Prexasertib in Treating Patients with Advanced Solid Tumors Exhibiting Replicative Stress or Homologous Recombination Repair Deficiency

Status: Active

Description

This phase II trial studies how well prexasertib works in treating patients with advanced solid tumors exhibiting replicative stress or homologous recombination repair deficiency. Prexasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Participants must have a pathologically confirmed advanced solid tumor for which standard therapy proven to provide clinical benefit does not exist or is no longer effective.
  • Participants must have one of the following (confirmed via targeted NextGen Sequencing using the DFCI/BWH OncoPanel or another Clinical Laboratory Improvement Act [CLIA]-certified method): * For the replicative stress cohort: MYC amplification, CCNE1 amplification, Rb loss, FBXW7 mutation, or another genomic abnormality indicative of replicative stress as agreed upon with the principal investigator -OR- * For the HR deficiency cohort: genomic or somatic mutation in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATR, ATM, CHK2, the Fanconi anemia pathway genes, or another genomic or somatic mutation in a known HR gene as agreed upon with the principal investigator. * For enrollment to the CCNE1 cohort: CCNE1 amplification of 6-fold or greater. Patients with borderline amplification levels may be considered following approval from the overall principal investigator.
  • Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam.
  • Eastern Cooperative Oncology Group (ECOG) performance status < 2.
  • Absolute neutrophil count >= 1.5 K/uL within 14 days prior to start of protocol therapy.
  • Platelet count >= 100 K/uL within 14 days prior to start of protocol therapy.
  • Hemoglobin >= 9 g/dL (with or without transfusion support) within 14 days prior to start of protocol therapy.
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) within 14 days prior to start of protocol therapy.
  • Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x institutional ULN, unless liver metastases are present and then =< 5 x institutional ULN is acceptable within 14 days prior to start of protocol therapy.
  • Serum creatinine =< 1.5 x institutional ULN within 14 days prior to start of protocol therapy.
  • Participants enrolling to the HR or replicative stress cohorts during stage 1 must have disease that is amenable to biopsy and be willing to undergo a pre-treatment tumor biopsy.
  • The potential effects of prexasertib (LY2606368) use during pregnancy and lactation are not known. Nonclinical studies of prexasertib on pregnancy and fetal development have not been performed; to minimize any potential risks, men and women with reproductive potential should use medically approved contraceptive precautions during treatment and for 3 months following the last dose of prexasertib; 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 for 3 months after completion of prexasertib administration.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Fridericia’s corrected QT (QTcF) value of =< 470 msec on screening electrocardiogram (EKG) within 14 days prior to start of protocol therapy.

Exclusion Criteria

  • Participants who have had chemotherapy, other investigational or biologic therapy, major surgery, or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the planned first dose of prexasertib (LY2606368) therapy.
  • Participants who have not recovered to eligibility levels from prior toxicity or adverse events as a result of previous treatment prior to the study.
  • Participants who have received prior treatment with a CHK1 inhibitor.
  • Participants who have received prior radiation therapy to > 25% of the bone marrow.
  • Participants with known untreated brain metastases should be excluded from this clinical trial; participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for at least one month following the end of treatment are permitted.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to prexasertib.
  • Participants with a personal or family history of long QT syndrome.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, New York Heart Association (NYHA) class III/IV heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction within 3 months of enrollment, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant or breastfeeding females; the potential effects of prexasertib use during pregnancy and breastfeeding are not known and prexasertib has the potential for teratogenic or abortifacient effects.
  • Known human immunodeficiency virus (HIV)-positive participants are ineligible; appropriate studies will be undertaken in HIV-positive participants when indicated.
  • Participants enrolling to the HR or replicative stress cohort during stage 1 may not be on anticoagulant therapy unless the treating investigator has deemed it safe to temporarily hold to facilitate the pre-treatment tumor biopsy.

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Geoffrey Ira Shapiro
Phone: 617-632-4942
Email: Geoffrey_Shapiro@dfci.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Geoffrey Ira Shapiro
Phone: 617-632-4942
Email: Geoffrey_Shapiro@dfci.harvard.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To evaluate the activity of the CHK1 inhibitor prexasertib in patients with tumors exhibiting either replication stress, HR deficiency, or CCNE1 amplification; specifically, to determine the proportion of patients alive and progression-free at 4 months in these cohorts.

SECONDARY OBJECTIVES:

I. To assess toxicity following CHK1 inhibition among participants in these cohorts.

II. To examine the objective response and overall survival rate following CHK1 inhibition in these patient cohorts.

EXPLORATORY OBJECTIVES:

I. Pre-treatment biopsies will be obtained from patients in the first stage of the study in both the replicative stress and HR deficiency arms, and will be subjected to whole exome sequencing (WES) to explore potential genomic determinants of sensitivity and resistance to CHK1 inhibition.

II. Cell-free DNA (cfDNA) will be collected from patients on study and analyzed for mutations associated with the replicative stress and HR deficiency pathways.

OUTLINE:

Patients receive prexasertib intravenously (IV) over 60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3-4 months.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Geoffrey Ira Shapiro

Trial IDs

Primary ID 16-281
Secondary IDs NCI-2016-01564
Clinicaltrials.gov ID NCT02873975