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Evaluation Of The Treatment Effectiveness Of Glioblastoma / Gliosarcoma Through The Suppression Of The PI3K/Akt Pathway In Compared With MK-3475

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ClinicalTrials.gov Identifier: NCT02430363
Recruitment Status : Unknown
Verified February 2016 by Ms. Jann Lee, Medical Research Council.
Recruitment status was:  Enrolling by invitation
First Posted : April 30, 2015
Last Update Posted : February 24, 2016
Sponsor:
Collaborators:
Department of Experimental Clinical Oncology, Aarhus University Hospital
NCRI Clinical Studies Groups
ECCO - the European CanCer Organisation
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ms. Jann Lee, Medical Research Council

Brief Summary:

It is known that after application of MK-3475 activated PD -1 negatively regulates the activation of T cells through suppression of the path of PI3K / Akt.

This study will identify the effectiveness of oral inhibitors of PI3K / Akt pathway in comparison with MK-3475 (pembrolizumab).


Condition or disease Intervention/treatment Phase
Glioblastoma Drug: MK - 3475 Biological: Suppressor of the PI3K/Akt pathways Phase 1 Phase 2

Detailed Description:

A humanized monoclonal IgG4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1) with potential immunopotentiating activity. Upon administration, pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells. The ligands for PD-1 include PD-L1, which is expressed on antigen presenting cells (APCs) and overexpressed on certain cancer cells, and PD-L2, which is primarily expressed on APCs. Activated PD-1 negatively regulates T-cell activation through the suppression of the PI3K/Akt pathway.

This study will identify the effectiveness of oral inhibitors of PI3K / Akt pathway in comparison with MK-3475 (pembrolizumab).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase IIb Trial Evaluations Of The Effectiveness Of Treatment Glioblastoma / Gliosarcoma Through The Suppression Of The PI3K/Akt Pathway In Compared With MK-3475 (Pembrolizumab)
Study Start Date : March 2013
Actual Primary Completion Date : January 2016
Estimated Study Completion Date : June 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: MK-3475

Pembrolizumab (MK-3475) is a humanized monoclonal antibody. Information from these studies suggests that Pembrolizumab (MK-3475) may be beneficial in Glioblastoma / Gliosarcoma.

  • Patients enrolling in phase 1 receive MK-3475 every 3 weeks, with the dose to be determined.
  • MK-3475 will be given intravenously over the course of 30 minutes
Drug: MK - 3475
Administered Intravenously
Other Names:
  • Pembrolizumab
  • Keytruda

Experimental: Suppressor of the PI3K/Akt pathways

Pictilisib (GDC-0941) is a potent inhibitor of PI3Kα/δ. Patients will take the Pictilisib (capsules) orally with food. The dose should be taken every 3 weeks.

BEZ235 (NVP-BEZ235) is a dual ATP-competitive PI3K and mTOR inhibitor. Inhibits ATR whileshown to be a poor inhibitor to Akt and PDK1.

Patients will take the BEZ235 (capsules) orally with food. The dose should be taken every 3 weeks.

Ipatasertib (GDC-0068) is a highly selective pan-Akt inhibitor targeting Akt1/2/3 .

Patients will take the Ipatasertib (capsules) orally with food. The dose should be taken every 3 weeks.

The suggested dosage of inhibitors of the PI3K/Akt pathway orally as a single dose in capsule and Packed in plastic boxes, so that preparations can be taken at home

Biological: Suppressor of the PI3K/Akt pathways
Capsules orally with food
Other Names:
  • Pictilisib
  • GDC-0941
  • BEZ235
  • NVP-BEZ235
  • Ipatasertib
  • GDC-0068




Primary Outcome Measures :
  1. Progression Free Survival [ Time Frame: Time Frame: 12 months ]
    To evaluate the anti-tumor activity of pembrolizumab among subjects with recurrent glioblastoma when treated with pembrolizumab (Cohort A), and when treated with inhibitors PI3K/Akt pathways monotherapy (Cohort B) as assessed by the 12-month progression-free survival (PFS-12) rate.


