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S1300: Pemetrexed Disodium With or Without Crizotinib in Treating Patients With Stage IV Non-Small Cell Lung Cancer That Has Progressed After Crizotinib

NCT02134912

Description:

This randomized phase II trial studies how well pemetrexed disodium with or without crizotinib works in treating patients with stage IV non-small cell lung cancer that has progressed after crizotinib. Drugs used in chemotherapy, such as pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Crizotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving pemetrexed disodium is more effective with or without crizotinib in treating patients with non-small cell lung cancer that has progressed after crizotinib.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

S1300: <span class="go-doc-concept go-doc-intervention">Pemetrexed Disodium</span> With or Without <span class="go-doc-concept go-doc-intervention">Crizotinib</span> in Treating Patients With Stage IV Non-Small Cell <span class="go-doc-concept go-doc-disease">Lung Cancer</span> That Has Progressed After <span class="go-doc-concept go-doc-intervention">Crizotinib</span>

Title

  • Brief Title: S1300: Pemetrexed Disodium With or Without Crizotinib in Treating Patients With Stage IV Non-Small Cell Lung Cancer That Has Progressed After Crizotinib
  • Official Title: S1300: A Randomized, Phase II Trial of Crizotinib Plus Pemetrexed Versus Pemetrexed Monotherapy in ALK-Positive Non-squamous NSCLC Patients Who Have Progressed Systemically After Previous Clinical Benefit From Crizotinib Monotherapy
  • Clinical Trial IDs

    NCT ID: NCT02134912

    ORG ID: S1300

    NCI ID: NCI-2014-00685

    Trial Conditions

    Adenocarcinoma of the Lung

    Stage IV Non-small Cell Lung Cancer

    Large Cell Lung Cancer

    Recurrent Non-small Cell Lung Cancer

    Trial Interventions

    Drug Synonyms Arms
    crizotinib c-met/hepatocyte growth factor receptor tyrosine kinase inhibitor PF-02341066, c-met/HGFR tyrosine kinase inhibitor PF-02341066, MET Tyrosine Kinase Inhibitor PF-02341066, PF-02341066 Arm I (crizotinib, pemetrexed disodium)
    pemetrexed disodium ALIMTA, LY231514, MTA Arm I (crizotinib, pemetrexed disodium), Arm II (pemetrexed disodium)

    Trial Purpose

    This randomized phase II trial studies how well pemetrexed disodium with or without
    crizotinib works in treating patients with stage IV non-small cell lung cancer that has
    progressed after crizotinib. Drugs used in chemotherapy, such as pemetrexed disodium, work
    in different ways to stop the growth of tumor cells, either by killing the cells, by
    stopping them from dividing, or by stopping them from spreading. Crizotinib may stop the
    growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet
    known whether giving pemetrexed disodium is more effective with or without crizotinib in
    treating patients with non-small cell lung cancer that has progressed after crizotinib.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To evaluate the efficacy of the combination of crizotinib and pemetrexed (pemetrexed
    disodium) compared to pemetrexed monotherapy as measured by progression-free survival (PFS)
    in anaplastic lymphoma kinase (ALK)+ non-squamous non-small cell lung cancer (NSCLC)
    patients who achieved clinical benefit with crizotinib monotherapy and subsequently
    progressed systemically.

    SECONDARY OBJECTIVES:

    I. To compare the response rate (confirmed and unconfirmed, complete and partial responses)
    in patients randomized to receive pemetrexed monotherapy to historical data.

    II. To assess overall survival in both arms. III. To evaluate the patterns of failure
    (central nervous system [CNS], extra-CNS) of the combination of crizotinib and pemetrexed
    and of pemetrexed monotherapy in ALK+ non-squamous NSCLC after progression on crizotinib.

    IV. To evaluate the frequency and severity of toxicities resulting from the administration
    of crizotinib and pemetrexed compared to pemetrexed monotherapy.

    V. To evaluate PFS and the response rate in patients treated with crizotinib following
    progression on the pemetrexed monotherapy arm.

    TERTIARY OBJECTIVES:

    I. To compare progression-free survival (PFS) and response rates (RR) between ALK dominant
    and ALK non-dominant patients in the entire study population and within each treatment arm.

    II. To evaluate if the magnitude of difference in these outcomes between ALK dominant and
    ALK non-dominant patients varies by treatment arm.

