In tring to figure out why my therapy has worked so far, I came across a major discrepancy in dosage used compared to the clinical trial by Dr. Rosenberg. His maximum was 3.0 mg/Kg of CTLA-4 and I did 15 mg/Kg.
That is a 5 fold increase. I do know he used Ipilimumab and I used Tremelimumab (from Pfizer). They are both anti-CTLA-4. They both have a molecular weight of 145.4 kDa. and ~150 kDa respectively.
Half lives of 15 days and 21 days simular. So why the great Disparity in dosage. Could that be a flaw in the trial?
Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.
Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Haworth LR, Levy C, Kleiner D, Mavroukakis SA, Yellin M, Rosenberg SA.
Surgery Branch, National Cancer Institute, National Institutes of Health, CRC Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, MD 20814, USA.
BACKGROUND: Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma.
METHODS: Thirty-six patients received anti-CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses). RESULTS: Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti-CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis.
CONCLUSIONS: There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.
Hi Mr. Breitfeller,
As this study is currently closed, I am now in charge of follow-up so your request was directed to me (I worked with Heather Blair while she was here so I’m familiar with your case). Hopefully this excerpt from the full protocol (UPCI #05-120) answers your question, but please let me know if you need further information. (CP-675,206 is the technical name for anti-CTLA-4)
Patients will receive intravenous administration of CP-675,206 at a dose of 15 mg/kg on Day 1 ofevery 90-day cycle. For purposes of treatment visits and scheduling, each cycle is defined as a 90-day (3 month) period. Patients may receive up to 4 doses (4 cycles) in a 12-month period
until progression of disease or intolerable toxicity. At a minimum, scheduled visits for clinical study safety assessments will occur monthly. Additional visits may be necessary at the discretion
of the Investigator.
Long term exposure to CP-675,206 is not known to be required to sustain clinical benefit.
Patients will be allowed to receive up to 4 doses in a 12-month period. By mutual agreement
between the Investigator and the Pfizer Clinician, patients exhibiting clinical benefit after 12 months may be eligible to continue therapy with CP-675,206 up to 2 additional doses for patients with a
Complete Response or 4 doses for patients with a Partial Response or Stable Disease up to a maximum of 24 months after enrollment
So I contacted Dr. Oncologist
Dear Mr Breitfeller,
"I don’t think we can draw any conclusions yet based on your experience with a single dose. However, one thing we do know is that dose does matter. Last year at ASCO, we presented data showing that higher doses of ipilimumab (10 mg/kg) were better than 3 mg/kg or 0.3 mg/kg. I once again applaud you for your efforts to understand the excellent response which you have had."
So, If a higher dose is better, don't you think we should repeat the trial with higher doseage of CTLA-4
Jimmy B
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