Pocket Oncology (Pocket Notebook Series), 1st Ed.

PHASE I CLINICAL TRIALS

Connie Lee Batlevi and David R. Spriggs

Phase 0 Trials

• Proof of concept trials designed to be first in human (Nat Rev Cancer 2007;7:131) administered while toxicology studies are being performed for IND submission

• Single doses of new drug given at low concentrations not expected to cause tox: Correlated w/biomarker assay, imaging technique, of drug activity w/drug administration in vivo

Phase I Trials

• One of the initial phases of clinical experimentation

First-in-human trials: Promising preclinical data, clinical efficacy unproven novel Rx combinations of existing and/or new agents (eg, carboplatin/paclitaxel + PI3K inhibitor)

• Primary objectives: Identify drug tox, describe drug pharmacology (PK, PD), identify RP2D

• Population: Heterogeneous (eg, nonhistology specific), newer trials of molecular agents may select pts based on genotype, often includes pts who have failed multiple lines of prior tx

• Starting dose: Dose chosen to treat first cohort of pts based on animal studies, commonly 1/10–1/3 of mouse LD10 (dose resulting in death of 10% of mice), other animal species may be used

Types of Phase I Designs

• Rule-based designs

Egs: Standard 3+3, AT, PGDE

Traditional phase I designs w/no prior assumptions of dose-tox curve, allow dose escalation & reduction, easily implemented w/o need for special mathematical software → relatively inefficient at establishing MTD, RP2D based on current dose level & does not incorporate all tox data

• Model-based designs

Egs: CRM, escalation w/O/D control, TITE-CRM, EffTox, TriCRM

Statistical model: Starts w/initial dose-tox curve → model modified by tox experienced by pts on trial; allows the incorporation of all available tox data, RP2D estimated w/confidence interval

Traditional 3+3

• Classic phase I clinical trial design where pts are treated initially in cohorts of 3s at escalating dose levels, dose level escalation or de-escalation follows modified Fibonacci sequence: 100% → 67% → 50% → 40% → 33%, intra-pt dose escalation is typically not allowed

• Relatively simple to implement, provides more info on PK inter-pt variability per dose level, defined sequence of escalation & de-escalation

• MTD definition = Highest dose where 0–1/16 pts w/DLT (estimates MTD at 33%) or next higher dose level

• Pitfalls: Grossly underestimate MTD, dose escalation is slow, many pts treated at subtherapeutic (below RP2D) dose levels

Accelerated Titration (J Natl Cancer Inst 1997;89:1138)

• Affords rapid initial dose escalation, wide variety of designs, intra-pt dose escalation permitted in some designs

• Design eg: Initial dose-escalation phase w/single-pt cohorts, dose is escalated rapidly at 96–100% of previous dose → defined stopping rule is hit (eg, 1 DLT or 2 mod. tox observed) → reverts to 3+3 design w/40% dose increments between cohorts

• MTD is estimated using all tox data collected during trial, some designs may use 3+3 rules to determine MTD

• Advantages: Reduces number of pts treated at subtherapeutic doses, designs w/intra-pt dose escalation affords tx at higher & potentially more effective doses, disadvantages: Intra-pt dose escalation may mask cumulative/delayed tox, aggressive & may expose more pts to higher doses, requires acute tox (chronic/cumulative tox not captured)

Pharmacologically-Guided Dose Escalation (J Natl Cancer Inst 1990;82:1321)

• Assumes DLT predictable by plasma drug concentrations: Plasma exposure defined by AUC extrapolated from preclinical data

• Design: Single-pt dose escalation (based on PK data, typically 100%) → stopping rule hit (eg, target AUC reached or DLTs occur) → switch to 3+3

• Provides rapid dose escalation but not widely used due to difficulty obtaining real-time PKs, dose escalation may be hampered by inter-pt variability

Continual Reassessment Method (Biometrics 1990;46:33)

• Bayesian approach: Starts w/defined acceptable probability of DLT (20–33%), 1–3 pts selected per cohort depending on accrual & desired DLT rate, starts at dose thought to be close to MTD

• Mathematical model for dose-tox curve continuously modified as each enrolled pt experiences a DLT → dose is then escalated & de-escalated accordingly (next pt is treated at new estimated dose close to MTD) → trial stopped if prespecified condition met or precision in probability of DLT at estimated MTD level is achieved

• Requires intensive statistical assistance, thought to provide more precise MTD estimate, may be safer w/fewer pts treated at toxic doses

Other Model-Based Designs

• Modified CRM design: Escalation w/O/D control(Stat Med 1998;17:1103)

• TITE-CRM (Biometrics 2000;56:1177): Incorporates time-to-event of tox for each pt, assumes hazard of tox remains constant

• Efficacy & tox models: EffTox defines acceptable dose combination based on trade-offs between probabilities of efficacy & tox, TriCRM w/3 potential trial outcomes (no efficacy no tox, efficacy only, tox only)