Pediatric Cancers
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
NCI-10-C-0178, NCT01182896
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Investigator(s): |
Brigitte Widemann, M.D.
Principal Investigator
Phone: 301-496-7387
widemanb@mail.nih.gov
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Pediatric Oncology
Phone: 301-496-4256
1-877-624-4878 (Toll free)
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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:
- 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 anaplastic large cell lymphoma (ALCL)
- Define and describe the toxicities of PF-02341066 administered on this schedule
- Characterize the pharmacokinetics of PF-02341066 in children with refractory cancer
- Secondary Objectives:
- Preliminarily determine the antitumor activity within the confines of a Phase 1 study
- Obtain initial Phase 2 data on the anti-tumor activity of PF-02341066 in children with relapsed/refractory neuroblastoma (NB) and ALCL
- 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
Key Eligibility Criteria:
- > 12 months and ≤ 21 years of age
- Histological verification of malignancy at time of original diagnosis or relapse
- Diagnosis for each phase:
- Phase 1: Part A1 diagnosis: relapsed or refractory solid tumors, CNS tumors or anaplastic large cell lymphoma (ALCL) (excluding primary cutaneous ALCL)
- Phase 1: Part A2 diagnosis: confirmed ALK fusion proteins, ALK mutations, or ALK amplification
- Phase 1: Part A3 diagnosis: relapsed or refractory neuroblastoma (NB) not eligible for Part A1 or A2
- Phase 2: Part B diagnosis: relapsed or refractory NB
- Phase 2: Part C diagnosis: 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
Study Outline:
- 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/m2/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 neuroblastoma (NB) and anaplastic large cell lymphoma (ALCL)
- The Phase 2 component utilizes a Simon’s 2-stage design with the primary outcome being objective response using RECIST criteria
Additional Information:
- This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
- There is no charge for medical care received at NIH Clinical Center.
Reviewed: 12/14/12
Updated: 2/21/12
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