Clinical Trials /

A Phase I/II Study of Radiation Therapy, Paclitaxel Poliglumex and Cetuximab in Advanced Head and Neck Cancer

NCT00660218

Description:

This study involves two phases. Phase I of this study is designed to find out the maximum dose of paclitaxel poliglumex which can be safely given to subjects when combined with cetuximab and radiotherapy in head and neck cancer. Once the maximum safe dose of paclitaxel poliglumex is found, Phase II of the study will continue to find out whether the addition of paclitaxel poliglumex increases tumor response and survival compared to treatment with cetuximab and radiotherapy alone. An additional 20 patients have been added, to balance data. These patients must be HPV negative.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Unknown status

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

A Phase I/II Study of <span class="go-doc-concept go-doc-intervention">Radiation</span> Therapy, <span class="go-doc-concept go-doc-intervention">Paclitaxel Poliglumex</span> and <span class="go-doc-concept go-doc-intervention">Cetuximab</span> in Advanced Head and Neck <span class="go-doc-concept go-doc-disease">Cancer</span>

Title

  • Brief Title: A Phase I/II Study of Radiation Therapy, Paclitaxel Poliglumex and Cetuximab in Advanced Head and Neck Cancer
  • Official Title: A Phase I/II Study of Radiation Therapy, Paclitaxel Poliglumex and Cetuximab in Advanced Head and Neck Cancer
  • Clinical Trial IDs

    NCT ID: NCT00660218

    ORG ID: X90003

    Trial Conditions

    Carcinoma, Squamous Cell

    Trial Interventions

    Drug Synonyms Arms
    paclitaxel poliglumex PPX, Xyotax, CT-2103 Radiation therapy, cetuximab, paclitaxel poliglumex

    Trial Purpose

    This study involves two phases. Phase I of this study is designed to find out the maximum
    dose of paclitaxel poliglumex which can be safely given to subjects when combined with
    cetuximab and radiotherapy in head and neck cancer. Once the maximum safe dose of paclitaxel
    poliglumex is found, Phase II of the study will continue to find out whether the addition of
    paclitaxel poliglumex increases tumor response and survival compared to treatment with
    cetuximab and radiotherapy alone.

    An additional 20 patients have been added, to balance data. These patients must be HPV
    negative.

    Detailed Description

    Patients with locally advanced (stage III and IV) head and neck cancer are often managed by
    radiotherapy with or without chemotherapy because most of them have unresectable tumor,
    require too extensive surgery, or are medically unfit to go through radical surgery.
    However, the treatment results from conventionally fractionated radiotherapy for locally
    advanced head and neck cancers are poor in terms of local control and survival. Therefore,
    combinations of radiation and chemotherapy have been studied to improve treatment results.

    Sequential radiation-chemotherapy (most given in neo-adjuvant setting) has been studied
    extensively in prospective pilot and large randomized trials. So far, a survival advantage
    over standard radiotherapy has not been demonstrated, but organ preservation has been
    achieved in many patients. Response rates to chemotherapy are high, and decrease in distant
    metastases has been demonstrated in some trials. Despite a high response rate in trials
    comparing neoadjuvant chemotherapy and radiotherapy to radiotherapy alone, improved
    locoregional control (LRC) has not been shown. Concurrent radiation and cisplatin-based
    chemotherapy has shown survival advantage over radiotherapy alone in meta-analysis. However,
    the administration of cisplatin-based chemotherapy is associated with significantly
    increased local and systemic toxic effects, which may preclude many patients from proceeding
    with combined therapy. Therefore, there is a great interest in defining an active regimen
    that does not contain cisplatin.

    An alternative approach to concurrent chemotherapy and radiotherapy has emerged with the
    development of molecular targeted agents. A recently reported randomized phase III study
    demonstrated improved duration of control of locoregional disease and overall survival with
    the addition of the antibody against the epidermal growth factor receptor, cetuximab, to
    definitive radiotherapy in patients with squamous cell carcinoma of the head and neck.
    Importantly, cetuximab administration did not increase radiation-related toxicity.

