Supportive Phase 1 & Phase 2 Studies

Study RIT-II-002

Title: Randomized Study of Iodine I 131 Tositumomab vs. Anti-B1 Antibody Alone in Chemotherapy-Relapsed and Refractory Low-Grade or Transformed Low-Grade NHL.

Design

Study RIT-II-002 was a randomized two-arm, open-label, multi-center study conducted in patients with chemotherapy-relapsed or refractory low-grade or transformed low-grade NHL. The study was designed to determine the incremental benefit of the radioconjugate compared to the unlabeled antibody. The study compared the safety and efficacy of the radiolabeled labeled antibody (Arm A) versus the unlabeled antibody (Arm B). A one-way cross-over at the time of disease progression was permitted for patients in the unlabeled arm (to receive iodine I-131 tositumomab).

Protocol activated- March 18, 1996

Accrual was from September 18,1996 to June 1, 2000

Principal Investigators and Study Sites

John Leonard, M.D., New York Hosp.-Cornell Medical Center
Arnold Friedman M.D., Dana-Farber Cancer Institute
Mary Wilkinson M.D. Inova Fairfax Hospital
Stanley Frankel M.D., Georgetown University
Andrew Zelenetz M.D. , Ph.D., Memorial Sloan-Kettering Cancer Center
Rush-Presbyterian-St. Luke’s Medical Center
Susan Know M.D., Ph.D., and Ronald Levy M.D., Stanford University Medical Ct.
Mark Kaminiski, M.D. & Richard Wahl M.D., University of Michigan Medical Ctr.
Aldo Serafini, M.D. , University of Miami Hospital and Clinic
Frank Hsu, M.D. Yale University School of Medicine

Objectives (Final protocol)

Primary objective:

The comparison of the rates of complete response between the Iodine I-131 Anti-B1 antibody (iodine – I 131 tositumomab) and the unlabeled anti-B1 ("cold" tositumomab) arms.

Secondary objectives included comparisons between the Iodine I-131 Anti-B1 antibody and the unlabeled anti-B1 arms for:

Inclusion criteria (final protocol after the inclusion amendments 1-6)

  1. Patients must have a histologically-confirmed initial diagnosis of low grade non-Hodgkin’s B-cell lymphoma [according to International Working Formulation for Clinical Usage A, B, and C] or low-grade lymphoma that has transformed to intermediate- or high-grade histology. The following low-grade histologies are to be included: small lymphocytic (with or without plasmacytoid differentiation); follicular, small-cleaved; and follicular, or mixed small-cleaved and follicular large cell (<50% large cell component).
  2. Patients must have evidence that their tumor tissue expresses the CD20 antigen. Immunoperoxidase stains of paraffin-embedded tissue showing positive reactivity with --- antibody or immunoperoxidase stains of frozen tissue showing positive reactivity with Anti-B1 Antibody (Coulter Clone®) or similar commercially-available CD20 antibody (greater than 50% of tumor cells are positive) or evidence of CD20 positivity by flow cytometry (greater than 50% of tumor cells are positive) are acceptable evidence of CD20 positivity. Testing of tumor tissue from any time in the course of the patient’s disease is acceptable.
  3. Patients must have received at least one chemotherapy regimen that included an anthracycline, an anthracenedione, or an alkylating agent. Patients must have progressive disease [at least a 25% increase in tumor size at one or more site(s) of disease or new site(s) of disease] within 12 months of receiving their last chemotherapy regimen.
  4. Patients must have a performance status of at least 60% on the Karnofsky Scale and an anticipated survival of at least 3 months.
  5. Patients must have an absolute neutrophil count >1,500/mm3 and a platelet count >100,000/mm3 within 14 days of study entry. These blood counts must be sustained without support of hematopoietic cytokines or transfusion of blood products.
  6. Patients must have adequate renal function (defined as serum creatinine <1.5 x ULN) and hepatic function (defined as total bilirubin <1.5 x ULN and AST <5 x ULN) within 14 days of study entry
  7. Patients must have evaluable, bi-dimensionally measurable disease. At least one lesion must be 2 x 2 cm by CT scan.
  8. Patients must be at least 18 years of age.

 

Exclusion Criteria (final protocol after the inclusion amendments 1-6)

  1. Patients with more than an average of 25% of the intratrabecular marrow space involved by lymphoma in bone marrow biopsy specimens as assessed microscopically within 42 days of study entry. Bilateral posterior iliac crest core biopsies are required if the percentage of intratrabecular space involved exceeds 10% on a unilateral biopsy. The mean of bilateral biopsies must no more than25%.
  2. Patients who have received cytotoxic chemotherapy, radiation therapy, immunosuppressants, or cytokine treatment within 4 weeks prior to study entry (6 weeks for nitrosourea compounds) or who exhibit persistent clinical evidence of toxicity. The use of steroids must be discontinued at least 1 week prior to study entry.
  3. Patients who have undergone prior stem cell transplant.
  4. Patients with active obstructive hydronephrosis.
  5. Patients with evidence of active infection requiring intravenous antibiotics at the time of study entry.
  6. Patients with New York Heart Association class III or IV heart disease or other serious illness that would preclude evaluation.
  7. Patients with prior malignancy other than lymphoma, except for adequately-treated skin cancer, in situ cervical cancer, or other cancer for which patient has been disease-free for 5 years.
  8. Patients with known HIV infection.
  9. Patients with known brain or leptomeningeal metastases.
  10. Patients who are pregnant or nursing. Patients of childbearing potential must undergo a pregnancy test within 7 days of study entry and antibody is not to be administered until a negative result is obtained. For those patients in Arm B, the pregnancy test must be repeated within 7 days of crossover. Males and females must agree to use effective contraception for 6 months following the therapeutic dose, as applicable.
  11. Patients with previous allergic reactions to iodine. This does not include reactions to intravenous iodine-containing contrast materials.
  12. Patients who were previously given monoclonal or polyclonal antibodies.
  13. Patients who previously received radioimmunotherapy.
  14. Patients with progressive disease within one year of irradiation arising in a field that has been previously irradiated with >3500 cGy.
  15. Patients with de novo intermediate- or high-grade lymphoma.
  16. Patients who have received >3 chemotherapy regimens (different or identical agents).

