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Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/HER2- Breast Cancer

NCT02626507

Description:

This is a dose-escalation Phase Ib clinical trial in 18 patients with newly diagnosed Stage I-IV ER+/HER2- breast cancer, with the primary cancer in place. These patients have not received prior therapy for their breast cancer and intend to undergo surgery after four cycles of therapy. This is an open-label study, and investigators and subjects are not blinded to the treatment. The reason for using an open-label study design is because this is a dose-escalation trial, and the investigators need to determine the potential toxicity before a decision can be made to continue the dose escalation procedures. The assignment of patients will not be randomized, as this is a dose-escalation trial.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/<span class="go-doc-concept go-doc-biomarker">HER2</span>- Breast Cancer

Title

  • Brief Title: Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/HER2- Breast Cancer
  • Official Title: Phase I Dose-Escalation Study of Combination of Gedatolisib (a Dual Inhibitor of PI3-K and mTOR) With Palbociclib and Faslodex in the Neoadjuvant Setting in Previously Untreated Patients With ER+/HER2- Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02626507

    ORG ID: CL- Gedatolisib-001

    Trial Conditions

    Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Gedatolisib Code name PF-05212384, PKI-587 Gedatolisib ER+/HER2- Breast Cancer
    Faslodex Fulvestrant Gedatolisib ER+/HER2- Breast Cancer
    Palbociclib Ibrance Gedatolisib ER+/HER2- Breast Cancer
    Zoladex goserelin Gedatolisib ER+/HER2- Breast Cancer

    Trial Purpose

    This is a dose-escalation Phase Ib clinical trial in 18 patients with newly diagnosed Stage
    I-IV ER+/HER2- breast cancer, with the primary cancer in place. These patients have not
    received prior therapy for their breast cancer and intend to undergo surgery after four
    cycles of therapy.

    This is an open-label study, and investigators and subjects are not blinded to the
    treatment. The reason for using an open-label study design is because this is a
    dose-escalation trial, and the investigators need to determine the potential toxicity before
    a decision can be made to continue the dose escalation procedures.

    The assignment of patients will not be randomized, as this is a dose-escalation trial.

    Detailed Description

    Palbociclib (Ibrance) is an orally active highly selective reversible inhibitor of
    cyclin-dependent kinase (CDK) 4 and CDK 6. Faslodex (Fulvestrant) is a potent anti-estrogen
    drug that binds and degrades estrogen receptors (ERs). Interim results from the Phase 3
    trial (Study PALOMA-3) have shown that combination of palbociclib and Faslodex increases
    progressive-free survival (PFS) from 3.8 to 9.2 months in patients with metastatic estrogen
    receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast
    cancer that progressed during or after anti-endocrine therapy (Turner et al. 2015). The
    palbociclib/Faslodex combination was found to be well tolerated. Additionally, there is
    growing data indicating that this combination can be safely and effectively administered up
    front in anti-endocrine therapy-naive patients in the neoadjuvant setting.

    Gedatolisib (code name PF-05212384, formerly known as PKI-587) is an intravenous (IV)
    adenosine triphosphate (ATP) competitive, highly selective and potent inhibitor of pan-class
    I isoform phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3-K) and mammalian target of
    rapamycin (mTOR) (Fry et al. 2004). Preclinical and first-in-human studies have shown a
    manageable safety profile with predictable toxicity for this class of drugs.

    Activation of the PI3-K/Akt/mTOR/p-S6 pathway has been associated with endocrine resistance
    in ER+ breast cancer. There is ample evidence that inhibition of this pathway, in
    combination with anti-hormonal therapy, increases PFS (Baselga et al. 2012). There is also
    clinical evidence that combination therapy targeting all three pathways is feasible, safe
    and effective (Sweeney et al. 2014). The advantage of Gedatolisib is its potential to
    inhibit signaling through different PI3-K isoforms. Also important is the fact that once a
    week administration may be as effective, but less toxic, than chronic oral dosing. If
    hyperglycemia is a surrogate for effective PI3-K/Akt/mTOR/p-S6 inhibition, once weekly
    dosing of Gedatolisib would appear to accomplish equivalent degrees of hyperglycemia as
    chronically oral dosing and with less toxicity.

