THYR01605: Follow-up of Thyroid Cancer Patients from Study THYR-008-00 Who Received Thyroid Remnant Ablation Using Either the Hypothyroid or the Thyrogen Method.

Thyrogen^® (thyrotropin alfa)

Drug Name	Generic Name	Therapeutic Area and FDA Approved Indications	Approved U.S. Drug Label
Thyrogen®	thyrotropin alfa	Thyrogen (thyrotropin alfa for injection) is indicated for use as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well differentiated thyroid cancer.	Prescribing Info

These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert

PUBLICATION (REFERENCE)

Publications

NAME OF SPONSOR/COMPANY:

Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142

TITLE OF STUDY:

THYR01605: Follow-up of Thyroid Cancer Patients from Study THYR-008-00 Who Received Thyroid Remnant Ablation Using Either the Hypothyroid or the Thyrogen Method

INVESTIGATORS AND STUDY CENTER(S)

This was a multicenter study conducted at 4 sites in the US, 4 sites in the EU, and 1 site in Canada.

STUDIED PERIOD

03 May 2006 (first patient enrolled) to
21 July 2006 (last patient completed)

PHASE OF DEVELOPMENT

Phase 3

OBJECTIVES

Primary objective:
- To confirm the status of thyroid remnant ablation by using Thyrogen-stimulated radioiodine static neck imaging in patients previously treated in the THYR-008-00 study.

Secondary objectives:
- To learn if there was recurrence of thyroid cancer in any of the patients previously treated in the THYR-008-00 study.
- To assess Thyrogen-stimulated serum thyroglobulin (Tg) measurements in patients previously treated in the THYR-008-00 study.
- To assess safety information on repeat exposure to Thyrogen in patients previously treated in the THYR-008-00 study.

METHODOLOGY

Study THYR01605 was a Phase 3 follow-up study to THYR-008-00. In THYR-008-00, patients were randomized to be prepared for post-thyroidectomy thyroid remnant ablation with either standard hypothyroidism or use of Thyrogen while euthyroid. All patients received 100 millicuries (mCi) (3.7 Gigabecquerels [GBq]) 131 radioiodine (131I) to ablate thyroid remnants and had follow-up diagnostic whole body scan (WBS) and static neck imaging performed approximately 8 months later. The last patient completed the final study visit on 26 September 2003.
In this Phase 3 follow-up study (THYR01605), Investigators, patients, and site staff were unblinded to the original treatment assignment in THYR 008 00. To provide information on their current status, patients were asked to undergo Thyrogen-stimulated diagnostic whole-body scanning and static neck imaging to assess neck uptake visually and by neck-uptake quantitation. Patients received Thyrogen on 2 consecutive days, then 131I orally (PO) 24 ±6 hours after the second injection of Thyrogen, followed 48 ±6 hours after the isotope (4 mCi [148 Megabecquerels (MBq)] of 131I was used) by the WBS and static neck imaging. Neck scans were read in a blinded manner by 3 independent, expert central readers (ie, “central readers”) who were blinded as to original treatment assignment in THYR-008-00 and the Dosimetry Coordination Centre (DCC) at the University of Würzburg, Würzburg, Germany. The definition of successful ablation by scanning was no visible thyroid bed uptake, or if visible, then thyroid bed uptake <0.1% of administered isotope.
A basal serum Tg sample was drawn just before the first injection of Thyrogen, and a second serum Tg sample was drawn 72 ± 6 hours after the second injection of Thyrogen. Each serum sample also had the level of anti-Tg antibodies determined. Patients whose samples contained clinically significant levels of anti-Tg antibodies were excluded from final analyses of Tg values. The definition of successful ablation by serum Tg assessment was Thyrogen-stimulated serum Tg level <2 ng/mL.
Of note, different criteria for successful ablation could give slightly different response rates. Scan results were chosen as the primary endpoint. After exclusion of patients with anti-Tg antibodies, success of ablation was also assessed using Thyrogen-stimulated Tg levels as a secondary endpoint.
Serum thyroid-stimulating hormone (TSH), free thyroxine (T4), a pregnancy test in women of child-bearing potential, and a physical exam was conducted at the start of prospective medical testing.
Adverse events (AEs) and concomitant medications were recorded for the period between signing of the informed consent form and completion of protocol-specified procedures at Visit 4.

NUMBER OF PATIENTS (PLANNED AND ANALYZED)

Up to 61 patients from the THYR-008-00 study were planned. A total of 51 patients participated in study THYR01605: 48 patients were analyzed, and 3 patients had only retrospective medical data collected.

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION

Subjects who met the following inclusion criteria were eligible to participate in this study:
- Completed the THYR-008-00 study;
- Had a negative serum pregnancy test within 8 days prior to the start of the week during which the patient received Thyrogen and radioiodine (required for all pre-menopausal women of child bearing potential, with menopause defined as age >50 years with >2 years without a menstrual period).
Patients were excluded from the study if they were currently taking amiodarone or other prescribed iodine-containing medication or if they had received iodine-containing X-ray contrast material within the prior 3 months.

TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION

Thyrogen 0.9 mg daily, administered intramuscularly (IM) in the buttock on 2 consecutive days.
For WBS and static neck imaging, each patient received 4 mCi (148 MBq) ± 0.4 mCi ¹³¹I PO.

DURATION OF TREATMENT

The screening period lasted up to 28 days after obtaining patient informed consent to participate in the follow-up study.
The Treatment Period for each patient lasted 5 days. The study period was defined as the time from the signing of informed consent to up to 10 days following the completion of Visit 4.

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION

None.

CRITERIA FOR EVALUATION

Efficacy:
Primary Endpoint
Static neck imaging: Treatment success was defined as patients having a negative neck scan (i.e., “no visible uptake or if visible below 0.1% uptake in the thyroid bed”), as determined visually by the 3 central readers (blinded as to original treatment assignment) following the diagnostic scan, and by the quantified result by DCC.

Secondary Endpoints
Disease recurrence: An assessment as to whether thyroid cancer had recurred at any time since the completion of THYR-008-00 was completed for each patient by the Investigator.
Serum Tg levels: Successful ablation, as assessed by the serum Tg level, required that the Thyrogen-stimulated Tg level was <2 ng/mL. Results of serum Tg level assays and tests for anti-Tg antibody were provided by the central laboratory and interpreted by the Investigators.

Safety: Safety and tolerability of Thyrogen were assessed through patient-reported AEs and serious adverse events (SAEs). In addition, safety was also assessed by changes in laboratory assessments, vital signs (including blood pressure [BP], temperature, heart rate [HR], and respiratory rate [RR]), and changes in medical history or physical exam findings.

STATISTICAL METHODS

Efficacy: Efficacy analyses were based on the Intent-to-Treat (ITT) and Per Protocol (PP) populations for purposes of assessing overall response. The ITT population was defined as all patients who completed the THYR-008-00 study, provided consent and enrolled in this study, and were confirmed to be eligible for entry into the study. The PP population was a subset of the ITT and consisted of ITT patients who did not have protocol violations or deviations that impacted the efficacy assessments.
The difference in the proportion of patients in each treatment group in the THYR-008-00 study demonstrating treatment success, as indicated by neck scan results (primary endpoint) and/or Thyrogen-stimulated Tg levels (secondary endpoint), were reported with a 95% CI. Patients whose samples contained clinically significant levels of anti-Tg antibodies were excluded from the final analyses of Tg values. Patients who received additional therapeutic radioiodine since the close of the THYR-008-00 study were also excluded from the final analyses of ablation success, but these patients were not excluded from the assessment of cancer recurrence since the close of the prior study.
As an additional secondary efficacy endpoint, medical data collected since the completion of the THYR-008-00 study and during the present study were assessed by the Investigator as to whether thyroid cancer had recurred at any time since the completion of the THYR-008-00 study. The assessment regarding recurrence was designated as definitive cancer recurrence, possible cancer recurrence, no evidence of cancer recurrence, or “cannot assess” (with the reason specified).

Safety: Safety assessment began at the time of informed consent and continued up to the completion of visit 4. Information collected during the screening period was presented separately from treatment-emergent signs and symptoms. Safety assessments were based on the incidence of treatment-emergent AEs, SAEs, AEs leading to withdrawal and AEs related to study treatment. The analysis of laboratory values was based on the frequency of abnormal values and the frequency of clinically significant abnormal values. AEs were also categorized and tabulated, based on treatment group (“Euthyroid” versus “Hypothyroid”) in study THYR-008-00. Changes from baseline in laboratory parameters, TSH and free T4 were summarized by the treatment group in the previous study.

SUMMARY / CONCLUSIONS

EFFICACY:
Primary Endpoint
Central readers observed no radioiodine uptake on all but 5 WBS images. For those 5 scans (1 patient in the former Hypothyroid group and 4 patients in the former Euthyroid group), the amount of uptake was far below the a priori primary endpoint cut-off of < 0.1%. Therefore, the neck scans performed a median of 3.7 years after the ablation performed during the THYR-008-00 study showed 100% of patients in both treatment groups with interpretable scans were still successfully ablated. The percentage of successfully ablated patients was still 100% when excluding 9 patients who received additional therapeutic radioiodine since the end of the THYR-008-00 study.