Randomization (Final protocol, after the inclusion of amendments 1-6)

Randomization was performed at an external site. There were no stratification criteria specified and no details regarding the randomization procedure in the protocol other than that the randomization would allocate patients equally (1:1) to the two study arms.

Treatment Plan (Final protocol, after the inclusion of amendments 1-6):

Arm A

The treatment program consisted of two intravenous infusions; an initial dosimetric infusion followed in 7 to 14 days by a therapeutic infusion.

Arm B

Concomitant medications:

Dose modifications

 

Monitoring Plan

(Final study protocol, after the inclusion of amendments 1-6):

Tumor response was assessed at baseline, at 6 weeks, 3 months and then at 3-month intervals until 2 years. AE, SAE and morbidity/mortality data were collected at each contact. Hematologic data were obtained at baseline, and weeks 3 through 13 unless more frequent counts were indicated. After grade 0 toxicity has been observed on 2 or more occasions the protocol stated that weekly hematology testing could be discontinued. After week 13, the follow up phase began with collection of hematology & serum chemistry test samples, TSH levels, physical and history and HAMA every 13 weeks until year two or death or the patient is withdrawn from study for disease progression or concomitant therapy. The final HAMA measurement was at week 26. Withdrawn patients were entered into long term follow up [LTFU] which collected information on disease and vital status, history of thyroid medication, history regarding myelodysplastic disease or other malignancy and any subsequent therapy for NHL. In amendment 1 samples for HAMA and TSH were added to LTFU requirements.

Original analytic plan

A sample size of 28 patients was selected based on a comparison of CR rates between Arms A and B. The sample size was stated to be sufficient to detect a clinically important difference in CR rates with a one-sided test at the 0.05 level. Comparisons of complete response duration, overall response rates, overall response durations, and time to progression between study arms were planned, however the timing and statistical methods to be employed were not provided. In addition, CR rates, ORR, response durations and TTP would be compared in the subset of patients enrolled in Arm B who progressed and crossed over to anti-B1 radioimmunotherapy following progression. Formal hypotheses to be tested and the timing of the analyses were not stated. Comparisons of response rates would be performed using a Fisher’s exact test and time to event comparisons (response durations, TTP, TTF) were to be performed using the log-rank test. Comparisons of ³ grade 3 adverse events would be performed using Fisher’s exact test. Comparison of the changes in laboratory values from baseline would be compared using the log-rank test.

Final Analytic Plan

(Final study protocol, after the inclusion of amendments 1-6):

The primary endpoint was the comparison (using Fischer’s Exact Test) of the complete response rates between the two treatment arms (A and B), as determined by the assessment of an independent review of films and medical information (MIRROR Panel). A single interim analysis was performed by the Data Safety Monitoring Board (DSMB), who applied the Lan-DeMets implementation of O’Brien-Fleming boundary for correction for the interim look; based on this interim analysis, the final analysis level of significance was adjusted to 0.049.

The secondary endpoints included comparison of overall response rate, the duration of response, time to progression and time to death. Based on results from RIT-I-000 and RIT-II-001, a 30% CR rate was estimated for treatment arm patients (Arm A) and a 5% rate for Arm B patients exposed to the "cold" antibody. Using a 2 sided alpha of 5%, it was calculated that equal randomization of 78 patients would result in 80% power to demonstrate a difference in CR rate. The primary analysis was a comparison of the complete response rate between arms of the intent-to-treat population with calculation of 2 sided 95% confidence intervals. P values would be calculated without adjustments except for any interim analyses. Secondary analyses would be performed for crossover patients for response rate and duration of response (McNemar’s test). Mean and median durations of response, time to treatment failure and survival will also be calculated.

Based on amendment 6 to the protocol, the analyses of study endpoints were based upon the determination of responses and response durations derived from an assessment of the CRFs and clinical data by an independent reviewer (MIRROR) panel. The MIRROR panel was composed of two teams of radiologists and oncologists who reviewed the CTs and determined the response assignment and duration of response. MIRROR panel radiographs were masked as to information on treatment arm of the patient and to investigators’ assessment of response.

AMENDMENTS TO THE STUDY (BY DATE OF ACTIVATION)

Amendment 1- -------------------

Amendment 2- -------------------------

 

Amendment 3- ----------------

Amendment 4- ----------------

Amendment 5- --------------

No significant changes

 

Amendment 6- -------------------

 

RESULTS

Conduct of the Study

Bioresearch Monitoring

FDA did not conduct audits of this study at clinical sites.

Disclosure: Financial Interests and Arrangements of clinical Investigators

The following are investigators disclosing (Form FDA 3455) any significant payments of other sorts made on or after February 2, 1999 from the sponsor of the covered study such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria.

Patient disposition

A total of 78 subjects were enrolled. One subject was removed from study due to reactivation of hepatitis prior to receipt of the therapeutic dose. Of the 78, 42 were randomized to receive Iodine I 131 tositumomab (Arm A) and 36 to received unlabelled tositumomab (Arm B). At the time of the study report, 31 patients had withdrawn from Arm A (29 for disease progression) and 33 had withdrawn from Arm B (32 for disease progression). No patient dropped out due to adverse events.

Patients randomized to unlabeled antibody (Arm B) who experienced disease progression within 3 months of treatment with unlabeled antibody were permitted to receive I 131 tositumomab (the tositumomab therapeutic regimen) in a cross-over arm (denoted Arm X). Among the 36 patients randomized to arm B, there were 32 who experienced progressive disease. Nineteen of the 32 withdrawn subjects were crossed over to Arm X. The remaining 13 were not crossed over for a variety of reasons; the major reason was development of a human anti-murine antibody (HAMA) immune response after exposure to cold anti-B1 antibody. Three patients randomized to Arm B had not experienced disease progression and one patient withdrew from the study.