    Preoperative or neoadjuvant systemic chemotherapy, once reserved for patients with locally
    advanced breast cancer in whom the goal was to render large breast cancers operable, has
    become increasingly common due to the improvement in disease-free survival and overall
    survival. Historically, the endpoint of pathological Complete Response (pCR) in neoadjuvant
    therapy against ER+/HER2- breast cancer has been of limited value. However, new targeted
    agents, with higher response rates, have the potential to use pCR assessment as a strong
    clinical endpoint in drug development. Given the systemic response rate in previously
    treated Stage 4 breast cancer patients, the expectation will be a similar high rate of
    pathological improvement which can lead to greater use of targeted agents in the neoadjuvant
    setting.

    In addition to the potential of better pathological improvement, the advantage of clinical
    studies involving neoadjuvant therapy is that they can provide response information in
    patients that are treatment-nave. This type of clinical trial can also be used to assess
    cellular and molecular changes with serial biopsies while on neoadjuvant therapy, which can
    aid in development of companion tissue and/or imaging biomarkers, and further the
    development of preclinical models.

    Accordingly, this investigation assesses the safety and efficacy of the combination of
    Gedatolisib, palbociclib and faslodex in the neoadjuvant setting in previously untreated
    patients with ER+/HER2- breast cancer. Being the first clinical trial using this combination
    in neoadjuvant setting, one of the main objectives for the current trial is to determine the
    Maximum Tolerated Dose (MTD) of Gedatolisib when used in combination with palbociclib and
    faslodex. Subsequent Phase II clinical trials will be conducted to assess the safety and
    efficacy of the Gedatolisib/palbociclib/faslodex combination, with the dose of Gedatolisib
    being the MTD determined from the current trial.

    Trial Arms

    Name Type Description Interventions
    Gedatolisib ER+/HER2- Breast Cancer Experimental Gedatolisib at escalating doses of 180, 215 and 260 mg via a 3-6 dose-escalation scheme is administered once weekly on the first day for each of the four weeks during the four 4-week cycles. Faslodex at 500 mg is administered IM into the buttocks slowly (over 1 - 2 minutes per injection) as two 5-mL injections, one in each buttock, on Days 1 and 15 of Cycle 1 and on Day 1 of the remaining three 4-week treatment cycles. Palbociclib at 125 mg is administered PO with food daily on Days 1-21 for each of the four 4-week cycles Zoladex is used to render menopause in pre-menopausal subjects, given once every 28 days starting at least 14 days prior to treatment. Gedatolisib, Faslodex, Palbociclib, Zoladex

    Eligibility Criteria

    Inclusion Criteria:

    A. Stage I-IV, with primary cancer in place, non-inflammatory invasive breast cancer
    confirmed by core needle or incisional biopsy (excisional biopsy is not allowed):

    - the disease is ER+ (defined as ER expression >10% of invasive cancer cells according
    to immunohistochemical [IHC] staining)

    - HER2- (defined as IHC staining of 0 to 1+ or fluorescence in situ hybridization
    [FISH] ratio of HER2 gene copy/chromosome 17 of <2.0.)

    - the disease is previously untreated for breast cancer, operable and intend to undergo
    surgery for her disease (e.g., a mastectomy or lumpectomy) after completion of
    neoadjuvant therapy

    - the disease must be measurable, defined as clinically or radiographically measureable
    target lesion in the breast that is 1 cm in diameter

    - the disease cannot be axillary disease only (i.e., no identifiable tumor in the
    breast that is 1 cm on physical exam or radiographic study)

    - the disease can be multi-centric or bilateral disease, provided the target lesion
    meets the above eligibility criteria

    - breast cancer patients with lobular and luminal histology will be included. However,
    patients with lobular histology should not be more than a quarter of the total number
    of patients in this trial, as the investigational drugs are likely to have greater
    activities in patients with luminal histology.

    (Note 1: In patients with Stage III disease, imaging studies is performed to rule out
    overt metastatic disease. In patients with clinically positive axillae, histologic
    confirmation by biopsy or fine-needle aspiration is performed. Patients with clinically
    negative axillae can undergo pretreatment sentinel lymph node sampling.) (Note 2: In
    patients with Stage IV disease, the disease must be of low burden. Low burden is defined
    in this study as no more than one metastatic site in the liver or lung, or up to three
    metastatic sites in the bone, regardless of the number of lymph nodes per latest
    radiographic scan. If a patient is found to have metastatic disease on scan(s) performed
    after patient completes study neoadjuvant therapy, surgery will not be performed and
    patients will be excluded from this study.)

