Trillium Therapeutics : ASH 2017 Abstract 4076

A Single Direct Intratumoral Injection of TTI-621 (SIRPαFc) Induces Antitumor Activity in Patients with Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Preliminary Findings Employing an Immune Checkpoint Inhibitor Blocking the CD47 "Do Not Eat" Signal

ASH 2017

Abstract 4076

Christiane Querfeld1, John A Thompson2, Matthew Taylor3, Raju K Pillai1, Lisa DS Johnson4, Tina Catalano4, Penka S Petrova4, Robert A Uger4, Meghan Irwin4, Eric L Sievers4, Oleg Akilov5

1City of Hope, Duarte, CA, USA; 2University of Washington/SCCA, Seattle, WA, USA; 3Oregon Health and Science University, Portland, OR, USA; 4Trillium Therapeutics Inc., Mississauga, Ontario, Canada; 5University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Background

Intratumoral TTI-621 is Very Well Tolerated

•  Tumor cells frequently evade macrophage-mediated destruction by overexpressing CD47, an immune checkpoint that binds SIRPα and delivers an anti-phagocytic ("do not eat") signal.

  Rapid Tumor Regression is Observed in MF Patients Receiving Intratumoral TTI-621 Monotherapy

  Table 2. Adverse Events in >10% of Subjects

  All Events*

  Related EventsPreferred Term

•  TTI-621 (SIRPαFc) is an immune checkpoint inhibitor consisting of SIRPα linked to an IgG1 Fc domain. It is designed to block the CD47 "do not eat" signal and deliver an activating signal through Fcγ receptors.

  All grades (%)

  ≥ Grade 3 (%)All grades (%)

  ≥ Grade 3 (%)

  Fatigue

  7 (37)

  Chills

  6 (32)

•  TTI-621-02 (NCT02890368) is a multi center, open label, Phase 1 study for subjects with relapsed or refractory mycosis fungoides (MF) and Sézary syndrome or other percutaneously accessible solid tumors.

  Decreased appetite

  3 (16)

  0 0 0

  4 (21)

  6 (32)

  1 (5)

  0 0 0

•  Direct intratumoral injection is employed to enhance both local and systemic antitumor activity.

Headache Injection site pain Pruritus generalized

3 (16)

3 (16)

3 (16)

0 0 0

2 (11)

0

2 (11) 1 (5)

0 0

Diarrhea

2 (11)

0

2 (11)

0

Influenza like illness

2 (11)

Insomnia

2 (11)

0 0

2 (11)

1 (5)

0 0

Figure 2. An 85 year old man (Patient #10) with Stage IIB mycosis fungoides with large cell transformation in whom 4 prior systemic therapies, PUVA and radiation therapy failed received a single 10 mg injection of TTI-621 delivered directly into the proximal lesion on the left foot. By week 4, both proximal and distal lesions demonstrated considerable improvement.

Pyrexia

• 2 (11)

  0

  1 (5)

  0

  Thrombocytopenia

• 2 (11)

  White blood cell count increased

• 2 (11)

0 1 (5)

2 (11)

1 (5)

0 0

* n=19, one patient treated twice

Based upon the observation of no DLTs, 10 mg M/W/F x 2 was selected as the optimal induction dose.

Rapid Decline in CAILS Scores in 9/10 MF Patients

Figure 3. A 61 year old man (Patient #19) with Stage IIB mycosis fungoides in whom 3 prior systemic therapies and radiation therapy failed received six 10 mg injections (M/W/F X 2) of TTI-621 delivered directly into the anterior tumor lesion denoted by "I" at Baseline. At week 1, confluent, loco-regional tumor masses had resolved and this clinical improvement was maintained at week 3.

Table 3. CAILS (Composite Assessment of Index Lesion Severity) Scores

TTI-621-02 Study Design

•  Objectives: Characterize the safety profile and MTD of intratumoral injection of TTI-621 in a 3+3 dose escalation and determine the optimal delivery schedule.

