Patient 1. Baseline: 2449 ml. Cycle 22: 1477 ml (-40%)

Transcription

1 A Phase I Study of the MEK 1/2 Inhibitor AZD6244 (Selumetinib) in Children and Young Adults with Neurofibromatosis Type 1 (NF1) and Plexiform Neurofibromas (PN) Brigitte Widemann, MD NCI Pediatric Oncology Branch

2 Background Rationale: Inhibition of Ras pathway signaling Objectives: MTD determined based on cycle 1-3 (1 cy=28 d) toxicity PK, chronic toxicity, 3D MRI of PN Adherence Eligibility: Children 3-18 y/o NF1 and inoperable PN that have the potential to cause substantial morbidity Drug administration: BID (capsules) continuous dosing (1 cycle = 28 days) Response evaluation: Post cycle 5, 10, then every 6 cycles PR = Decrease in PN volume 20%

3 Trial Status Twelve patients enrolled: 7 males, 5 females Median age 14 years (range, 5-18 years) Four patients < 12 years Dose (mg/m 2 ) Enrollment and Toxicities Patients Enrolled Evaluable DLT Grade 3 CPK (n=1) Grade 3 EF (n=1) Grade 3 infection (n=1) Median cycle number: 8 (range 1-22)

4 Non Dose-Limiting Toxicities Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea, mucositis Skin: Acneiform rash Musculoskeletal: CPK elevation, myalgia Other: Fatigue Pain: Tumor, extremity Hair color change, lighter Cellulitis Decrease LV EF Myalgia and decreased LV EF only observed at DL 2 Toxicity appears dose related and not cumulative No acneiform rash in prepubertal children Rash and CPK elevation are related

5 Response Evaluation Patient 1 Baseline: 2449 ml Cycle 22: 1477 ml (-40%)

6 Response Evaluation Patient 2 Baseline: 211 ml Cycle 16: 152 ml (-28%)

7 Response Evaluation Four years prior: 4506 ml Baseline: 7210 ml Cycle 5: 5479 ml (-24%)

8 Response Evaluation Dose level 1: 2 PR (-40%, -28%) 1 SD (-17%) 3 no MRI yet Dose level 2: 2 PR (-23%, 24%) 2 SD (-14%, -13%) 2 no MRI yet

9 AZD6244 Plasma Concentration x Time Curves C max : DL1 (n=2): 513 (range, ) ng/ml C max : DL2 (n=5): 841 ( ) ng/ml

10 AZD6244 Trial Summary Toxicities: Most frequent dose related toxicities: Acneiform rash and asymptomatic CPK elevation DLTs: CPK, decreased LV EF, infection (labial cellulitis) Toxicities appear to be dose related and not cumulative The 20 mg/m 2 (50% of adult recommended dose) dose level is being expanded PN shrinkage observed at 20 and 30 mg/m 2 All patients remain on trial No disease progression to date

11 Proposal for Phase II Trial AZD6244 in NF1 PN (Amendment of Current Trial) Primary objective: Objective response rate ( 20% decrease in target PN volume) Partial response = 20% decrease in volume Eligibility: 3-18 y/o with progressive or symptomatic unresectable PN Progressive = 20% increase in PN volume within approximately 1 year ( 15 months) of trial entry Target response rate: 30%

12 Secondary Trial Objectives Progression free survival QOL and pain (all subjects) Functional outcomes: PN affecting motor function: Strength, walk test PN affecting airway: PFT PN affecting vision/orbit: Ophthalmology evaluation In subjects with spinal cord compression: Changes in spinal cord deformity by MRI Changes in neurological exam

13 Statistical Considerations Primary Objective Small optimal two-stage phase II design: Rule out 5% response rate (p0=0.05) Target response rate 30% (p1=0.30) alpha=0.10, beta=0.10 Enrollment of 7 subjects initially If >1/7 respond, expand enrollment to 21 subjects If 3 responders in an expanded stratum AZD6244 will be considered active

14 Statistical Considerations: Secondary Objectives Progression free survival: Kaplan-Meier curves Informal comparison to placebo arm of tipifarnib trial Morbidity (function, quality of life, pain) Stability, improvement or worsening will be assessed in all subjects relative to their initial level of morbidity Descriptive analysis, paired statistical tests

15 Future Plans PNs Analyze relationship of PN growth and morbidity in NH study Develop endpoints, which represent benefit: Patient reported and functional outcomes (REiNS) Define optimal dose and schedule Trials combining active agents Target very young patients to prevent PN morbidity Age 3 Age 5 11 mo. 17 mo. 25 mo. 36 mo.

16 CTEP: Austin Doyle Astra Zeneca NCI, POB Eva Dombi Acknowledgements Trish Whitcomb, Andy Gillespie Andrea Baldwin, Joanne Derdak Srivandana Akshintala, Rachel Ershler Staci Peron, Pam Wolters Participating sites and investigators CHOP: Michael Fisher CNMC: AeRang Kim Cincinnati Children s: Brian Weiss, Nancy Ratner Children s Tumor Foundation NTAP

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20 Response Evaluation Four years prior: 892 ml Baseline1646ml Cycle 5: 1421 ml (-14%)