Reasons cited for 13 patients with progressive disease who did not cross over were:

Protocol Violations:

Thirty-one violations were reported in 29 patients. Patient 200-030-004 [arm B] and 200-030-904*[arm X] were reported to have had protocol violations both during participation in Arm B and after being crossed over to arm X. Two protocol violations were reported for Patient 002-034-009. Eligibility or treatment/dosing reasons are listed below. Serious eligibility violations were encountered for 002-011-002 (question of disease progression at baseline), possibly for 002-030-004 and 002-030-015 (question of appropriate studies for disease staging) and patient 002-034-007 (progressive disease not shown until 18 months after last chemotherapy).The number of discrepancies in therapeutic dose and incorrect SSKI dosing were substantial.

TABLE 002-1

VIOLATIONS

Patient

Grade

Arm

Day

Type

Violation

002-011-002

L

B

-215

ENTRY

Did not have progression on CT, enrolled -------------- first dose ------------

Disease staging

002-011-007

L

B

-37

ENTRY

Disease staging done 37 days prior to dosimetric dose (protocol requires 28)

002-023-001

L

A

-38

ENTRY

Disease staging done 38 days prior to dosimetric dose (protocol requires 28)

Incorrect timing or absence radiologic studies

002-030-004

L

B

0

ENTRY

Neck CT at baseline performed 1 day after dosimetric dose

002-034-018

L

B

-3

ENTRY

Head/neck and chest CT scans obtained 1/---/00, 4 days after randomization

002-030-015

T

B

-2

ENTRY

Baseline radiologic tests for CAP were obtained 51 days prior to enrollment

Other eligibility or timing violations

002-034-007

L

B

-3

ENTRY

Progression shown 18 months post last chemotherapy (protocol requires <12)

002-011-009

T

A

-8

ENTRY

Bone marrow biopsy 43 days before enrollment (protocol requires 42)

002-011-020

L

A

-3

ENTRY

Bone marrow biopsy 46 days before enrollment (protocol requires 42)

002-030-001

L

B

0

ENTRY

Pregnancy test not done at baseline

002-030-011

L

A

-5

ENTRY

Patient is CD20 positive at entry but >50% positive cells not quantified

002-030-013

T

B

0

ENTRY

Karnofsky performance status not done at baseline

002-030-017

L

B

-6

ENTRY

Baseline bone marrow biopsy not assessable- poor quality of specimen

002-030-020

L

A

-37

ENTRY

CBC/chemistry for study entry obtained 35 days prior to enrollment

002-030-023

L

A

-40

ENTRY

Baseline bone marrow biopsy result 20% involvement by unilateral biopsy

002-030-904

L

X

-5

ENTRY

Crossover to arm A 10 months following disease progression

002-034-015

L

A

-7

ENTRY

Baseline platelet count 99,000 cells/mm3, protocol requires 100,000

002-034-016

L

A

-7

ENTRY

History of prostate cancer >4 years ago, PSA level is low normal

002-034-913

L

X

13

ENTRY

Received therapeutic dose on 2/---/00 prior to HAMA results

Treatment violations

002-011-003

L

A

0

TREATMENT

SSKI started same day as dosimetric dose

002-011-005

L

A

5

TREATMENT

2nd gamma camera scan done day 5 instead of Day 2,3, or 4 per protocol

002-025-003

L

A

0

TREATMENT

Patient not treated until 20 days after randomization

002-026-004

T

A

0

TREATMENT

Patient not treated until 20 days after randomization

002-026-005

T

A

0

TREATMENT

SSKI started same day as dosimetric dose

002-030-009

T

A

0

TREATMENT

SSKI started same day as dosimetric dose

002-030-012

L

A

0

TREATMENT

Patient not treated until 27 days after randomization

002-030-925

L

X

21

TREATMENT

2nd dosimetric dose given due to manufacturing delay in therapeutic dose

002-033-001

L

A

15

TREATMENT

15 days between dosimetric and therapeutic doses

002-034-009

L

A

7

TREATMENT

Site did not resolve dose calculation discrepancy

002-034-009

L

A

9

TREATMENT

SSKI stopped on day 9 due to mouth sores

002-034-011

L

A

7

TREATMENT

Site did not resolve dose calculation discrepancy

 

Study Population

A total of 78 patients with previously treated low-grade or transformed low-grade NHL were enrolled in this multi-center study. The median follow up was 24.9 months (range: 1.9–52.0 months).

Protocol RIT-II-002 Enrollment by Protocol Amendment

 

Amendment date

Effective date

Cumulative enrollment

Original protocol

--------------

--------------

0

Amendment 1

--------------

--------------

5

Amendment 2

--------------

--------------

15

Amendment 3

--------------

--------------

20

Amendment 4

--------------

--------------

41

Amendment 5

--------------

--------------

73

Amendment 6

--------------

--------------

78

     

78

 

The baseline entry characteristics for the study population by treatment arm and for the patients who cross-over in Arm B are presented in the table below.

