Gozellix

Description for Gozellix

Drug Characteristics

GOZELLIX (kit for the preparation of gallium Ga 68 gozetotide injection), after radiolabeling with Ga 68, is a radioactive diagnostic agent for intravenous use. Gozetotide is also known as PSMA-11.

Gallium Ga 68 gozetotide is a radioconjugate composed of a human prostate specific membrane antigen (PSMA)-targeting ligand peptide conjugated via the acyclic radiometal chelator, N,N’-bis [2-hydroxy-5- (carboxyethyl)benzyl] ethylenediamine-N,N’-diacetic acid (HBED-CC) to the radioisotope Ga 68. The amino acid sequence of the gozetotide peptide is Glu-NH-CO-NH-Lys(Ahx), (Ahx = 6-aminohexanoic acid). Gallium Ga 68 gozetotide has a molecular weight of 1011.9 g/mol and its chemical structure is shown in Figure 6.

Figure 6 : Chemical Structure of Gallium Ga 68 Gozetotide

Kit Characteristics

GOZELLIX is supplied as a kit which contains the non-radioactive ingredients needed to produce Gallium Ga 68 Gozetotide Injection. There are two configurations, A or B, available to allow preparation of Gallium Ga 68 Gozetotide Injection using Ga 68 from different generator or cyclotron sources. Each configuration consists of gozetotide (Vial 1), acetate buffer (Vial 2A or Vial 2B), and ascorbic acid stabilizer (Ampule).

• Vial 1 (Gozetotide): Each vial contains 25 mcg gozetotide and 10 mcg D-mannose.
• Vial 2A (Acetate Buffer): Each vial contains 150 mg anhydrous sodium acetate in 2.5 mL of 0.292 M hydrochloric acid.
• Vial 2B (Acetate Buffer): Each vial contains 150 mg anhydrous sodium acetate in 6.4 mL of 0.175 M hydrochloric acid.
• Ampule (Ascorbic Acid Stabilizer): Each ampule contains 500 mg of ascorbic acid (USP injection grade), 3 mg sodium metabisulfite, sodium hydroxide for pH adjustment, and water for injection in a volume of 2 mL.

The prepared Gallium Ga 68 Gozetotide Injection is a sterile, pyrogen free, clear, colorless to slightly yellow, buffered solution containing up to 18,500 MBq (500 mCi) of gallium Ga 68 gozetotide in 10 mL with a pH between 4.0 to 5.0.

Nuclear Physical Characteristics

Gallium-68 (Ga 68) decays with a half-life of 68 minutes to stable zinc-68. Table 4, Table 5, and Table 6 display the principal radiation emission data, radiation attenuation by lead shielding, and physical decay of Ga 68.

Table 4: Principal Radiation Emission Data (>1%) for Ga 68

Radiation/ Emission	% Disintegration	Mean Energy (MeV)
beta+	88%	0.8360
beta+	1.1%	0.3526
gamma	178%	0.5110
gamma	3.0%	1.0770
X-ray	2.8%	0.0086
X-ray	1.4%	0.0086

Table 5: Radiation Attenuation of 511 keV Photons by Lead (Pb) Shielding

Shield Thickness (Pb) mm	Coefficient of Attenuation
6	0.5
12	0.25
17	0.1
34	0.01
51	0.001

Table 6: Physical Decay Chart for Ga 68

Minutes	Fraction Remaining
0	1
15	0.858
30	0.736
60	0.541
90	0.398
120	0.293
180	0.158
360	0.025

Side Effects for Gozellix

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of GOZELLIX has been established based on two prospective studies of another formulation of gallium Ga 68 gozetotide in patients with prostate cancer [see Clinical Studies (14.1, 14.2)]. Below is a display of the adverse reactions in these studies.

The safety of gallium Ga 68 gozetotide was evaluated in 960 patients in the PSMA-PreRP and PSMABCR studies, each receiving one dose of gallium Ga 68 gozetotide. The average injected activity was 188.7 ± 40.7 MBq (5.1 ± 1.1 mCi) [see Clinical Studies (14.1, 14.2)]. The most commonly reported adverse reactions were nausea, diarrhea, and dizziness, occurring at a rate of <1%.

