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Testing the Safety of M6620 (VX-970) When Given With Standard Whole Brain Radiation Therapy for the Treatment of 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 berzosertib (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 (brain metastases). Berzosertib 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 berzosertib together with radiation therapy may work better compared to standard of care treatment, including brain surgery and radiation therapy, in treating patients with non-small cell lung cancer, small cell lung cancer, or neuroendocrine tumors.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Safety of M6620 (VX-970) When Given With Standard Whole Brain Radiation Therapy for the Treatment of 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 M6620 (VX-970) When Combined With Whole Brain Radiotherapy (WBRT) in Patients With Brain Metastases From Lung Cancer

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

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

Interventions

DrugSynonymsArms
Berzosertib2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970, VX-970, VX970Group I (VX-970, whole-brain radiation therapy)

Purpose

This phase I trial studies the side effects and best dose of berzosertib (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 (brain metastases). Berzosertib 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 berzosertib 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.) M6620 (VX-970) administered concurrent with conventionally
      fractionated whole brain radiotherapy (WBRT), with M6620 (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 observe and record anti-tumor activity. IIa. To estimate the radiological response
      rates (RR) at 6 months including bi-directional and volumetric measurements of lesion size.

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

      EXPLORATORY/HYPOTHESIS GENERATING 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) M6620 (VX-970) levels, tumor M6620 (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 berzosertib. 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 berzosertib 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 berzosertib IV over 60-90 minutes 2-4 hours prior to surgery.
      After surgery, patients undergo whole-brain radiation therapy and receive berzosertib 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 berzosertib 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.
  • Berzosertib
Group II (VX-970, surgery, whole-brain radiation therapy)ExperimentalPatients receive berzosertib IV over 60-90 minutes 2-4 hours prior to surgery. After surgery, patients undergo whole-brain radiation therapy and receive berzosertib as in Group I.
  • Berzosertib

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%)

               -  Note: though patients with ECOG performance status of 3 due to neurological
                  deficits who are otherwise fit to receive systemic therapy per clinician
                  assessments will be allowed

          -  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) or alanine aminotransferase (ALT)/serum glutamic
             pyruvic transaminase (SGPT) < 2 x ULN; if known liver metastases, then: AST/SGOT < 5 x
             ULN

          -  Creatinine within normal institutional limits for age OR creatinine clearance >= 45
             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

               -  The effects of M6620 (VX-970) on the developing human fetus are unknown; for this
                  reason and because radiation therapy is known to have teratogenic potential,
                  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 M6620
                  (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

          -  Greater than 1 cm mid-line shift, severe uncal herniation or significant
             hemorrhage/hydrocephalus (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 and/or, immunotherapy or
             other intravenous standard therapy for 2 weeks before initiation of planned WBRT, for
             oral targeted agents 3-7 days per clinician discretion or patients who have not
             recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or less
             from serious (CTCAE grade 3 or more) adverse events form the previously received
             agents; for 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 2 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 because M6620 (VX-970) as a DNA-damage
             response (DDR) inhibitor may have the potential for teratogenic or abortifacient
             effects; further, radiation therapy is known to have the potential for teratogenic or
             abortifacient effects; because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with M6620 (VX-970),
             breastfeeding should be discontinued if the mother is treated with M6620 (VX-970)

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to M6620 (VX-970)

          -  M6620 (VX-970) is primarily metabolized by cytochrome P450, family 3, subfamily A,
             polypeptide 4 (CYP3A4); therefore, concomitant administration with strong inhibitors
             or inducers of CYP3A4 should be avoided; ecause 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; as part of the
             enrollment/informed consent procedures, the patient will be counseled on the risk of
             interactions with other agents, and what to do if new medications need to be
             prescribed or if the patient is considering a new over-the-counter medicine or herbal
             product; 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 M6620 (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 because of the potential for pharmacokinetic interactions with
             M6620 (VX-970) and the uncertainties of any impact thereof on the radiation
             toxicities; in addition, these patients are at increased risk of lethal infections
             when treated with marrow-suppressive therapy; appropriate studies will be undertaken
             in patients receiving combination antiretroviral therapy when indicated

          -  Patients with known diagnoses that are associated with germline DDR defects such as Li
             Fraumeni syndrome and ataxia telangiectasia are excluded from the study as M6620
             (VX-970) is a DDR inhibitor
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicity
Time Frame:Up to 3 weeks post completion of whole brain radiotherapy (WBRT)
Safety Issue:
Description: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 berzosertib (M6620 [VX-970]) and/or whole brain radiotherapy

Secondary Outcome Measures

Measure:Incidence of delayed neurological toxicity
Time Frame:Up to 6-months post-completion of WBRT
Safety Issue:
Description:Assessed using Hopkins Verbal Learning Test-Revised. Incidence of events will be expressed as proportions with exact 95% confidence limits.
Measure:Changes in quality of life
Time Frame:Baseline to up to 6 months post-completion of WBRT
Safety Issue:
Description:Measured by the Functional Assessment of Cancer Therapy-Brain. 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
Time Frame:6 months
Safety Issue:
Description:Measured by morphological criteria.
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 M6620 (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

March 20, 2020