Il disegno e la conduzione delle sperimentazioni cliniche nell’era dell’oncologia di precisione: cosa sta cambiando? Emmanuele De Luca Scuola di Specializzazione Oncologia Medica, AO Ordine Mauriziano, Torino Dipartimento di Oncologia Università di Torino
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Il disegno e la conduzione delle sperimentazioni cliniche...C1 crizotinib MET amp 35 (14) C2 crizotinib MET exon 14 sk 35 (16) E AZD9291 EGFR T790M 35 (4) F crizotinib ALK transloc
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Il disegno e la
conduzione delle
sperimentazioni cliniche
nell’era dell’oncologia di
precisione: cosa sta
cambiando?
Emmanuele De Luca
Scuola di Specializzazione Oncologia Medica,
AO Ordine Mauriziano, Torino
Dipartimento di Oncologia
Università di Torino
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ASCO 2001 Grand Rounds: Molecular Oncology Symposium
Jaap Verweji, 2001:
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Tuesday, May 23rd, 2017
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Approval agnostic of cancer site:
The case of pembrolizumab (MSI-H- dMMR
tumors)
Lemery S, Keegan P, Pazdur R.
N Engl J Med. 2017 Oct 12;377(15):1409-1412.
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Approval agnostic of cancer site:
The case of pembrolizumab
Lemery S, Keegan P, Pazdur R.
N Engl J Med. 2017 Oct 12;377(15):1409-1412.
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Woodcock J, LaVange LM.
Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.
N Engl J Med. 2017 Jul 6;377(1):62-70.
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Woodcock J, LaVange LM.
Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.
N Engl J Med. 2017 Jul 6;377(1):62-70.
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Woodcock J, LaVange LM.
Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.
N Engl J Med. 2017 Jul 6;377(1):62-70.
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Woodcock J, LaVange LM.
Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both.
N Engl J Med. 2017 Jul 6;377(1):62-70.
Basket trials
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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.
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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.
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Statistical Analysis
• An adaptive Simon two-stage design was used
for all tumor-specific cohorts in order to minimize
the number of patients treated if vemurafenib
was deemed ineffective for a specific tumor type.
• The primary efficacy end point was the response
rate at week 8.
Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.
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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.
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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.
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Hyman DM, et al. N Engl J Med. 2015 Aug 20;373(8):726-36.
• In conclusion, we found that the BRAF V600
mutation is a targetable oncogene in some, but not
• Adult patients with any kind of metastatic solid tumour
refractory to standard of care
• The molecular profile of each patient's tumour was
established with a mandatory biopsy of a metastatic
tumour and large-scale genomic testing.
Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.
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Holistic approach: the SHIVa trial
• Included only patients for whom a molecular alteration
was identified within one of three molecular pathways
(hormone receptor, PI3K/AKT/mTOR, RAF/MEK),
which could be matched to one of ten regimens including
11 available molecularly targeted agents (erlotinib,
lapatinib plus trastuzumab, sorafenib, imatinib,
dasatinib, vemurafenib, everolimus, abiraterone,
letrozole, tamoxifen).
• Patients randomly assigned (1:1) to receive a matched
molecularly targeted agent (experimental group) or
treatment at physician's choice (control group).
Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.
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The SHIVa trial
Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.
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Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.
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The SHIVa trial
Le Tourneau C, et al. Lancet Oncol. 2015 Oct;16(13):1324-34.
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The SHIVa trial
"So far, no evidence from randomised clinical trial supports
the use of molecularly targeted agents outside their
indications on the basis of tumour molecular profiling"
"Our findings suggest that off-label use of molecularly
targeted agents outside their indications should be
discouraged, and enrolment into clinical trials encouraged,"
Le Tourneau C,
Institut Curie, Paris, France
https://www.medscape.com/viewarticle/851399
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Conclusions
Traditionally, trials were designed to investigate 1 drug at a time in homogeneous patient populations.
New trial designs have the potential: - To accelerate efforts to identify effective treatments, tailored to specific subgroups of patients, for challenging diseases - To evaluate multiple treatments, in heterogeneous patient populations, with the possibility to add new treatments in the future and eliminate investigational treatments lacking efficacy.
To realize this approach, continuous teamwork and innovation in statistical methodology, clinical trial logistics and coordination are mandatory.