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A Study of Abemaciclib in Recurrent Glioblastoma

This study is currently recruiting participants.
Verified June 2017 by Eudocia Quant Lee, MD, Dana-Farber Cancer Institute
Sponsor:
ClinicalTrials.gov Identifier:
NCT02981940
First Posted: December 5, 2016
Last Update Posted: June 28, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Eudocia Quant Lee, MD, Dana-Farber Cancer Institute
  Purpose

This research study is studying a targeted therapy as a possible treatment for recurrent glioblastoma (GBM).

The following intervention will be used in this study:

-Abemaciclib


Condition Intervention Phase
Glioblastoma Drug: Abemaciclib Procedure: Surgery Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Abemaciclib in Recurrent Glioblastoma

Resource links provided by NLM:


Further study details as provided by Eudocia Quant Lee, MD, Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Intratumoral abemaciclib concentration [ Time Frame: 2 years ]
  • 6-Month Progression Free Survival (PFS6) [ Time Frame: 6 months ]

Secondary Outcome Measures:
  • pRB expression level of tumor tissue [ Time Frame: 2 years ]
  • Incidence of Treatment-Emergent Adverse Events [ Time Frame: 2 years ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  • Area under the plasma concentration versus time curve (AUC) [ Time Frame: 4 months ]
    PK measurements expressed as Area under the plasma concentration versus time curve (AUC) of Abemaciclib [Time Frame C1D1 (pre-treatment), C2D1, C3D1 and C4D1 (each cycle is 28 days)].

  • Peak Plasma Concentration (Cmax) [ Time Frame: 4 months ]
    PK measurements expressed as Peak Plasma Concentration (Cmax) of Abemaciclib [Time Frame C1D1 (pre-treatment), C2D1, C3D1 and C4D1 (each cycle is 28 days)]

  • Radiographic Response Rate [ Time Frame: 2 years ]
  • Median Progression Free Survival [ Time Frame: 2 years ]
  • Overall Survival [ Time Frame: 2 years ]

Estimated Enrollment: 47
Actual Study Start Date: February 9, 2017
Estimated Study Completion Date: April 2024
Estimated Primary Completion Date: April 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Abemaciclib with Surgery
  • Abemaciclib will be administered on a continuous twice daily dosing schedule
  • Patients who require re-operation will receive a short preoperative course of Abemaciclib
  • Tissue will be used to investigate the ability of Abemaciclib to pass through the blood brain barrier.
  • After recovery from surgery, participants will resume Abemaciclib. Each cycle lasts 28 days.
Drug: Abemaciclib
Abemaciclib capsule
Other Name: LY2835219
Procedure: Surgery
Surgery
Experimental: Abemaciclib without Surgery
  • Abemaciclib will be administered on a continuous twice daily dosing schedule
  • Each Cycle last 28 days
Drug: Abemaciclib
Abemaciclib capsule
Other Name: LY2835219

Detailed Description:

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved abemaciclib as a treatment for any disease.

Many brain cancers show over expression of a protein called cyclin D1. That means that the body makes too much cyclin D1, which affects enzymes called CDK 4 and CDK 6. Enzymes are substances in the body that help reactions between cells happen. Too much cyclin D1 triggers CDK 4 and CDK 6 to make more cells than normal. This extra cell production leads to the growth of tumors.

In laboratory studies, Abemaciclib was able to enter the brain, stop CDK 4 and CDK 6 from making cells, and slow growth of mice Glioblastoma.

In this research study, the investigators are looking to see how safe and effect Abemaciclib is with the participant type of cancer. In the surgical participants, the investigators are looking to see if Abemaciclib reached the brain tumor.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants must be able to understand and willing to sign a written informed consent document.
  • Participants must be able to adhere to the dosing and visit schedules, and agree to record medication times accurately and consistently in a daily diary.
  • Participants must be at least 18 years old on day of signing informed consent.
  • Participants must have a Karnofsky Performance Status (KPS) ≥ 60
  • Participants must be able to swallow capsules. Nature of illness and treatment history
  • Participants must undergo central pathology review to histologically confirm the diagnosis of glioblastoma or variants (1 unstained slide or 1 H&E slide must be submitted to and reviewed by a pathologist at the DFCI Coordinating Center prior to enrollment of the participant for central pathology review). Participants will not be eligible if the prior diagnosis was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants was made (e.g. secondary GBM).
  • To be eligible for the study all participants (Cohort 1 and 2) are required to provide genomic profiling data from assays performed in a CLIA-certified lab that demonstrate the following with respect to relevant biomarkers required for enrollment to the study as listed below. Results from genomic profiling must be sent to the DFCI Coordinating Center prior to enrollment of the participant for central pathology review.

    • Inactivation of CDKN2A/B or C in the tumor by homozygous deletion (evidence for more than single copy loss for any of the genes defined as array CGH log2 ratio of <0.3 by array CGH; or from sequencing data with sufficient coverage for evaluation).

