Combination of CMC-544 and Rituximab Produces High Response Rates in Relapsed FL and DLBCL Patients

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Combination of CMC-544 and Rituximab Produces High Response Rates in Relapsed FL

and DLBCL Patients

Posting Date: December 11, 2008

a.. Preliminary results of ongoing nonrandomized phase I/II study[1]

Summary of Key Conclusions

a.. Inotuzumab ozogamicin (CMC-544) added to rituximab produced high response

rates in patients with relapsed follicular lymphoma (FL) and diffuse large

B-cell lymphoma (DLBCL)

a.. Maximum tolerated dose (MTD) of inotuzumab ozogamicin achieved

b.. CR and PR achieved at all dose levels of inotuzumab ozogamicin

b.. Thrombocytopenia most frequent and dose-limiting toxicity but manageable

c.. Long-term follow-up ongoing

Background

a.. CD22 expressed in > 90% of B-cell lymphomas

a.. Represents novel therapeutic target in non-Hodgkin's lymphomas (NHL)

b.. Inotuzumab ozogamicin

a.. Cytotoxin calicheamicin conjugated to a humanized polyclonal IgG4

anti-CD22 antibody

b.. Active at MTD in phase I study of heavily treated patients with FL and

DLBCL[2]

c.. Active in murine model resistant to rituximab

d.. Effective as single-agent in heavily treated NHL patients

a.. Thrombocytopenia and neutropenia most common hematologic toxicities

c.. Current study sought to evaluate safety and efficacy of inotuzumab

ozogamicin plus rituximab in patients with recurrent CD22+ B-cell lymphomas

a.. FL and DLBCL

Summary of Study Design

a.. Eligibility criteria

a.. CD22+ B-cell NHL with progression after 1-2 previous therapies

b.. Rituximab-sensitive FL and DLBCL

a.. Remains responsive to rituximab > 6 months from treatment initiation

c.. ECOG performance score 0-2

d.. Absolute neutrophil count ? 1500 cells/mm3

e.. Platelet count ? 75,000 cells/mm3

b.. Exclusion criteria

a.. Previous allogeneic bone marrow transplantation

b.. Previous autologous stem cell transplantation < 6 months from study

entry

c.. Dosing regimen

a.. Rituximab 375 mg/m2 on Day 1

b.. Inotuzumab ozogamicin 0.8, 1.3, or 1.8 mg/m2 on Day 2

c.. Four 28-day cycles

a.. Up to 8 cycles for patients with clinical benefit after 4 cycles

d.. Patients restaged after every 2 cycles

e.. 2-part study

a.. Dose escalation of inotuzumab ozogamicin up to MTD

b.. Preliminary efficacy evaluated in patients receiving MTD

a.. FL: n = 30

b.. DLBCL: n = 30

f.. Dose-limiting toxicity defined as

a.. Grade 3/4 nonhematologic toxicity

b.. Neutropenia with fever

c.. Grade 3 thrombocytopenia requiring platelet transfusion

d.. Grade 4 thrombocytopenia lasting ? 3 days

e.. Delayed recovery from any toxicity which delays next dose by > 2 weeks

Baseline Characteristics

Characteristic

Study Cohort

(n = 74)

Male, %

58

Median age, yrs (range)

65 (29-85)

Tumor histology, %

a.. FL

55

a.. DLBCL

45

Elevated LDH, %

30

Tumor size, %

a.. > 5.0 cm

35

a.. > 7.5 cm

14

Prior ASCT, %

11

Disease stage III/IV, %

68

ASCT, autologous stem cell transplantation; LDH, lactate dehydrogenase.

Main Findings

a.. Most patients received MTD of 1.8 mg/m2 inotuzumab ozogamicin

a.. ORR: 70% (CR plus unconfirmed CR [CRu] plus PR)

b.. Inotuzumab ozogamicin at MTD equally effective in FL and DLBCL

c.. PFS rate at 6 months in intent-to-treat population receiving MTD

a.. FL: 93% (80% confidence interval [CI]: 83% to 97%)

b.. DLBCL: 65% (80% CI: 48% to 78%)

a.. Median PFS: 460 days

Response Rate, %

Inotuzumab Ozogamicin Dose

0.8 mg/m2

1.3 mg/m2

1.8 mg/m2

All Doses

FL

n = 1

n = 2

n = 29

n = 32

a.. OR

100

100

72

75

a.. CR/CRu

100

50

45

47

a.. PR

0

50

27

28

DLBCL

n = 5

n = 1

n = 24

n = 30

a.. OR

20

100

79

70

a.. CR/CRu

20

0

37

33

a.. PR

0

100

42

37

a.. Thrombocytopenia most common hematologic toxicity

a.. Clinically manageable, self limiting

b.. 1 patient experienced dose-limiting toxicity due to low absolute

neutrophil counts

Hematologic Adverse Events, n (%)

Study Cohort*

(n = 74)

Any Grade

Grade 3/4

Thrombocytopenia

28 (38)

15 (20)

Neutropenia

16 (22)

11 (15)

Lymphopenia

4 (5)

4 (5)

*Inotuzumab ozogamicin MTD: 1.8 mg/m2 (n = 59); 0.8 mg/m2 (n = 5); 1.3 mg/m2 (n

= 3); 1.8 mg/m2 (n = 7).

a.. Nausea and fatigue most common nonhematologic toxicities

b.. Nearly 1/3 of patients with elevated aspartate aminotransferase level

Nonhematologic Adverse Events (Any Grade),

n (%)

Study Cohort*

(n = 74)

Nausea

30 (41)

Fatigue

24 (32)

Pyrexia

14 (19)

Chills

13 (18)

Vomiting

13 (18)

Headache

10 (14)

Elevated AST

21 (28)

Elevated ALT

11 (15)

Elevated alkaline phosphatase

13 (18)

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

*Inotuzumab MTD: 1.8 mg/m2 (n = 59); 0.8 mg/m2 (n = 5); 1.3 mg/m2 (n = 3); 1.8

mg/m2 (n = 7).

a.. Pharmacokinetics (n = 34)

a.. Inotuzumab ozogamicin exposure dependent on dose and treatment cycles

a.. Comparable to single-agent exposure

b.. No patients developed anti-inotuzumab ozogamicin antibodies during

treatment

c.. Mean free calicheamicin levels remained < 3 ng/mL

References

1. Fayad L, Patel H, Verhoef G, et al. Safety and clinical activity of the

anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) in combination with

rituximab in follicular lymphoma or diffuse large B-cell lymphoma: preliminary

report of a phase 1/2 study. Program and abstracts of the 50th American Society

of Hematology Annual Meeting and Exposition; December 6-9, 2008; San Francisco,

California. Abstract 266.

2. Fayad L, Patel H, Verhoef G, et al. Clinical activity of the immunoconjugate

CMC-544 in B-cell Malignancies: Preliminary report of the expanded maximum

tolerated dose (MTD) cohort of a phase I study. Program and abstracts of the

American Society of Hematology Annual Meeting and Exposition; December 9-12,

2006; Orlando, Florida. Abstract 2711.