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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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%) - 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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT02589522
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

National Cancer Institute (NCI)
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Pranshu Mohindra
Principal Investigator Affiliation Mayo Clinic Cancer Center LAO
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

NIH
Overall Status Recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Lung Carcinoma Metastatic in the Brain, Lung Neuroendocrine Neoplasm, Stage IV Lung Non-Small Cell Cancer AJCC v7, Stage IV Lung Small Cell Carcinoma AJCC v7
Additional Details

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.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Case Western Reserve University, Cleveland, Ohio

Status

Recruiting

Address

Case Western Reserve University

Cleveland, Ohio, 44106

Site Contact

Site Public Contact

CTUReferral@UHhospitals.org

800-641-2422

Washington University School of Medicine, Saint Louis, Missouri

Status

Active, not recruiting

Address

Washington University School of Medicine

Saint Louis, Missouri, 63110

Mayo Clinic, Rochester, Minnesota

Status

Recruiting

Address

Mayo Clinic

Rochester, Minnesota, 55905

Site Contact

Site Public Contact

855-776-0015

Baltimore, Maryland

Status

Suspended

Address

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287

Baltimore, Maryland

Status

Recruiting

Address

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, 21201

Site Contact

Site Public Contact

800-888-8823

Lexington, Kentucky

Status

Recruiting

Address

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, 40536

Site Contact

Site Public Contact

859-257-3379

Sacramento, California

Status

Recruiting

Address

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817

Site Contact

Site Public Contact

916-734-3089

City of Hope Comprehensive Cancer Center, Duarte, California

Status

Suspended

Address

City of Hope Comprehensive Cancer Center

Duarte, California, 91010

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