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

NCT ID: NCT02430363

Last Updated: 2016-02-24

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 58 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-03-31
• Study Completion Date: 2018-06-30

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).

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).

Conditions

Glioblastoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

MK - 3475

Intervention Type: DRUG

Administered Intravenously

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

Group Type: EXPERIMENTAL

Suppressor of the PI3K/Akt pathways

Intervention Type: BIOLOGICAL

Capsules orally with food

Interventions

MK - 3475

Administered Intravenously

Intervention Type: DRUG

Suppressor of the PI3K/Akt pathways

Capsules orally with food

Intervention Type: BIOLOGICAL

Other Intervention Names

Pembrolizumab; Keytruda; Pictilisib; GDC-0941; BEZ235; NVP-BEZ235; Ipatasertib; GDC-0068

Eligibility 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
• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aarhus University Hospital

OTHER

Sponsor Role: collaborator

NCRI Clinical Studies Groups

UNKNOWN

Sponsor Role: collaborator

ECCO - the European CanCer Organisation

UNKNOWN

Sponsor Role: collaborator

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Medical Research Council

OTHER_GOV

Sponsor Role: lead

Responsible Party

Ms. Jann Lee

PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jann Lee, PhD

Role: PRINCIPAL_INVESTIGATOR

MRC Clinical Trials Unit

Locations

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

M D Anderson Cancer Center

Houston, Texas, United States

UCL- Cliniques Universitaires Saint Luc

Brussels, , Belgium

St Johannes Hospital

Duisburg, , Germany

Spedali Civili di Brescia

Brescia, , Italy

IRCCS San Raffaele

Milan, , Italy

Lower-Silesian Oncology Centre

Wroclaw, Lower Silesian Voivodeship, Poland

Pavlov State Medical University

Saint Petersburg, , Russia

Hospital Universitario Germans Trias I Pujol

Barcelona, , Spain

Universitätsklinik für Frauenheilkunde

Bern, , Switzerland

Regional Cancer Center

Dnipro, , Ukraine

National Institute of Cancer

Kiev, , Ukraine

Royal Victoria Hospital

Belfast, Ulster, United Kingdom

Countries

United States; Belgium; Germany; Italy; Poland; Russia; Spain; Switzerland; Ukraine; United Kingdom

Other Identifiers

ETIK-W/33-15

Identifier Type: -

Identifier Source: org_study_id