What is CUSP9?

CUSP9 is an experimental regimen of 9 drugs "re-purposed" for the treatment of recurrent glioblastoma multiforme (GBM). It is generally combined with low-dose daily temozolomide +/- other chemotherapeutic agents (e.g. bevacizumab).

 

CUSP9 version 3 regimen & target doses

  1. Aprepitant 80 mg daily
  2. Auranofin 3 mg BID
  3. Captopril 50 mg BID
  4. Celecoxib 400 mg BID
  5. Disulfiram 250 mg BID
  6. Itraconazole 200 mg BID
  7. Minocycline 100 mg BID
  8. Ritonavir 400 mg BID
  9. Sertraline 100 mg BID

CUSP9 version 4 regimen & target doses

As above, except

  • Removed ritonavir
  • Added quetiapine 50 mg qHS added
  • Increased target dose of captopril to 100 mg PO BID
  • Increased dose of temozolomide to 50 mg/m^2 PO daily

 

Rationale

  • There are no published human trials of CUSP9 (any version)
  • To date, no published literature exists demonstrating a survival or quality of life benefit of any CUSP9 drug, either in isolation or combined with other drugs
  • No dose-ranging study exists to determine the optimal dose for these drugs as part of CUSP9. In general, the doses used in CUSP9 are at the maximum doses used for approved indications
  • The drugs included in the CUSP9 regimen have demonstrated activity against cancer cells via different pathways in laboratory models
    • The goal of CUSP9 is to boost temozolomide effectiveness by adding drugs with in vitro activity against various cancer cell growth/survival pathways

 

CUSP9v3 suggested titration schedule (coincides with qMon/Thur changes)

Day 1: Start temozolomide 20 mg/m^2; start aprepitant 80 mg PO daily

Day 4: Start celecoxib 400 mg PO daily (1/2 target dose)

Day 8: Start disulfiram 250 mg PO BID

Day 11: Start minocycline 100 mg PO BID, increase celecoxib to 400 mg PO BID

Day 15: Start sertraline 50 mg PO BID (1/2 target dose)

Day 18: Start captopril 25 mg PO BID (1/2 target dose)

Day 22: Start itraconazole 200 mg PO daily (1/2 target dose)

Day 25: Start ritonavir 200 mg PO daily (1/4 target dose), increase captopril to 50 mg PO BID

Day 29: Start auranofin 3 mg PO daily (1/2 target dose)

Day 32: Increase itraconazole to 200 mg PO BID

Day 36: Increase ritonavir to 200 mg PO BID (1/2 target dose)

Day 39: Increase auranofin to 3 mg PO BID

Day 43: Increase ritonavir to 400 mg PO BID

Day 47: Increase sertraline to 100 mg PO BID

 

CUSP9v4 titration schedule proposed in unpublished protocol

Day 1:

  • Start
    • Temozolomide 50 mg/m^2 PO daily 
    • Aprepitant 80 mg PO daily
    • Auranofin 3 mg PO daily (1/2 target dose)
    • Celecoxib 200 mg PO BID (1/2 target dose)
    • Disulfiram 250 mg PO daily (1/2 target dose)
    • Minocycline 100 mg PO daily (1/2 target dose)

Day 8:

  • Start (1/2 target dose)
    • Captopril 50 mg PO BID
    • Itraconazole 200 mg PO daily
    • Quetiapine 25 mg PO HS
    • Sertraline 100 mg PO daily
  • Increase
    • Auranofin to 3 mg PO BID
    • Celecoxib to 400 mg PO BID
    • Disulfiram to 250 mg PO BID
    • Minocycline to 100 mg PO BID

Day 15:

  • Increase
    • Captopril to 100 mg PO BID
    • Itraconazole to 200 mg PO BID
    • Quetiapine to 50 mg PO HS
    • Sertraline to 100 mg PO BID

 

Monitoring, recommended frequency & possible management strategies

Vital signs

  • At least weekly while titrating captopril, celecoxib & quetiapine
  • Managing abnormalities: 
    • Hypotension
      • Inpatient: Hold captopril if systolic blood pressure <110 mm Hg
      • Outpatient: If dizziness, postural hypotension or systolic blood pressure <110 mm Hg, hold captopril x1 week, then re-introduce at half previous dose
    • Hypertension: Celecoxib is the likely culprit; discontinue, or treat according to latest Canadian hypertension guidelines