    III. To assess blood biomarkers of sensitivity and resistance to crizotinib and pemetrexed
    in an exploratory manner. The blood biomarkers include cell free circulating
    deoxyribonucleic acid (DNA), micro ribonucleic acid (microRNA) before treatment, during
    treatment (after 2 cycles) and at treatment progression.

    IV. To assess pharmacogenomic factors in peripheral blood that might affect the drug level
    and treatment outcomes in an exploratory manner.

    V. To assess proteomic/immunologic parameters that might affect the treatment outcomes in an
    exploratory manner.

    VI. To evaluate the frequency of individual mechanisms of resistance (copy number gain
    [CNG], mutation, alternate oncogene).

    VII. To identify alternative driver mechanisms in ALK fluorescence in situ hybridization
    positive (FISH+) otherwise unknown.

    OUTLINE: Patients are randomized to 1 of 2 treatment arms.

    ARM I: Patients receive crizotinib orally (PO) twice daily (BID) on days 1-21 and pemetrexed
    disodium intravenously (IV) over 10 minutes on day 1.

    ARM II: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Upon disease
    progression or symptomatic deterioration, patients may crossover to Arm I.

    In both arms, courses repeat every 21 days in the absence of disease progression or
    unacceptable toxicity.

    After completion of study treatment, patients are followed up for 3 years.

    Trial Arms

    Name Type Description Interventions
    Arm I (crizotinib, pemetrexed disodium) Experimental Patients receive crizotinib PO BID on days 1-21 and pemetrexed disodium IV over 10 minutes on day 1. crizotinib, pemetrexed disodium
    Arm II (pemetrexed disodium) Experimental ARM II: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Upon disease progression or symptomatic deterioration, patients may crossover to Arm I. pemetrexed disodium

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have histologically or cytologically proven primary non-squamous
    non-small cell lung cancer (adenocarcinoma, large cell carcinoma, adenocarcinoma in
    situ, mixed histology with < 50% squamous or unspecified); patients with tumors
    having squamous cell components >= 50% are not eligible; disease must be stage IV

    - Patients must have documented ALK positivity at the time of initial crizotinib
    monotherapy using the Vysis Break-Apart FISH assay (or other Food and Drug
    Administration [FDA]-approved diagnostic test); samples are deemed to be
    FISH-positive if greater than or equal to 15% of scored tumor cells had split ALK 5'
    and 3' probe signals or had isolated 3' signal; FISH status must be documented on the
    Onstudy Form and a copy of the pathology report from the Vysis Break-Apart FISH assay
    (or other FDA-approved diagnostic test) must be submitted

    - Prior to registration, patients must have achieved clinical benefit with crizotinib
    monotherapy and subsequently have systemically progressed; clinical benefit is
    defined as having stable disease on crizotinib monotherapy for at least 90 days or
    achieving a confirmed partial or complete response; systemic progression is defined
    as progressive disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
    version 1.1, excluding progression based on brain/CNS metastases alone

    - Patients must have received crizotinib monotherapy at 250 mg BID on a continuous
    dosing schedule for at least 90 days; patients must be planning to start treatment at
    least three days, but no more than 30 days after discontinuing crizotinib
    monotherapy; patients who were not able to tolerate 250 mg BID of crizotinib are not
    eligible for this study

    - Patients must be pemetrexed-nave; patients may have received any number of prior
    chemotherapy or molecularly targeted agents; if crizotinib was used in the 1st line
    setting then chemotherapy naive patients are also eligible; if patient received
    crizotinib in combination with chemotherapy, prior chemotherapy must have been
    discontinued at least 14 days prior to registration and all adverse events must have
    resolved to =< grade 1

    - Patients must have measurable disease per RECIST documented by computed tomography
    (CT) or magnetic resonance imaging (MRI); the CT from a combined positron emission
    tomography (PET)/CT may be used to document only non-measurable disease unless it is
    of diagnostic quality; measurable disease must be assessed within 28 days prior to
    registration; pleural effusions, ascites and laboratory parameters are not acceptable
    as the only evidence of disease; non-measurable disease must be assessed within 42
    days prior to registration; all disease must be assessed and documented on the
    Baseline Tumor Assessment Form RECIST 1.1

    - Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within
    42 days prior to registration; patient must not have brain metastases unless: (1)
    metastases have been treated and have remained controlled for at least 14 days
    following treatment or was not treated, but is asymptomatic, AND (2) patient has no
    residual neurological dysfunction off corticosteroids or anti-convulsants for at
    least 14 days

