Complete remissions with SGN-35 weekly dosing: a phase 1 dose-escalation

study in relapsed/refractory HL or systemic ALCL

patientsNancy L Bartlett, Andres Forero-

Torres, Joseph D Rosenblatt, Michelle

Fanale,Sandra J Horning, Sarah Thompson,

Eric L Sievers, Dana A Kennedy.

Disclosures-Nancy L Bartlett, MD• Research funding for conducting the

clinical study received from Seattle Genetics, Inc.

• Study Sponsored by Seattle Genetics, Inc.

SGN-35 Targets CD30• CD30 Antigen

– Transmembrane glycoprotein receptor, member of the TNF receptor superfamily

– Cell surface antigen highly expressed in Hodgkin Lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL)

– Normal distribution restricted to activated leukocytes (T and B cells, macrophages)

SGN-35 Mechanism of Action• SGN-35 antibody-

drug conjugate– CD30-targeted

antibody (cAC10) conjugated to an auristatin (MMAE), an anti-tubulin agent

• Selectively induces apoptosis in HL and ALCL cells: – Binds to CD30– Becomes internalized– Releases MMAE

SGN-35 Antibody-Drug Conjugate

SGN-35 binds CD30

Endocytosis

ADC traffics to lysosome

Enzymatic linker cleavage releases MMAE

from ADC

MMAE binds tubulin

G2/M cell cycle arrest & apoptosis

CD30

SGN-35 Antibody-Drug Conjugate

SGN-35 binds CD30

Endocytosis

ADC traffics to lysosome

Enzymatic linker cleavage releases MMAE

from ADC

MMAE binds tubulin

G2/M cell cycle arrest & apoptosis

CD30

Background• Phase 1 SGN-35 Q3wk study, N = 45

– Outpatient infusions of SGN-35 were well tolerated; MTD was defined as 1.8 mg/kg

• DLTs at 2.7 mg/kg: febrile neutropenia (prostatitis), hyperglycemia, unrelated acute renal failure

– Among 28 evaluable patients treated at doses ≥ 1.2 mg/kg

• Objective response (CR+PR) = 54% (n = 15)• CR = 32% (n = 9)• Reduced tumor size = 93% (n = 26)• Median progression-free survival >6 months

• Phase 1 SGN-35 weekly study rationale – lower Cmax, higher Cmin while maintaining equivalent exposure may– Improve on-target CD30-directed activity– Reduce off-target toxicity

Study Objectives• Primary

– Define safety profile– Determine maximum tolerated dose

(MTD)

• Secondary– Describe pharmacokinetics– Assess immunogenicity– Evaluate anti-tumor activity

Eligibility Criteria• Relapsed or refractory CD30-positive

hematologic malignancies• Age ≥ 12 years • Bi-dimensional measurable disease ≥ 1.5 cm• ECOG performance status ≤ 2• Adequate organ function• No limit to prior number of therapies• Prior autologous stem cell transplant

(ASCT) allowed• No prior allogeneic transplant

Study Schema

Follow-up

Treatment

Restage

• SGN-35 IV administration: Weekly for 3 wks, no dose wk 4

• Doses: 0.4, 0.6, 0.8, 1.0, 1.2, 1.4 mg/kg

Cycle 128 days

Cycle 128 days

Cycle 228 days

Cycle 228 days

Stable disease or better may

receive additional cycles

Stable disease or better may

receive additional cycles

D1 D8 D15Dosing

DaysDosing Days

D1 D8 D15

Patient Characteristics N = 34

† Median (range)

Diagnosis Hodgkin lymphoma Systemic ALCL ALK-1 negative

29 (85%)5 (15%)4 (80%)

Age 34 (13-82)†

ECOG status 0/1 2

30 (88%)4 (12%)

Prior Treatment Regimens Number of chemo regimens ASCT

5 (1-13)†

21 (62%)

Adverse Events• SGN-35 was generally well tolerated in 34 treated patients

• Related Grade 3-4 AEs (no Gr 5 events occurred)

• Related AEs in ≥10% patients (includes Gr 3-4 events above)

– Nausea 26% (9 patients) – Neutropenia 18% (6)

– Fatigue 24% (8) – Dizziness 12% (4)

– Peripheral neuropathy 18% (6)

– Hyperglycemia 12% (4)

– Paresthesia 12% (4)

Grade 3 Grade 4

– Neutropenia (3) – Neutropenia (1)

– Diarrhea (1) – Hyperglycemia (1)

– Paresthesia (1)

– Vomiting (1)

– Leucopenia (1)

Additional Safety Information• Dose delays or reductions

– AEs resulting in dose delays (1 patient each)

– Dose reductions: Grade 3 diarrhea in 2 patients• 1.0 mg/kg to 0.8 mg/kg• 1.4 mg/kg to 1.0 mg/kg

• Dose limiting toxicity (DLT)– 1 of 6 pts at 1.0 mg/kg: G3 diarrhea– 2 of 6 pts at 1.4 mg/kg: G4 hyperglycemia, G3 diarrhea

