Clinical Trials /

A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer

NCT02370238

Description:

Reparixin oral tablets are being tested as a CSC targeting agent in patients with metastatic non- human epidermal growth factor receptor (HER2)-amplified BC. An open label Phase 1b clinical study (REP0111) is ongoing (enrollment completed) in five US sites, under IND # 112502, to test safety, tolerability, pharmacokinetics and detect early signs of antitumor activity of increasing doses of reparixin oral tablets in combination with a fixed dose of weekly paclitaxel. The study has demonstrated safety and tolerability of the combination across the three dose levels explored and recorded objective responses in the published range for single agent weekly paclitaxel in the target population. The highest dose level explored (i.e., 1200 mg t.i.d.) was identified as the recommended phase 2 dose. Durable responses have been recorded in patients with TNBC. The current phase 2 study thus aims to evaluate the Progression Free Survival of patients with metastatic TNBC [newly diagnosed metastatic or relapsed following (neo)adjuvant chemotherapy] receiving reparixin in combination with paclitaxel versus paclitaxel alone.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

A Double-blind Study of <span class="go-doc-concept go-doc-intervention">Paclitaxel</span> in Combination With <span class="go-doc-concept go-doc-intervention">Reparixin</span> or <span class="go-doc-concept go-doc-intervention">Placebo</span> for Metastatic Triple-Negative <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer
  • Official Title: A Randomized, Double-blind, Placebo-controlled Phase 2 Study of Paclitaxel in Combination With Reparixin Compared to Paclitaxel Alone as Front-line Therapy for Metastatic Triple- Negative Breast Cancer (FRIDA)
  • Clinical Trial IDs

    NCT ID: NCT02370238

    ORG ID: REP0114

    NCI ID: 2014-004796-23

    Trial Conditions

    Metastatic Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    paclitaxel paclitaxel+reparixin, paclitaxel+placebo
    Reparixin paclitaxel+reparixin
    placebo paclitaxel+placebo

    Trial Purpose

    Reparixin oral tablets are being tested as a CSC targeting agent in patients with metastatic
    non- human epidermal growth factor receptor (HER2)-amplified BC. An open label Phase 1b
    clinical study (REP0111) is ongoing (enrollment completed) in five US sites, under IND #
    112502, to test safety, tolerability, pharmacokinetics and detect early signs of antitumor
    activity of increasing doses of reparixin oral tablets in combination with a fixed dose of
    weekly paclitaxel. The study has demonstrated safety and tolerability of the combination
    across the three dose levels explored and recorded objective responses in the published
    range for single agent weekly paclitaxel in the target population. The highest dose level
    explored (i.e., 1200 mg t.i.d.) was identified as the recommended phase 2 dose. Durable
    responses have been recorded in patients with TNBC.

    The current phase 2 study thus aims to evaluate the Progression Free Survival of patients
    with metastatic TNBC [relapsed following (neo)adjuvant chemotherapy] receiving reparixin in
    combination with paclitaxel versus paclitaxel alone.

    Detailed Description

    According to the cancer stem cell (CSC) model, tumors are initiated and maintained by a
    cellular subcomponent that displays stem cell properties. These properties include
    self-renewal, which drives tumorigenesis, and differentiation (albeit aberrant), which
    contributes to tumor cellular heterogeneity. The existence of CSCs has been described in a
    variety of haematologic and solid tumors including those of the breast, brain, colon,
    pancreas, lung, liver, and head and neck.

    In addition to driving tumorigenesis, CSCs may contribute to tumor metastasis as well as to
    tumor recurrence after treatment. Although currently available drugs can shrink metastatic
    tumors, these effects are usually transient and often do not appreciably extend the life of
    patients. One reason for the failure of these treatments is the acquisition of drug
    resistance by the cancer cells as they evolve; another non-mutually exclusive possibility is
    that existing therapies fail to kill CSCs. The ability to shrink a tumor mass mainly
    reflects an ability to kill bulk, non CSC tumor cells. This is because CSCs represent only a
    tiny percentage of the total tumor cells in a neoplastic lesion and the majority of the bulk
    tumor cells have limited proliferative potential. It seems that normal stem cells from
    various tissues tend to be more resistant to chemotherapeutics than mature cell types from
    the same tissues. The reasons for this are not clear, but may relate to high levels of
    expression of anti- apoptotic proteins or ATP-binding cassette (ABC) transporters such as
    the multidrug resistance gene. If the same were true of CSCs, then one would predict that
    these cells would be more resistant to chemotherapeutics than bulk tumor cells with limited
    proliferative potential. Even therapies that cause complete regression of tumors might spare
    enough CSCs to allow regrowth of the tumors. Thus, therapies that are more specifically
    directed against CSCs might result in much more durable responses and even cures of
    metastatic tumors.

