at least one dimension.

          -  Unequivocal evidence of new and/or progressive brain metastases, and at least one of
             the following scenarios:

               -  Treated with 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 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.

          -  All Cohorts:

          -  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.

          -  The participant is ≥18 years old.

          -  Participants must have normal organ and marrow function as defined below:

               -  Absolute neutrophil count ≥1,000/μl

               -  Platelets ≥75,000/μl

               -  Hemoglobin ≥9 g/dL

               -  Total bilirubin ≤1.5mg/dL (upper limit of normal) except subject with documented
                  Gilbert's syndrome (≤5 x ULN) or liver metastasis, who must have a baseline total
                  bilirubin ≤3.0 mg/dL;

               -  AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN OR ≤ 5.0 × 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 MRI (e.g., due to pacemaker, ferromagnetic
             implants, claustrophobia, extreme obesity, hypersensitivity, etc.). However, head 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.

          -  QT 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. Please see Appendix M for
             the list of medications. 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 such as
             http://medicine.iupui.edu/clinpharm/ddis/table.aspx; 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate in the CNS
Time Frame:2 years
Safety Issue:
Description:ORR in the CNS according to response assessment in neuro-oncology-brain metastases (RANO-BM) criteria

Secondary Outcome Measures

Measure:CBR
Time Frame:24 weeks
Safety Issue:
Description:rate of patients with clinical benefit at 18 and 24 weeks
Measure:DOR
Time Frame:2 years
Safety Issue:
Description:to measure the duration of response in the CNS
Measure:Objective extra-CNS response rates
Time Frame:2 years
Safety Issue:
Description:the rate of patients who have an objective response outside of the CNS
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:2 years
Safety Issue:
Description:to evaluate the number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Measure:Progression Free Survival
Time Frame:2 years
Safety Issue:
Description:measured by RANO-BM and RECIST 1.1
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:to evaluate overall survival

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Breast Cancer

Last Updated