Abemaciclib, DNA-PK / TOR Kinase Inhibitor CC-115, or Neratinib in Treating Patients with Brain Tumors after Biomarker Screening

Status: Active

Description

This randomized phase II trial studies how well abemaciclib, DNA-PK / TOR kinase inhibitor CC-115, or neratinib works in treating patients with brain tumors after biomarker screening. Drugs such as abemaciclib, DNA-PK / TOR kinase inhibitor CC-115, or neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Screening tumor samples for biomarkers may help doctors to determine if certain treatments work better on patients with certain biomarkers. Giving abemaciclib, DNA-PK / TOR kinase inhibitor CC-115, or neratinib may work better in treating patients with brain tumors.

Eligibility Criteria

Inclusion Criteria

  • Participants must have histologically confirmed intracranial glioblastoma or gliosarcoma following maximum surgical resection; tumors primarily localized in the infratentorial compartment will be excluded
  • Participants may have had prior surgery for glioblastoma or gliosarcoma but no systemic or radiation therapy
  • Karnofsky performance status >= 60
  • Leukocytes >= 3,000/mL
  • Absolute neutrophil count >= 1,500/mL
  • Platelets >= 100,000/mL
  • Hemoglobin >= 9 g/dl
  • Total bilirubin within normal institutional limits (except for participants with Gilbert’s disease)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine =< institutional upper limit of normal OR
  • Creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
  • Potassium within normal institutional range, or correctable with supplements
  • Serum amylase =< 1.5 x institutional upper limit of normal
  • Serum lipase =< 1.5 x institutional upper limit of normal
  • International normalized ratio (INR) < 2.0
  • Partial thromboplastin time =< institutional upper limit of normal, unless receiving therapeutic low molecular weight heparin
  • Must be able to swallow pills
  • Participants must plan to begin radiation therapy 14-42 days after surgical resection
  • Immunohistochemically negative for IDH1 R132H mutation
  • Evidence that the tumor MGMT promoter is unmethylated by standard of care assays
  • Genotyping data available or in process (data must be available at time of initial registration if randomization probabilities differ across biomarker subgroups as determined by the Dana-Farber Cancer Institute [DFCI] Coordinating Center) to assign biomarker subgroups through whole exome sequencing, whole genome copy number analysis, or a combination
  • Magnetic resonance imaging (MRI) with gadolinium should be obtained within 21 days prior to beginning treatment; patients without measurable disease are eligible; participants must be able to undergo MRIs (computed tomography scans [CTs] are not allowed for response assessment on study)
  • Women of child-bearing potential (women who are not free from menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation unless otherwise specified in sub-study appendix that the participant is randomized to; 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
  • For women of child bearing potential (women who are not free from menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized) a negative serum pregnancy test must be documented prior to initial registration
  • Ability to understand and the willingness to sign a written informed consent document
  • Eligibility criteria specific to the control arm: * Participants must be willing and able to provide written informed consent/assent for the control arm of the INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) trial
  • Eligibility criteria specific to the abemaciclib arm: * Participants must be willing and able to provide written informed consent/assent for the abemaciclib arm of the INSIGhT trial * Women of child bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from date of initial dose and for 3 months following the last dose of abemaciclib
  • Eligibility criteria specific to the CC-115 arm: * Participants must be willing and able to provide written informed consent for the CC-115 arm of the INSIGhT trial * Women of child bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from date of initial dose and for 28 days following the last dose of CC-115; men (including those who have had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging in sexual activity with a woman of child bearing potential from date of initial dose and for 28 days following the last dose of CC-115
  • Eligibility criteria specific to the neratinib arm: * Participants must be willing and able to provide written informed consent/assent for the neratinib arm of the INSIGhT trial * Women of child bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from date of initial dose and for 28 days following the last dose of neratinib; men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during intercourse with women of childbearing potential from date of initial dose and for 3 months following the last dose of neratinib