Secondary Outcome Measures :
  1. Safety and tolerability of Pembrolizumab (Assessed by reported adverse events using CTCAE version 4.0) [ Time Frame: Time Frame: 12 months ]
    Assesed by reported adverse events using CTCAE version 4.0. Progression Free Survival


Other Outcome Measures:
  1. Safety and tolerability of inhibitors PI3K/Akt pathways as monotherapy (adverse events using CTCAE version 4.0) [ Time Frame: Time Frame: 12 months ]
    Assesed by reported adverse events using CTCAE version 4.0. Progression Free Survival



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Have histologically confirmed World Health Organization Grade IV malignant glioma (glioblastoma or gliosarcoma). Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made.
  • Previous first line therapy with at least radiotherapy and temozolomide
  • Be at first or second relapse.
  • Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan.
  • CT or MRI within 14 days prior to start of study drug.
  • An interval of at least 4 weeks (to start of study agent) between prior surgical resection or one week for stereotactic biopsy.
  • 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 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: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.
  • Payment of charitable contributions may be required

Exclusion Criteria:

  • Current or planned participation in a study of an investigational agent or using an investigational device.
  • Has a diagnosis of immunodeficiency.
  • Has tumor primarily localized to the brainstem or spinal cord.
  • Has presence of diffuse leptomeningeal disease or extracranial disease.
  • Has received systemic immunosuppressive treatments within 6 months of start of study drug
  • 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 start of study drug.
  • Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or therapeutics delivered by local injection or convection enhanced delivery.
  • Requires therapeutic anticoagulation with warfarin at baseline; patients must be off warfarin or warfarin-derivative anti-coagulants for at least 7 days prior to starting study drug; however, therapeutic or prophylactic therapy with low-molecular weight heparin is allowed.
  • Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of start of study drug
  • Has evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than those that are grade ≤ 1 and either post-operative or stable on at least 2 consecutive MRI scans.
  • Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3 within 6 months of start of study drug.
  • Has a known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
  • Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
  • Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial
  • Has a known history of HIV
  • Has known active Hepatitis B or Hepatitis C
  • Has received a live vaccine within 30 days prior to the first dose of study drug.
  • Has a known hypersensitivity to any of the study therapy products.
  • Has received anti-angiogenic or anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc)
  • Has a history of non-healing wounds or ulcers, or bone refractures within 3 months of fracture
  • Has a history of arterial thromboembolism within 12 months of start of study drug.
  • Has inadequately controlled hypertension
  • Has a history of hypertensive crisis or hypertensive encephalopathy
  • Has had clinically significant cardiovascular disease within 12 months of start of study drug
  • Has a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to start of study drug.

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): NCT02430363


Locations
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United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Belgium
UCL- Cliniques Universitaires Saint Luc
Brussels, Belgium
Germany
St Johannes Hospital
Duisburg, Germany, 47166
Italy
Spedali Civili di Brescia
Brescia, Italy
IRCCS San Raffaele
Milan, Italy
Poland
Lower-Silesian Oncology Centre
Wroclaw, Lower-Silesian, Poland, 53413
Russian Federation
Pavlov State Medical University
St. Petersburg, Russian Federation, 197089
Spain
Hospital Universitario Germans Trias I Pujol
Barcelona,, Spain
Switzerland
Universitätsklinik für Frauenheilkunde
Bern, Switzerland
Ukraine
Regional Cancer Center
Dnepropetrovsk, Ukraine, 49000
National Institute of Cancer
Kiev, Ukraine, 03035
United Kingdom
Royal Victoria Hospital
Belfast, Ulster, United Kingdom, BT12 6BA
Sponsors and Collaborators
Medical Research Council
Department of Experimental Clinical Oncology, Aarhus University Hospital
NCRI Clinical Studies Groups
ECCO - the European CanCer Organisation
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Jann Lee, PhD MRC Clinical Trials Unit
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Responsible Party: Ms. Jann Lee, PhD, Medical Research Council
ClinicalTrials.gov Identifier: NCT02430363    
Other Study ID Numbers: ETIK-W/33-15
First Posted: April 30, 2015    Key Record Dates
Last Update Posted: February 24, 2016
Last Verified: February 2016
Keywords provided by Ms. Jann Lee, Medical Research Council:
pembrolizumab
MK-3475
Glioblastoma
Gliosarcoma
Suppressor of the PI3K/Akt pathways
Pictilisib
GDC-0941
BEZ235
NVP-BEZ235
Ipatasertib
GDC-0068
Additional relevant MeSH terms:
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Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Pembrolizumab
Dactolisib
Antineoplastic Agents, Immunological
Antineoplastic Agents