Preliminary Results of a Phase 1 Study of FP-1039 (FGFR1:Fc), A Novel Antagonist Of Multiple Fibroblast Growth Factor (FGF) Ligands, In Patients With Advanced Malignancies

2009 AACR-EORTC-NCI Molecular Targets and Cancer Therapeutics Conference • November 15-18, 2009 • Boston, MA

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Authors: Anthony Tolcher, Kyri Papadopoulos, Jim Agnew, John Marshall, Carolyn Tanzola, Jim Zanghi, Li Long, Tom Harding, Kevin P. Baker, Harold N. Keer, Amita Patniak. START, San Antonio, TX, Georgetown University Hospital, Washington, DC, Five Prime Therapeutics Inc., San Francisco, CA 94158

• Primary Objectives: – To evaluate the safety and tolerability of FP-1039 – To determine dose-limiting toxicities (DLTs), the

maximum tolerated dose (MTD), and the recommended Phase 2 dose of FP-1039

• Secondary Objectives: – To assess preliminary antitumor activity within the

context of a Phase 1 study – To characterize the pharmacokinetics (PK) of FP-1039

• Methods: – Phase 1, non-randomized, open-label, safety and PK

dose escalation study – Study Design (Figure 3)

• Key Inclusion/Exclusion Criteria: – Subjects with histologically or cytologically proven

metastatic or locally advanced unresectable solid tumors for which standard curative or palliative measures do not exist or are no longer effective

– ECOG PS 0-2 – Washout of prior anticancer therapy – No risk factors for bevacizumab-associated

bowel perforation* – Luminal intestinal cancers and/or abdominal

carcinomatosis – History of abdominal fi stula, GI perforation, peptic ulcer

disease, or intra-abdominal abscess within 6 months prior to enrollment

- Other potential risk factors for GI perforation * Note: this exclusion was added after a subject developed DLT of

bowel perforation and sepsis at 1 mg/kg. No subsequent similar events have occurred.

• Study Treatment: – FP-1039 is administered intravenously over 30 minutes

once a week for 4 infusions followed by a 2-week observation period

– After completion of the initial treatment and observation period, subjects with no evidence of disease progression or DLT after 4 infusions may receive additional weekly infusions of FP-1039

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This Poster is available in PDF format at www.fi veprime.com

• The Fibroblast Growth Factor (FGF)-Fibroblast Growth Factor Receptor (FGFR) signaling pathway has been widely implicated in the development and maintenance of many different cancers

• FP-1039 is a soluble fusion protein consisting of the extracellular domains of human FGFR1 linked to the Fc region of human IgG1

• FP-1039 is designed to bind to multiple FGFs and prevent them from activating multiple FGF receptors (Figure 1). FP-1039 has three potential mechanisms of action in cancer:

— Direct anti-tumor activity in cancers dependent on the FGF-FGFR pathway (Figure 2)

— Inhibition of tumor angiogenesis

— Inhibition of cancer stem cell maintenance

• In preclinical models, FP-1039 demonstrates:

— Signifi cant anti-tumor activity in a variety of different xenograft models

— Enhanced anti-tumor activity when combined with cytotoxic or targeted anti-cancer drugs

— Inhibition of both FGF- and VEGF-mediated angiogenesis

• This study presents preliminary data from the fi rst clinical trial with FP-1039

INTRODUCTION

1 2 3 …23

1b 1c 2c

FGF Receptors

FGF Ligands

4 3b 3c FP-1039

Figure 1. Targeting the FGF/FGFR Pathway by FP-1039. The FGF axis contains 4 FGF receptors with many splice forms and 22 FGF family ligands. There is selective binding of overlapping sets of ligands to the different receptors. FP-1039 is an FGFR1 extracellular domain and human IgG1 Fc fusion protein. It is designed to bind and sequester multiple FGFs.

Day 39 Day 45 Day 57

%TGI* vs. Control (p value)** 90 (p<0.001) 96 (p<0.001) 98 (p<0.001)

* %TGI, Percentage of tumor growth inhibition: 1-(Tumor volumetreated/Tumor volumecontrol)x100

** One way ANOVA followed by Tukey test

Figure 2. Effi cacy of FP-1039 in an MFE-280 human endometrial cancer xenograft model. Five million MFE-280 cells were implanted subcutaneously over the right fl ank of SCID mice (n=10 per group). One day post tumor implantation, FP-1039 or albumin was administered intraperitoneally twice a week at a dose of 15 mg/kg.

• Assessments: – Safety: AEs assessed at each visit and graded by CTCAE v3.0 – DLTs: defi ned as any FP-1039-associated Adverse Event of

CTCAE grade 3 or higher – PK: plasma samples drawn for PK analysis at various times after

the fi rst infusion, on Days 8, 15, and 22 immediately prior to dosing, and at various times following dosing on Day 22

– Pharmacodynamics (PD): Selected PD sampling was performed pre-dose (Day 1) and at Day 8 and Day 36 post-dosing

– Immune Response: Samples were taken for Immune Response Analysis on Days 1, 15, 36 and every 3 months following initial dose

– Effi cacy: Tumor evaluation at baseline and at end of treatment period (36 days), then every 8 weeks

• Results: – Note: This study is ongoing and hence the data are

preliminary, and have not yet been subject to full monitoring, edit checks, and reconciliation required for a fi nal study report. SAEs are reported as of 10NOV2009. Enrollment and AEs are reported as of 5NOV2009.

– Patient Population: This study enrolled patients with advanced solid tumors. Tumor types are listed in Table 1. The disposition and best response by cohorts are displayed in Table 2.

– Safety: – Adverse events of grade 2 or higher as reported to date

are summarized in Table 3. Events observed are primarily asymptomatic laboratory abnormalities.

