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Glasdegib (PF-04449913) With Temozolomide Newly Diagnosed Glioblastoma (GEINOGLAS)

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.
 
ClinicalTrials.gov Identifier: NCT03466450
Recruitment Status : Recruiting
First Posted : March 15, 2018
Last Update Posted : May 31, 2019
Sponsor:
Information provided by (Responsible Party):
Grupo Español de Investigación en Neurooncología

Tracking Information
First Submitted Date  ICMJE February 27, 2018
First Posted Date  ICMJE March 15, 2018
Last Update Posted Date May 31, 2019
Actual Study Start Date  ICMJE March 15, 2018
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 8, 2018)
  • Glasdegib Dose [ Time Frame: 12 weeks ]
    For Phase Ib, The recommended dose for phase 2 (RDP2) of Glasdegib administered with temozolomide during and after RT.
  • Overall survival [ Time Frame: 15 months ]
    For Phase II, time between the start of treatment to death
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03466450 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 8, 2018)
  • Progression Free Survival [ Time Frame: 24 months ]
    Time between the start of treatment and progression of disease
  • Adverse events (safety) [ Time Frame: 24 months ]
    Based on the number and type of adverse events reported since the start of treatment and throughout the study period.
  • Response to treatment [ Time Frame: 24 months ]
    Based on RANO criteria
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Glasdegib (PF-04449913) With Temozolomide Newly Diagnosed Glioblastoma
Official Title  ICMJE Phase Ib/II Multicentric Study Combining Glasdegib (PF-04449913) With Temozolomide in Patients With Newly Diagnosed Glioblastoma, Safety and Preliminary Efficacy for the Combination
Brief Summary

Glioblastomas (GBMs) are the most common malignant primary brain tumors. Despite multimodality aggressive therapies (surgery followed by chemoradiotherapy based on TMZ and adjuvant TMZ), median overall survival is only 12 to 15 months. This dramatic behavior is mainly due to the high invasiveness and proliferation rate of GBM.

In addition, GBM exhibits a high resistance to standard chemotherapy and radiotherapy. Current strategies for the treatment of GBM are only palliative, and include surgical resection (which is frequently incomplete due to the proximity of the tumour to vital brain structures) and focal radiotherapy. A large number of chemotherapeutic agents (e.g. alkylating agents such as TMZ and nitrosoureas such as carmustine) have also been tested, but they display limited efficacy.

The current gold standard first line treatment for glioma for patients less than 70 years old includes radiation and concurrent TMZ followed by adjuvant TMZ (i.e., the "Stupp regimen"). However, results are disappointing and there is an unmet medical need of new drugs in this setting.

Glasdegib (SHH pathway inhibitor) is a rational therapeutic agent for patients with newly diagnosed Glioblastoma since inhibits SHH pathway interfering with cancer stem cells and endothelial migration.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Intervention Model Description:
Phase Ib/II, multicentric, non-randomized, open label
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Drug: PF-04449913

    Glasdegib (3 dose levels will be evaluated: 100mg QD, 150mg QD and 200mg QD, or 75-50mg) will be administered:

    During concurrent phase concomitantly with radiation and Extended to the resting period (glasdegib will not be stopped in the 4 weeks of radiotherapy resting period).

    During adjuvant therapy with Temozolomide Oral Capsule. Additional treatment with glasdegib beyond 6 sequential TMZ cycles will continue until progression, unacceptable toxicity, non-compliance, consent withdrawal and/or 2 years of glasdegib administration.

    Other Name: Glasdegib
  • Drug: Temozolomide Oral Capsule

    During RT, patients will receive Temozolamide (TMZ). All patients will be given TMZ at 75 mg/m2

    /d concurrently with RT for a maximum of 42 days. At 4 weeks after RT completion, patients will start taking TMZ at 150 mg/m2/d for the first 5 days of a 28-day cycle. If first cycle is well tolerated, patients will receive TMZ at 200 mg/m2/d for the first 5 days of every subsequent 28-day cycle for another 5 cycles.

Study Arms  ICMJE Experimental: Glasdegib and Temozolomide Oral Capsule

During Phase Ib, Four to six weeks after surgical diagnosis, concurrent with radiotherapy (STUPP) + temozolomide (75mg/m2/day for 42 days) + PF-04449913 (Glasdegib) (3 dose levels will be evaluated: 100mg QD, 150mg QD and 200mg QD, or 75-50mg) will be administered.

