Clinical Trials /

VX-970 and Whole Brain Radiation Therapy in Treating Patients With Brain Metastases From Non-small Cell Lung Cancer, Small Cell Lung Cancer, or Neuroendocrine Tumors

NCT02589522

Description:

This phase I trial studies the side effects and best dose of ATR kinase inhibitor M6620 (VX-970) when given together with whole brain radiation therapy in treating patients with non-small cell lung cancer, small cell lung cancer, or neuroendocrine tumors that have spread from the original (primary) tumor to the brain. ATR kinase inhibitor M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving ATR kinase inhibitor M6620 together with radiation therapy may be a better treatment for non-small cell lung cancer, small cell lung cancer, or neuroendocrine tumors.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: VX-970 and Whole Brain Radiation Therapy in Treating Patients With Brain Metastases From Non-small Cell Lung Cancer, Small Cell Lung Cancer, or Neuroendocrine Tumors
  • Official Title: Phase 1 Trial to Determine the Recommended Phase 2 Dose (RP2D) of VX-970 When Combined With Whole Brain Radiotherapy (WBRT) in Patients With Brain Metastases From Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01779
  • SECONDARY ID: NCI-2015-01779
  • SECONDARY ID: HP-00068292
  • SECONDARY ID: 9952
  • SECONDARY ID: 9952
  • SECONDARY ID: UM1CA186644
  • SECONDARY ID: UM1CA186686
  • SECONDARY ID: UM1CA186690
  • NCT ID: NCT02589522

Conditions

  • Lung Carcinoma Metastatic in the Brain
  • Lung Neuroendocrine Neoplasm
  • Stage IV Lung Non-Small Cell Cancer AJCC v7
  • Stage IV Lung Small Cell Carcinoma AJCC v7

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor M6620M 6620, M6620, VX-970Group I (VX-970, whole-brain radiation therapy)

Purpose

This phase I trial studies the side effects and best dose of ATR kinase inhibitor M6620 (VX-970) when given together with whole brain radiation therapy in treating patients with non-small cell lung cancer, small cell lung cancer, or neuroendocrine tumors that have spread from the original (primary) tumor to the brain. ATR kinase inhibitor M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving ATR kinase inhibitor M6620 together with radiation therapy may be a better treatment for non-small cell lung cancer, small cell lung cancer, or neuroendocrine tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To conduct a phase 1 dose escalation trial in patients with brain metastases from
      non-small cell lung cancer (NSCLC) to determine the recommended phase 2 dose (RP2D) of twice
      weekly intravenous (i.v.) VX-970 administered concurrent with conventionally fractionated
      whole brain radiotherapy (WBRT), with VX-970 starting 18-30 hours after the first dose of
      radiation (but prior to the second fraction of radiation).

      SECONDARY OBJECTIVES:

      I. To estimate the incidence of >= grade 3 delayed neurological toxicity at 2, 4 and 6-months
      post-completion of whole-brain radiotherapy (for patients without intracranial progression).

      II. To estimate the radiological response rates (RR) at 6 months including bi-directional and
      volumetric measurements of lesion size.

      III. To estimate the intracranial 6-month progression-free survival (PFS).

      TERTIARY OBJECTIVES:

      I. Changes in dynamic susceptibility contrast enhancement (DSC-magnetic resonance imaging
      [MRI]) perfusion and mean apparent diffusion coefficient (ADC) measurements in
      diffusion-weighted magnetic resonance imaging (DWI). (Group I) II. To measure cerebrospinal
      fluid (CSF) VX-970 levels, tumor VX-970 levels, and pATR T1989, pCHK1 S345 and RAD51
      multiplex foci. (Group II) III. Changes in DSC-MRI perfusion and mean ADC measurements in
      DWI. (Group II)

      OUTLINE: This is a dose-escalation study of ATR kinase inhibitor M6620. Patients are assigned
      to 1 of 2 treatment groups.