AND

  • Validation of wild-type RB status (no deletion/losses more than single copy by copy number or sequencing data; and/or no inactivating mutations by sequencing).

    • Participants must be at first relapse of GBM. Relapse is defined as progression following initial therapy (i.e. radiation+/- chemo if that was used as initial therapy). The intent therefore is that patients had no more than 1 prior therapy (initial treatment). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered to constitute 1 relapse.
    • Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan.
  • For Cohort 2 subjects, CT or MRI within 14 days prior to study registration. For Cohort 2, corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI or CT scan and the start of treatment, a new baseline MRI or CT is required.
  • For Cohort 1 subjects, CT or MRI should be performed ideally within 14 days prior to study registration, but because the screening MRI for this subset of subjects will not be used for evaluation of response, it is acceptable for this MRI/CT to have been performed greater than 14 days prior to registration if unavoidable. Furthermore, for this same reason, fluctuation in corticosteroid dose around this MRI does not warrant repeat scan so long as there is documented unequivocal evidence of tumor progression available.

    • Confirmation of availability of sufficient tissue from a prior surgery for correlative studies is required prior to enrollment; these samples must be sent to the DFCI Coordinating Center within 60 days of registration. Cohort 1 participants must have sufficient FFPE tissue from any surgery. Cohort 2 participants must have tissue from biopsy or resection from the most recent recurrence surgery.

The following amount of tissue is required:

  • 25 unstained formalin fixed paraffin embedded (FFPE) sections (standard 4-5 micrometer thickness)
  • AND 1 H&E stained slide (or 1 additional unstained 4-5 um slide for staining)
  • AND one of the following for genomics/nucleic acid extraction:
  • At least 10 (preferably 20) unstained FFPE sections of 10 micrometer thickness OR
  • At least 8 tissue cores from an FFPE block (200 micrometer total thickness of tissue from a block with a total surface area of 0.5 cm2) OR
  • At least 200 mg of frozen tissue

    • An interval of at least 12 weeks from the completion of radiation therapy to start of study drug unless there is a new area of enhancement consistent with recurrent tumor outside the radiation field (defined as the region outside the high-dose region or 80% isodose line) or there is unequivocal histologic confirmation of tumor progression.
    • Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (including but not limited to exceptions of alopecia, laboratory values listed per inclusion criteria, and lymphopenia which is common after therapy with temozolomide).
    • From the projected start of scheduled study treatment, the following time periods must have elapsed:
  • 4 weeks or 5 half-lives (whichever is shorter) from any investigational agent;
  • 4 weeks from cytotoxic therapy (except 23 days for temozolomide; 6 weeks from nitrosoureas);
  • 6 weeks from antibodies;
  • 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies.
  • 2 days from Novo-TTF

    • Participants with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of progressive disease based upon nuclear imaging, MR spectroscopy, perfusion imaging or histopathology.
    • Participants having undergone recent resection or open biopsy or stereotactic biopsy of recurrent or progressive tumor will be eligible for Cohort 2 as long as the following conditions apply:
  • They have recovered from the effects of surgery.
  • Residual disease following resection of recurrent tumor is not mandated for eligibility. To best assess the extent of residual disease post-operatively, an MRI or CT scan should ideally have been performed no later than 96 hours following surgery, or at least 28 days post-operatively, but scans performed outside of this window are considered acceptable if no alternative is available. In either case, the baseline/screening MRI must be performed within 14 days prior to registration. If the participant is taking corticosteroids, the dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI or CT scan and the start of treatment, a new baseline MRI or CT is required.

Clinical labs - performed within 14 days prior to registration

  • Hematology:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Platelet count ≥ 100 x 109/L
    • Hemoglobin ≥ 8.0 g/dL
  • Biochemistry:

    • Total serum calcium (corrected for serum albumin as needed) or ionized calcium within institution's normal range.
    • Magnesium within institution's normal range.
    • AST (SGOT) and ALT (SGPT) ≤ 3.0 x institution's ULN
    • Serum bilirubin ≤ 1.5 x institution's ULN
    • Serum creatinine ≤ 1.5 x institution's ULN or calculated 24-hour creatinine clearance ≥ 50 mL/min
    • Serum amylase ≤ 1.5 x institution's ULN
    • Serum lipase ≤ 1.5 x institution's ULN
  • Coagulation studies:

    • INR < 2.0
    • PTT ≤ institution's ULN, unless receiving therapeutic low molecular weight heparin Pregnancy and Reproduction
  • The effects of abemaciclib on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) must agree to use a medically approved contraceptive method during the treatment period and for 3 months following the last dose of abemaciclib. Men must agree to use a reliable method of birth control and to not donate sperm during the study and for at least 3 months following the last dose of abemaciclib. Contraceptive methods may include an intrauterine device [IUD] or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection.

