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Phase Ib Dose-escalation Trial of Taselisib (GDC-0032) in Combination With Anti-HER2 Therapies in Participants With Advanced HER2+ Breast Cancer

NCT02390427

Description:

This research study is a way of gaining new knowledge about the combination of Taselisib with other drugs in the treatment of metastatic breast cancer. Taselisib is an investigational drug which works by blocking a protein called PI3K (phosphoinositide 3-kinase) that helps cancer cells grow. This drug has been used in laboratory experiments and information from these studies suggests that this drug may help to prevent or slow the growth of cancer cells. The main purpose of this study is to find the appropriate dose of Taselisib to be used with other drugs in further clinical studies. This is an open-label, 3+3 dose-escalation phase Ib study to identify the Maximum Tolerated Dose(s) (MTD) and to identify the recommended phase 2 dose (RP2D) of Taselisib. This study will be conducted in 4 separate arms. (A-D).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Phase Ib Dose-escalation Trial of <span class="go-doc-concept go-doc-intervention">Taselisib</span> (GDC-0032) in Combination With Anti-<span class="go-doc-concept go-doc-biomarker">HER2</span> Therapies in Participants With Advanced <span class="go-doc-concept go-doc-biomarker">HER2</span>+ <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: Phase Ib Dose-escalation Trial of Taselisib (GDC-0032) in Combination With Anti-HER2 Therapies in Participants With Advanced HER2+ Breast Cancer
  • Official Title: Phase Ib Dose-escalation Trial of Taselisib (GDC-0032) in Combination With Anti-HER2 Therapies in Participants With Advanced HER2+ Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02390427

    ORG ID: 15-024

    Trial Conditions

    Metastatic Breast Cancer

    Recurrent Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Taselisib GCD-0032 Arm A, Arm B, Arm C, Arm D
    Trastuzumab emtansine T-DM1, Kadcyla Arm A, Arm B
    Pertuzumab Perjeta Arm B, Arm C, Arm D
    Trastuzumab Herceptin Arm C, Arm D
    Paclitaxel Taxol, Onxal Arm D

    Trial Purpose

    This research study is a way of gaining new knowledge about the combination of Taselisib
    with other drugs in the treatment of metastatic breast cancer. Taselisib is an
    investigational drug which works by blocking a protein called PI3K (phosphoinositide
    3-kinase) that helps cancer cells grow. This drug has been used in laboratory experiments
    and information from these studies suggests that this drug may help to prevent or slow the
    growth of cancer cells. The main purpose of this study is to find the appropriate dose of
    Taselisib to be used with other drugs in further clinical studies. This is an open-label,
    3+3 dose-escalation phase Ib study to identify the Maximum Tolerated Dose(s) (MTD) and to
    identify the recommended phase 2 dose (RP2D) of Taselisib. This study will be conducted in 4
    separate arms. (A-D).

    Detailed Description

    This study is divided in two parts, a combination dose finding escalation part (Part 1) and
    a dose combination expansion part (Part 2). Participants will enter only one Part (either 1
    or 2) and receive study drugs from only one combindation of study drugs, know as arms, as
    assigned by the main study physician. The study includes four different arms as listed
    below:

    - Arm A: Taselisib with Trastuzumab emtansine (also called T-DM1)

    - Arm B: Taselisib with Trastuzumab emtansine and Pertuzumab

    - Arm C: Taselisib with Pertuzumab and Trastuzumab

    - Arm D: Taselisib with Pertuzumab, Trastuzumab, and Paclitaxel

    Part 1: Since we are looking for the highest dose of Taselisib that can be administered
    safely without severe or unmanageable side effects in participants that have breast cancer,
    not everyone who participates in Part 1 of this research study will receive the same dose of
    the Taselisib. The dose participants get will depend on the number of participants who have
    been enrolled in the study before and how well they have tolerated their doses.

    Each combination dose will only be given to a group of 3 - 6 participants. The results from
    each group will be reviewed and depending on the results, a different combination dose or
    schedule may be investigated in the next group of participants or the same combination dose
    taken by a participant may be repeated with the next group of participants to investigate
    these results further (a different schedule means that instead of taking doses once every
    day, participants may take them only on some days in the week).

