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Everolimus

InterventionmTOR inhibitorsRapamycin analogsApproved 2009

9 papers19 findings

PubChem 6442177ChEBI 68478MeSH D000068338

C, W, M, H: cells, worms or flies, mice, humans. Dark: independent labs found the same change there. Light: one lab or one study. Outline: nothing yet.

Labs are independent when their papers share no last author and no institution.

Against: findings that point the other way from most findings on the same outcome.

No results posted: trials that ended more than a year ago with no results on ClinicalTrials.gov and no paper in ARN’s record.

Company ties: findings with an author at a company, or from a paper whose competing-interests statement declares ties to one.

  • 8 independent labs in 2 countries
  • 1 finding against
  • 642 trials, 214 with no results posted
  • Funders: National Cancer Institute and 3 more
  • 6 of 19 findings with company ties
  • 300 of 642 trials sponsored by its developers
  • Human trial8
  • Humans1

Outcomes

10

Progression-free survival

upin humans3HR 0.43–0.77

3 studies

  1. Everolimus improves progression-free survival in humans (11·0 months vs 3·9 months).

    Human trialadvanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal originoral10 mg per dayn = 302

    Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study

    Lancet (London, England)17 Dec 2015

  2. Everolimus improves progression-free survival in humans (6.9 vs 2.8 months, HR 0.43, 95% CI 0.35-0.54).

    Human trialhormone-receptor-positive advanced breast cancer

    Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer

    The New England journal of medicine7 Dec 2011

  3. Everolimus improves progression-free survival in humans (16.4 vs 11.3 months, HR 0.77 (95% CI 0.59-1.00)).

    Human trialadvanced neuroendocrine tumours associated with carcinoid syndrome10 mg per day everolimus + 30 mg intramuscular octreotide LAR every 28 daysn = 429

    Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study

    Lancet (London, England)25 Nov 2011

Seizure frequency

downin humans2

2 studies

  1. Everolimus decreases seizure frequency in humans (29.3% vs 14.9% placebo (p=0.0028)).

    Human trialtreatment-resistant seizures in tuberous sclerosis complextarget trough 3-7 ng/mL12-week maintenance

    Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

    Lancet (London, England)6 Sep 2016

  2. Everolimus decreases seizure frequency in humans (median change, -1 seizure; P=0.02).

    Human trialtuberous sclerosis complex6 monthsn = 16

    Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis

    The New England journal of medicine4 Nov 2010

Subependymal giant-cell astrocytoma volume

downin humans2

2 studies

  1. Everolimus decreases subependymal giant-cell astrocytoma volume in humans (35% vs 0%, difference 35%, 95% CI 15-52, p<0.0001).

    Human trialtuberous sclerosis complex4.5 mg/m2 per dayn = 117

    Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial

    Lancet (London, England)14 Nov 2012

  2. Everolimus decreases subependymal giant-cell astrocytoma volume in humans (reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%)).

    Human trialtuberous sclerosis complex3.0 mg per square meter6 monthsn = 28

    Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis

    The New England journal of medicine4 Nov 2010

Treatment response rate

upin humans1

1 study

  1. Everolimus increases treatment response rate in humans (28.2% vs 15.1% placebo (p=0.0077)).

    Human trialtreatment-resistant seizures in tuberous sclerosis complextarget trough 3-7 ng/mL12-week maintenance

    Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

    Lancet (London, England)6 Sep 2016

PD-1+ CD4 and CD8 T lymphocytes

downin humans1

1 study

  1. Everolimus decreases PD-1+ CD4 and CD8 T lymphocytes in humans.

    Human trial

    mTOR inhibition improves immune function in the elderly

    Science translational medicine24 Dec 2014

More on PD-1+ CD4 and CD8 T lymphocytes

Influenza vaccine response

upin humans1+20%

1 study

  1. Everolimus improves influenza vaccine response in humans (about 20%).

    Human trial

    mTOR inhibition improves immune function in the elderly

    Science translational medicine24 Dec 2014

More on Influenza vaccine response

Angiomyolipoma volume

downin humans1

1 study

  1. Everolimus decreases angiomyolipoma volume in humans (at least a 50% reduction in total volume).

    Human trialtuberous sclerosis complex or sporadic lymphangioleiomyomatosisoral10 mg per dayn = 118

    Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial

    Lancet (London, England)9 Mar 2013

Angiomyolipoma response rate

upin humans1

1 study

  1. Everolimus increases angiomyolipoma response rate in humans (42% vs 0%, p<0·0001).

    Human trialtuberous sclerosis complex or sporadic lymphangioleiomyomatosisoral10 mg per dayn = 118

    Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial

    Lancet (London, England)9 Mar 2013

Adverse events

upin humans1

1 study

  1. Everolimus increases adverse events in humans (stomatitis 62% vs 14%, rash 37% vs 12%, fatigue 31% vs 23%, diarrhoea 27% vs 16%).

