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NCT02337491

Pembrolizumab +/- Bevacizumab for Recurrent GBM

Completed Phase 2 Results posted Last updated 22 December 2020
What this trial tests

Phase 2 trial testing Pembrolizumab in Glioblastoma in 80 participants. Completed in 14 September 2020.

Timeline
9 February 2015
Primary endpoint
28 August 2016
14 September 2020

Quick facts

Lead sponsorDana-Farber Cancer Institute
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment80
Start date9 February 2015
Primary completion28 August 2016
Estimated completion14 September 2020
Sites8 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Dana-Farber Cancer Institute

Who can join

18 and older, any sex, with Glioblastoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Pembrolizumab Maximum Tolerated Dose (MTD) [Cohort A Safety Lead-In] Primary · one cycle/42 days

The MTD of pembrolizumab in combination with bevacizumab 10 mg/kg intravenously (IV) on days 1, 15 and 29 of each 42 day cycle is determined by the number of participants who experience a dose limiting toxicity (DLT) at the various regimens of dosing frequency of pembrolizumab 200 mg IV administered under evaluation. See subsequent primary outcome measure for the DLT definition. The MTD is defined as the pembrolizumab dose frequency regimen at which fewer than one-third of participants experience a DLT. If de-escalation does not occur per design, then the starting dose is the Recommended Phase

GroupValue95% CI
Cohort A Safety Lead-In: Pembrolizumab (DL 0) + Bevacizumab200
Pembrolizumab Dose Limiting Toxicity (DLT) [Cohort A Safety Lead-In] Primary · The evaluation for MTD occurred continuously through one cycle of treatment (42 days).

A DLT is defined as an adverse event (AE) that (a) is \>= grade 3 and related to the pembrolizumab with an attribution of possible, probably or definite, and (b) occurs during and/or begins during the first 42 days of study treatment, and (c) does not meet any of the following exception criteria: grade 3 immune-related AE that downgrades to \<= grade 2 within 5 days, or \<= grade 1/baseline within 14 days of onset; grade 3 asymptomatic endocrinopathy; grade 3 inflammatory reaction attribution to anti-tumor response; grade 3 pneumonitis, neurologic event, or uveitis that downgrades to \<=grade

GroupValue95% CI
Cohort A Safety Lead-In: Pembrolizumab (DL 0) + Bevacizumab0
6-Month Progression-Free Survival (PFS6) Primary · Disease was assessed radiographically for response every cycle on treatment. Treatment duration in cycles (cycle=42 days) was a mean (SD) of 4.5 (4.4) for Cohort A and 2.5 (2.7) for Cohort B. Assessment at week 72/cycle 12 pertains to the 6-month PFS.

PFS6 is the proportion of patients remaining alive and progression-free at 6-months from study entry. Progressive disease was established based on Response Assessment in Neuro-Oncology (RANO) criteria. PD is a \>25% increase in sum of perpendicular diameters of all measurable enhancing lesions, significant increase of non-enhancing lesions, any new lesions, clear clinical deterioration, failure to return for evaluation due to death or deteriorating condition.

GroupValue95% CI
Cohort A: Pembrolizumab + Bevacizumab0.260.146 – 0.403
Cohort B: Pembrolizumab0.0670.009 – 0.221
Progression-Free Survival (PFS) Secondary · Disease was assessed radiographically for response every cycle on treatment and every 6 weeks long-term. Median PFS follow-up (months) was 25 for Cohort A and 26 for Cohort B.

PFS based on Kaplan-Meier is defined as the time from study entry to the earliest documentation of disease progression (PD) or death. Participants alive without evidence of PD were censored at the date of last disease assessment. Per Response Assessment in Neuro-Oncology (RANO) criteria, PD is a \>25% increase in sum of perpendicular diameters of all measurable enhancing lesions, significant increase of non-enhancing lesions, any new lesions, clear clinical deterioration, failure to return for evaluation due to death or deteriorating condition.

GroupValue95% CI
Cohort A: Pembrolizumab + Bevacizumab4.12.8 – 5.5
Cohort B: Pembrolizumab1.41.4 – 2.7
Overall Survival (OS) Secondary · Participants were followed long-term for survival every 3 months from the end of treatment until death or lost to follow-up. Median survival follow-up was 25 months for each cohort.

OS based on Kaplan-Meier is defined as the time from study entry to death or date last known alive.

GroupValue95% CI
Cohort A: Pembrolizumab + Bevacizumab8.87.7 – 14.2
Cohort B: Pembrolizumab10.38.5 – 12.5
Overall Radiographic Response (ORR) Secondary · Disease was assessed radiographically for response every cycle on treatment. Treatment duration in cycles (each cycle=42 days) was a mean (SD) of 4.5 (4.4) for Cohort A and 2.5 (2.7) for Cohort B.

ORR was established based on Response Assessment in Neuro-Oncology (RANO) criteria. RANO criteria has 5 potential categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive disease (PD) and Unknown. CR: disappearance of all enhancing lesions, stable or improved non-enhancing lesions, and stable or improved clinically. PR: \>= 50% decrease in sum of perpendicular diameters of all measurable enhancing lesions, no progression of non-measurable disease, stable or improved non-enhancing lesions, and stable or improved clinically. PD: \>25% increase in sum of perpend

GroupValue95% CI
Cohort A: Pembrolizumab + Bevacizumab0.200.11 – 0.32
Cohort B: Pembrolizumab0.00.0 – 0.095

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events (AEs) were assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment for unresolved AEs and up to day 90 for serious adverse events. AEs were evaluated over treatment which was a maximum duration of 16 cycles (approximates 22 months).. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort A: Pembrolizumab + Bevacizumab
Serious: 22/50 (44%)
Deaths: 3/50
Cohort B: Pembrolizumab
Serious: 10/30 (33%)
Deaths: 1/30