Secondary Endpoints:
Disease Recurrence: Since the end of the THYR-008-00 study, no patients had a definitive cancer recurrence reported by the study Investigators and 48/51 patients (94%) had no evidence of cancer recurrence as measured by various scanning or biopsy techniques. One patient (in the former Euthyroid group) had possible cancer recurrence and 2 patients (1 in each of the former Hypothyroid and Euthyroid groups) could not be assessed. Among the 9 patients who received radioiodine therapy after completion of THYR-008-00, 3 patients required completion of ablation based on persistent elevated serum Tg levels, rather than actual remnant determination by scanning.
The mean percent of radioiodine (¹³¹I) uptake on the static neck scans at Visit 4 was very low (0.009%) for patients with radioiodine uptake data in both the former Hypothyroid (n=18) and Euthyroid (n=25) groups.
Interpretation of the WBS/static neck imaging results can be reader-dependent; the Investigator’s interpretations did not completely agree with the central readers’ assessments for 3 patients. Trace uptake in the thyroid bed is believed to have no long term pathological significance.
Serum Tg Levels: In the former Hypothyroid and Euthyroid groups, there were 20 and 25 patients, respectively, who had evaluable serum Tg levels after Thyrogen stimulation (Day 5). The mean stimulated Tg values were 0.6 ng/mL and 0.2 ng/mL in the former Hypothyroid and Euthyroid groups, respectively. In this study, a Thyrogen-stimulated serum Tg level < 2 ng/mL was chosen as the criterion for remnant ablation success. Applying a Thyrogen-stimulated serum Tg level < 2 ng/mL as the criterion for remnant success, 95% and 96% of the patients in the former Hypothyroid and Euthyroid groups, respectively, had been ablated. At a 1 ng/mL threshold, 90% and 92% of the patients in the former Hypothyroid and Euthyroid groups, respectively, were considered to be ablated. Excluding the 9 patients who received additional ¹³¹I therapy after completing study THYR-008-00 (because the additional therapy would have made low levels of Tg easier to achieve), 16/16 patients (100%) in the former Hypothyroid group and in 22/22 patients (100%) in the former Euthyroid group had a stimulated Tg level < 2 ng/mL.
Excluding the 9 patients who received additional ¹³¹I therapy during the period between the 2 studies, all (100%) patients who had antibody levels ≤ 5 units/mL (14/14 patients in the former Hypothyroid group and 18/18 patients in the former Euthyroid group) had stimulated Tg levels < 2 ng/mL. This analysis applied a Tg antibody cut-off of 5 units/mL, which was the level recommended by the Tg test kit manufacturer.

Safety Results: Treatment with Thyrogen during this follow-up study was well tolerated. There were no deaths, SAEs, or withdrawals due to AEs reported during the conduct of this study.
During the 28-day Pre-treatment (Screening) period, only 3 AEs (anxiety, skin lesion and urticaria) were observed, among 2 patients. During the 5-day study period, 2 patients (8.7%) in the former Hypothyroid group and 6 patients (21.4%) in the former Euthyroid group experienced at least 1 treatment-emergent AE. Treatment-related AEs were reported in 3 patients (10.7%), all in the former Euthyroid group. All treatment-emergent AEs resolved during the course of the study, except for 1 AE of mild headache that was considered to possibly be related to treatment. Because most (48/51; 94%) patients in this follow-up study received Thyrogen, apparent differences between the former Hypothyroid and Euthyroid groups from the THYR-008-00 study are not considered to be clinically meaningful. No patients experienced severe treatment-emergent AEs during this 5-day follow-up study.
Apparent differences between the former Hypothyroid and Euthyroid groups during this follow-up study in the proportion of patients with treatment-emergent AEs (8.7% and 21.4%, respectively), and in the frequency of all AEs and treatment-related AEs, are not considered to be clinically meaningful, because a median of 3.7 years (range 3.4 to 4.4 years) have passed since the end of the THYR-008-00 study, and all patients in this follow-up study received Thyrogen. These differences were not thought to be due to the patient treatment group assignment (Euthyroid group versus Hypothyroid group) during the THYR-008-00 study, but possibly due to group differences in the patients’ past medical histories. Due to relatively small numbers of patients in each group, it is difficult to assign group-related causality since results from only a few patients could skew the results for a group.
Mean TSH and free T4 values were similar for both groups at Screening, and although several TSH and free T4 values were out of range for both groups, none were considered to be clinically significant.

Conclusion: The neck scans performed a median of 3.7 years after the ablation performed during THYR-008-00 showed the same results observed in the THYR-008-00 study: that 100% of patients in both treatment groups with interpretable scans had successful ablation, using the primary endpoint of “no visible uptake or, if visible, <0.1% uptake”. Treatment with Thyrogen during this follow-up study was well tolerated, with no deaths, SAEs, or withdrawals due to AEs reported during the conduct of this study.

COMMENTS

Like the results of the THYR-008-00 study the safety results from this follow-up study (THYR01605) suggest that Thyrogen can be safely administered to enhance radioiodine uptake for remnant ablation in patients with well-differentiated thyroid cancer, with no long-term effects observed a median of 3.7 years after initial treatment.