    The CSC (Cancer stem cell) concept has important implications for understanding
    carcinogenesis as well as for the development of cancer therapeutics. According to this
    concept, tumors are initiated and maintained by a cellular subcomponent that displays stem
    cell properties. These properties include self-renewal, which drives tumorigenesis, and
    differentiation (albeit aberrant), which contributes to tumor cellular heterogeneity. The
    existence of CSCs has been described in a variety of hematologic and solid tumors including
    those of the breast, brain, colon, pancreas, lung, liver, and head and neck. In addition to
    driving tumorigenesis, CSCs may contribute to tumor metastasis as well as to tumor
    recurrence after treatment.

    One of the therapeutic strategies being pursued to target CSCs involves inhibition of self
    renewal or survival pathways in these cells. These pathways include NOTCH (Notch signaling
    pathway), Hedgehog, and WNT (Wnt signaling pathway). Such strategies may be limited by the
    role of these pathways in normal stem cell function, which could result in systemic
    toxicities from pathway inhibition. In addition to intrinsic pathways regulating stem cell
    functions, normal and malignant stem cells are regulated by extrinsic signals generated in
    the microenvironment or CSC niche. In the breast, this niche is composed of immune cells,
    mesenchymal elements that include fibroblasts, endothelial cells, adipocytes, and
    extracellular matrix components. These components play an important role in normal breast
    development and carcinogenesis. If the cellular microenvironment plays an important role in
    the regulation of CSC growth and survival, then strategies aimed at interfering with these
    interactions represent a rational approach to target breast CSCs.

    There are limited data on the impact of treatment tailoring based on CSCs detection. Gene
    profiling of CSCs could lead to identification of therapeutic targets on CSCs (e.g. hormone
    receptors, HER-2 [Human epidermal growth factor receptor-2] expression, EGFR [Epidermal
    growth factor receptor] expression), and could represent tumor biopsy in "real time".
    Several groups showed frequent discordance of HER-2 status between primary tumor and CSCs,
    and case reports showed clinical utility to use of trastuzumab-based therapy based on HER-2
    CSCs status. Similarly, the hormonal status of CSCs could be different from that of the
    primary tumor, which could lead to increase the number of patients suitable for endocrine
    therapy, but also could explain why endocrine therapy fails in a subset of hormone
    receptor-positive patients. The study provided the in vivo demonstration that CXCR-1
    (Chemokine receptor 1) targeting with specific blocking antibodies or reparixin is
    associated with reduced systemic metastases. The experimental data provides another
    therapeutic target in metastatic disease and warrants a pilot study investigation in humans
    to further explore effects of reparixin on breast CSCs and the tumoral microenvironment.

    Reparixin seems to be a good candidate for use in breast cancer patients because of its very
    acceptable toxicity profile shown in the Phase I and II clinical trials conducted so far,
    along with its observed activity in vitro against breast cancer cell lines and in vivo in
    tumor xenografts in mice. It potentially addresses another therapeutic target in metastatic
    disease. The current phase 2 study thus aims to evaluate the Progression Free Survival of
    patients with metastatic TNBC [relapsed following (neo)adjuvant chemotherapy] receiving
    reparixin in combination with paclitaxel versus paclitaxel alone.