    Part 2: The doses in this part will be based on the best combination doses from Part 1.
    This part will look at the potential side effects and see how your cancer responds to the
    drug.

    Trial Arms

    Name Type Description Interventions
    Arm A Experimental Arm A - Taselisib with Trastuzumab emtansine (also called T-DM1) Taselisib administered orally, daily in each treatment cycle (3 weeks). Trastuzumab emtansine (also called T-DM1) administered once via IV per treatment cycle (3 weeks). Taselisib, Trastuzumab emtansine
    Arm B Experimental Arm B -Taselisib with T-DM1 and Pertuzumab Taselisib is administered oral, daily or every other day per treatment cycle (3 weeks). Trastuzumab emtansine (also called T-DM1) administered once via IV per treatment cycle (3 weeks). Pertuzumab- administered once via IV per treatment cycle (3 weeks). Taselisib, Trastuzumab emtansine, Pertuzumab
    Arm C Experimental Arm C: Taselisib with Pertuzumab and Trastuzumab Cohort C will not open without additional authorization from Genentech Taselisib is administered oral, daily in each treatment cycle (3 weeks). Trastuzumab administered once via IV per treatment cycle (3 weeks). Pertuzumab- administered once via IV per treatment cycle (3 weeks). Taselisib, Pertuzumab, Trastuzumab
    Arm D Experimental Arm D Taselisib with Pertuzumab, Trastuzumab, and Paclitaxel Cohort will not be opened without additional authorization from Genentech Taselisib- administered oral, daily in each treatment cycle (3 weeks). Pertuzumab- administered once via IV per treatment cycle (3 weeks). Trastuzumab administered once via IV per treatment cycle (3 weeks). Paclitaxel- administered via IV, weekly for 3 weeks within each cycle. Taselisib, Pertuzumab, Trastuzumab, Paclitaxel

    Eligibility Criteria

    Inclusion Criteria:

    - Metastatic, locally advanced , or locally recurrent breast cancer

    - Histologically confirmed HER2+ invasive breast cancer

    - Measurable or non-measurable disease per RECIST v1.1

    - Prior therapy - Prior trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine
    (T-DM1) are allowed. Patients who have received prior therapy with Taselisib
    (GDC-0032) or BYL-719 are excluded. There is no limit on the number of prior lines of
    therapy.

    - ECOG performance status 0 or 1

    - Normal organ and marrow function as defined below:

    - Absolute neutrophil count 1,500/mm3

    - Platelets 100,000/mm3

    - Total bilirubin < 1.5 X institutional upper limit of normal. For patients with
    Gilbert syndrome, the direct bilirubin should be within the institutional normal
    range

    - AST (SGOT) and ALT (SGPT) < 2.5 X institutional upper limit of normal

    - Serum creatinine 1.5 x ULN or creatinine clearance 50 mL/min

    - Fasting glucose 120 mg/dL and HbA1c < 7%

    - Left ventricular ejection fraction 50%

    - Women of childbearing potential (including those who have had a tubal ligation) must
    have a documented negative pregnancy test within 14 days prior to planned initiation
    of Taselisib.

    - Ability to understand and the willingness to sign a written informed consent
    document.

    - For Part 2: patients must have tissue that is amenable to biopsy and must be willing
    to undergo research biopsy. Patients who undergo an attempted research biopsy
    procedure for the purpose of this protocol, and in whom inadequate tissue is
    obtained, are not required to undergo a repeat biopsy in order to continue on
    protocol.

    Exclusion Criteria:

    - Anti-cancer therapy within 2 weeks prior to entering the study or those who have not
    recovered from acute adverse events due to agents administered more than 2 weeks
    earlier. Palliative radiation to bony metastases 2 weeks prior to study entry is
    allowed.

