Clinical Trials /

A Study of Abemaciclib in Recurrent Glioblastoma

NCT02981940

Description:

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

Related Conditions:
  • Glioblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Abemaciclib in Recurrent Glioblastoma
  • Official Title: A Phase 2 Study of Abemaciclib in Recurrent Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 16-383
  • NCT ID: NCT02981940

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
AbemaciclibLY2835219Abemaciclib with Surgery

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

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.
    

Trial Arms

NameTypeDescriptionInterventions
Abemaciclib with SurgeryExperimentalAbemaciclib 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.
  • Abemaciclib
Abemaciclib without SurgeryExperimentalAbemaciclib will be administered on a continuous twice daily dosing schedule. Each Cycle last 28 days. NOTE: enrollment to this arm is complete
  • Abemaciclib

Eligibility 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/tablets

          -  Participants with a prior or concurrent malignancy whose natural history or treatment
             does not have the potential to interfere with the safety or efficacy of the trial are
             eligible.

        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. A
             sequencing-based assay is required and must include reporting of the RB1 gene in
             explicit terms within the report. Only sequencing assays that include coverage of all
             exons of the RB1 gene are able to be utilized (most commonly called a targeted exome
             assay; e.g. Oncopanel, Impact, FoundationOne). In addition, patients must provide a
             report of copy assessment which reports status of RB1. The reporting may be from a
             copy array (ideally Oncoscan SNP array or Agilent array CGH) or can also be from
             sequencing assay if copy status is explicitly provided with quantitative information
             regarding the status of relevant genes. Specifically, the reporting should provide the
             following information 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/SNP log2
                  ratio of <0.3 by array CGH; or from sequencing data with sufficient coverage for
                  evaluation). Rearrangement/evidence or intragenic breaks by copy or sequencing
                  assay also will be considered eligible for study (any copy status).

               -  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.

               -  For Cohort 1 subjects, there must be > 2cm2 enhancing tissue available for
                  resection and submission for study correlatives as determined by local treating
                  team.

          -  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 archived tissue is required:

               -  20 unstained formalin fixed paraffin embedded (FFPE) sections (standard 4-5
                  micrometer thickness)

               -  NOTE: if the above-mentioned tissue is not available from the most recent surgery
                  revealing GBM, participants may be enrolled with tissue available from any prior
                  surgery revealing GBM with prospective approval from the Overall PI.

          -  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);

               -  4 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 K/µL

               -  Platelet count ≥ 100 x K/µL

               -  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 or oral factor Xa inhibitors 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.

          -  Requires treatment with high dose systemic corticosteroids defined as dexamethasone >
             4 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of
             registration.

        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.

          -  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 documented 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Intratumoral abemaciclib concentration
Time Frame:2 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:pRB expression level of tumor tissue
Time Frame:2 years
Safety Issue:
Description:
Measure:Incidence of Treatment-Emergent Adverse Events
Time Frame:2 years
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Measure:Area under the plasma concentration versus time curve (AUC)
Time Frame:4 months
Safety Issue:
Description: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)].
Measure:Peak Plasma Concentration (Cmax)
Time Frame:4 months
Safety Issue:
Description:PK measurements expressed as Peak Plasma Concentration (Cmax) of Abemaciclib [Time Frame C1D1 (pre-treatment), C2D1, C3D1 and C4D1 (each cycle is 28 days)]
Measure:Radiographic Response Rate
Time Frame:2 years
Safety Issue:
Description:
Measure:Median Progression Free Survival
Time Frame:2 years
Safety Issue:
Description:
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Brain Tumor

Last Updated

March 20, 2020