During Phase II, Radiation therapy, temozolomide and glasdegib will be administered. This last, as the dose that have been selected previously, based on the Phase Ib results. Glasdegib ( PF-04449913) recommended dose until progresion of disease, unacceptable toxicity, non-compliance, consent withdrawal up to 2 years.

Interventions:
  • Drug: PF-04449913
  • Drug: Temozolomide Oral Capsule
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 8, 2018)
75
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Ability to understand and the willingness to sign a written informed consent document.
  • Male or Female ≥18 years old.
  • Newly diagnosed GBM confirmed by biopsy or resection no more than 4 to 6 weeks before registration.
  • Patients candidates for Stupp treatment
  • Patients must have at least 15 unstained slides or 1 tissue block (frozen or paraffin embedded) available from a prior biopsy or surgery (archival tumor material).
  • Patients must have sufficient time for recovery from prior surgery (at least 4 weeks).
  • ECOG ≤ 1.
  • Adequate hematologic function: Hematocrit ≥ 29%, Leukocytes > 3,000/mcL, ANC ≥ 1,500 cells/ul, platelets ≥ 100,000 cells/ul.
  • Adequate liver function: Bilirubin ≤ 2 x ULN; AST (SGOT) ≤ 2.5 X ULN
  • Creatinine within normal institutional limits or creatinine clearance > 60 mL/min for subjects with creatinine levels above institutional normal.
  • The effects of SHH pathway inhibitors on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence; surgical sterilization) prior to study entry and for the duration of study participation and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate.

Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. All female patients with reproductive potential must have a negative pregnancy test (serum/urine) within 2 weeks prior to starting treatment.

  • Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.

Exclusion Criteria:

  • Presence of extracranial metastatic disease.
  • Participants may not be receiving any other investigational agents.
  • Patients must not have received prior Gliadel wafers.
  • Any surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 weeks of baseline disease assessments; or not fully recovered from any side effects of previous procedures.
  • Any psychiatric or cognitive disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol.
  • Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication in tablet form.
  • Congenital or known history of long QT syndrome, Torsades de pointes, arrhythmias (including sustained ventricular tachyarrhythmia, right or left bundle branch block and bifascicular block, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Association class III or IV).
  • Current (or within 6 months) significant cardiovascular disease, including, but not limited to myocardial infarction, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism, bradycardia defined as <50 bpms.
  • Active cardiac dysrhythmias of NCI CTCAE Grade ≥2 (eg, atrial fibrillation) or QTcF interval (QTc using Fridericia's formula) >470 msec.
  • Active and clinically significant infections.
  • Current use or anticipated requirement for drugs known to be moderate or strong cytochrome p450 inhibitors.
  • Individuals with a history of a different malignancy are ineligible except for the following circumstances: Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years 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 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.

Patients will not be eligible if they have evidence of other malignancy requiring therapy other than surgery within the last 3 years.

  • Patients who have had prior stereotactic radiotherapy, convection enhanced delivery or brachytherapy (as gliosis/scarring from these modalities may limit delivery).
  • Patients will not be eligible if they present with leptomeningeal dissemination.
  • Pregnant women are excluded from this study because the potential for teratogenic or abortifacient effects is unknown (glasdegib has been shown to be teratogenic in nonclinical embryo-fetal development studies in rats and mice at subtherapeutic exposures). Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated.
  • HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to glasdegib.
  • Other severe acute or chronic medical condition, uncontrolled intercurrent illness or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into this trial.
  • Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of the study treatment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Federico Nepote +34 93 434 44 12 investigacion@mfar.net
Contact: Verónica Roca +34 93 434 44 12 investigacion@mfar.net
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03466450
Other Study ID Numbers  ICMJE GEINO-1602
2017-002410-31 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Grupo Español de Investigación en Neurooncología
Study Sponsor  ICMJE Grupo Español de Investigación en Neurooncología
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: María Angeles Vaz, M.D. Hospital Universitario Ramón y Cajal
PRS Account Grupo Español de Investigación en Neurooncología
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP