Wednesday 13 December 2017

Plerixafor - new drug to cocktail?

Hello!
1. There is one promising report on the treatment of TMZ+Plerixafor (+Lapatinib  pulse dosing) for glioblastoma:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965258/
Plerixafor was administered subcutaneously 1 time per week for 2 years.


Plerixafor was administered via continuous intravenous infusion of 400 micrograms/kg/day starting one week prior to end of RT and continuing for 4 weeks.


Stephen wrote that 1 shot of Plerixafor is very expensive, but I am in Delhi (India) and here Plerixafor 24mg/1.2 ml (Celrixafor by Celon Labs) is $ 1000.

What do You think about this medication and what are the tactics of its use more effective?


What do You think about Lapatinib used in the first case, pulse dosing? If it is suitable for all types of glioblastoma? clinical research is also going on:
https://clinicaltrials.gov/show/NCT01591577
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20 comments:

  1. Stephen W13 December 2017 at 13:32

    Seems to me the biggest limiting factor is still going to be the expense.

    There's a trial for newly diagnosed (which you mentioned) and a trial for recurrent high grade glioma.

    https://clinicaltrials.gov/ct2/show/NCT01339039 (recurrent HGG trial)
    https://clinicaltrials.gov/ct2/show/NCT01977677 (newly diagnosed GBM trial)

    If using the first protocol of 16.6 mcg/kg/hr (= 398.4 mcg/kg/day) as a continuous infusion for 4 weeks, you'd be going through one of those 24 mg vials per day. At 72,000 rupees per vial ($1120 USD) per day, that would work out to over $31,000 USD for a 4-week protocol.

    The trial for recurrent GBM used a protocol of 320 mcg/kg/day (again, approximately one vial per day) for 21 days of each 28 day cycle. ($23,500 USD per 28 day cycle, assuming one vial used per day).

    Are the expected benefits enough to make these costs worthwhile? I don't know, but I attended a presentation on the results of the phase 1 trial of plerixafor + Avastin for recurrent high grade glioma at this year's SNO conference. For n=23 patients in part 1 of the trial (dose escalation), median survival was 7.1 months and median PFS was 2.87 months. Granted, this was a dose escalation trial, so some patients were not treated with optimal dose of plerixafor, and we don't know the baseline patient characteristics (how many prior recurrences or therapies did each patient have? etc.), but those statistics don't look so impressive. This study was actually closed due to poor patient accrual after only three patients were recruited to part 2. The trial never made it to part 3 (all patients treated at maximum tolerated dose).

    It's possible the trial for newly diagnosed GBM will show better outcomes, but personally if I had >$30,000 USD to spare I'd be looking at vaccine/immunotherapy options (especially if residual tumor volume were minimal).

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  2. Stephen W13 December 2017 at 13:39

    Lapatinib is a dual EGFR/HER2 inhibitor. It (as well as other drugs targeted to EGFR) would be most appropriate for GBMs with EGFR amplification or overexpression.

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    1. Semyon13 December 2017 at 16:05

      incredible! Your answer is probably the most detailed analysis of Plerixafor for glioblastoma on the Internet!

      1. Stephen, how would you comment on the good effect of Plerixafor+Lapatinib in the first case?
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965258
      $ 4000 per month for Plerixafor - reasonable price.

      2. What test should be ordered to understand that the patient's need for pulse Lapatinib?

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    2. Stephen W13 December 2017 at 16:54

      1) I'll try to read that study and get back to you later.

      2) I would ask for testing for a) EGFR amplification, which is the presence of many copies of the EGFR gene in a cell rather than the normal two copies and/or b) EGFR overexpression in the tumor tissue by immunohistochemistry testing (IHC). Also you can ask for testing for the EGFRvIII mutation, which is an immunological target for peptide vaccines (rindopepimut) and some CAR T-cell therapies.

      However, all EGFRvIII positive cases will also be EGFR amplified, while an EGFR amplified tumor does not necessarily have the EGFRvIII mutation. So my first priority would be asking about EGFR amplification or overexpression. If it is EGFR amplified or shows EGFR overexpression by IHC, then you could consider an EGFR inhibitor (lapatinib or another one). Newer EGFR/HER2 inhibitors like afatinib are also being tested in GBM:

      https://www.researchgate.net/publication/320904600_ACTR-33_A_PHASE_I_DOSE_ESCALATION_AND_CENTRAL_NERVOUS_SYSTEM_CNS_PHARMACOKINETIC_STUDY_OF_PULSATILE_AFATINIB_IN_PATIENTS_WITH_BRAIN_CANCER

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    3. Unknown13 December 2017 at 21:53

      My husband did Plerixafor study at Stanford last year. Had GTR (gross total resection) GBM stage IV at end of October/2016. MGMT Neg (unmethylated and IDH wild type). Did standard treatment (42 days radiation and Temodar). Then 28 days Plerixafor study (28 days of continuous IV infusion). I can't recall dose. Study covered cost. Had picc line placed and attached to small IV pump machine (which he got used to)--we named it "Plexy"...humor helps. Minimal side effects from medication. After Plerixafor, he started 5 days on 23 days off of Temodar cycles. MRI's good for 10 months and got to 10 cycles of Temodar,then changes started occuring. At 1 yr. and he had another resection for tumor recurrence. High quality 10 montsh (working, travel, etc.). Recovering well from 2nd surgery and we are figuring out next steps. Hope that helps.

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    4. Semyon14 December 2017 at 04:32

      Can you send a picture of "Plexy"? sem.bryansk@gmail.com
      I want to repeat this treatment for my mother and look for all the information!
      Your husband wore "Flexy" constantly 4 weeks - 24 hours a day?
      These 4 weeks he was in the hospital or lived at home? how often was it necessary to visit the hospital?
      Did Plerixafor affect platelets in the blood?
      Thank you very much!

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    5. Semyon24 December 2017 at 11:19

      Stephen,
      Where can I ask to test for EGFR amplification and EGFR overexpression?
      I found a branch "Foundation one" in Germany.
      But now holidays and they do not answer.

      I can also order a test there, how for this treatment report?
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965258

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    6. Stephen W24 December 2017 at 12:28

      FoundationOne, Caris Molecular Intelligence, and CeGaT offer comparable sequencing services.

      FoundationOne: sequences 315 genes, 500x coverage, list price $5800 USD, but could possibly get a discount price if paying out-of-pocket (no insurance coverage).

      Caris Molecular Intelligence (European office in Basel Switzerland). Sequences 592 genes, >750x coverage, $3500 USD for Next Generation Sequencing only, $6500 USD for complete Molecular Intelligence testing (including next generation sequencing).

      CeGaT (Tubingen, Germany). Sequences 710 genes at high coverage (1000x), 4950 Euros/ ~5870 USD at current exchange rates.

      If interested only in next generation sequencing, I would probably choose Caris, which seems to offer the best deal. If interested in the potential for a vaccine (at much higher expense), I would choose CeGaT to do the sequencing.

      None of these three companies do drug sensitivity testing on live cells however, as in the Onconomics test.

      The cost of testing only the EGFR gene for amplification/mutation should be much less than any of these comprehensive panels. Your mother's oncologist should be able to tell you where you can have that done.

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    7. Semyon29 December 2017 at 01:02

      It is interesting, if the indication for the use of Lapatinib is ampfication or overexpression of the EGFR gene, why then these clinical trials recruit all patients, regardless of the EGFR?

      https://clinicaltrials.gov/ct2/show/study/NCT01591577
      https://clinicaltrials.gov/ct2/show/NCT02101905

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    8. Stephen W29 December 2017 at 14:45

      It never made sense to me why trials with targeted kinase inhibitors didn't include expression of drug's target as an inclusion criteria.

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  3. Semyon14 December 2017 at 11:30

    Stephen,

    1. Tell me, please, if you know, how make the continuous infusion of Plerixafor? Outpatient or inpatient? What kind of portable "pump"?
    I told our doctors, that i can buy Plerixafor, but they don't know how to implement a continuous infusion 24 hours.

    2. How would You interpret the "results" section of the study Plerixafor on the website: http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.2058
    I can't seem to fully understand(

    3. Is it possible to take DCA with Plerixafor?

    I am sorry for these difficult questions, but I flew to Delhi for the Plerixafor and now trying to figure out the details.

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    1. Stephen W14 December 2017 at 14:44

      1. I have no knowledge of the practical details. Perhaps the anonymous commenter who commented above can provide more details.

      It appears that the two clinical trials of plerixafor for GBM were using two different methods of administration: In the trial for newly diagnosed GBM, they used a continuous iv dosing. In the trial for recurrent GBM, they used a single subcutaneous injection once per day. I would imagine (but can't confirm) the continuous iv infusion would be done as an inpatient in the hospital and that the sc injection once per day could be done as an outpatient. I'd also guess you'll have difficulty finding a doctor who would agree to administer the continuous infusion protocol outside of a clinical trial.

      Of course the once weekly subcutaneous plerixafor injection used in the case study along with lapatinib etc. would be much more affordable (at least 7-fold less expensive over the course of a month). It's very difficult to estimate the contribution of plerixafor to the good outcomes in the case report, since that patient was on a cocktail of different meds (TMZ, lapatinib, etc).

      2. "There was a significant reduction in rCBV measured by DSC-MRI within the 95% isodose field one month after radiation therapy in patients receiving Plerixafor compared to control (p < 0.02)."

      Plerixafor in supposed to prevent bone-marrow derived cells from colonizing the tumor and initiating vasculogenesis ("the 2 principal ways in which a tumor can expand its vasculature as it grows is by angiogenesis involving sprouting of endothelial cells from nearby normal vessels or by
      vasculogenesis, which occurs by the recruitment into the tumor
      of circulating endothelial and other cells. Source- https://www.ncbi.nlm.nih.gov/pubmed/20179352)

      So the results section is saying that the plerixafor-treated patients had significantly less cerebral blood volume in the radiation-treated area versus patients who received standard treatment only without plerixafor. This is suggesting that plerixafor is indeed working as intended. However it also goes on to say that there was a higher-than-expected rate of recurrence outside the radiation field in the plerixafor treated patients.

      One interpratation of this is that plerixafor can help prevent tumor growth within the radiation field by preventing vasculogenesis induced by bone marrow derived cells, but it can't prevent recurrence outside the radiation field, where the tumor can co-opt normal blood vessels or engage in normal angiogenesis in parts of the brain where the vasculature is still intact (hasn't been destroyed by radiation).

      3. I'm not aware of any contraindication of DCA and plerixafor.

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  4. Semyon14 December 2017 at 11:46

    Stephen,

    What are the options of vaccination/immunotherapy in Europe could You tell me for my mother:

    27.10.2017 the tumor was completely removed.
    MRI 16.11.2017 showed that almost 3 weeks, the tumor grew again on the same spot of the same size!!! The doctors were in shock. Said it was an early relapse.

    We are now completing radiotherapy+TMZ(5 days a week).
    + Metformin, DCA, Agomelatine

    I hope now You understand why I'm grasping at any opportunity (such as for the continuous infusion Plerixafor)

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    1. Stephen W14 December 2017 at 14:55

      IOZK clinic in Köln Germany can create tumor lysate-pulsed and Newcastle Disease Virus primed dendritic cell vaccines for patiens with properly preserved (flash frozen) tumor tissue, and they are also capable of isolating tumor antigens from the blood for patients who don't have properly preserved tumor tissue.

      Other clinics in Germany are capable of creating personalized peptide vaccines based on exome sequencing, provided enough suitably immunogenic mutations are discovered.