Baseline Entry Characteristics: Study RIT-II-002 (N = 78)

Baseline Entry Variable

Arm A

N= 42

Arm B

N= 36

Arm B patients

Cross-over

n=19

Age (years)

Median (range)

56 (28-75)

55 (32-85)

59 (37-81)

Q1; Q3

50, 67

46, 65

53, 70

Gender

     

Males (%)

23 (50%)

18 (50%)

11 (58%)

Race

     

Caucasian (%)

39 (93%)

33 (92%)

18 (95%)

Histologic diagnosis at entry

     

Without transformation

     

Low grade

36 (86%)

28 (78%)

17 (89%)

Intermediate grade

0

0

0

High grade

0

 

0

With transformation

     

Low grade

3(7%)

2 (5%)

1 (5%)

Intermediate grade

3 (7%)

6 (17%)

1(5%)

High grade

0

0

0

Stage of disease

     

I

0

1 (3%)

0

II

5 (12%)

3 (8%)

3 (16%)

III

10 (24%)

9 (25%)

7 (37%)

IV

27 (64%)

23 (64%)

9 (47%)

Missing

0

0

0

IPI category

     

0

0

0

0

1

11 (26%)

9 (25%)

3 (11%)

2

17 (40%)

18 (50%)

5 (26%)

3

8 (19%)

7 (19%)

4 (21%)

4

4 (10%)

1 (3%)

2 (11%)

5

0

0

0

Missing

0

0

0

Max. tumor diameter

     

< 5 cm

20 (48%)

24 (67%)

9 (47%)

³ 5, <10 cm

18 (43%)

11 (31%)

9 (48%)

> 10 cm

4 (9%)

1 (3%)

1 (5%)

# Prior chemotherapy regimens

     

Median (range)

2 (1-4)

2 (1-5)

2 (1-4)

25th, 75th quartiles

1, 3

1, 3

1, 3

# Prior radiation therapy regimens

     

Median (range)

0 (0-4)

0 (0-5)

0 (0-5)

25th, 75th quartiles

0,0

0,0

0,0

No Prior BMT

42 (100%)

36 (100%)

19 (100%)

Time from diagnosis to entry (yrs)

     

Median (range)

2.6 (0.5-15.4)

2.4 (0.6-19.7)

2.6 (1.7 -20.2)

25th, 75th quartiles

1.6, 3.7

1.9, 3.7

2.3, 4.6

 

Efficacy Results

There was a significantly higher complete response rate in patient randomized to Arm A as compared to Arm B as well as a significantly increased overall response rate in Arm A. The duration of response however, not significantly different in the two arms; 10 of the 23 responding patients have relapsed in Arm A and 4 of the 7 responding patients have relapsed in Arm B. There was also no difference in overall survival between the two study arms. The median survival has not been reached in either study arm, with 16 of 42 patients dead in Arm A and 12 of 36 patients dead in Arm B. However, there was a significant difference in time to death or progression between the study arms (p=0.031). The survival curves for duration of response, time to progression or death, and time to death are displayed below.

 

Efficacy Outcomes

MIRROR Panel–Assessed Outcomes: Study RIT-II-002

Efficacy Endpoint

Arm A
(N = 42)

Arm B
(N = 36)

P-value

Primary endpoint

     

Complete response

14/42 (33%)

3/36 (8%)

0.01

Secondary endpoints

     

Overall Response

23/42 (55%)

7/36 (19%)

0.001

Median duration (yrs) of response (95% CI)

NR (0.5–NR)

2.3 (0.4, NR )

0.9

Median duration (mos) of complete response (95% CI)

NR (NR, NR)

NR (28, NR)

0.4

Median time to progression or death (yrs) (95% CI)

0.52 (0.35, NR)

0.45 (0.24, 0.5)

0.031

Fisher’s exact test for response rates

Log-rank test for duration measures

NR = Not reached

CI = 95% confidence interval

 

Duration of Response for study RIT-II-002 (n=78)

Time to Progression or death in Years Hot (Arm A, n=42) vs Cold (Arm B, n=36) -- Study RIT-II-002

Product-Limit Survival Fit

Survival Plot

 

 

Safety Assessment

Adverse events: The most frequent adverse events were nausea, asthenia, fever, rash, chills and pain. Adverse events, both the incidence of all adverse events and of serious adverse events (26% vs. 11%), were higher in patients receiving I 131 tositumomab than in those who received the unlabeled antibody. Gastrointestinal adverse events, particularly nausea, were significantly more frequent in patients receiving radiolabeled antibody as compared to those receiving unlabeled antibody. NCI CTC grade 3-4 non-hematologic adverse events that were reported in >5% of patients included myeloproliferative disorder, chronic leukemia, and lymphoma like reaction and pneumonia. Adverse events reported in ³ 5% of patients, regardless of relationship to study drug, are shown in the following table.

 

 

 

 

 

 

 

 

 

Per-patient incidence of adverse events regardless of severity or relationship to study agent

Body System

COSTART Preferred term

Arm A

Arm B

%

Arm X

%

Body system

COSTART Preferred term

Arm A

%

Arm B

%

Arm X

%

N

42

36

19

 

42

36

19

Body as a Whole

Abdominal pain

Asthenia

Back pain

Chest pain

Chills

Face edema

Fever

Headache

Infection

Injection site pain

Malaise

Neck pain

Pain

Pelvic pain

Sepsis

Cardiovascular

Palpitation

Vasodilatation

Syncope

Digestive system

Anorexia

Constipation

Diarrhea

Dyspepsia

Dysphagia

Flatulence

Nausea

Vomiting

17

40

12

10

24

0

33

14

5

10

10

10

10

21

7

7

14

0

14

7

17

10

5

5

48

7

 

8

36

8

11

19

8

22

19

17

6

3

10

3

6

0

11

8

8

6

11

6

0

3

17

6

16

42

11

0

16

5

16

21

16

0

0

16

21

0

0

0

0

0

0

0

5

11

0

5

11

0

Metabolic system

Edema

Peripheral edema

Weight loss

Dehydration

Musculoskeletal

Arthalgia

Myalgia

Nervous system

Anxiety

Dizziness

Insominia

Depresson

Parasthesia

Somnolence

Respiratory system

Cough increased

Dyspnea

Pharyngitis

Rhinitis

Bronchitis

Epistaxis

Lung disorder

Pleural effusion

Skin & appendages

Pruritus

Rash

Sweating

 

5

7

5

0

19

17

5

7

10

0

2

 

17

14

19

10

2

5

5

2

5

31

14

6

8

0

6

19

17

3

8

8

6

6

8

3

11

14

8

0

0

8

14

14

8

0

11

16

0

5

0

5

0

5

0

5

 

32

16

16

16

5

0

0

5

11

16

11

Hematologic toxicity:

The most frequent adverse event (all severity) and the most frequent severe adverse events were hematologic. In the 19 subjects in arm X there were 11 patients with documented hematologic toxicity and 3 with undocumented toxicity for a cumulative total of 14 (74%). Source was FDA analysis using CRTs submitted ------------.

