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

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.

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