Errata - AC clinical briefing document

 

 

  1. Page 2, 2nd paragraph, 10th line: delete the text, “ but survival data were collected as part of the safety evaluation.”

 

  1. Page 3, safety results, 1st paragraph, replace the phrase “compared to none in APC-Placebo treated subjects” with: “compared to 2.6% (2 out of 78) in APC-Placebo treated subjects.”  

 

  1. Page 4, Table 1, row 2, column 5: replace “p = 0.012” with “p = 0.010”.

 

  1. Page 8, Table 3 continued, 1st row, 2nd column: delete the text “D9901 and”.

 

  1. Page 9, Table 3 continued, 4th row, 1st column: change the text “10 Aug” to be “21 Aug” of the date of the clinical BLA submission.

 

  1. Page 14, section iv: Add the following text to the end of this section: “In addition, the statistical analytical plan of the clinical protocol contained the following description regarding the use of survival as supporting analyses in the analysis methodology section for the primary endpoint of time to disease progression:

 

      “Primary endpoint

 

The analysis of time to disease progression will be conducted on the ITT and Efficacy Evaluable Populations. The primary analysis will be on the ITT population.

 

The primary null hypothesis is that the time to disease progression curve of the APC8015 group is not different from that of the control group. The corresponding alternative hypothesis is that there is a difference between these curves. Time to disease progression curves will be constructed using Kaplan- Meier technique for the two treatment groups and the primary hypothesis tested using the log-rank test.

 

As supporting analyses, estimates of survival rate and progression free frequencies at three, six, nine, twelve and every six months thereafter, and median survival will be provided based on the Kaplan-Meier curves, with corresponding confidence intervals; and the Cox proportional hazards model will be used to adjust for prognostic variables.”

 

  1. Page 16, Section I, 1st paragraph, 1st line: change the text “Amendment #2 (4-8-00)” to be “Amendment #2 (3-27-00)”.

 

  1. Page 16, Section I, 2nd paragraph, 1st line: change the text “Amendment #5 (no date provided)” to be “Amendment #5 (3-12-01)”.
  2. Page 16, Section I, 2nd paragraph Amendment #5, 2nd line: Delete the text “and to exclude prior strontium therapy”. Replace with the following text “including strontium therapy if at least 1 year had elapsed and the patient remained pain-free.”

 

  1.  Page 19, 2nd paragraph, 2nd line, replace the text “All subjects except on in APC8015 arm had a baseline bone scan.” with “All subjects in APC8015 arm had a baseline bone scan.”

 

  1. Page 19, Table 6, 6th row, 2nd column: add the text “N = 82”; same row, 3rd column: add the text “N = 45”

 

  1. Page 20, Table 7, 6th row, 2nd column: change the text “7 (8.5)” to “3 (3.7)”.

 

  1. Page 23, Replace Table 10 with the following Table.

 

Progression Event

APC8015

APC-Placebo

Total

 

(N = 82 )

(N = 45 )

(N = 127)

Objective Disease Progression Observed

71 (86.6)

44 (97.8)

115 (90.6)

     Radiological progression

63 (76.8)

35 (77.8)

98 (77.2)

    Clinical progression

4 (4.9)

6 (13.3)

10 (7.9)

    Objective Pain Progression

4 (4.9)

3 (6.7)

7 (5.5)

No  Disease Progression Observed

11 (13.4)

1 (2.2)

12 (9.4)

   Off Study

4 (4.9)

1 (2.2)

5 (3.9)

   No Follow-up After Randomization

1 (1.2)

0 (0.0)

1 (0.8)

   Censored (no events as of the data cut-off date)

6 (7.3)

0 (0.0)

6 (4.7)

 

 

  1. Page 23, section E, line 1: change the text “June” to be “July”.

 

  1. Page 24, section H, 1st paragraph: delete the text “and a primary method of survival analysis was not pre specified in the protocol. A three-year survival analysis was performed as part of the safety monitoring plan.”

 

  1. Page 25, replace Figure 5 with the following graph:

 

 

 

 

  1. Page 25, Table 12, 4th row, 6th column: change the text “0.011” to be “0.010”.

 

  1. Page 28, the paragraph under Figure 6, 1st and 2nd lines: Delete the text “There was no information on the cell counts or other characteristics in the placebo group.” Replace with the text “The APC-Placebo cells did not undergo the same manufacturing process as APC8015.”