      GROUP I: Patients undergo whole-brain radiation therapy once daily (QD), 5 days a week for 15
      fractions. Patients also receive ATR kinase inhibitor M6620 intravenously (IV) over 60-90
      minutes twice a week, 18-30 hours after first radiation therapy. Treatment continues for 3
      weeks in the absence of disease progression or unacceptable toxicity.

      GROUP II: Patients receive ATR kinase inhibitor M6620 IV over 60-90 minutes 2-4 hours prior
      to surgery. After surgery, patients undergo whole-brain radiation therapy and receive ATR
      kinase inhibitor M6620 as in Group I.

      After completion of study treatment, patients are followed up every 2 months for 6 months,
      every 3-4 months for 6 months, then every 6 months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (VX-970, whole-brain radiation therapy)ExperimentalPatients undergo whole-brain radiation therapy QD 5 days a week for 15 fractions. Patients also receive ATR kinase inhibitor M6620 IV over 60-90 minutes twice a week, 18-30 hours after first radiation therapy. Treatment continues for 3 weeks in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor M6620
Group II (VX-970, surgery, whole-brain radiation therapy)ExperimentalPatients receive ATR kinase inhibitor M6620 IV over 60-90 minutes 2-4 hours prior to surgery. After surgery, patients undergo whole-brain radiation therapy and receive ATR kinase inhibitor M6620 as in Group I.
  • ATR Kinase Inhibitor M6620

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with a histologically confirmed diagnosis of non-small cell lung cancer
             (NSCLC), including neuroendocrine tumors or small cell lung cancer (SCLC) who are
             being evaluated for palliative WBRT (with or without neurosurgical resection or
             stereotactic radiosurgery [SRS]) for radiologically or histologically diagnosed brain
             metastases presumed to be from the lung cancer are eligible for this Phase I study;
             group 2 will only include NSCLC patients

          -  Life expectance of greater than two months to allow completion of study treatment and
             assessment of dose-limiting toxicity

          -  Group 2 patients should have archived or fresh tumor tissue available from the
             non-craniotomy site and will have fresh tumor tissue available from the planned
             craniotomy

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 3,000/mcL

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

          -  Platelets >= 100,000/mcL

          -  If no known liver metastases: total bilirubin < 1.5 x institutional upper limit of
             normal (ULN); if known liver metastases, then: total bilirubin < 2.5 x ULN

          -  If no known liver metastases: aspartate aminotransferase (AST)/serum glutamic
             oxaloacetic transaminase (SGOT) < 2 x ULN; if known liver metastases, then: AST/SGOT <
             5 x ULN

          -  Creatinine within normal institutional limits for age OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above ULN

          -  Negative serum or urine pregnancy test result for females of child bearing potential

               -  Note: Women of child-bearing potential and men must agree to use adequate
                  contraception (hormonal or barrier method of birth control; abstinence) prior to
                  study entry and for the duration of study participation; should a woman become
                  pregnant or suspect she is pregnant while she or her partner is participating in
                  this study, she should inform her treating physician immediately; men treated or
                  enrolled on this protocol must also agree to use adequate contraception prior to
                  the study, for the duration of study participation, and 6 months after completion
                  of VX-970 administration

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

        Exclusion Criteria:

          -  Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, with stable systemic
             disease and ECOG score of 0-2, who would otherwise be eligible for SRS/stereotactic
             radiation therapy (SRT) alone should not be enrolled into this study unless WBRT is
             recommended due to any medical reasons or logistic limitations as determined by the
             treating physician; patients who develop recurrence post-SRS/SRT or surgery alone and
             are recommended WBRT will be eligible for the protocol

          -  Presence of diffuse leptomeningeal carcinomatosis (focal/localized involvement is
             acceptable), > 1 cm mid-line shift, uncal herniation or significant
             hemorrhage/hydrocephalous (small intra-lesional hemorrhage is acceptable); patients
             with seizure at presentation who have been started on levetiracetam and have been
             stable for 48 hours prior to study registration are eligible at the discretion of
             treating physician