    - Prior treatment with a PI3 kinase, AKT or mTOR inhibitor in which the patient
    experienced a Grade 3 drug related adverse event or otherwise would be at increased
    risk for additional PI3K related toxicity

    - Currently receiving any other investigational agents. Treatment with an
    investigational agent within 2 weeks prior to planned initiation of study therapy is
    allowed provided that any drug related toxicity has completely resolved

    - Major surgical procedure within 4 weeks prior to planned initiation of study therapy

    - Significant traumatic injury within 3 weeks prior to planned initiation of study
    therapy

    - Known untreated brain metastases are excluded. History of treated CNS metastases is
    okay, provided the following criteria are met:

    - Disease outside the CNS is present.

    - No evidence of interim progression between the completion of CNS directed
    therapy and the screening radiographic study

    - No history of intracranial hemorrhage or spinal cord hemorrhage

    - Not requiring anti-convulsants for symptomatic control

    - Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 and
    recovery from significant (Grade 3) acute toxicity with no ongoing requirement
    for corticosteroid

    - History of allergic reactions or hypersensitivity attributed to compounds of similar
    chemical or biologic composition to the Taselisib drug formulation or other agents
    used in this study.

    - Receiving any medications or substances that are inhibitors of CYP3A4.

    - Malabsorption syndrome or other condition that would interfere with enteral
    absorption

    - Active small or large intestine inflammation such as Crohn's disease or ulcerative
    colitis

    - Type 1 or 2 diabetes requiring anti hyperglycemic medication (e.g. metformin,
    glipizide, insulin)

    - Leptomeningeal disease as the only manifestation of the current malignancy

    - Congenital long QT syndrome or QTc > 500 msec

    - Active congestive heart failure or ventricular arrhythmia requiring medication

    - Uncontrolled ascites requiring weekly large volume paracentesis for 2 consecutive
    weeks prior to initiation of study treatment

    - Active infection requiring intravenous (IV) antibiotics

    - Patients requiring any daily supplemental oxygen

    - Uncontrolled hypomagnesemia, hypokalemia or hypocalcemia, defined as values below the
    lower limit of normal (LLN) for the institution despite adequate electrolyte
    supplementation or management

    - Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab
    therapy

    - Clinically significant history of liver disease, including viral or other hepatitis,
    current alcohol abuse, or cirrhosis

    - Grade 2 peripheral neuropathy

    - Any other diseases, active or uncontrolled intercurrent illness including, but not
    limited to, ongoing or active infection, symptomatic congestive heart failure,
    unstable angina pectoris, pulmonary dysfunction, metabolic dysfunction, psychiatric
    illness/social situations, physical examination finding, or clinical laboratory
    finding that would limit compliance with study requirements.

    - Women of childbearing potential (< 1 year amenorrheic) or sexually active males who
    are not employing adequate contraception (or practicing complete abstinence).

    - Female patients of childbearing potential must commit to using a reliable and
    appropriate method of contraception until at least 7 months after the end of
    last dose of study treatment.

    - Male patients with a partner of childbearing potential must agree to use a
    barrier method of contraception (condom) in addition to having their partner use
    another contraceptive method during the trial and for 7 months after the last
    dose of study treatment.

    - Pregnant women and women who are lactating.

    - Known human immunodeficiency virus (HIV) infection

    - Inability or unwillingness to swallow pills

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum Tolerated Dose (MTD) of Taselisib in combination with anti-HER2 therapy(ies) and/or paclitaxel.

    Secondary Outcome Measures

    Clinical Benefit Rate (CBR) for efficacy of Taselisib in combination with anti-HER2 therapy(ies) and/or paclitaxel.

    Progression Free Survival (PFS) for efficacy of Taselisib in combination with anti-HER2 therapy(ies) and/or paclitaxel.

    Overall Survival for efficacy of Taselisib in combination with anti-HER2 therapy(ies) and/or paclitaxel.

    Occurrence of AEs and SAEs during treatment with Taselisib in combination with anti-HER2 therapy(ies) and/or paclitaxel.

    Occurrence of dose delays or holds

    Occurrence of dose reductions

    Dose Limiting Toxicity of Taselisib in combination with anti-HER2 therapy(ies) and/or paclitaxel.

    Trial Keywords

    Metastatic Breast Cancer

    Advanced Breast Cancer

    Recurrent Breast Cancer