    Trial Arms

    Name Type Description Interventions
    paclitaxel+reparixin Experimental paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15) + reparixin oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle paclitaxel, Reparixin
    paclitaxel+placebo Active Comparator paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15) + placebo oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle paclitaxel, placebo

    Eligibility Criteria

    Inclusion Criteria:

    1. Female aged > 18 years.

    2. Patients with pathologically documented metastatic triple negative breast cancer
    (TNBC), eligible for treatment with paclitaxel. Paraffin-embedded tissue must be
    available from metastatic sites, if reasonably accessible, or from the primary tumor,
    to confirm the diagnosis of TNBC and for correlative studies (only on metastatic
    tissue). Fifteen slides can be obtained if the full block is not available to be sent
    or released.

    TNBC will be defined as breast cancer with <1% ER+ and <1% PgR+ cells, and HER2
    immunohistochemistry score of 0 or 1+ and/or in situ hybridization (ISH) with HER2
    gene copy number <4 or a ratio of less than 2 between HER2 gene copy number and
    centromere of chromosome 17. Patients whose metastatic disease is TNBC are eligible
    even when their primary tumor expressed hormone receptors and/or HER2.

    3. Patients must have relapsed following a prior (neo)adjuvant chemotherapy regimen. If
    a taxane (i.e., paclitaxel or docetaxel) was administered as part of the
    (neo)adjuvant regimen, PD must have occurred > 12 months from the end of previous
    (neo)adjuvant treatment. For non-taxane (neo)adjuvant regimen, PD must have occurred
    > 6 months from the end of previous (neo)adjuvant treatment

    4. Patients with at least one baseline measurable lesion according to RECIST criteria
    version 1.1.

    5. Zubrod (Eastern Co-operative Oncology Group [ECOG]) Performance Status (PS) of 0-1.

    6. Life expectancy of at least three months.

    7. Patients must be able to swallow and retain oral medication (intact tablet).

    8. Able to undergo all screening assessments outlined in the protocol.

    9. Adequate organ function (defined by the following parameters):

    1. Serum creatinine < 140 mol/L (< 1.6 mg/dL) or creatinine clearance > 60 mL/min.

    2. Serum hemoglobin 9 g/dL; absolute neutrophil count 1.5 x 109/L; platelets
    100 x 109/L.

    3. Serum bilirubin 1.5 x upper normal limit (UNL) except patients with Gilbert's
    syndrome

    4. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) 2.5 x
    UNL but 5.0 x UNL in case of liver metastases; alkaline phosphatase (ALP)
    UNL but 2.5 x ULN in case of liver metastases; albumin within normal limits.

    10. No history or evidence by CT scan or MRI, of brain metastases or leptomeningeal
    disease.

    11. No known hepatitis B virus (not due to immunization), hepatitis C virus, human
    immunodeficiency virus-I and -II positive status.

    12. Dated and signed IEC/IRB-approved informed consent.

    Exclusion Criteria:

    1. Newly diagnosed metastatic TNBC and TNBC not previously treated with (neo)adjuvant
    chemotherapy

    2. Prior therapy for metastatic TNBC (chemotherapy, hormone therapy or biological
    therapy), Patients may receive bisphosphonates and other therapies to treat bone
    metastases, however if used, bone lesions will not be considered as measurable
    disease.

    3. Less than four weeks since last radiotherapy (excluding palliative radiotherapy).

    4. Pregnancy or lactation or unwillingness to use adequate method of birth control.

    5. Neurological or psychiatric disorders which may influence understanding of study and
    informed consent procedures.

    6. Active or uncontrolled infection.

    7. Malabsorption syndrome, disease significantly affecting gastrointestinal function.

    8. G>1 pre-existing peripheral neuropathy

    9. Any other invasive malignancy from which the patient has been disease-free for less
    than 5 years with the exception of curatively treated basal or squamous cell skin
    cancer

    10. Hypersensitivity to:

    1. paclitaxel

    2. ibuprofen or to more than one non-steroidal anti-inflammatory drug.

    3. medications belonging to the class of sulfonamides, with the exception of
    sulfanilamides (e.g., sulfamethoxazole).

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Progression Free Survival (PFS)

    Secondary Outcome Measures

    Median PFS (mPFS)

    Overall Survival

    Objective Response Rate

    AE

    AE

    AST

    ALT

    ALP

    WBC

    Trial Keywords

    Triple negative metastatic breast cancer

    Cancer Stem Cells