# Presentation: 808459

## Rationale for Developing New Drugs

**25% of children with cancer will not survive 5 years**
**The acute toxicity of dose-intensive chemotherapy is life-threatening**
**The long-term effects of cancer therapy can be debilitating or life-threatening**
**Growth delay**
**Cognitive effects**
**Hormonal/reproductive problems**
**Permanent tissue/organ damage**
**Second cancers**

## Toxicity in IRS-III

**Worst Degree of Any Toxicity (n=1062)**

**No. of Patients**

**Severity of Toxicity**

**Notes:**
This graph shows the number of patients from a recent front line treatment protocol for rhabdomyosarcoma that experienced one of these toxicity grades as their worst toxicity on the trial.  A total of 1062 patients were treated on one of seven regimens.
Over 80% of patients had at least one toxicity that was severe, life-threatening or fatal.
22 of the 32 deaths were from sepsis during neutropenia. Other drug-related causes of death include ADRS (1), cardiac toxicity (2), radiation toxicity (3), metabolic complications (2), CNS toxicity (1), and hemorrhage during thrombocytopenia (1).
This is standard therapy for childhood cancer cancer.

## Clinical Drug Development

## Separate Pediatric Clinical Trials

**Developmental changes affect:**
**Drug disposition (pharmacokinetics)**
**Tissue/organ sensitivity (pharmacodynamics)**
**Childhood cancers differ from adult cancers**
**Tissue of origin**
**Pathogenesis (genetic alterations)**
**Disease manifestations**
**Drug sensitivity**

**Notes:**
Scaling adult doses for children based on body weight or surface area does not account for developmental changes that affect drug disposition or tissue/organ sensitivity.
This can lead to differences in:
Tolerance/MTD
Spectrum of Toxicity
Pharmacokinetics

## Pediatric vs. Adult MTD (1970s)

**% Difference between Pediatric and Adult MTD**

**MTDs in mg/m****2**

**Notes:**
11 of 13 myleosuppression was the DLT in children (13/13 it was DLT in adults)
11/13 there was concordance between children and adults as to what DLT was.  Hepatotoxicity was DLT in children for Indicin N-oxide and ICRF-187

## Pediatric vs. Adult MTD (1990s)

**% Difference between Pediatric and Adult MTD**

## Clinical Anticancer Drug Development

**DRUGS**

**PATIENTS**

## Docetaxel Phase I Trials

**Docetaxel Phase I Trials**

*** <500/μL for >7 days was considered dose-limiting**

**Notes:**
In our phase I trials, docetaxel was administered as a 1 hour IV infusion every 21 days.
Using standard pediatric phase I entry criteria, which captures a heavily pretreated patient population, the maximum tolerated dose of docetaxel in children was 65 mg/m2, which is well below the adult recommended dose of 100 mg/m2.  The dose-limiting toxicity was neutropenia.
Rather than moving into a phase II trial using this low dose, [CLICK] we redefined the entry criteria to include a less heavily pretreated patient population by excluding patients who had received prior central axis radiation therapy or more than 2 prior chemotherapy regimens.  In this group, we were able to escalate the dose to 150 mg/m2, and the MTD was 2-fold higher (125 mg/m2).
This approach has been widely used in adults but has not been applied to a pediatric phase I trial.
We then performed a dose escalation study of docetaxel + G-CSF, because neutropenia was the primary dose-limiting toxicity, but thrombocytopenia was minimal.  With G–CSF the dose of docetaxel was escalated to 235 mg/m2 where non-hematological toxicities became dose-limiting.  G-CSF permitted significant dose intensification of docetaxel.  The MTD with G-CSF is 50% higher in the same patient population.
By altering the trial design we defined an MTD that was higher than the adult MTD rather than moving to phase II with a dose that was 35% lower than the adult recommended dose.
Of note, the responses observed to docetaxel on this trial were at dose exceeding 65 mg/m2, the original MTD.

## Determinants of Chemotherapy

**Selection of front line treatment regimen**
**Tumor histology**
**Stage of cancer**
**Prognostic characteristics**
**Studying activity of new agents**
**Stratified by tumor histology**

## Molecularly-Targeted Drugs

**Specific for molecular target (e.g., mutant *****ras*****) rather than histology**
**Patient treated based on presence of molecular lesion rather than tumor histology**
**Phase II trials not stratified by histology**
**Molecular pathogenesis of adult and childhood cancers different**
**Endpoint of dose finding (phase I) trials may be blocking target rather than toxicity**
**Toxicity profile and dose-limiting toxicity may be different than for cytotoxic agents**