# Presentation: 355547

## 

Up-Front Phase II Windows in 
Children with Cancer

Victor M. Santana, M.D.

**Up-Front Phase II Windows in **
**Children with Cancer**
**Victor M. Santana, M.D.**

## Phase II Study Designs

## Therapeutic Intent

-  Window study are design to provide effective therapy
-  Assessment of risks and benefits should consider that:
- – the phase II window is part of the complete protocol
- – “standard therapy” in pediatric oncology is usually an investigational trial

## Scientific Validity of Phase II Windows

-  Classical Phase II trials
- 	– often underestimate the activity of new agents
- 	– may overestimate the toxicity of new agents
-  Phase II windows most accurately assess antitumor activity

## Impact: Classic Phase II Trials 

- 	Identify agents that improve outcome
- 	– All-trans retinoic acid in APML
- 	– Ifosfamide/etoposide in Ewing family
-  Problems in pediatrics include:
- 		– slow, often inadequate accrual
- – agents with modest activity moved into front-line therapy

## Not all agents active in classic phase II trials improve survival

-  Ependymoma (vs radiotherapy alone)
- 	 – CCNU, vincristine (40 vs 44% survival, NS)
- 	 – CCNU, vincristine plus procarbazine (44 vs 35%
-        survival, NS)
-  Rhabdomyosarcoma (multimodality therapy)
- 	 – cisplatin; IRS regimen 35 and 36 (NS)
-  Metastatic Ewing sarcoma
- – ifosfamide/etoposide (NS - intergroup)
- – 5-FU(NS-IESS 1 and 2)

## Too early to judge impact of window phase II studies Long developmental cycle

-  Ifosfamide window trials: osteosarcoma
- 	– SJCRH OS-86 (6/1986 - 12/1991)
- 	– POG 8759 (6/1987 - 10/1990)
-  Intergroup prospective randomized trial of ifosfamide in osteosarcoma (PG9357)
- 	– activated 12/1993, closed 11/97
-  Intergroup trial of irinotecan in rhabdomyosarcoma
-         – activated 9/99; still accruing

## Patient Benefits:  Phase II Windows

-  Prompt tumor response, often with non-cross resistant agent
- – Topotecan and Irinotecan in RMS
- – Topotecan in NBL
-  Improved outcome
- – Ifosfamide/etoposide window in metastatic RMS
-  Decreased toxicity
- – Ifosfamide/carboplatin in osteosarcoma

## Phase II Windows: Agent selection

-  Use predictive preclinical models (e.g. xenografts)
-  Prioritization of agents
- – novel mechanisms of action
- – analogues of known effective agents with improved toxicity profile

## Phase II Windows: Patient selection

-  Higher risk of ultimate treatment failure
-  Careful assessment of risk:benefit
- – preclinical scientific rationale for agent selection
- – prior experience with agent
- – agent toxicity profile

## Phase II Windows: Consent

-  Enrollment is voluntary
-  Consent must be informed and carefully obtained
-  By federal rules, discretion is “lodged primarily with the parents and the local IRBs.”

## Phase II Windows: Summary

-  Scientifically justified
-  Ethically acceptable
-  An effective mechanism to identify active agents,
-    within the overall new agent development program
-  Too early to judge overall impact on treatment outcome

## Consensus meeting July 22, 1997Points to Consider

-   Risk and Benefits
-  Informed Consent

## Risks and Benefits

- – risk of tumor progression
- – additional unique toxicities
- – jeopardizing future therapy
- – benefit of early response/incorporation into
-    subsequent treatment
- – duration of participation must be as short as possible

## Informed Consent

- – clear identification/separation from the main treatment/study
- – option not to participate in the “window” component
- – explantation of how “window” treatment differs from subsequent therapy
- – risks of delaying therapy or eligibility for future therapies

## Informed Consent

- – impart on quality of life (additional procedures, extending duration of therapy)
- – pre-clinical/clinical data supporting the use of the agent(s)
- – treatment alternatives
- – provision for assent or refusal