Le nuove tossicità in oncologia: gli
studi di fase 1
Marco Maruzzo, MD PhD
Regione del Veneto
UOC Oncologia Medica 1 Dipartimento di Oncologia
Istituto Oncologico Veneto IRCCS, Padova
Agenda
Phase 1 trials: what are we speaking about?
Define toxicity profiles: MTD Define toxicity profiles: DLT
Heterogeneity in MTA, mAB and IT
What’s going on?
Phase 1 Clinical Trials
«La sperimentazione clinica di fase I comprende un insieme di studi sul soggetto volontario sano o ammalato, che riguarda la determinazione del profilo di tollerabilità e quello farmacocinetico/metabolico di un farmaco. Nei soggetti ammalati, questi studi possono includere la valutazione di indici di efficacia nel caso di farmaci per i quali l’attesa di un effetto terapeutico giustifica la somministrazione di sostanze che presentano rischi non accettabili nei volontari sani»
DPR 439/2001
Phase 1 Clinical Trials
Determine
Maximum tolerated dose (MTD)
Optimal biological dose (OBD)
Recommend phase II dose (RPTD)
Define toxicity profiles
Dose limiting toxicities (DLT)
NCI Common Toxicity Criteria (CTC 2.0), CTCAE v3.0 and 4.0
WHO Common Toxicity Criteria
Study PK/PD
Pharmacokinetics: body does to the drug
Pharmacodynamics: drug does to the body
Initial assessment of treatment efficacy
Phase 1 Clinical Trials
Define toxicities profiles: MTD
The highest dose of a drug or treatment that does not cause unacceptable side effects. The maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.
DLT
The MTD is strictly related to the DLT (dose limiting toxicities).
DLT is traditionally defined as any grade 3–4 non-haematological or grade 4 haematological toxicity at least possibly related to the treatment, occurring during the first cycle of treatment.
Some adjustments to this definition have been widely accepted, such as febrile neutropenia, or neutropenia grade 4 lasting more than 7 days or abnormal laboratory values rated as a DLT only in the presence of clinical symptoms.
There is no consensus about DLT in phase I cancer clinical trials
Heterogeneity in DLT
Defining DTL in MTA
The classical definition of DLT for cytotoxic agents raises concerns in phase 1 trials of molecularly targeted agents (MTA) because of:
- their specific toxicity profiles - their mechanism of action
- often continuous and oral administration - the duration of treatment.
25% of studies reported some NCI CTCAE grade 2 toxicities as DLT.
Defining DTL in MTA
Features to consider in a new definition should include:
(a) worsening from baseline for non-life-threatening events,
(b) requirement of a minimum dose intensity of 70% to conclude on the tolerance of a treatment
(c) incorporating some moderate grade 2 side-effects in the DLT composite end-point
Defining DTL in MTA
Defining DTL in mABs
Defining DTL in IT
IT has distinct toxicity profile compared to other therapies characterized by immune-related adverse events (irAE) that are rare (absolute risk of all- grade irAE of ~ 10%) but when present can result in life-threatening events.
Defining DTL in IT
Defining DTL in IT
What’s going on?
• Marked increase in MTA and IT
• Need for innovative trial design to reduce toxicities risk
• Increase enrollment in phase 1 trials
Conclusion
Are we managing new toxicities or toxicities in a new way?
• DLT is heterogeneously described and defined across phase 1 trials
• Definition used with conventional chemotherapy is no longer acceptable
• MTA, mABs, IT trials often do not reach DLT / MTD
• There is a great variability in MTD/SD and SD/DL ratio
• We need innovative trial design to reduce toxicities risk and coinvestigate other end points
Grazie per l’attenzione!
marco.maruzzo@iov.veneto.it @marcodoc