    - Patients may have received palliative radiotherapy to non-target lesions within 14
    days prior to registration provided all radiotherapy related toxicities have resolved
    to =< grade 1 prior to registration; patients must not have received any major
    surgery within 28 days prior to registration

    - Patients must not have had any prior exposure to heat shock protein (HSP)90
    inhibitors (such as IPI-504 or ganetespib) or non-crizotinib ALK inhibitors (such as
    AP26113 or LDK378)

    - Patients must be offered participation in the translational medicine studies;
    additionally if patient has biopsy accessible disease they must be offered
    participation in the translational medicine studies

    - Absolute neutrophil count (ANC) >= 1,500/ul

    - Platelet count >= 100,000/ul

    - Hemoglobin >= 9 g/dL

    - Serum bilirubin =< 2 X institutional upper limit of normal (IULN)

    - Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
    serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5
    x IULN

    - Estimated (calculated) or measured glomerular filtration rate >= 45 mL/min (or 45
    mL/min/1.73 m^2); creatinine (mg/dl) used in calculation (Cockroft-Gault) must be
    obtained within 28 days prior to registration

    - Male patients must have free and total testosterone level obtained within 28 days
    prior to registration

    - Pre-study history and physical must be obtained with 28 days prior to registration

    - Patients must have Zubrod performance status 0-2 within 28 days prior to registration

    - Patients must be able to swallow capsules

    - Patients must have corrected QT (QTC) interval =< 480 msec on electrocardiogram (EKG)
    at baseline; patient with congenital long QT syndrome are not eligible

    - No other prior malignancy is allowed except for the following: adequately treated
    basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
    stage I or II cancer from which the patient is currently in complete remission, or
    any other cancer from which the patient has been disease free for five years

    - Patients must not be pregnant or nursing; women/men of reproductive potential must
    have agreed to use an effective contraceptive method; a woman is considered to be of
    "reproductive potential" if she has had menses at any time in the preceding 12
    consecutive months; in addition to routine contraceptive methods, "effective
    contraception" also includes heterosexual celibacy and surgery intended to prevent
    pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
    bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
    previously celibate patient chooses to become heterosexually active during the time
    period for use of contraceptive measures outlined in the protocol, he/she is
    responsible for beginning contraceptive measures

    - REGULATORY CRITERIA: Patients or their legally authorized representative must be
    informed of the investigational nature of this study and must sign and give written
    informed consent in accordance with institutional and federal guidelines

    - REGULATORY CRITERIA: As a part of the Oncology Patient Enrollment Network (OPEN)
    registration process the treating institution's identity is provided in order to
    ensure that the current (within 365 days) date of institutional review board approval
    for this study has been entered in the system

    - CROSSOVER (STEP 2) REGISTRATION: Patients must have progressed systemically on Arm 2
    of this study (pemetrexed monotherapy)

    - CROSSOVER (STEP 2) REGISTRATION: Patients must be registered to crossover (Step 2)
    within 30 days of discontinuing treatment on Arm 2 of this study

    - CROSSOVER (STEP 2) REGISTRATION: ANC >= 1,500/ul

    - CROSSOVER (STEP 2) REGISTRATION: Platelet count >= 100,000/ul

    - CROSSOVER (STEP 2) REGISTRATION: Serum bilirubin =< 2 X IULN

    - CROSSOVER (STEP 2) REGISTRATION: SGOT (AST) or SGPT (ALT) =< 2.5 x IULN

    - CROSSOVER (STEP 2) REGISTRATION: estimated (calculated) or measured glomerular
    filtration rate >= 45 mL/min (or 45 mL/min/1.73 m^2) within 28 days prior to
    registration; creatinine (mg/dl) used in calculation (Cockroft-Gault) must be
    obtained within 28 days prior to registration

    - CROSSOVER (STEP 2) REGISTRATION: male patients must have free and total testosterone
    level obtained within 28 days prior to Crossover (Step 2) Registration

    - CROSSOVER (STEP 2) REGISTRATION: patients must have Zubrod performance status 0-2
    within 28 days prior to Crossover (Step 2) Registration

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    PFS between patients randomized to receive pemetrexed disodium monotherapy versus crizotinib and pemetrexed disodium combination therapy

    Secondary Outcome Measures

    Incidence of adverse events of crizotinib in combination with pemetrexed disodium, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

    Response rate (confirmed and unconfirmed) with pemetrexed disodium monotherapy

    Response rates (confirmed and unconfirmed) of crizotinib with pemetrexed disodium

    Patterns of failure

    Overall survival

    Trial Keywords