 

 

 

Grade 3-4 hematologic toxicity in patients receiving I-131 tositumomab

Toxicity Measure

Arm A

N=42

Arm X

N=19

Neutropenia

   

% Documented Grade 3-4 toxicity

33%

58%

Median days to nadir

47 (42, 49)

43 (39, 47)

Median duration of documented Grade 3-4 toxicity

21 (14, 36)

31 (15,49)

Thrombocytopenia

   

% Documented Grade 3-4 toxicity

33%

47%

Median days to nadir (95% CI)

36 (29, 38)

35 (28,36)

Median duration of documented Grade 3-4 toxicity

29 (22, 54)

28 (16,90)

Anemia

   

% Documented Grade 3-4 toxicity

14%

11%

Median days to nadir

48 (40, 51)

47 (36, 61)

Median duration of documented Grade 3-4 toxicity

18 (6, ---)

35 (10, ---)

 

 

Hematologic toxicity in crossover population: The table below compares documented hematologic toxicity in the three arms and shows a higher incidence of grade 3-4 toxicity in arm A as compared to B, as well as a higher incidence of hematologic grade 3-4 toxicity in arm X as compared to Arm A. Notable is the rate of grade 3-4 neutropenia (8%) with the unlabeled tositumomab, which exceeds that generally observed with other anti-CD20 antibodies. If this is a real finding, the mechanism is unclear. In addition, the incidence of severe cytopenias and of bleeing events in patients who were treated in Arm B and crossed over to treatment with iodine I 131 tositumomab in the 3-month interval permitted in this study is higher than observed in patients in Arm A (initial treatment with the iodine I 131 tositumomab therapeutic regimen. Again, given the small patient numbers it is unclear whether this finding is real or a chance event.

Recovery from hematologic toxicity was evaluated at week 13. There were 35 (of the 42 patients) actively followed in Arm A for hematologic toxicity at week 13. Two patients among the 35 had persistent hematologic toxicity (grade 3 and one grade 4 neutropenia). There were 2 patients, among the 22 being actively followed for toxicity at week 13 in Arm B, who had persistent toxicity (both had Grade 4 neutropenia).

Percent subjects with grade 3-4 hematologic toxicity

 

Arm A

n=42

Arm B

N=36

Arm X

n=19

%

%

%

 

3&4 3 4

3&4 3 4

3&4 3 4

Hematologic toxicity

ANC < 1000 cells/mm

Platelets < 20,000/ mm

Hgb

Bleeding events

33 17 17

33 21 12

8

10

8 6 3

0 0 0

0

3

58 21 37

47 21 26

11

16

HAMA: HAMA was detected at week 7 (5 cases), week 13 (2 cases) and at 6 months in one case. As noted, 32 patients in Arm B with progressive disease had an option of a one-way cross-over to Arm X. Nineteen of the 32 patients crossed over to arm X (to receive iodine I 131 tositumomab therapy). The 13 patients with progressive disease who did not crossover included 8 who could not be crossed over because of positive HAMA tests.

Serious adverse events:

There were 15 patients in the randomized portion of the study who suffered one or more serious adverse events. The iodine I 131 tositumomab arm had an approximately 2-fold higher rate of SAE. A similarly high rate of SAE were observed in the patients who crossed over to iodine I 131 tositumomab after disease progression on Arm B.

Deaths: There were 13 total deaths in RIT-II-002 of which 2 were prior to day 90, 3 by day 189, 4 by day 270, and 8 by one year. Arm A had 2 deaths (weeks 8 & 10) and 6 patients who withdrew (weeks 3, 6, 7,9 and 11) during the first 90 study days.

Patients who died in first ninety days of study

Patient ID # Age in yrs Sex NHL grade* Study arm Study Day of death

002-030-002 69 F L A 54

002-030-009 51 M T A 69

002-030-018 62 F T B 53

 

 

 

 

 

Studies supporting dosing Strategy

STUDY RIT-I-000 Phase 1

Title: Phase I/II Study of Radiolabeled Anti-B1 Monoclonal Antibody for the Treatment of B-Cell Lymphomas

Background: This initial study of iodine I 131 tositumomab was a Phase 1/2, single-center, open-label, dose-escalation study. The study was conducted in two Phases. Phase A assessed the impact of a range of cold antibody loading doses on the biodistribution of I 131 tositumomab while simultaneously assessing the toxicity and maximum tolerated dose of I 131 labeled antibody in patients with low-grade, transformed low-grade, intermediate-grade, or high-grade NHL and no prior stem cell transplantation. Phase B assessed the maximum tolerated dose, the dose-limiting toxicity of I 131 labeled antibody in patients with potentially impaired marrow reserve (due to prior hematopoietic stem cell transplants), and the activity at the MTD in patients who had not undergone transplantation.

Study initiated April 24, 1990

Phase B initiated October 5, 1994

Closed on January 17, 1996

Date cut-off: Dec. 1, 2000

Study Sites:

University of Michigan Medical Center

Objectives:

  1. To evaluate the activity (response) of a pan anti-B cell antibody, B1, that has been conjugated with I-131 in patients with refractory B cell lymphomas
  2. To define the toxicity of B1 conjugated with I-131 in patients with refractory B cell lymphomas
  3. To determine if B1 conjugated with I-131 can be used as a vehicle to deliver effective radiation to tumor sites and establish the biodistribution, dosimetric parameters, clearance, and tumor specificity
  4. To assess the effect of total antibody protein dose on the biodistribution of radiolabeled B1
  5. To assess degrees of localization and antigen saturation within tumors by immunohistochemical techniques
  6. To assay for human anti-murine antibody (HAMA) production following administration of the murine antibody