          -  Patients who have received systemic cytotoxic chemotherapy, immunotherapy for 3 weeks
             before initiation of planned WBRT or patients who have not recovered from serious
             (Common Terminology Criteria for Adverse Events [CTCAE] grade 3 or more) adverse
             events from the previously received agents; for oral targeted agents or any other
             investigational agents, at least 4 half-lives of the agent (6 weeks for nitrosoureas
             or mitomycin C) should have elapsed prior to starting study treatment

          -  Patients must not have received prior WBRT (previous SRS/SRT done at least 4 weeks
             from the planned start of WBRT is acceptable); patients planned upfront to undergo
             SRS/SRT/fractionated boosts or neurosurgery after WBRT are not eligible; however,
             these treatments/procedures can be performed once the dose limiting toxicity (DLT)
             assessment has been completed, if felt clinically necessary

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with VX-970

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to VX-970

          -  Concomitant administration with strong inhibitors or inducers of cytochrome P450,
             family 3, subfamily A, polypeptide 4 (CYP3A4) should be avoided; because the lists of
             these agents are constantly changing, it is important to regularly consult a
             frequently-updated medical reference for a list of drugs to avoid or minimize use of;
             ongoing phenytoin should be either discontinued if clinically safe or transitioned to
             non-enzyme-inducing antiepileptics like levetiracetam with a 8-day washout period
             (half-life 18-22 hours, time to steady-state 4-8 days) prior to first dose of VX-970
             (7-days prior to WBRT)

          -  Patients needing more than 8 mg dexamethasone per day at the time of start of WBRT
             will not be eligible to participate in the study; however, patients will be allowed
             entry into the study if it is medically safe to reduce the daily dose of dexamethasone
             to 8 mg or less from the day of the start of WBRT; the dexamethasone dose for such
             patients may be increased beyond 8 mg per day during the course of treatment if
             medically necessary; this increased need for dose should be communicated to the
             study's principal investigator, Dr Mohindra at the University of Maryland

          -  Uncontrolled intercurrent illness that would increase the risk of toxicity or limit
             compliance with study requirements; this includes but is not limited to, ongoing
             uncontrolled serious infection requiring i.v. antibiotics at the time of registration,
             symptomatic congestive heart failure, unstable angina pectoris,
             symptomatic/uncontrolled cardiac arrhythmia, or psychiatric illness/social situations
             that would limit compliance with study requirements

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible

          -  Patients with known diagnoses that are associated with germline DDR defects such as Li
             Fraumeni syndrome and ataxia telangiectasia are excluded from the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity, defined as any grade 3 or more non-hematological toxicity requiring more than 5 day interruption in therapy or any grade 4 or higher hematological toxicity that is attributable to the VX-970 and/or whole brain radiotherapy
Time Frame:Up to 3 weeks post completion of whole brain radiotherapy (WBRT)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence of delayed neurological toxicity using Hopkins Verbal Learning Test-Revised
Time Frame:Up to 6-months post-completion of WBRT
Safety Issue:
Description:Incidence of events will be expressed as proportions with exact 95% confidence limits.
Measure:Changes in quality of life as measured by the Functional Assessment of Cancer Therapy-Brain
Time Frame:Baseline to up to 6 months post-completion of WBRT
Safety Issue:
Description:Descriptive statistics of the actual change scores will also be provided. The median change score and quartiles will be reported. Where relevant the proportion of patients experiencing a clinically significant change in score will be reported with 95% confidence limits.
Measure:Radiological response rate measured by morphological criteria
Time Frame:6 months
Safety Issue:
Description:
Measure:Intracranial progression-free survival (icPFS)
Time Frame:6 months
Safety Issue:
Description:Kaplan-Meier estimates of median icPFS will be calculated. Patients alive without intracranial progression at last follow-up will be censored at the date of the last radiologic assessment.
Measure:Overall survival (OS)
Time Frame:12 months
Safety Issue:
Description:Kaplan-Meier estimates of OS will be calculated. For calculation of OS, patients alive at last follow-up will be censored. Exploratory Cox regression analysis with VX-970 dose as a covariate will be performed.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

November 1, 2019