 

  1. Page 29, section J, 1st Paragraph, 4th and 5th lines: Delete the text “Two subjects were lost to follow up, and 125 subjects were followed until 36 months or death.” Replace with the text “Two subjects were lost to follow up for disease progression, and all 127 subjects were followed until 36 months or death.” 

 

  1. Page 29, section J, 1st paragraph, 6th line: delete the text “The median time to disease progression observed in the APC8015 and APC placebo treated subjects was 10.9 weeks and 9.9 weeks, respectively. The 1.0-week difference was not statistically significant with a p-value of 0.085 by log-rank test.” Replace with the text “The median time to disease progression observed in the APC8015 and APC placebo treated subjects was 11.1 weeks and 10.0 weeks, respectively. The 1.9-week difference was not statistically significant with a p-value of 0.085 by log-rank test.

 

  1. Page 29, section J,  2nd paragraph, 1st line: delete the sentence “Although a survival comparison analysis was not pre-specified, a 3-year survival analysis of D9901 was performed as part of the safety follow up.” Same paragraph, 5th line: change the text “0.012” to be “0.010”.

 

  1. Page 31, Replace Table 16 with the following Table:

 

Deviations

APC8015

APC placebo

 

N = 65

N = 33

Major

1 (1.5%)

1(3 %)

Testosterone ≥ 50 ng/dl

a

a

No metastatic diseases

a

 

Minor

17 (26.2%)

11 (33.3)

 

 

 

 

 

 

 

 

 

  1. Page 31, Section D.a, 1st line: change the text “There were 19 clinical study sites involved in this study across the United States.” Replace with the text “There were 27 clinical study sites involved in this study across the United States.

 

  1. Page 36, Section g, 1st bullet section: delete the last sentence “CD54 expression was not measured in the APC-Placebo cells.” Replace with the text “The APC-Placebo cells did not undergo the same manufacturing process as APC8015.”

 

  1. Page 38, section 4.1, 1st paragraph, 1st line: delete the text “147 patients who received”. Replace with the text “147 patients, 146 of whom received” based on a sponsor’s clarification and revision of the infusion dataset.

 

  1. Page 38, Section 4.1, 2nd Paragraph, 2nd to last sentence: delete the text “However, 5.4% (8 out of 147) APC8015 treated subjects experienced CVA-related SAEs, compared to none in APC-Placebo treated subjects in D9901 and D9902A.” Replace with the text “However, 5.4% (8 out of 147) APC8015 treated subjects experienced CVA-related SAEs (including death), compared to 2.6 % (2 out of 78) in APC-Placebo treated subjects in D9901 and D9902A, including an additional CVA event from D9902A. This additional CVA event was reported in the sponsor’s information update described in section 4.3.C. of this document.

 

  1. Page 39, Replace Table 24 with the following Table based on the sponsor’s clarification and revision of the infusion dataset:

 

Infusions

APC8015

APC-Placebo

N = 147

N = 78

#

%

#

%

 

3

132

89.8

71

91

 

2

10

6.8

4

5.1

 

1

4

2.7

3

3.8

 

0

1

0.7

0

0

 

  1. Page 39, Table 25, 2nd row from the bottom, 1st column: change the text “TIA” to be “CVA” based on a sponsor’s clarification of the dataset.

 

  1. Page 40, Section B, 1st Paragraph, 4th line: change the text “Twenty Four per cent (53/147) of APC8015 treated subjects” to be “Twenty Four per cent (35/147) of APC8015 treated subjects”.

 

  1. Page 40, Section B, Replace Table 26 with the following Table:

 

 

           

       APC8015

 

                            

 APC-Placebo

 

 

 N = 147

 

N = 78

 

SAE

#

%

#

 %

Chills

5

3.4

0

0

Dyspnea

4

2.7

1

1.3

Pyrexia

4

2.7

0

0

Cerebrovascular accident

3

2.0

1

1.3

Dehydration

3

2.0

2

2.6

Anemia

2

1.4

1

1.3

Back pain

2

1.4

1

1.3

Catheter sepsis

2

1.4

0

0

Chest wall pain

2

1.4

0

0

Hematuria

2

1.4

2

2.6

Hypertension

2

1.4

0

0

Sepsis

2

1.4

1

1.3

Spinal cord compression

2

1.4

0

0

Urinary retention

2

1.4

3

3.8

Urinary tract infection

2

1.4

0

0

 

  1. Page 42, the paragraph below Table 28, 6th line; change the text “Canadian” to “Cardiovascular”.