Inclusion Criteria

  1. Histologically documented non-Hodgkin’s lymphoma, of low, intermediate or high grade by the IWF
  2. Failed previous standard therapies
  3. Lymphoma must be immunologically determined to be of the B cell lineage and reactive with the B1 antibody
  4. Life expectancy > 3 months, KPS ³ 60%
  5. Serum creatinine < 2.0 mg/dL, bilirubin <3.0 mg/dL
  6. Free of acute and chronic infections and off antibiotics for at least one week
  7. Must not have received cytotoxic chemotherapy, radiation therapy, and/or immunosuppressants within 4 weeks prior to entry
  8. ANC > 1500, platelets > 100, 000, and <25% of cells in the marrow composed of tumor cells
  9. Must not have received extensive prior external beam radiotherapy, such as total or subtotal lymphoid irradiation
  10. Must have measurable or evaluable disease
  11. Must have easily accessible sites of disease for biopsy prior to entry
  12. Must be able to give informed consent

Monitoring Plan: CBCs weekly for 8 weeks (twice weekly CBCs for > grade 1 toxicity), serum chemistries at baseline, day 14, weeks 6 and 12. Tumor restaging studies at baseline and weeks 6 and 12.

Treatment Plan:

The study was modified numerous times over the course of the study.

Phase A: The general treatment plan for Phase A remained unchanged, however the dose cohorts were modified several times. All patients were to receive two or more dosimetric doses of anti-B1 antibody. The dosimetric doses were administered 7-14 days apart. The amount of unlabeled antibody was varied (generally increased) between the initial and subsequent dosimetric doses given to an individual patient so that an assessment of the impact of the amount of unlabeled antibody [administered within 30 minutes prior to the radiolabeled tracer dose] on the biodistribution could be assessed and compared within an individual patient. In addition, the dose of unlabeled antibody on the initial dosimetric dose was increased in successive groups of patients in a manner not prospectively defined in the protocol, although the analytic plan indicated that intra-patient comparisons in groups of 3 to 6 patients should be sufficient to identify within patient differences in biodistribution.

The dosimetric dose consisted of 35 mg of unlabeled anti-B1 antibody administered intravenously (IV) over one or more hours, following by an IV dose over 1-2 hours, followed 30-60 minutes later with 1 mg of B1 antibody labeled with 5 mCi I 131 co-administered with additional unlabeled anti-B1antibody (10-15 mg of antibody total) as an IV infusion over minutes to hours.

The amount of unlabeled antibody administered in the initial part of the dosimetric infusion varied over the course of the study. The unlabeled doses of antibody administered at the initial dosimetric infusion included 0 mg, 95 mg, 475 mg,

In addition, the therapeutic dose was increased in successive cohorts of 3-6 patients to determine the maximum tolerated therapeutic dose. Although modified several times, the treatment plan incorporated the scheme of starting at 25 cGy total body dose (TBD) and increasing by 10 cGy TBD in subsequent cohorts until the MTD was reached or exceeded. Gamma counts were measured daily for 7 days following the dosimetric dose. The gamma count data were then used to determine each patient’s clearance of the drug (i.e., total body residence time: TBRT), which was utilized to determine the patient-specific activity (mCi) required to deliver a desired uniform TBD (cGy) of radiation.

Phase B was introduced by an amendment to the protocol in ------------------. During Phase B, there was exploration of the activity of treatment regimen at the MTD for 131-Iodine labeled anti-B1 and the optimal dose of unlabeled antibody in the dosimetric/therapeutic in 12 patients with CD20 positive NHL who had not undergone a prior hematopoeitic stem cell transplantion. In addition, during Phase B, the MTD of the therapeutic dose of 131-Iodine labeled anti-B1 was determined in patients with CD20 expressing NHL with a history of prior hematopoeitic stem cell transplantion. The treatment plan was not described for these patients, however a range of doses beginning at a dose of 45 cGy TBD and escalating/de-escalating in 10 cGy increments was administered in groups of patients (1-3).

Analytic Plan

The analytic plan was modified over time. The major objectives were to determine the optimal biologic dose of unlabeled antibody as a component of the dosimetric dose and the maximum tolerated dose (MTD) of the therapeutic dose. The definition of dose-limiting toxicity (DLT), upon which the MTD was based, was revised during the course of the study. The final protocol defined the MTD as the level below the dose level at which there was a one-third or greater incidence of DLT. DLT was defined as any non-hematologic Grade 3 or 4 dose-related toxicity, any Grade 3 hematologic toxicity of >2 weeks duration, or any Grade 4 hematologic toxicity of >1 week duration. The determination of the optimal biologic dose of unlabeled antibody was described in qualitative terms in the analytic plan.

Amendments to the study

There were 3 amendments to Phase A [dated --------------------------------------------------------------------] and 2 amendments to Phase B [----------------------------]

RESULTS:

Conduct of the study:

The results of this study were not audited by FDA at the clinical study sites

The sponsor reports 11 protocol violations among 9 patients; all were violations of the eligibility criteria.

Disclosure: Financial Interests and Arrangements of clinical Investigators

The following are investigators disclosing (Form FDA 3455) any significant payments of other sorts made on or after February 2, 1999 from the sponsor of the covered study such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria.

 

 

 

 

Patient Enrollment and Disposition:

A total of 59 patients were enrolled. The first 47 were enrolled in Phase A and 12 additional patients were enrolled in Phase B.

Dropouts

Patient Disposition

In Phase A, patients were sequentially enrolled into treatment cohorts, which included a simultaneous intra-patient escalation of the dose of unlabeled tositumomab, administered as multiple dosimetric doses, and intra-patient dose escalation, in cohorts of three to six patients, of the total body dose of iodine I 131 tositumomab. The enrollment into the various cohorts are summarized in the table below.