Serious adverse events (38 terms)

ReactionSystemCohort A: Pembrolizumab + …Cohort B: Pembrolizumab
HeadacheNervous system disorders
Surgical and medical procedures - OtherSurgical and medical procedures
Intracranial hemorrhageNervous system disorders
DiarrheaGastrointestinal disorders
Gait disturbanceGeneral disorders
HypertensionVascular disorders
Nervous system disorders - OtherNervous system disorders
SeizureNervous system disorders
Thromboembolic eventVascular disorders
VomitingGastrointestinal disorders
Alanine aminotransferase increasedInvestigations
AnemiaBlood and lymphatic system disorders
ConfusionPsychiatric disorders
Death NOSGeneral disorders
DizzinessNervous system disorders
DysphasiaNervous system disorders
Edema cerebralNervous system disorders
EncephalopathyNervous system disorders
FatigueGeneral disorders
FeverGeneral disorders
Gastric ulcerGastrointestinal disorders
HemorrhoidsGastrointestinal disorders
Infections and infestations - OtherInfections and infestations
Infusion related reactionGeneral disorders
LethargyNervous system disorders
Other adverse events (184 terms — click to expand)

ReactionSystemCohort A: Pembrolizumab + …Cohort B: Pembrolizumab
HypertensionVascular disorders
FatigueGeneral disorders
HeadacheNervous system disorders
HyperglycemiaMetabolism and nutrition disorders
NauseaGastrointestinal disorders
Skin and subcutaneous tissue disorders - OtherSkin and subcutaneous tissue disorders
CoughRespiratory, thoracic and mediastinal disorders
DiarrheaGastrointestinal disorders
White blood cell decreasedInvestigations
ArthralgiaMusculoskeletal and connective tissue disorders
DysphasiaNervous system disorders
HoarsenessRespiratory, thoracic and mediastinal disorders
MyalgiaMusculoskeletal and connective tissue disorders
SeizureNervous system disorders
Gait disturbanceGeneral disorders
HyponatremiaMetabolism and nutrition disorders
Neutrophil count decreasedInvestigations
Platelet count decreasedInvestigations
PruritusSkin and subcutaneous tissue disorders
Aspartate aminotransferase increasedInvestigations
ConfusionPsychiatric disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
HypocalcemiaMetabolism and nutrition disorders
HypokalemiaMetabolism and nutrition disorders
ProteinuriaRenal and urinary disorders
Alanine aminotransferase increasedInvestigations
AnxietyPsychiatric disorders
InsomniaPsychiatric disorders
ConstipationGastrointestinal disorders
DizzinessNervous system disorders
Generalized muscle weaknessMusculoskeletal and connective tissue disorders
Lymphocyte count decreasedInvestigations
Nervous system disorders - Other, specifyNervous system disorders
Postnasal dripRespiratory, thoracic and mediastinal disorders
VomitingGastrointestinal disorders
Abdominal painGastrointestinal disorders
AnemiaBlood and lymphatic system disorders
Dry skinSkin and subcutaneous tissue disorders
Eye disorders - OtherEye disorders
Memory impairmentNervous system disorders

Most-reported serious reactions: Headache, Surgical and medical procedures - Other, Intracranial hemorrhage, Diarrhea, Gait disturbance, Hypertension, Nervous system disorders - Other, Seizure.

Data from ClinicalTrials.gov NCT02337491 adverse events section.

Sponsor's own description

In this research study, the investigators are looking to determine the effectiveness of Pembrolizumab (MK-3475) when given with bevacizumab or when given alone for the treatment of recurrent glioblastoma multiforme (GBM). This study will also test the safety and tolerability of Pembrolizumab (MK-3475) when given alone or with bevacizumab.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.
    Fukumura D, Kloepper J, Amoozgar Z, Duda DG, et al · · 2018 · cited 1560× · PMID 29508855 · DOI 10.1038/nrclinonc.2018.29
  2. Targeting cancer stem cell pathways for cancer therapy.
    Yang L, Shi P, Zhao G, Xu J, et al · · 2020 · cited 1354× · PMID 32296030 · DOI 10.1038/s41392-020-0110-5
  3. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.
    Wu M, Huang Q, Xie Y, Wu X, et al · · 2022 · cited 336× · PMID 35279217 · DOI 10.1186/s13045-022-01242-2
  4. Prospects of immune checkpoint modulators in the treatment of glioblastoma.
    Preusser M, Lim M, Hafler DA, Reardon DA, et al · · 2015 · cited 296× · PMID 26260659 · DOI 10.1038/nrneurol.2015.139
  5. Recurrent glioma clinical trial, CheckMate-143: the game is not over yet.
    Filley AC, Henriquez M, Dey M. · · 2017 · cited 284× · PMID 29207684 · DOI 10.18632/oncotarget.21586
  6. Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma.
    Nayak L, Molinaro AM, Peters K, Clarke JL, et al · · 2021 · cited 220× · PMID 33199490 · DOI 10.1158/1078-0432.ccr-20-2500
  7. Tumor microenvironment signaling and therapeutics in cancer progression.
    Goenka A, Khan F, Verma B, Sinha P, et al · · 2023 · cited 203× · PMID 37005490 · DOI 10.1002/cac2.12416
  8. Targeting the tumor stroma for cancer therapy.
    Xu M, Zhang T, Xia R, Wei Y, et al · · 2022 · cited 195× · PMID 36324128 · DOI 10.1186/s12943-022-01670-1

Verify or expand the search:

Other trials of Pembrolizumab

Trials testing the same drug.

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Other Dana-Farber Cancer Institute trials

Trials by the same sponsor.

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