    Human trialadvanced neuroendocrine tumours associated with carcinoid syndrome10 mg per day everolimus + 30 mg intramuscular octreotide LAR every 28 daysn = 429

    Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study

    Lancet (London, England)25 Nov 2011

Quality of life

upin humans1

1 study

  1. Everolimus improves quality of life in humans (62.1±14.2 vs baseline 57.8±14.0).

    Human trialtuberous sclerosis complex6 months

    Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis

    The New England journal of medicine4 Nov 2010

Associations

3

Stomatitis

upin humans3

3 studies

  1. Everolimus raises the risk of stomatitis in humans (48% vs 8%).

    Human trialtuberous sclerosis complex or sporadic lymphangioleiomyomatosisoral10 mg per dayn = 118

    Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial

    Lancet (London, England)9 Mar 2013

  2. Everolimus raises the risk of stomatitis in humans (31% vs 21%).

    Human trialtuberous sclerosis complex4.5 mg/m2 per dayn = 117

    Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial

    Lancet (London, England)14 Nov 2012

  3. Everolimus raises the risk of stomatitis in humans (8% vs 1%).

    Human trialhormone-receptor-positive advanced breast cancer

    Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer

    The New England journal of medicine7 Dec 2011

More on Stomatitis

Disease progression or death

downin humans1

1 study

  1. Everolimus lowers the risk of disease progression or death in humans (HR 0·48 (95% CI 0·35-0·67), p<0·00001).

    Human trialadvanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal originoral10 mg per dayn = 302

    Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study

    Lancet (London, England)17 Dec 2015

Mouth ulceration

upin humans1

1 study

  1. Everolimus raises the risk of mouth ulceration in humans (32% vs 5%).

    Human trialtuberous sclerosis complex4.5 mg/m2 per dayn = 117

    Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial

    Lancet (London, England)14 Nov 2012

More on Mouth ulceration

Trials

642

Approved

  • FDA Afinitor

    30 Mar 2009Neuroendocrine Tumors, HER2-negative Breast Cancer

  • EMA Afinitor

    2 Aug 2009Carcinoma, Renal Cell, Breast Neoplasms, Pancreatic Neoplasms, Carcinoma, Recurrence, Advanced Breast Cancer, tumours

  • FDA Zortress

    20 Apr 2010

  • EMA Votubia

    2 Sep 2011Tuberous Sclerosis, Angiomyolipoma, Renal Angiomyolipoma, Subependymal Giant Cell Astrocytoma, Tuberous Sclerosis Complex