Enrollment into Phase A by Cohort

Patients without Prior Bone Marrow Transplantation

Total Body Dose

Cohort

(cGy)

Anti-B1 Antibody Predose (mg)

# of evaluable Patients/total at

dose level

Number of Patients with Dose-Limiting Toxicity

Patient ID

25

95, 0, 95

3/4

0

(000-002-[001, 002,004])

35

0, 475, 95, 475

4/4

0

000-002-[005, 006, 007, 008]

45

95, 95, 475

3/5

0

000-002-[009, 010, 013]

55

All 475

3/5

0

000-002-[014, 015, 016]

65

All 475

3/4

0

000-002-[019, 020, 023]

75

All 475

6/6

1

000-002-[024, 025, 026, 031, 032, 034]

85

All 475

3/3

2

000-002-[027, 028, 029]

During Phase B, there were 15 additional patients without a history of prior bone marrow transplantation enrolled at a fixed dose of 75mCi TBD. There was a separate dose ranging assessment in patients with prior bone marrow transplantation. Dose cohorts and number of patients enrolled are summarized in the following table. This approach was not well described in the protocol and the enrollment did not appear to follow entry into sequential cohorts with dose escalation between cohorts. Rather, dose selection appeared to be somewhat random.

Enrollment into Phase B by Cohort

Patients with Prior Bone Marrow Transplantation

TBD cohort

(cGy)

# patients enrolled

65

2

55

5

45

6

Study Population:

The study population contained a mixture of patients with chemosensitive and chemotherapy-refractory disease. Of the 59 patients enrolled, 30 (51%) had responded to the most recent chemotherapeutic regimen. Of these 19 (33% of the overall study population) had achieved a complete or clinical complete response to the most recent treatment regimen.

 

BASELINE ENTRY CHARACTERISTICS

RIT-II-000

Total enrollment

n=59

Age (years)

Median (range)

50 (23-75)

Q1; Q3

41, 59

Gender

 

Males (%)

37 (63%)

Race

 

Caucasian (%)

54 (92%)

Histologic diagnosis at entry

 

W/o transformation

 

Low grade

28 (48%)

Intermediate grade

15 (25%)

High grade

2 (3%)

With transformation

 

Low grade

0

Intermediate grade

12 (22%)

High grade

2 (3%)

Stage of disease

 

I

3 (5%)

II

4 (7%)

III

13 (22%)

IV

39 (66%)

Missing

 

IPI category

 

0

2 (3%)

1

11 (19%)

2

24 (41%)

3

19 (32%)

4

3 (5%)

5

0

Missing

0

Max. tumor diameter

 

< 5 cm

41 (70%)

³ 5, <10 cm

16 (27%)

> 10 cm

2 (3%)

# Prior chemotherapy regimens

 

Median (range)

3 (1-11)

25th, 75th quartiles

2, 5

# Prior radiation therapy regimens

 

Median (range)

0 (0-4)

25th, 75th quartiles

0, 1

No Prior BMT

45 (76%)

Time from diagnosis.

to entry (mos)

 

Median (range)

3.8 (0.5-17.8)

25th, 75th quartiles

2.5, 7.2

 

Efficacy Analyses

The study enrolled a heterogenous group of patients and was not intended to provide more than anectodotal information on clinical activity. In addition, because of the patient heterogeneity and the small numbers of patients who received a particular TBD, it is difficult to draw conclusions regarding the dose-response relationship. The data presented below are not an ITT analysis. For example, no patient was intended to receive "0 cGy" TBD- each of these patients was unable to receive study drug in a treatment cohort for various reasons, including toxicity with dosimetric infusion, development of HAMA, and/or disease progression. The dose selected by the sponsor for use in Phase 2 studies is based upon determination of the MTD and not necessarily the optimal biologic dose (OBD), which cannot be determined in a study of this size and with this degree of heterogeneity. The data presented in the table below are provided only for information.

Response Rate Analysis for RIT-I-000 by Total Dose (cGy) received

Response Variable

0 cGy

n=6

25 cGy

n=3

35 cGy

n=4

45 cGy

n=9

55 cGy

n=8

65 cGy

n=6

75 cGy

n=20

85 cGy

n=3

All

n=59

CR

   

1

   

1

2

1

5

CCR

   

1

1

3

2

4

 

11

PR

1

1

 

3

2

3

2

 

12

% ORR

17%

33%

50%

44%

62%

100%

40%

33%

48%

95% CI

(0.4, 64)

(0.8, 91)

(1, 99)

(14, 79)

(24, 91)

(54,100)

(19, 64)

(0.8,91)

(34, 61)

 

Safety Analyses

Study RIT-I-000 was designed to determine the optimal unlabeled (cold) predose of Anti-B1 Antibody to maximize tumor targeting and the maximum tolerated non-myeloablative radiation dose level.

The sponsor anticipated that bone marrow toxicity would be dose limiting. The sponsor elected the dose escalation design based on whole body radiation-absorbed dose, on the assumption that the whole body radiation dose would be more closely related to levels of bone marrow toxicity as compared to an escalation based on mCi/kg, mCi/m2, or mCi.

Because the direct estimation of radiation dose to bone marrow is not feasible with unsealed source radiation therapy and marrow dosimetry from blood is not considered to be reliable in NHL subjects with normal B-cell populations as well as variable bone marrow involvement, the Total Body Dose (TBD) of radiation exposure was utilized as a surrogate for bone marrow dosimetry. Therefore, dose cohorts were escalated based on TBD and subjects were followed for dose-limiting toxicity (DLT) with expectations that the DLT would be related to declines in peripheral blood assessments, e.g. neutropenia, thrombocytopenia and anemia.

The MTD was set at one level below the dose level at which there was a one-third or greater incidence of DLT. The DLT was defined as any non-hematologic Grade 3 or 4 dose-related toxicity, a Grade 3 hematologic toxicity of >2 week’s duration, or a Grade 4 hematologic toxicity of >1 week duration.

The dose escalation was performed in subjects without prior bone marrow transplantation (BMT).

