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Complete remissions with SGN-35 weekly dosing: a phase 1 dose-escalation study in relapsed/refractory HL or systemic ALCL patients Nancy L Bartlett,

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Presentation on theme: "Complete remissions with SGN-35 weekly dosing: a phase 1 dose-escalation study in relapsed/refractory HL or systemic ALCL patients Nancy L Bartlett,"— Presentation transcript:

1 Complete remissions with SGN-35 weekly dosing: a phase 1 dose-escalation study in relapsed/refractory HL or systemic ALCL patients Nancy L Bartlett, Andres Forero-Torres, Joseph D Rosenblatt, Michelle Fanale, Sandra J Horning, Sarah Thompson, Eric L Sievers, Dana A Kennedy.

2 Disclosures-Nancy L Bartlett, MD
Research funding for conducting the clinical study received from Seattle Genetics, Inc. Study Sponsored by Seattle Genetics, Inc.

3 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)

4 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

5 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

6 Study Objectives Primary Secondary Define safety profile
Determine maximum tolerated dose (MTD) Secondary Describe pharmacokinetics Assess immunogenicity Evaluate anti-tumor activity

7 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

8 Stable disease or better may receive additional cycles
Study Schema Treatment Follow-up Cycle 1 28 days Cycle 2 28 days Stable disease or better may receive additional cycles Restage D1 D8 D15 D1 D8 D15 Dosing Days Dosing Days 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

9 Patient Characteristics N = 34
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%) † Median (range)

10 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) Grade 3 Grade 4 Neutropenia (3) Neutropenia (1) Diarrhea (1) Hyperglycemia (1) Paresthesia (1) Vomiting (1) Leucopenia (1) Nausea 26% (9 patients) Neutropenia 18% (6) Fatigue 24% (8) Dizziness 12% (4) Peripheral neuropathy 18% (6) Hyperglycemia 12% (4) Paresthesia 12% (4)

11 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

12 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 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

13 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

14 Best Clinical Response (N=27)*
Dose mg/kg (N) CR PR SD PD 0.4 (4) 4+ 0.6 (3) 1 0.8 (6) 4++ 1 1.0 (6) 1.2 (5) 3 1.4 (3) 2 Total (27) 10 3 11 * 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)

15 Maximum Reduction in Target Lesions
81% of patients achieved tumor reductions

16 Treatment Duration & Best Clinical Response
† ^ Median duration of response is at least 16 wks, range 0.1+ to wks † 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.

17 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

18 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 /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 Top image: L hilar LN, 1.9 x 1.6 cm Bottom image: subQ scalp nodule, 2.5 x 2 cm Complete resolution of nodal and subcutaneous involvement

19 Systemic ALCL (sALCL) Rare disease Encouraging SGN-35 activity noted
<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

20 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) % (9/22) 80% (4/5) CR % (10/27) % (6/22) 80% (4/5) Tumor Reductions 81% (22/27) Phase 2 HL (pivotal) and systemic ALCL studies currently enrolling Sources: See packet

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