GlioblastomaPhase 1/2NCT02430363
Evaluation Of The Treatment Effectiveness Of Glioblastoma / Gliosarcoma Through The Suppression Of The PI3K/Akt Pathway In Compared With MK-3475
A Phase 1/2 study testing MK - 3475 and Suppressor of the PI3K/Akt pathways in people with Glioblastoma, run by Medical Research Council at 13 sites in 10 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Glioblastoma
- What is being tested?
- MK - 3475 and Suppressor of the PI3K/Akt pathways
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 58 participants
- Where
- 13 sitesin 10 countries
- Study dates
- Mar 2013to Jun 2018
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
13 sites in 10 countries.
13 sites in 10 countries
United States2 sites
Dana-Farber Cancer Institute
Boston, Massachusetts, 02115
M D Anderson Cancer Center
Houston, Texas, 77030
Ukraine2 sites
Regional Cancer Center
Dnipro, 49000
National Institute of Cancer
Kiev, 03035
Poland1 site
Lower-Silesian Oncology Centre
Wroclaw, Lower Silesian Voivodeship, 53413
About this study
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)
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).
Read the 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
- Being tested
- MK - 3475, Suppressor of the PI3K/Akt pathways
- Keywords
- pembrolizumab, MK-3475, Glioblastoma, Gliosarcoma, Suppressor of the PI3K/Akt pathways, Pictilisib, GDC-0941, BEZ235, NVP-BEZ235, Ipatasertib, GDC-0068
- Medical subject headings
- Glioblastoma, Gliosarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MK - 3475Drug
Also called Pembrolizumab, Keytruda
Administered Intravenously
Suppressor of the PI3K/Akt pathwaysBiological
Also called Pictilisib, GDC-0941, BEZ235, NVP-BEZ235
Capsules orally with food
| Study group | Role | What they receive |
|---|---|---|
| MK-3475 | Active comparator | 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 Receives: Drug: MK - 3475 |
| Suppressor of the PI3K/Akt pathways | Experimental | 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 Receives: Biological: Suppressor of the PI3K/Akt pathways |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival
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.
Measured: Time Frame: 12 months
Secondary outcomes (1)
Safety and tolerability of Pembrolizumab (Assessed by reported adverse events using CTCAE version 4.0)
Assesed by reported adverse events using CTCAE version 4.0. Progression Free Survival
Measured: Time Frame: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Apr 2015 (estimated)
- Study startMar 2013
- Primary completionJan 2016
- Study completionJun 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for GlioblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 58 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Medical Research Council
- Sponsor type
- Other government
- Collaborators
- Aarhus University Hospital, NCRI Clinical Studies Groups, ECCO - the European CanCer Organisation, Merck Sharp & Dohme LLC
- Responsible party
- Principal investigator, Ms. Jann Lee, Medical Research Council
- Investigators
- Jann Lee, PhD, Principal investigator, MRC Clinical Trials Unit
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02430363
- Sponsor's protocol ID
- ETIK-W/33-15
- Status last verified
- Feb 2016
- First submitted
- 23 Apr 2015
- Last updated
- 24 Feb 2016
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02430363
- Acronym / sponsor ID
- ETIK-W/33-15
- Conditions
- Glioblastoma
- Keywords
- pembrolizumab, MK-3475, Glioblastoma, Gliosarcoma, Suppressor of the PI3K/Akt pathways, Pictilisib, GDC-0941, BEZ235
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 58 participants (estimated)
- Lead sponsor
- Medical Research CouncilOther government
- Collaborators
- Aarhus University Hospital, NCRI Clinical Studies Groups, ECCO - the European CanCer Organisation, Merck Sharp & Dohme LLC
- Study start
- Mar 2013
- Primary completion
- Jan 2016 (actual)
- Study completion
- Jun 2018 (estimated)
- First posted
- 30 Apr 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| MK-3475 | Active comparator | Drug: MK - 3475Pembrolizumab (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 |
| Suppressor of the PI3K/Akt pathways | Experimental | Biological: Suppressor of the PI3K/Akt pathwaysPictilisib (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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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.
Key exclusion criteria (29 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MK - 3475Also: Pembrolizumab, KeytrudaAdministered Intravenously | Drug | MK-3475 |
| Suppressor of the PI3K/Akt pathwaysAlso: Pictilisib, GDC-0941, BEZ235, NVP-BEZ235Capsules orally with food | Biological | Suppressor of the PI3K/Akt pathways |
Primary outcome
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.
1 secondary outcome
Safety and tolerability of Pembrolizumab (Assessed by reported adverse events using CTCAE version 4.0)
Time frame: Time Frame: 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Feb 2016.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jann Lee, PhD principal investigator
MRC Clinical Trials Unit
13 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing MK - 3475 and Suppressor of the PI3K/Akt pathways in people with Glioblastoma, run by Medical Research Council at 13 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 24 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United States, Italy, Ukraine, Belgium, Germany and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression Free Survival (time frame: Time Frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Feb 2016.