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



Status:Recruiting
Conditions:Lung Cancer, Lung Cancer, Cancer, Brain Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - Any
Updated:8/4/2018
Start Date:July 21, 2016

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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)

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.

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
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22 South Greene Street
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Phone: 800-888-8823
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Phone: 855-776-0015
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Phone: 916-734-3089
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