A Phase 1/2 Study of PF-02341066, An Oral Small Molecule Inhibitor of Anaplastic Lymphoma Kinase (ALK) and C-Met, in Children With Relapsed/Refractory Solid Tumors and Anaplastic Large Cell Lymphoma

Background:

- PF-02341066 is an orally bioavailable small molecule inhibitor of the c-Met/hepatocyte
growth factor receptor (HGFR) and anaplastic lymphoma kinase (ALK) receptor tyrosine
kinase.

- The c-Met/HGFR kinase is frequently altered or dysregulated in advanced cancers and has
been implicated in tumor progression.

- ALK and its mutant translocation with the nucelophosmin gene (NPM-ALK) results in a
constitutively active ALK receptor tyrosine kinase expressed in the majority of
anaplastic large cell lymphomas (ALCL).

- Activating mutations in the tyrosine kinase domain of the ALK oncogene are responsible
for the majority of heritable neuroblastoma (NB) and these mutations can also be
somatically acquired.

- PF-02341066 has demonstrated pre-clinical anti-tumor activity in vitro and in vivo in a
variety of solid tumors including brain tumors, NB, and ALCL.

Objectives:

Primary Objectives:

- To estimate the maximum tolerated dose (MTD) and recommend a Phase 2 dose of
PF-02341066 administered orally twice daily to children with relapsed/refractory solid
tumors and ALCL.

- To define and describe the toxicities of PF-02341066 administered on this schedule.

- To characterize the pharmacokinetics of PF-02341066 in children with refractory cancer.

Secondary Objectives:

- To preliminarily determine the antitumor activity within the confines of a phase 1
study.

- To obtain initial Phase 2 data on the anti-tumor activity of PF-02341066 in children
with relapsed/refractory NB and ALCL.

- To examine the relationship between ALK status (e.g. presence of a mutation,
duplication, amplification, and/or translocation) in patients with NB or ALCL and
response to PF-02341066, and examine the relationship between MRD status and clinical
response to PF-02341066 in patients with ALCL.

Eligibility:

- Patients > 12 months and less than or equal to 21 years of age with histological
verification of malignancy at time of original diagnosis or relapse.

- Diagnosis:

- Phase 1 Part A1 diagnosis: relapsed or refractory solid tumors, CNS tumors or ALCL
(excluding primary cutaneous ALCL).

- Phase 1 Part A2: confirmed ALK fusion proteins, ALK mutations, or ALK
amplification.

- Phase 1 Part A3: relapsed or refractory NB not eligible for Part A1 or A2.

- Phase 2 Part B: relapsed or refractory NB.

- Phase 2 Part C: relapsed or refractory ALCL (excluding primary cutaneous ALCL).

- Current disease state must be one for which there is no known curative therapy or
therapy proven to prolong survival with acceptable quality of life.

Design:

- PF-02341066 will be administered orally twice daily continuously on a 28 day cycle.
Therapy may continue for up to 24 cycles in the absence of progressive disease or
unacceptable toxicity.

- Phase 1 Part A1 is the phase 1 dose escalation component of the trial using a rolling 6
phase 1 trial design with the starting dose at 100 mg/m(2)/dose BID.

- Phase 1 Part A2 will accrue to a separate stratum enrolled at one dose level below that
of patients in part A1, or at the starting dose level if dose escalation has not yet
occurred. Intra-patient escalation is allowed.

- Phase 1 Part A3: will accrue to a separate stratum enrolled at one dose level below
that of patients in part A1. Intra-patient escalation is allowed.

- The study includes a Phase 2 expansion (Part B and C) at the recommended dose from the
Phase 1 component of this trial to obtain preliminary efficacy data for patients with
relapsed refractory NB and ALCL. The Phase 2 component utilizes a Simon's 2 stage
design with the primary outcome being objective response using RECIST criteria.