Labs

  • CBC with differential
    • Recommended frequency: At least twice weekly while uptitrating drugs
      • Then once weekly x2 weeks, then every other week x1 month, then monthly
    • Managing abnormalities
      • Neutrophils <1.5: Discontinue auranofin & ritonavir, hold temozolomide until neutrophils >1.5
      • Hemoglobin reduction >20 g/L since previous: Consider GI bleed from celecoxib
      • Platelets <100: Hold temozolomide & ritonavir until >100
  • Electrolytes, serum creatinine & BUN
    • Recommended frequency: At least twice weekly while uptitrating drugs
      • Then once weekly x2 weeks, then every other week x1 month, then monthly
    • Managing abnormalities:
      • Serum creatinine increase >25% or >22 micromol/L:
        • Hold celecoxib
        • If increase >30% since starting/increasing captopril, hold captopril and consider restarting at half previous dose once serum creatinine normalizes
  • Liver enzymes & liver function tests (AST, ALT, GGT, ALP, bilirubin, INR, albumin)
    • Recommended frequency: At least weekly while uptitrating drugs
      • Then once every other week x1 month, then monthly
    • Managing abnormalities:
      • AST / ALT / GGT / ALP elevated <5x upper limit of normal or bilirubin elevated <1.5x upper limit of normal: Hold temozolomide, auranofin, disulfiram, itraconazole, ritonavir. May reintroduce one at a time once liver enzymes return to normal
      • AST / ALT / GGT / ALP elevated >5x upper limit of normal or bilirubin elevated >1.5-2x upper limit of normal: Hold temozolomide, permanently discontinue auranofin, disulfiram, itraconazole, and ritonavir

EKG, 12-lead (QTc assessment)

  • Recommended frequency: Prior to starting itraconazole, quetiapine ritonavir, sertraline (these all prolong QTc)
    • Repeat prior to adding/increasing the dose of any of the above agents if no prior EKG or if prior EKG indicated QTc ~450 msec or greater

 

Key adverse events & recommended management

CNS

  • Dizziness, presyncope or syncope
    • Most likely culprits: Captopril, quetiapine, ritonavir, sertraline
    • Management: Check sitting + standing blood pressure & ask about dizziness in both positions
      • If hypotension or postural hypotension: Decrease/hold captopril
      • If not related to blood pressure: Consider holding/decreasing ritonavir and/or sertraline (note: do not stop setraline cold turkey; wean)
  • Drowsiness
    • Most likely culprit: Quetiapine

GI

  • Nausea/vomiting
    • Most likely culprits: Any, especially disulfiram
    • Management: Ask about recent alcohol use (including possible sources such as mouthwashes), as disulfiram causes nausea/vomiting (as well as a number of other unpleasant effects) for 30-60 minutes after consumption of alcohol
  • Heartburn/dyspepsia
    • Most likely culprit: Celecoxib (also, dexamethasone)
    • Management:
      • If intermittent & brief: Try an antacid PRN
      • If intermittent & long-lasting: Try a histamine-2 receptor antagonist (H2RA) PRN
      • If >3x weekly: Try a regularly-scheduled H2RA, or proton pump inhibitor if the H2RA provides inadequate relief
      • If ongoing despite acid-suppression: Discontinue celecoxib
  • Diarrhea
    • Possible culprits: Any, especially itraconazole, minocycline, ritonavir, sertraline
    • Management: Hold most recently introduced of the above possible culprits
      • If improvement: Consider permanently stopping that drug
      • If no improvement: Hold next drug in line
  • Constipation
    • Most likely culprits: Aprepitant, sertraline
    • Management: Hold most recently introduced of the above possible culprits (note: wean sertraline)

Others

  • Cough, dry
    • Captopril is the most likely culprit (incidence ~20%)
    • Management: Discontinue captopril if cough is bothersome, and it should resolve within a month
  • Sexual dysfunction (decreased libido; erectile or ejaculatory dysfunction in men)
    • Sertraline is the most likely culprit, followed by quetiapine
    • Management: Discontinue sertraline (if receiving for over 2 weeks, wean over 2-4 weeks to avoid SSRI withdrawal)

 

Clinically important drug-drug interactions to consider

Between drugs in the regimen:

  • Aprepitant
    • + itraconazole, ritonavir: Increase serum levels of aprepitant 5-fold = increased side-effects
  • Captopril
    • + celecoxib: Combination can cause/worsen acute kidney injury, especially when dehydrated/hypovolemic
    • + ritonavir, sertraline: Increased serum levels of captopril = increased side-effects
  • QTC-prolonging drugs (itraconazole, quetiapine, ritonavir, sertraline)
    • These agents each prolong QTc and increase risk of ventricular arrhythmias individually & have additive effects when combined
    • traconazole & ritonavir inhibit CYP3A4 metabolism, & therefore increase serum concentrations of all 4 of these agents, further increasing the risk of QTc prolongation & ventricular arrhythmias

Between drugs in the regimen, specific formulations

  • Disulfiram + ritonavir oral solution (contains 43% ethanol): Disulfiram reaction (flushing, chest pain, N/V)

With other drugs commonly used in GBM

  • Dexamethasone
    • + aprepitant, itraconazole, ritonavir: Increased serum concentrations of dexamethasone = increased side-effects
    • + celecoxib: Both damage gastric mucosa = greatly increased risk of upper GI bleed
    • + quetiapine: Both can cause hyperglycemia and induce type 2 diabetes & metabolic syndrome
  • Phenytoin
    • + disulfiram, itraconazole, ritonavir, sertraline: Unpredictable effects on metabolism of CY3A4 substrates as phenytoin induces & the other 2 inhibit

 

References & resources

 

Prepared by Ricky Turgeon, BSc(Pharm), ACPR, PharmD

Updated on June 29, 2016