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

NCT02873975 | Completed Phase 2 Results DMC

• 1 other identifier: 16-281
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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, genetic alterations that indicate replication stress, or with CCNE1 amplification.

Conditions

Advanced Cancers

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Progression-Free Rate at 4 Month

  Progression-Free Rate defines as the percentage of participants progression-free at 4 months in all arms, by RECIST 1.1 criteria. Progression-free rate will be estimated as binomial proportion and overall survival and progression-free survival estimates and curves will be generated using the Kaplan-Meier method.

  at 4 month

Secondary Outcomes (3)

• Incidence of Grade 4 Treatment-Related Toxicity

  Assessed cycle 1 at day 1, 8, 15 and 22, and cycle 2 at day 1 and 15, from time of first dose and up to day 30 post-treatment. Median treatment duration for this study cohort was 55 day (range 6 - 539 days).

• Objective Response Rate

  Disease was evaluated radiologically at baseline and on treatment; Treatment continued until disease progression or unacceptable toxicity. Median treatment duration for this study cohort was 55 day (range 6 - 539 days).

• Median Overall Survival (OS)

  Participants were followed long-term for survival months from the end of treatment until death or lost to follow-up. Median (range) follow-up was 133 days (15-862 days) in this study cohort.

Study Arms (3)

Homologous Repair (HR) Deficiency Cohort

EXPERIMENTAL

Prexasertib (LY2606368) will be administered as an IV infusion in patients with homologous repair (HR) deficiency 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

Replicative Stress Cohort

EXPERIMENTAL

Prexasertib (LY2606368) will be administered as an IV infusion in patients with advanced solid tumors exhibiting replicative stress 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

CCNE1 Amplification Cohort

EXPERIMENTAL

Prexasertib (LY2606368) will be administered as an IV infusion in patients with CCNE1 amplification 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

Interventions

LY2606368 DRUG

Also known as: Prexasertib

CCNE1 Amplification Cohort; Homologous Repair (HR) Deficiency Cohort; Replicative Stress Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• For 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 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

You may not qualify if:

• 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.
• 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 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.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead

Study Sites (1)

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Fanconi Anemia

Interventions

prexasertib

Condition Hierarchy (Ancestors)

Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Geoffrey Shapiro M.D., PhDDana-Farber Cancer Institute
• Organization: Dana-Farber Cancer Institute

Geoffrey_Shapiro@dfci.harvard.edu

617-632-6594

Study Officials

• Geoffrey Shapiro, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Geoffrey Shapiro M.D., PhD

Study Record Dates

• First Submitted: August 17, 2016
• First Posted: August 22, 2016
• Study Start: October 12, 2016
• Primary Completion: September 30, 2020
• Study Completion: July 1, 2021
• Last Updated: October 21, 2022
• Results First Posted: February 9, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)