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.
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, berzosertib) administered concurrent with
conventionally fractionated whole brain radiotherapy (WBRT), with M6620 (VX-970, berzosertib)
starting 18-30 hours after the first dose of radiation (but prior to the second fraction of
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, berzosertib) levels, tumor M6620 (VX-970, berzosertib) 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
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
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.
- 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
- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of M6620 (VX-970, berzosertib) in patients < 18 years of age, children are
excluded from this study, but will be eligible for future pediatric trials.
- 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 of
ALT/SGPT < 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, berzosertib) 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, berzosertib)
- Ability to understand and the willingness to sign a written informed consent document
- 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
- 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
- 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, berzosertib) as a
deoxyribonucleic acid (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, berzosertib), breastfeeding should be discontinued if the
mother is treated with M6620 (VX-970, berzosertib).
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to M6620 (VX-970, berzosertib).
- M6620 (VX-970, berzosertib) 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. 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. 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, berzosertib) (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,
or psychiatric illness/social situations that would limit compliance with study
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
M6620 (VX-970, berzosertib) 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, berzosertib) is a DDR inhibitor.