Phase I Studies in Oncology (L5;E2)

Phase I Studies in Oncology

• Phase I studies introduce a drug into human subjects for the first time.
• The primary objective is identifying the safe dose for further testing in Phase II studies (target dose).
• Safety is the primary concern during these studies.
• Patients enrolled are typically those with advanced disease resistant to standard therapies, having good functional status, and representing all tumor types. Other fields may use normal volunteers in some studies.
• There are various phase I studies, mostly involving single drugs but sometimes combinations of approved drugs with novel agents.
• Dose escalation studies define doses beforehand. A typical starting point is 1/10th of the lethal dose (LD10) in mice.
• Doses are increased within patient groups (cohorts), with cohort size based on disease progression models; often employing Fibonacci sequences, continuous reassessment method (CRM), or Bayesian methods.
• Pharmacokinetic and pharmacodynamic parameters are also determined throughout these studies.
• The use of 1/10th of the mouse LD10 provides a suitable starting dose in 83% of cases, and 97% with 2-3 species.
• This method sometimes results in exceeding the maximum tolerated dose (MTD), requiring dose de-escalation. Using more animal models may solve this problem.
• Dose escalation is simpler in oncology than in normal patients, focusing on the absence of grade 3 or higher toxicity, which usually signals unacceptable toxicity.
• The response is binary: toxicity versus no toxicity.
• National Cancer Institute (NCI) toxicity criteria are established for every organ system, with graded responses ranging from 0-4.
• Traditional dose escalation (3+3 design) utilizes 3 patients per dose level. If one develops grade 3 toxicity, another 3 patients are added at this dose; if fewer than 2/6 patients develop grade 3 toxicity, the dose is increased. If more than 2/6 patients develop this toxicity grade, the previous dose is considered the maximum tolerated dose (MTD). The process is repeated until a sufficient number of patients (10) have been screened to determine the target dose for subsequent phase II trials.
• Statistical properties of this design are often unpredictable, resulting in population toxicity rates ranging from 10-29%.
• Fibonacci-based progression for dose escalation involves a methodical and incremental approach to escalating doses (e.g., level 1 = 1, level 2 = 2, level 3 = 3, and so forth).
• The CRM method estimates toxicity probabilities before and after each dose, using prior data to update estimates for every new patient's toxicity response. This is done to mitigate the risks of inappropriately high doses that could be assigned to very early trial patients. In some models, a two-stage approach uses standard Fibonacci progression until the first toxicity incident (in one or three patients).
• A typical dose-response curve demonstrates the increased probability of toxicity as doses increase.
• Bayesian decision methods involve determining the full dose-response curve with a specific focus on target dose, employing a two-parameter logistic regression analysis in log dose.
• All of the methods re-evaluate toxicity in earlier doses before escalation.
• Pharmacokinetic studies determine how the body processes the drug (e.g., behavior in patients, sampling blood at specified intervals, calculating drug concentrations like Cmax, half-life, and volume/area under curve of distribution.).
• Alternative endpoints in phase I studies (e.g., pharmacokinetic/pharmacodynamic endpoints, molecular target endpoints, off-target effects) allow examination of responses not traditionally considered critical factors for efficacy, unlike toxicity.
• Phase I trials regarding targeted therapies frequently show objective responses in the 20-30% range, regardless of dose.

Clinical Trials Related to Targeted Therapy in Phase I

• Targeted therapies often differ from cytotoxic drugs regarding dose-response curves, frequently reaching optimal levels of efficacy at different levels or a completely different range of doses.
• A targeted agent often requires the investigation of the specific objective responses often seen between 20-30% rather than the typical 10% seen with cytoxic agents usually in high doses right before hitting the MTD.
• Genetic polymorphisms in drug-metabolizing enzymes, and drug transporters affect patient variability in plasma levels and therefore treatment efficacy.
• Drug efficacy can occasionally stem from off-target effects in a treated patient response; although often not targeted, these should be considered when establishing appropriate doses for phase II trials.
• Dose escalation in these types of cases is frequently by powers of two, as opposed to the more common Fibonacci progression method. Administration with or without food can influence pharmacokinetic and toxicity variables.

Phase I Pharmacokinetic and Pharmacodynamic Study of TK1258

• This study involved a protocol for intermittent dosing followed by continuous dosing for a receptor tyrosine kinase inhibitor (TK1258) in patients with advanced solid tumors. Doses escalated from 25-200 mg in continuous dosing protocols.
• The patients initially received intermittent dosing from day 1 to 7, then transitioned to 7 days without the drug.
• The results showed dose proportionality of the plasma pharmacokinetic of TKI258 (as quantified by C-max and AUC (area under the curve)) for 25-175 mg dosing.

Baseline Characteristics & Clinical Adverse Events of Studied Population

• The population studied had baseline characteristics including; patients, gender, median age and range, ECOG Performance Status.
• A variety of tumor types and prior chemotherapy history.
• Clinical adverse events such as fatigue, anemia, nausea, vomiting, diarrhhea, headache, anorexia, reduced LVEF, hypertension, pulmonary embolism were assessed throughout the trails.

Plasma Pharmacokinetics of TK1258

• Pharmacokinetics of TK1258 (plasma Cmax and AUC) demonstrated dose-proportionality across various administered doses.
• Initial analyses showed average half-lives of approximately 17 hours on the day when administering the drug, but reduced amounts when administering intermittently followed by a 7-day washout.

Intravenous Pharmacokinetics of Gefitinib

• Pharmacokinetics data for gefitinib, an intravenous agent, were presented including the following variables; volume of distribution, plasma clearance rate, elimination half-life (range and mean values), and other figures in both healthy volunteers and patients with cancer.

Pictures/Examples

• Pictures of skin rashes and CT scan images of patients were shown to illustrate various examples of adverse events or disease control at different times in trial.

Measuring Effects on Molecular Targets - Pharmacodynamics

• Study of pharmacodynamic response (e.g. measuring effects on pSTAT3, EGFR, and ERK) that illustrated various treatments and measurements under different timed periods (day 1, 7, 15).
• Presented data also included the use of immunohistochemical techniques to assess EGFR and MAPK levels in paired skin samples and the relationship between dose and disease control or skin rash.

This quiz focuses on the essential aspects of Phase I studies in oncology, including their objectives, patient criteria, and dose escalation methods. It delves into the safety concerns and methodologies used to determine safe dosages for drugs being tested for the first time in humans. Engage with the intricate details of drug testing protocols and patient selection.