  • FDA Afinitor Disperz

    29 Aug 2012Neuroendocrine Tumors, HER2-negative Breast Cancer

Repurposing

40 of 80

In trials

  • Neoplasm metastasis

    Phase 4Completed34 trials

  • Kidney neoplasm

    Phase 4Results posted23 trials

  • Renal transplantation

    Phase 4Results posted12 trials

  • Lung Neoplasms

    Phase 4Results posted9 trials

  • Leukemia, Lymphocytic, Chronic, B-Cell

    Phase 4Recruiting8 trials

  • Liver transplantation

    Phase 4Results posted7 trials

40 of 125

  • Carcinoid tumor

    Phase 4Results posted6 trials

  • Chronic kidney failure

    Phase 4Results posted6 trials

  • Hereditary Sensory and Autonomic Neuropathies

    Phase 4Results posted6 trials

  • Liver Transplant

    Phase 4Results posted6 trials

  • Waldenström macroglobulinemia

    Phase 4Recruiting6 trials

  • Chronic renal insufficiency

    Phase 4Results posted5 trials

  • Graft vs host disease

    Phase 4Results posted5 trials

  • Kidney transplant

    Phase 4Results posted5 trials

  • Plasma Cell Neoplasms

    Phase 4Recruiting5 trials

  • Heart transplantation

    Phase 4Results posted4 trials

  • Psychology Rejection

    Phase 4Completed4 trials

  • Autosomal Dominant Polycystic Kidney

    Phase 4Results posted3 trials

  • Breast Diseases

    Phase 4Results posted2 trials

  • Cardiac transplantation

    Phase 4Results posted2 trials

  • Kidney Transplant Rejection

    Phase 4Results posted2 trials

  • Motor Activity

    Phase 4Terminated2 trials

  • Virus Diseases

    Phase 4Status unknown2 trials

  • Disorder related to cardiac transplantation

    Phase 4Results posted1 trial

  • Large cell carcinoma

    Phase 4Results posted1 trial

  • Pancreatic neuroendocrine tumor

    Phase 4Results posted1 trial

  • Renal function

    Phase 4Results posted1 trial

  • Renal function and chronic allograft vasculopathy

    Phase 4Results posted1 trial

  • Renal transplanted recipient

    Phase 4Results posted1 trial

  • Triple Negative Breast Neoplasms

    Phase 3Status unknown14 trials

  • Lymphoma, large b-cell, diffuse

    Phase 3Results posted13 trials

  • Prostatic Neoplasms

    Phase 3Status unknown13 trials

  • Stomach neoplasm

    Phase 3Results posted10 trials

  • Astrocytoma

    Phase 3Results posted9 trials

  • Male Breast Neoplasms

    Phase 3Active, not recruiting5 trials

  • B-cell lymphoma

    Phase 3Results posted4 trials

  • Digestive System Neoplasms

    Phase 3Results posted3 trials

  • Renal transplant

    Phase 3Completed2 trials

  • Advanced neuroendocrine tumor of pancreatic origin

    Phase 3Results posted1 trial

  • De novo kidney transplant recipient

    Phase 3Results posted1 trial

Readouts due

Stopped

  • NCT02338570TerminatedRenal cell carcinoma

    Stopped on November 16th 2016, because of recruitment failure.

  • NCT00978432TerminatedRecurrence

    The toxicity seemed to outweigh the benefit.

  • NCT00640978TerminatedPancreatic neoplasms

    Significant Adverse Effects - Futility

  • NCT00332839TerminatedRenal transplantation

    The trial was terminated early due to slow enrollment. It was determined that the planned sample size of 300 could not be achieved.

  • NCT01276834TerminatedRenal transplantation

    insufficient patients enrolled

  • NCT01561404TerminatedMotor Activity

    lack of potential patients

All 38

  • NCT01878786TerminatedDelayed graft function

    Interim results suggested a concern for patient outcomes and safety

  • NCT00515086TerminatedGlioblastoma

    Early termination due to slow enrollment and protocol-defined stopping rule.

  • NCT01111058TerminatedHead and Neck Neoplasms

    Slow accrual

  • NCT01133678TerminatedHead and Neck Neoplasms

    Primary endpoint reached futility boundary

  • NCT00727207TerminatedMantle cell lymphoma

    Lack of participations (8 of 25)

  • NCT03352427TerminatedGlioma

    Low accrual

  • NCT02315625TerminatedNeuroendocrine carcinoma

    Study closed due to poor accrual.

  • NCT04305444TerminatedFollicular lymphoma

    Despite the efforts of our dedicated team and initial progress, we were unable to secure the necessary financial resources to continue the study. We appreciate the support and participation of all involved.

  • NCT01048723TerminatedSarcoma

    Novartis terminated funding

  • NCT00390364TerminatedColorectal neoplasm

    Withdrawn due to low accrual

  • NCT00402662TerminatedMelanoma

    unexpected level of toxicity

  • NCT00972335TerminatedMeningioma

    Study terminated early due to slow accrual

  • NCT03139747SuspendedThyroid neoplasm

    lack of accrual reevaluating feasibility

  • NCT02031536TerminatedIslet cell carcinoma

    Slow accrual

  • NCT02273752TerminatedIslet cell carcinoma

    Slow accrual

  • NCT01637090TerminatedLymphoma, T-Cell, Cutaneous

    Poor enrollment

  • NCT01345136TerminatedNeurofibromatosis 2

    slow accrual

  • NCT01374451TerminatedIslet Cell Adenoma

    The study was stopped for not meeting the primary endpoint for PFS.

  • NCT00843531TerminatedParaganglioma

    Low Accrual

  • NCT00933374TerminatedUrinary Bladder Neoplasms

    delayed recruitment

  • NCT01784978TerminatedMargins of Excision

    Lack of recruitment

  • NCT00809185TerminatedMyelodysplastic syndrome

    slow accrual

  • NCT01365468TerminatedNeurofibromatosis 1

    Poor patients' accrual

  • NCT02023905TerminatedOligodendroglioma

    Sponsor decision

  • NCT04203901TerminatedAdvanced Renal Cell Carcinoma

    Strategic corporate decision

  • NCT01412515TerminatedKaposi sarcoma

    results from interim analysis conducted to study interruption

  • NCT00811590TerminatedPeutz-Jeghers syndrome

    The study was ended early due to low enrollment.

  • NCT01226056SuspendedAdvanced solid tumor

    toxicity (protocol amendment under approval)

  • NCT01313390TerminatedTongue Neoplasms

    Lack of recruitment

  • NCT03878524TerminatedAnemia

    Low accrual

  • NCT04895748TerminatedVon Hippel-Lindau disease

    Business decision and not related to safety concerns

  • NCT03578432TerminatedXerostomia

    UACC-PHX is no longer able to support the study and Novartis is unable to provide drug beyond December 2019.

Trial sponsors

Funding

2 grants since 2026

Food and Drug AdministrationUS$648kNational Center for Advancing Translational SciencesUS$450k

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