– Four weekly doses of FP-1039 at doses of 0.5-0.75 mg/kg are well tolerated. A single protocol-defi ned DLT (grade 2 urticaria) was observed at 0.75 mg/kg.

– Two protocol-defi ned DLTs were observed at 1 mg/kg (bowel perforation in a subject with luminal bowel involvement with tumor and grade 3 neutropenia). The DLTs were clinically disparate, not related to drug exposure and confounding factors were present. The 1 mg/kg dose level is currently being explored. One additional subject has received FP-1039 at 1 mg/kg and is doing well.

Screening Period (up to 30 days)

Initial Treatment Period (4 Weekly Infusions of FP-1039)

Safety Observation Period (2 Weeks)

Extended Treatment Period (Weekly Infusions of FP�1039 for up

to 1 year)

End of Study Visit (4 Weeks after Last Infusion of FP-1039)

Figure 3. Schema of Study FP1039-001.

Table 2. Cohorts of Subjects Treated to Date

Encouraging Clinical Course In 53 Year-old Subject With Prostate Cancer

Diagnosed

32 mo

Hormonal treatment

22 mo 25 mo

Docetaxel- Based

therapy

Disease progression

FP1039 treatment

Tumor size (CT) SUV (PET)

Slight PSA

Disease progression

Disease progression

Time since diagnosis

Patient’s CT Scans

August 21, 2008 December 22, 2008

• FP-1039 is a FGFR1-Fc fusion protein that functions as an FGF “trap” to sequester multiple FGF ligands and block the activation of multiple FGFRs

• FP-1039 has been administered to 16 subjects to date

• Safety: 0.5-0.75 mg/kg doses are well tolerated, higher doses are being explored

• Pharmacokinetics: At the doses studied, FP-1039 has favorable pharmacokinetic properties, which support weekly or less frequent FP-1039 dosing

• Pharmacodynamics: FP-1039 administration results in target engagement as measured by free FGF-2 levels in plasma

• Clinical Activity: FP-1039 may have single agent activity

– One subject with prostate cancer had tumor shrinkage on CT scan (20%) and decreased SUV on PET scan

– 5 other subjects with stable disease

– Dose escalation is ongoing

• Future Plans

– Single agent study in selected population

– Combination studies with chemotherapy

SUMMARY

Figure 6. Mean (± SD) plasma FP-1039 concentration-time profi les after weekly dosing for 4 weeks. Arrows indicate time of dosing. FP-1039 concentrations were measured prior to dosing the 2nd and 3rd doses and represent trough levels at these times.

Table 4. Mean Pharmacokinetics Parameters

• PK profi le is typical of a large protein with an initial distribution phase and a second terminal/elimination phase

• Exposure increased with dose in the 0.5 to 1 mg/kg range• Mean terminal half life (T1/2) was 2.7 to 4.3 days

• PK profi le supports weekly or less frequent dosing

Figure 5. Free FGF-2 plasma levels in normal subjects and patients before and after a single dose of FP-1039.

Target Engagement: Free plasma FGF-2 levels• Our measure of target engagement was FGF-2 because it is

associated with poor prognosis in multiple tumor types• Clinical subjects had elevated mean FGF-2 plasma

concentrations prior to FP-1039 treatment relative to normal donors (22 pg/mL, range 6 - 90 pg/mL; vs. 3 pg/mL, range 2 - 6 pg/mL)

• FP-1039 sequesters FGF-2 present in the blood, resulting in apparent decrease in free plasma FGF-2 in every clinical subject (Figure 5)

Table 1. Subjects Enrolled to Study FP1039-001

Figure 4

Anti-drug antibodies• 12 subjects have had suffi cient sampling to test for anti-

drug antibodies• 1 subject tested positive prior to dosing• 4 subjects (33%) had transient, lower titer antibodies at

Day 15• All subjects negative by Day 39• No relationship of anti-drug antibodies to PK, target

engagement or safety observations

Serious Adverse Events and Protocol-defi ned Dose Limiting Toxicities:

• Neutropenia (DLT)Subject -003 received two doses of FP-1039 at 1 mg/kg and prior to a scheduled 3rd dose was noted to have grade 3 neutropenia (500-1000/mm3). This event was managed with dose delay and reduction with resolution of neutropenia. This subject tolerated weekly FP-1039 dosing at 0.5 mg/kg for 6 additional months without subsequent grade 3 neutropenia (See Figure 4). No other subjects have had grade 3 neutropenia to date.

• Bowel Perforation and Sepsis (SAE and DLT)Subject -001 received 2 doses of FP-1039 at 1 mg/kg and subsequently developed a communication between her bowel lumen and tumor (bowel perforation) and sepsis. Her tumor history was notable for malignant liposarcoma of the retroperitoneum with bowel involvement, 3 prior surgical resections, adjuvant abdominal radiotherapy, and chemotherapy. Patients at risk for bevacizumab-associated bowel perforation have been excluded from enrollment on this study (see key inclusion/exclusion criteria), and no similar events have been observed.

• Urticaria (DLT)Subject -012, a 65 yo woman with a malignant neoplasm of the small intestine and a history of allergies to aspirin (GI upset) and penicillins (hives) received 2 doses of FP-1039 at 0.75 mg/kg and subsequently developed an urticarial rash (Grade 2). She was treated with corticosteroids and recovered without sequelae.

• Atrial Fibrillation with Rapid Ventricular Response (SAE)

Subject -009, a 71 yo man with NSCLC, received FP-1039 at 0.5 mg/kg per protocol and subsequently developed atrial fi brillation with a rapid ventricular response that was attributed to his underlying COPD and use of an albuterol inhaler.

Table 3. Summary of Adverse Events