Exclusion Criteria

  • Participants will not be eligible if the original diagnosis was a lower grade glioma and a subsequent histologic diagnosis revealed glioblastoma
  • Planned major surgery
  • Participants who are receiving any other investigational agents
  • Participants who have had any prior cranial radiotherapy
  • Planned use of Optune
  • History of a different malignancy, unless (a) have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, and/or (b) malignancy was cervical cancer in situ, superficial bladder cancer or basal cell or squamous cell carcinoma of the skin, and malignancy has been treated; patients who meet the above listed criteria and are only on preventative treatment will be deemed eligible
  • History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician
  • Impaired cardiac function or clinically significant cardiac diseases, including any of the following: * Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia * Known history of congenital QT prolongation or Torsade de pointes (TdP) * Complete left bundle branch or bifascicular block * QTc interval > 450 ms for men or > 470 ms for women * Persistent or history of clinically meaningful ventricular arrhythmias or atrial fibrillation * Unstable pectoris or myocardial infarction =< 3 months prior to starting study treatment * Uncontrolled hypertension (blood pressure >= 160/95 mmHg) * Other clinically significant heart disease such as congestive heart failure requiring treatment
  • Uncontrolled diabetes mellitus, or subjects with either of the following: * Fasting blood glucose (FBG defined as fasting for at least 8 hours) >= 200 mg/dL (7.0 mmol/L), or * Glycosylated hemoglobin measurement (HbA1c) >= 8%
  • 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
  • Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] RNS [qualitative] is detected)
  • Known acute or chronic pancreatitis
  • Participants with active diarrhea >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2 despite medical management
  • Active infection requiring antibiotics
  • Pregnant or breastfeeding
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (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
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to any of the experimental agents or other agents used in study
  • Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, and felbamate; participant must be off any EIAEDs for at least 7 days prior to planned start of study treatment; among non-EIAED, caution is recommended with use of valproic acid due to potential for drug interaction
  • Participants taking a drug known to be strong inhibitors or inducers of isoenzyme CYP3A; participant must be off CYP3A inhibitors and inducers for at least 7 days prior to planned start of study treatment; NOTE: participants must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to planned start of study treatment and during the entire study treatment period due to potential CYP3A4 interaction
  • 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 planned start of study treatment
  • Current use of warfarin sodium or any other coumadin-derivative anticoagulant; participant must be off coumadin-derivative anticoagulants for at least 7 days prior to planned start of study treatment; low molecular weight heparin and factor Xa inhibitors are allowed

Locations & Contacts

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: Active
Contact: Louis Burton Nabors
Phone: 205-934-1432
Email: Bnabors@uab.edu

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Brian M Alexander
Phone: 617-732-7560
Email: Brian_Alexander@dfci.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Brian M Alexander
Phone: 617-732-7560
Email: Brian_Alexander@dfci.harvard.edu
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Brian M Alexander
Phone: 617-732-7560
Email: Brian_Alexander@dfci.harvard.edu

Minnesota

Rochester
Mayo Clinic
Status: Active
Contact: Evanthia Galanis
Phone: 507-284-2511
Email: Galanis.evanthia@mayo.edu

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: Active
Contact: Mary Roberta Welch
Phone: 212-342-0571
Email: mw2517@cumc.columbia.edu

Ohio

Cleveland
Cleveland Clinic Foundation
Status: Active
Contact: Manmeet Singh Ahluwalia
Phone: 216-444-6145
Email: Ahluwam@ccf.org

Pennsylvania

Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: Active
Contact: Jan Drappatz
Phone: 412-864-7791
Email: Drappatzj@upmc.edu

Rhode Island

Providence
Lifespan
Status: Active
Contact: Jaroslaw Tadeusz Hepel
Phone: 401-444-8311

Texas

Houston
M D Anderson Cancer Center
Status: Active
Contact: John Frederick de Groot
Phone: 713-792-8288
Email: Jdegroot@mdanderson.org

Utah

Salt Lake City
Huntsman Cancer Institute / University of Utah
Status: Active
Contact: Howard Colman
Phone: 801-587-4042
Email: Howard.colman@hci.utah.edu

Virginia

Charlottesville
University of Virginia Cancer Center
Status: Active
Contact: David Schiff
Phone: 434-924-5610
Email: Ds4jd@virginia.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine whether experimental arms improve overall survival (OS) in patients with glioblastoma (GBM) harboring unmethylated MGMT promoters compared with standard therapy.

SECONDARY OBJECTIVES:

I. To determine whether specific a priori defined biomarkers predict the benefit from experimental therapy.

II. To assess the toxicity of experimental arms.

III. To assess progression-free survival (PFS) among experimental arms and biomarker groups.

IV. To assess OS among experimental arms and biomarker groups.

V. To determine the association between PFS and OS effects of experimental agents.

OUTLINE: Patients are randomized to 1 of 4 treatment arms. After an equal randomization period, associations of biomarker signatures with drug efficacy may influence the randomization probability.

ARM I (CONTROL): Patients undergo standard of care radiation therapy and receive temozolomide orally (PO) once daily (QD) for 6 weeks. After a 4 week rest period, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM II (ABEMACICLIB): Patients with CDK positive tumors receive standard of care radiation and temozolomide for 6 weeks as in arm I. Beginning 4 weeks after completing standard of care treatment, patients receive abemaciclib PO twice daily (BID) on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

ARM III (CC-115): Patients with PI3K positive tumors undergo standard of care radiation therapy and receive DNA-PK/TOR kinase inhibitor CC-115 (CC-115) PO BID for 6 weeks. After 6 weeks, patients receive CC-115 PO BID on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

ARM IV (NERATINIB): Patients with EGFR positive tumors receive standard of care radiation and temozolomide for 6 weeks as in arm I. Beginning 4 weeks after completing standard of care treatment, patients receive neratinib PO QD on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then periodically for 1 year.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Brian M Alexander

Trial IDs

Primary ID 16-443
Secondary IDs NCI-2017-00433
Clinicaltrials.gov ID NCT02977780