The maximum non-myeloablative TBD level was established in study RIT-I-000, based on 2 of 3 patients who had a DLT at 85 cGy TBD. Therefore, the MTD was established to be 75 cGy TBD for patients with no prior BMT

Dose-Dependent Hematologic Toxicity for Study RIT-I-000:

Patients without Prior Bone Marrow Transplant

 

Dose Cohort

ANC

Platelets

Hemoglobin

TBD (cGy)

     

25–55

     

N

13

13

13

Mean Nadir

2000 cells/mm3

134,000 cells/mm3

11.5 g/dL

SD of Nadir

1000 cells/mm3

41,000 cells/mm3

1.4 g/dL

Grade IIIa (%)

1 (8%)

0 (0%)

0 (0%)

Grade IVa (%)

1 (8%)

0 (0%)

0 (0%)

65–75

     

N

24

24

24

Mean nadir

1300 cells/mm3

76,000 cells/mm3

10.7 g/dL

SD of nadir

1200 cells/mm3

49,000 cells/mm3

1.9 g/dL

Grade IIIa (%)

8 (33%)

4 (17%)

1 (4%)

Grade IVa (%)

4 (17%)

4 (17%)

1 (4%)

85

     

N

3

3

3

Mean nadir

900 cells/mm3

78,000 cells/mm3

8.8 g/dL

SD of nadir

1300 cells/mm3

115,000 cells/mm3

2.9 g/dL

Grade IIIa (%)

0 (0%)

0 (0%)

2 (67%)

Grade IVa (%)

2 (67%)

2 (67%)

0 (0%)

Narrative summaries of Serious Adverse Events

 

 

Study RIT-II-001

Title: Multicenter Phase II Dosimetry/Validation Study of Dosimetry for Iodine I 131 Tositumomab for the Treatment of Patients with Relapsed and Refractory Low-Grade and Transformed Low-Grade NHL

Design: Multicenter, single arm study to assess the reproducibility of the dosimetry methods developed in RIT-II-000.

Study initiated December 5, 1995

Study closed to enrollment November 20, 1996

Date cut-off December 1, 2000

Study Sites

Objectives

The primary objective of this multi-center study was to demonstrate that each independent site could reproducibly and accurately conduct the whole body dosimetry. Additional objectives of this study were to evaluate the efficacy and safety of iodine I 131 tositumomab therapy in a multicenter study. Dosimetry methods and calculations from each participating site were validated by a central dosimetry center at the University of Michigan.

Eligibility

Patients were eligible if they had progressive disease of either low-grade or transformed low-grade lymphoma within one year of completion of the last chemotherapy regimen administered. At least one of the previous chemotherapy regimens was required to contain an anthracycline or anthracenedione. Progression after single-agent steroids was not sufficient for study entry. Patients who were treated with chemotherapy for low-grade lymphoma and subsequently transformed to a higher grade were eligible even if they had not received specific treatment for their transformed lymphoma.

Treatment Plan

As described in RIT-II-OO2 for Arm A.

Patient Monitoring

Monitoring was similar to the other studies with the exception that gamma camera images for calculation of dosimetry were obtained daily on study days 0-7.

Analysis plan:

Descriptive statistics for assessment of toxicity, response rates and durations.

STUDY RESULTS

Bioresearch Monitoring Inspections

The University of Nebraska study site was inspected for Protocol RIT-II-001, entitled "Multicenter, Phase II Dosimetry/Validation Study of 131Iodine-AntiB1(murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas that have Transformed to Higher Grades" after the sponsor reported that data was missing. The inspections were conducted in accordance with CPGM 7348.811, the Inspection Program for Clinical Investigators. Specific questions concerning the studies were included.

Disclosure: Financial Interests and Arrangements of clinical Investigators

The following are investigators disclosing (Form FDA 3455) any significant payments of other sorts made on or after February 2, 1999 from the sponsor of the covered study such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria.

Inspectional Summary Statement

The results of bioresearch monitoring inspections indicate that the deviations are not substantive, with the exceptions noted (failure to calculate residual activity, eligibility entry violations), and that the submitted data can be considered reliable and accurate.

Patient Enrollment and Disposition

Forty-seven patients with relapsed/refractory low-grade or transformed low-grade NHL were enrolled. All 47 patients received the dosimetric dose, and 98% (46/47) of the patients received the therapeutic dose. The median follow-up from the dosimetric dose was 34.0 months (range: 0.2–58.3 months).

Patient Entry Characteristics Study RIT-II-001 (n=47)

 

Male/female

25/22

Median age (years) (range)

51
(23–74)

Time from diagnosis to study entry (months) (range)

41
(8–264)

Median number of prior chemotherapy regimens (range)

4
(1–8)

Grade

 

Low grade

33/47 (70%)

Transformed low grade

14/47 (30%)

Bone marrow involvement

24/47 (51%)

Bulky disease (>500 g)

17/47 (44%)

Elevated LDH

18/47 (38%)

Response to last chemotherapya

 

Response (PR + CCR + CR)

24/47 (51%)

Complete response (CCR + CR)

8/47 (17%)

a Unconfirmed response rates.

Source: 125001, Original BLA submission, RIT-II-001 Final Report, Amendment 1, Appendix C, Tables 2.1–2.3.

 

Dosimetry Endpoints

Assessment of all of the onsite calculations and the administered activity of iodine I 131 tositumomab (mCi) by the independent dosimetry center indicated that the calculations performed at the treating centers were within 10% of those calculated at the dosimetry center.

Activity Results

The overall response rate was 49% (23/47). The complete response rate (CR + CCR) was 30% (14/47).

Safety Results

Non-hematologic toxicities were qualitatively similar to that reported in other studies. Hematologic toxicities were somewhat more frequent than in the other studies.

 

Toxicity Measure

N=47

Neutropenia

 

% Documented Grade 3-4 toxicity

62%

Thrombocytopenia

 

% Documented Grade 3-4 toxicity

57%

Anemia

 

% Documented Grade 3-4 toxicity

21%

 

 

Narrative descriptions of serious adverse events