• MTD exceeded at 1.4 mg/kg• MTD determination in progress at lower doses

• diarrhea • neutropenia

• herpes zoster • polyneuropathy

• hypophosphatemia • pruritic rash

• hyponatremia

SGN-35 Pharmacokinetics: Weekly Dosing• SGN-35 ADC concentrations increase proportionally

over the dose range of 0.4 to 1.4 mg/kg

• Free MMAE levels over the 28-day dosing interval:– Peaked between 24-72 h after administration of SGN-35

– Maintained a plateau through Day 21

– Declined by Day 28

• 28-day cycle (3 weekly doses, 1 week break) prevented appreciable intercycle dose accumulation of ADC and MMAE

SGN-35 ADC and Free MMAE Concentration vs Time: Weekly Dosing

0.4 mg/kg 0.6 mg/kg 0.8 mg/kg

1 mg/kg 1.2 mg/kg 1.4 mg/kg

0 14 28 42 560.00001

0.00010.001

0.010.1

110

100ADCFree MMAE

Cycle 1 Cycle 2

Time (day)

An

alyt

e C

on

cen

trat

ion

( g

/mL

)

0 14 28 42 560.00001

0.00010.001

0.010.1

110

100

Cycle 2 Cycle 1 Cycle 2

0 14 28 42 560.00001

0.00010.001

0.010.1

110

100

Cycle 1 Cycle 2

0 14 28 42 560.00001

0.00010.001

0.010.1

110

100Free MMAEADC

Time (day)

An

alyt

e C

on

cen

trat

ion

( g

/mL

)

Cycle 1 Cycle 2

0 14 28 42 560.00001

0.00010.001

0.010.1

110

100

Cycle 1 Cycle 2

0 14 28 42 560.00001

0.00010.001

0.010.1

110

100

Best Clinical Response (N=27)* Dose mg/kg (N) CR PR SD PD

0.4 (4) 4+

0.6 (3) 1 1 1

0.8 (6) 4++ 1 1

1.0 (6) 4++ 1 1

1.2 (5) 1 3 1

1.4 (3) 2 1

Total (27) 10 3 11 3

* Based on International Working Group Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). BCR presented for patients eligible for restage after 2 cycles, or withdrew prior to restage with assessment at EOT visit; 7 patients not evaluable (pending Cycle 2 restage)

+ = 1 patient with systemic ALCL; ++ = 2 patients with systemic ALCL; each = 1 pediatric patient (12-17 years)

Maximum Reduction in Target Lesions

81% of patients achieved tumor reductions

Treatment Duration & Best Clinical Response

† Patient had DLT and dose reduced, treatment ongoing at 1.0 mg/kg dose

^ Patient had PR after 1 cycle of therapy, response measured at EOT visit.

†

^

Median duration of response is at least 16 wks, range 0.1+ to 27.1+ wks

Case Study 1: refractory HL

• 39 yr-old man diagnosed with Stage II HL 1996– MOPP/ABVD/XRT 1996 →CR– Biopsy confirmed relapse

4/07– ESHAP 5/07-8/07 → PR– BEC Auto 9/07 → CR– ICE 7/08 → PD

• SGN-35 1 mg/kg cohort 9/17/08– C2 restaging 11/12/08– CR by PET

• Received 4 cycles of SGN-35, off treatment in CR to receive reduced intensity allo transplant

9/11/08 - Baseline 11/12/08 after C2

Case Study 2: relapsed systemic ALCL• 50 year-old man dx with

Stage IIIA ALK-1 negative systemic ALCL in 12/07– CHOP x 6 cycles

12/07 – 4/08 → CR– Biopsy confirmed relapse

8/08

• SGN-35 1 mg/kg cohort 9/17/08– C2 restaging 11/13/08– CR by PET/CT

• Received 6 months of SGN-35, off treatment in CR

9/17/08 - Baseline 11/13/08 – After C2

Complete resolution

of nodal and subcutaneous involvement

Top image: L hilar LN, 1.9 x 1.6 cm

Bottom image: subQ scalp nodule, 2.5 x 2 cm

Systemic ALCL (sALCL)• Rare disease

– <5% of all cases of non-Hodgkin lymphoma– ~2870 new cases, 400 relapsed/refractory in US in

2007

• Encouraging SGN-35 activity noted – 2 pts with ALK+ sALCL in Phase 1 Q3wk study

• 2 CR– 5 pts with sALCL in Phase 1 Qwk study

• 4 CR, 1 SD

• Phase 2 study in relapsed/refractory sALCL ongoing

Conclusions: SGN-35 Weekly Dosing• Weekly SGN-35 infusions were generally well tolerated

– DLTs were hyperglycemia and diarrhea– SGN-35 MTD exceeded at 1.4 mg/kg – MTD determination is in progress at lower doses

• Robust anti-tumor activity observed in heavily pre-treated CD30+ Malignancies

All pts HL sALCL– ORR (CR+PR) 48% (13/27) 41% (9/22) 80% (4/5)– CR 37% (10/27) 27% (6/22) 80%

(4/5)– Tumor Reductions 81% (22/27)

• Phase 2 HL (pivotal) and systemic ALCL studies currently enrolling