    The most commonly used chemotherapy other than cisplatin chemotherapy for the treatment of
    advanced head and neck cancer is paclitaxel. There are many studies showing improvement of
    tumor control when paclitaxel was added to the radiotherapy. Paclitaxel poliglumex (PPX,
    CT-2103, Xyotax) is a macromolecule that consists of a biodegradable, water-soluble polymer
    of glutamic acid, a naturally-occurring amino acid, linked to paclitaxel. Preclinical
    studies suggest increased tumor uptake of PPX compared with paclitaxel, resulting in
    enhanced tumor cell kill. PPX may potentiate tumor radiocurability without affecting acute
    normal tissue injury. Moreover, a synergistic increase in tumor cell death was observed when
    paclitaxel poliglumex was administered with cetuximab in a preclinical tumor model.

    The proposed study will assess the rational combination of PPX with radiotherapy and
    cetuximab. This regimen is of great interest and has the potential to improve the
    therapeutic ratio compared with an approach of either cisplatin-based chemoradiotherapy or
    radiotherapy and cetuximab.

    There is also an optional tissue submission component of this study, in which subjects who
    require surgery following their treatment can give permission for a block of tumor tissue
    removed at the time of their surgery to be sent to Cell Therapeutics, Inc. (the manufacturer
    of PPX) for evaluation of PPX accumulation, level of cathepsin B, and estrogen receptor
    expression. This information will be used to correlate the tumor response and survival of
    patients in the future.

    Since the initiation of this study, the relationship of HPV to head and neck cancer has
    become very evident. Our initial results have many more HPV positive subjects, and therefore
    we have added 20 more HPV negative patients to the study, to determine if this status
    affects the outcome.

    Trial Arms

    Name Type Description Interventions
    Radiation therapy, cetuximab, paclitaxel poliglumex Experimental Radiation therapy to 69.96 Gy, 2.12 Gy per day for 33 treatments, starting week 2. Cetuximab loading dose of 400 mg/m week 1, 250 mg/m weekly for 7 weeks. Paclitaxel poliglumex starting week 2 40 mg/m. paclitaxel poliglumex

    Eligibility Criteria

    Inclusion Criteria:

    - Patients with histological proof (from the primary lesion and/or cervical lymph node)
    of squamous carcinoma of the oral cavity, oropharynx, hypopharynx, larynx, or unknown
    primary.

    - Patients should have stage III or IV disease

    - Patients must have ECOG Performance Status of 0-1

    - Patients must be >/= 18 years of age

    - Patients must have measurable disease

    - Patients should have adequate bone marrow function defined as an absolute peripheral
    granulocyte count (AGC) of >/= 1500 cells/mm3, platelet count of >/= 100,000 cells/
    mm3; adequate hepatic function with bilirubin </= 1.5mg/dl, AST and ALT </= 2x the
    upper limit of normal; serum creatinine </= 1.5mg/dl, creatinine clearance >/= 50
    ml/min and INR 0.8 - 1.2

    - Patients must sign a study specific informed consent form prior to study entry

    - Final 20 subjects must be HPV negative

    Exclusion Criteria:

    - Histology other than squamous cell carcinoma

    - Evidence of metastases (below the clavicle or distant) by clinical or radiographic
    examinations for phase II study subjects

    - History of malignancy other than non-melanoma skin cancer

    - Prior chemotherapy or anticancer biologic therapy for any type of cancer, or prior
    radiotherapy to the head and neck region except for radioactive iodine therapy

    - Prior history of allergy or hypersensitivity to cetuximab or paclitaxel

    - Weight loss > 10% in the past three months

    - Patients with uncontrolled intercurrent disease

    - Patients with currently active malignancy

    - Pregnant or lactating women

    - Female patients of childbearing potential who are unwilling to practice adequate
    contraception during study treatment and for two months after the last administration
    of study drug

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Phase I: the maximum tolerated dose of paclitaxel poliglumex in combination with radiotherapy and cetuximab for locally advanced head and neck cancer

    Phase II: the rate of locoregional control at one year

    Secondary Outcome Measures

    The overall response rate (complete and partial response)

    The acute and late toxicity profile associated with the study regimen

    The duration of control of locoregional disease

    Overall survival, disease-free survival, and distant relapse rates

    Tissue PPX accumulation, level of cathepsin B, and estrogen receptor expression

    Trial Keywords

    Stage III and IV head and neck cancer