complete remissions with sgn-35 weekly dosing: a phase 1 dose-escalation study in...
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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
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