    B. Females 18 years of age.

    C. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
    sterile) must use effective contraceptive methods (such as abstinence, intrauterine device
    [IUD], or double barrier device) during the study, and must have a negative serum or urine
    pregnancy test within one week prior to treatment initiation.

    D.Mentally competent, able to understand and willingness to sign the informed consent
    form.

    E.At least 4 weeks must have elapsed from any prior major surgery or hormonal therapy. The
    following procedures are not considered major surgical procedure:

    - Obtaining the required research needle biopsies

    - Placement of a radiopaque clip to localize a tumor or tumors for subsequent surgical
    resection

    - Placement of a port for central venous access

    - Fine needle aspiration of a prominent or suspicious axillary lymph node

    - Needle biopsy of a clinically or radiographically detected lesion to rule out
    metastatic diseaseF.Laboratory values 2 weeks must be:

    - Sampling of sentinel lymph node.

    F.Laboratory values 2 weeks must be:

    - Adequate glycemic balance (hemoglobin A1c or glycated hemoglobin 8%; fasting serum
    glucose 130 mg/dL, and fasting triglycerides 300 mg/dL).

    - Adequate hematology (white blood cell [WBC] 3500 cells/mm3 or 3.5 bil/L; Granulocytes
    1,000/L; platelet count 100,000 cells/mm3 or 100 bil/L; absolute neutrophil count
    [ANC] 1500 cells/mm3 or 1.5 bil/L; and hemoglobin (Hgb) 9 g/dL or 90 g/L).

    - Adequate hepatic function (aspartate aminotransferase [AST/SGOT] 3x upper normal
    limit [UNL], alanine aminotransferase [ALT/SGPT] 3x UNL (5x UNL if liver metastases
    present), bilirubin 1.5x UNL).

    - Adequate renal function (serum creatinine 1.5 mg/dL or 133 mol/L).

    - Adequate coagulation (International Normalized Ratio [INR] must be <1.5, <2.3 if
    patient is on stable, therapeutic doses of warfarin and has no active bleeding or
    pathologic condition that is associated with a high risk of bleeding)

    Exclusion Criteria

    A.Serious medical illness, such as significant cardiac disease (e.g. symptomatic
    congestive heart failure, unstable angina pectoris, symptomatic coronary artery disease,
    myocardial infarction within the past 6 months, uncontrolled or symptomatic cardiac
    arrhythmia, or New York Heart Association Class III or IV), or severe debilitating
    pulmonary disease, that would potentially increase patients' risk for toxicity.

    B. A marked baseline prolongation of QT/QTc interval (e.g., repeated exhibition of a QTc
    interval >470 ms).

    C. A history of additional risk factors for torsade de pointes (e.g., clinically
    significant heart failure, hypokalemia, family history of Long QT Syndrome).

    D. Arterial thrombotic event, stroke, or transient ischemia attack within the past 12
    months.

    E. Uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood
    pressure >90 mm Hg), or peripheral vascular disease grade 2.

    F.Active central nervous system (CNS), epidural tumor or metastasis, or brain metastasis.

    G.Any active uncontrolled bleeding, a bleeding diathesis (e.g., active peptic ulcer
    disease), or a history of bleeding (e.g., hemoptysis, upper or lower gastrointestinal
    bleeding) within the past 6 months.

    H.Dyspnea with minimal to moderate exertion. Patients with large and recurrent pleural or
    peritoneal effusions requiring frequent drainage (e.g. weekly). Patients with any amount
    of clinically significant pericardial effusion.

    I.Diabetes of any type, except non-insulin dependent diabetes mellitus .(NIDDM) that is
    controlled and with hemoglobin A1c <8%.

    J.Evidence of active infection during screening, or serious infection within the past
    month.

    K.Patients with known HIV infection.

    L.Serious or non-healing wound, skin ulcer, or bone fracture.

    M.Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the
    past 6 months.

    N.Neuropathy of grade 2.

    O.Albumin <2.5 g/dL or <25 g/L.

    P.Lactating females.

    Q.Any condition or abnormality which may, in the opinion of the investigator, compromise
    the safety of patients.

    R.Unwilling or unable to follow protocol requirements.

    S.Patients receiving any other standard or investigational treatment for their cancer, or
    any other investigational agent for any indication within the past 3 weeks prior to
    participating in the study.

    T.Requirement for immediate palliative treatment of any kind including surgery and
    radiation.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

    Secondary Outcome Measures

    Number of participants with treatment-related pathological Complete Response (pCR)

    Trial Keywords

    ER+/HER2