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  5. Semyon14 December 2017 at 11:54

    P.S. My mother has Glioblastoma, MGMT methyl­ated, IDH-Wildtyp

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  6. Semyon9 May 2018 at 14:24

    I read Stephen's article about the possible addition of Plerixafor:
    http://astrocytomaoptions.com/bevacizumab-avastin/
    "For bevacizumab to significantly increase survival for glioblastoma patients, this adaptive response must be anticipated and blocked with drugs which inhibit invasion and the influx of migration- and angiogenesis-promoting immune cells such as macrophages and neutrophils (with drugs such as plerixafor). Only then might the true potential of this drug be realized."

    Unfortunately, there is very little information about this combination.

    The clinical trial of Avastin + Plerixafor (https://clinicaltrials.gov/ct2/show/NCT01339039) was canceled because of the low number of participants.

    However, I found this study:
    ACTR-76. FINAL RESULTS FROM A PHASE I STUDY OF PLERIXAFOR AND BEVACIZUMAB IN RECURRENT HIGH-GRADE GLIOMA
    https://academic.oup.com/neuro-oncology/article-abstract/19/suppl_6/vi17/4590357?redirectedFrom=fulltext
    "Circulating biomarker data suggests that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF1 and PlGF. Plerixafor concentration in resected tumor tissue from patients pre-treated with plerixafor was 1000–1200 ng/mL. Combination treatment with bevacizumab and plerixafor was well tolerated in HGG patients. Plerixafor distributes to both the CSF and brain tumor tissue."

    My mom is already 5 months old on a low dose of Avastin. There is no progression in MRI. Maybe the benefit of adding Plerixafor at this stage? Or too late to add Plerixafor?

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    1. Stephen W9 May 2018 at 16:35

      I wrote the article before there was any actual evidence for this combination. In theory it would be a good combination, but even in the abstract there is only pharmacokinetic data, but no PFS or survival data. So we can't yet say whether the theory translates into good results. If this combination does really work as expected, it is probably not too late, because the tumor does not seem to have developed a resistance to Avastin yet. I do recall that you tried to (or did) get plerixafor before, but expenses would be large and there was the problem of finding someone to administer.

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    2. Semyon9 May 2018 at 22:32

      I was in touch with Dr Lawrence Recht of Stanford, who directs the study of Plerixafor during radiation therapy. I also was in New Delhi (India) and was ready to buy the right amount of Plerixafor. But doctors in Russia (in one of the most expensive clinics in Moscow!) could not and did not want to repeat this study. All they could do was the Stupp protocol!

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  7. Stephen W27 June 2018 at 09:39

    https://www.ncbi.nlm.nih.gov/pubmed/29941486
    Phase I and biomarker study of plerixafor and bevacizumab in recurrent high-grade glioma

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    1. Semyon28 June 2018 at 00:53

      Strangely, but with the theoretical validity of the combination Avastin + Plerixafor this study showed disappointing results:

      http://sci-hub.tw/https://doi.org/10.1158/1078-0432.CCR-18-1025

      "For all patients enrolled in Part 1 (nonsurgical cohort), median overall survival (OS) was 7.11 months [95% CI 5.6, 9.2] and median progression-free survival (PFS) was 2.87 months [95% CI 1.9, 3.8]. PFS6 was 14.5% [95% CI 3.9, 32.9]. For the GBM subset enrolled in Part 1, median OS was 6.4 months [95% CI 3.2, 7.4] and median PFS was 1.9 months [95% CI 1.7, 6.4]. Of the 20 patients with evaluable measurable enhancing tumor in Part 1, 3 patients (all of whom were bevacizumab-naïve at enrollment) had a partial response (PR) and 9 patients had stable disease (SD) as their best response. Of the 3 patients in Part 1 who had received prior bevacizumab, only one patient (with an anaplastic astrocytoma) achieved SD but progressed after 4 cycles of treatment. Of the 3 patients enrolled in Part 2 (surgical cohort), overall survival times were 1.78, 8 and 10.3 months and times to progression were 1.09, 3.2 and 7.43 months, respectively."

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