•  Biopsies from injected and non-injected lesions and blood samples were taken at baseline, maximum induration (if observed) and 7 days following the last injection of TTI-621.

•  Data cut-off: November 6, 2017.

Baseline

Day 3

Week 12

Dosing Scheme

1, 3 or 10 mg single injection

* One patient not shown: baseline data only available

† All CAILS measurements were made prior to patients receiving other therapies

10 mg M/W/F x 1

Nanostring Analysis

TTI-621 Treatment Decreased

10 mg M/W/F x 2

Week 1

Week 2

Circulating Sézary Cells

Table 1. Patient Demographics

Characteristic

All patients n=18 (%)

Age, median (range)

69 (32-85)

Sex, male

10 (56)

•  Preliminary differential gene expression of peripheral blood, pre- and end of treatment indicated significant fold changes in genes associated with complement activation, innate immunity, adaptive immunity, and responses to interferon.

  CD4 CD4

  800

  Figure 4. A 72 year old man (Patient #1) with Stage IIB mycosis fungoides with large cell transformation in whom prior topical therapy had failed received a single 1 mg injection of TTI-621 delivered directly into the lesion on the dorsal surface of the left foot. The injected lesion became edematous by day 3 and demonstrated steady and continued resolution to a loco-regional complete response over subsequent weeks. Skin biopsies were performed at baseline, day 3 and at week 12 following injection and stained for CD4 (T cells and histiocytes) and CD163 (macrophages). Following intratumoral injection, the skin biopsy on day 3 revealed a decreased lymphoid infiltrate and increased number of CD163+ macrophages. A biopsy performed at 12 weeks showed a scarce perivascular lymphohistiocytic infiltrate without evidence of lymphoid atypia.

  600

  Pre-TreatmentDay 7

  400

  Number of prior therapies, median (range)

  3 (1-16)

•  Down-regulation of genes associated with CTCL are consistent with decreased tumor burden following TTI-621 injection.

  CD4:CD8

  CD163 CD163

  200

  60

  50

  40

  30

  20

  10

  Conclusions

  0

  Patient #1

  Patient #7

  Prior radiation

  7 (39)

  •  Direct intratumoral injections of TTI-621 were very well tolerated.

    CQ has received research funding from Soligenix, Elorac, Kyowa, and Trillium Therapeutics, Inc. (TTI), received honoraria and research funding from Celgene, MiRagen, and Actelion, received honoraria from Medivir and Mallinckrodt, acted as a consultant for Mindera, and is an employee of City of Hope; JAT has received research funding from TTI; MT has acted as a consultant for and received honoraria from TTI and Blue Print Medicines, and acted as a consultant for, received honoraria from, and participated in a Speaker's Bureau for Eisai Inc. and Bristol-Meyers Squibb; RKP has received research funding from TTI; LDSJ is an employee of TTI; TC is an employee of TTI, and was previously an employee of Apotex Inc; MI is an employee of and has equity ownership in TTI, and was previously an employee of/has equity ownership in Hoffmann La Roche; PSP is an employee of and has equity ownership in TTI, RAU is an employee of, has equity ownership in, and holds patents/royalties in TTI, ELS is an employee of and has equity ownership in TTI, OA has acted as a consultant for Seattle Genetics, Medivir, and Actelion Pharmaceuticals and has received research funding from Actelion Pharmaceuticals and TTI.

•  Nanostring analysis and TCR Vβ sequencing of injected and non-injected lesions are ongoing.

Figure 1. A reduction in circulating Sézary cells was observed as a reduction in the clonal CD4+ TCR Vβ+ (top panel, Patient #3) or an improvement in the CD4:CD8 ratio a week following a single injection of TTI-621.

•  Rapid decreases in circulating Sézary cells and/or the size of mycosis fungoides tumors were observed among heavily pre-treated CTCL patients even after a single TTI-621 injection.

•  CTCL appears to be highly responsive to direct intratumoral injections of TTI-621; targeted T-cell lymphoma enrollment actively continues with weekly intratumoral (NCT02890368) and intravenous administration (NCT02663518)