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A Study of LY2606368 (Prexasertib) in Patients With Solid Tumors With Replicative Stress or Homologous Repair Deficiency

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ClinicalTrials.gov Identifier: NCT02873975
Recruitment Status : Recruiting
First Posted : August 22, 2016
Last Update Posted : February 5, 2018
Sponsor:
Information provided by (Responsible Party):
Geoffrey Shapiro, MD, PhD, Dana-Farber Cancer Institute

Brief Summary:
This research study is studying a checkpoint kinase 1 (CHK1) inhibitor as a possible treatment for advanced solid tumors that harbor genetic alterations in the homologous repair (HR) pathway or with genetic alterations that indicate replication stress.

Condition or disease Intervention/treatment Phase
Advanced Cancers Drug: LY2606368 Phase 2

Detailed Description:

This is an open label, phase II, two-arm study exploring the anti-tumor activity of the CHK1 inhibitor prexasertib (LY2606368) in patients with advanced solid tumors exhibiting one of the following:

  1. Replicative stress, including MYC amplification, CCNE1 amplification, Rb loss, or an FBXW7 mutation
  2. An HR deficiency, including tumors with genomic or somatic mutations of BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATR, ATM, CHK2, or the Fanconi anemia pathway genes

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of the CHK1 Inhibitor LY2606368 in Patients With Advanced Solid Tumors Exhibiting Replicative Stress or Homologous Recombination Repair Deficiency
Study Start Date : October 2016
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2021


Arm Intervention/treatment
Experimental: Homologous Repair (HR) Deficiency
Prexasertib (LY2606368) will be administered as an IV infusion on day 1 and day 15 of every 28 day cycle. Prexasertib will be given at the recommended phase 2 dose of 105 mg/m2 administered over approximately 1 hour.
Drug: LY2606368
Other Name: Prexasertib

Experimental: Replicative Stress
Prexasertib (LY2606368) will be administered as an IV infusion on day 1 and day 15 of every 28 day cycle. Prexasertib will be given at the recommended phase 2 dose of 105 mg/m2 administered over approximately 1 hour.
Drug: LY2606368
Other Name: Prexasertib




Primary Outcome Measures :
  1. Progression-Free Rate [ Time Frame: 4 months ]
    Participants progression-free at 4 months in both arms, by RECIST 1.1 criteria.


Secondary Outcome Measures :
  1. Objective Response Rate [ Time Frame: 2 years ]
    Objective response rate in both arms by RECIST 1.1 criteria.

  2. Toxicity [ Time Frame: 2 years ]
    Adverse event data in all participants, by CTCAE 4.03 criteria.

  3. Overall Survival Rate [ Time Frame: From date of registration until the date of death from any cause, assessed up to 2 years. ]
    Overall survival rate in both arms.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 NextGeneration sequencing [NGS] using the DFCI/BWH OncoPanel or another 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.
  • 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 CT scan, MRI, or calipers by clinical exam.
  • Age ≥ 18 years.
  • ECOG performance status < 2
  • Participants must have adequate organ and marrow function as defined below:

    • Absolute neutrophil count ≥ 1.5 K/uL
    • Platelet count ≥ 100 K/uL
    • Hemoglobin ≥ 9 g/dL (with or without transfusion support)
    • Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
    • AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN, unless liver metastases are present and then ≤ 5 × institutional ULN is acceptable
    • Serum creatinine ≤ 1.5 × institutional ULN
  • Participants enrolling to either cohort 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 LY2606368 use during pregnancy and lactation are not known. Nonclinical studies of LY2606368 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 LY2606368. 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 LY2606368 administration.
  • Ability to understand and the willingness to sign a written informed consent document.
  • QTcF value of ≤ 470 msec on screening electrocardiogram (EKG)

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 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.
  • For the HR deficiency cohort: participants who have received prior treatment with a PARP 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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. 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 LY2606368.
  • Participants with a personal or family history of long QT syndrome.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 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 LY2606368 use during pregnancy and breastfeeding are not known and LY2606368 has the potential for teratogenic or abortifacient effects.
  • Known HIV-positive participants are ineligible because these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in HIV-positive participants when indicated.
  • Participants enrolling to either 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02873975


Contacts
Contact: Geoffrey Shapiro, MD, PhD 617-632-4942 Geoffrey_Shapiro@dfci.harvard.edu

Locations
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Geoffrey Shapiro, MD, PhD    617-632-4942    Geoffrey_Shapiro@dfci.harvard.edu   
Principal Investigator: Geoffrey Shapiro, MD, PhD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Investigators
Principal Investigator: Geoffrey Shapiro, MD, PhD Dana-Farber Cancer Institute

Responsible Party: Geoffrey Shapiro, MD, PhD, Geoffrey Shapiro M.D., PhD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT02873975     History of Changes
Other Study ID Numbers: 16-281
First Posted: August 22, 2016    Key Record Dates
Last Update Posted: February 5, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Geoffrey Shapiro, MD, PhD, Dana-Farber Cancer Institute:
Advanced Cancers
Solid tumors
MYC amplification
CCNE1 amplification
Rb loss
FBXW7 mutation
BRCA1 mutation
BRCA2 mutation
PALB2 mutation
RAD51C mutation
RAD51D mutation
ATR mutation
ATM mutation
CHK2 mutation
Fanconi anemia