    --NOTE: Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

  • Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to first dose of abemaciclib .

Exclusion Criteria:

Pathology

  • Prior evidence of 1p/19q co-deletion.
  • IDH1/2 mutation in any prior biopsy.

Previous therapies

  • Participants who have received prior treatment with a CDK4/6 inhibitor.
  • Participants who have received anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL184, sunitinib etc).

Concomitant medications

  • Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, and felbamate. Participants must be off any EIAEDs for at least 14 days prior to starting study drug. A list of EIAEDs and other inducers of CYP3A4 can be found.
  • Participants taking a drug known to be a strong inhibitor or inducer of isoenzyme CYP3A . Participant must be off CYP3A inhibitors and inducers for at least 14 days prior to starting study drug. NOTE: participants must avoid consumption of Seville oranges (and juice), grapefruits or grapefruit juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to the first dose of study drug and during the entire study treatment period due to potential CYP3A4 interaction.
  • Participants receiving any other investigational agents.
  • Current use of herbal preparations/medications, including but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng. Participants should stop using these herbal medications 7 days prior to first dose of study drug.
  • Current use of warfarin sodium or any other coumadin-derivative anticoagulant. Participants must be off Coumadin-derivative anticoagulants for at least 7 days prior to starting study drug. Low molecular weight heparin is allowed.

Other illnesses

  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to abemaciclib.
  • History of intratumoral or peritumoral hemorrhage if deemed significant by the treating investigator. If there are questions, the treating investigator should contact the study Overall P.I., Eudocia Quant Lee, MD, at 617-632-2166 or eqlee@partners.org.
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), chronic renal disease, pancreatitis, chronic pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements. Subjects must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations.
  • Individuals with a history of a different malignancy except for the following circumstances: if they have been disease-free for at least 2 years prior to starting study drug and are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers are eligible if diagnosed and treated within the past 2 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
  • Participant has an active systemic fungal and/or known viral infection (for example, human immunodeficiency virus antibodies, hepatitis B surface antigen or hepatitis C antibodies).
  • Participants with diarrhea ≥ CTCAE grade 2
  • Participant has active cardiac disease including any of the following:

    • Angina pectoris that requires the use of anti-anginal medications
    • Ventricular arrhythmias except for benign premature ventricular contractions
    • Supraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication
    • Conduction abnormality requiring a pacemaker
    • Valvular disease with document compromise in cardiac function
    • Symptomatic pericarditis
  • Participant has a history of cardiac dysfunction including any of the following:

    • Myocardial infarction within the last 6 months prior to start of study drug, documents by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function
    • History of documents congestive heart failure (New York Heart Association functional classification III-IV, see Appendix B)
    • Documented cardiomyopathy
    • Congenital long QT syndrome
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of abemaciclib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive small bowel resection). Participants with unresolved diarrhea ≥ CTCAE grade 2 will be excluded as previously indicated.
  • Participants who have undergone major systemic surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
  • Participants who are pregnant or breastfeeding.
  • Participants with history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of start of study drug.
  Contacts and Locations
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): NCT02981940


Contacts
Contact: Eudocia Q Lee, MD MPH 617-632-2166 eqlee@partners.org
Contact: Sarah Gaffey 617-632-4341 sgaffey@partners.org

Locations
United States, California
University of California Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Timothy Cloughesy, MD    310-825-5321    tcloughesy@mednet.ucla.edu   
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143-0372
Contact: Jennie Taylor, MD    415-353-2966    jennie.taylor@ucsf.edu   
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Isabel Arrillaga-Romany, MD, PhD    617-724-8770    iarrillaga@mgh.harvard.edu   
Principal Investigator: Isabel Arrillaga-Romany, MD, PhD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Eudocia Q Lee, MD MPH    617-632-2166    eqlee@partners.org   
Contact: Lisa Doherty, NP    617-632-2166    ldoherty1@partners.org   
Principal Investigator: Eudocia Q Lee, MD MPH         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10021
Contact: Mariza Daras, MD    212-610-0239    darasm@mskcc.org   
United States, Texas
UT, M.D. Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: John de Groot, MD    713-745-3072    jdegroot@mdanderson.org   
United States, Utah
Huntsman Cancer Institute Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Howard Colman, MD    801-587-4042    howard.colman@hci.utah.edu   
Sponsors and Collaborators
Dana-Farber Cancer Institute
Eli Lilly and Company
Investigators
Principal Investigator: Eudocia Q Lee, MD MPH Dana-Farber Cancer Institute
  More Information

Responsible Party: Eudocia Quant Lee, MD, MD, MPH, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT02981940     History of Changes
Other Study ID Numbers: 16-383
First Submitted: October 7, 2016
First Posted: December 5, 2016
Last Update Posted: June 28, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eudocia Quant Lee, MD, Dana-Farber Cancer Institute:
Brain Tumor

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue