Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: 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

Summary: 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.

Eligibility: 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

Relevance to patient case: not relevant