Drug Interactions for Gozellix

Androgen deprivation therapy and other therapies targeting the androgen pathway

Androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such as androgen receptor antagonists, can result in changes in uptake of gallium Ga 68 gozetotide in prostate cancer. The effect of these therapies on performance of gallium Ga 68 gozetotide PET has not been established.

Warnings for Gozellix

Included as part of the PRECAUTIONS section.

Precautions for Gozellix

Risk for Misinterpretation

Image interpretation errors can occur with GOZELLIX PET. A negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. Gallium Ga 68 gozetotide uptake is not specific for prostate cancer and may occur with other types of cancer as well as non-malignant processes such as Paget’s disease, fibrous dysplasia, and osteophytosis. The performance of GOZELLIX for imaging of biochemically recurrent prostate cancer seems to be affected by serum PSA levels and by site of disease. The performance of GOZELLIX for imaging of metastatic pelvic lymph nodes prior to initial definitive therapy seems to be affected by Gleason score [see Clinical Studies (14.1, 14.2)].

Clinical correlation, which may include histopathological evaluation of the suspected prostate cancer site, is recommended.

Radiation Risks

Gallium Ga 68 gozetotide contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Ensure safe handling to minimize radiation exposure to the patient and health care providers. Advise patients to hydrate before and after administration and to void frequently after administration [see Dosage and Administration (2.1, 2.3)] .

Hypersensitivity Reactions to Sulfites

Ascorbic Acid Stabilizer contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies were performed to evaluate the carcinogenicity potential of gallium Ga 68 gozetotide.

Overdose Information for Gozellix

In the event of an overdose of gallium Ga68 gozetotide, reduce the radiation absorbed dose to the patient where possible by increasing the elimination of the drug from the body using hydration and frequent bladder voiding. A diuretic might also be considered. If possible, an estimate of the radiation effective dose given to the patient should be made.

Contraindications for Gozellix

None

Clinical Pharmacology for Gozellix

Mechanism Of Action

Gallium Ga 68 gozetotide binds to PSMA. It binds to cells that express PSMA, including malignant prostate cancer cells, which usually overexpress PSMA. Gallium-68 is a β+ emitting radionuclide that allows positron emission tomography.

Pharmacodynamics

The relationship between gallium Ga 68 gozetotide plasma concentrations and successful imaging was not explored in clinical trials.

Pharmacokinetics

Distribution

Intravenously injected gallium Ga 68 gozetotide is cleared from the blood and is accumulated preferentially in the liver (15%), kidneys (7%), spleen (2%), and salivary glands (0.5%). Gallium Ga 68 gozetotide uptake is also seen in the adrenals and prostate. There is no uptake in the cerebral cortex or in the heart, and usually lung uptake is low.

Elimination

A total of 14% of the injected dose is excreted in urine in the first 2 hours post-injection.

CLINICAL STUDIES

Imaging Prior to Initial Definitive Therapy

The efficacy of GOZELLIX for PET of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy has been established based on a study of another formulation of gallium Ga 68 gozetotide. Below is a display of the results of the prospective, open label study PSMA-PreRP (NCT03368547 and NCT02919111).

This two-center study enrolled 325 patients with biopsy-proven prostate cancer who were considered candidates for prostatectomy and pelvic lymph node dissection. All enrolled patients met at least one of the following criteria: serum prostate-specific antigen (PSA) of at least 10 ng/mL, tumor stage cT2b or greater, or Gleason score greater than 6. Each patient received a single gallium Ga 68 gozetotide PET/CT or PET/MR from mid-thigh to skull base.

A total of 123 patients (38%) proceeded to standard-of-care prostatectomy and template pelvic lymph node dissection and had sufficient histopathology data for evaluation (evaluable patients). Three members of a pool of six central readers independently interpreted each PET scan for the presence of abnormal gallium Ga 68 gozetotide uptake in pelvic lymph nodes located in the common iliac, external iliac, internal iliac, and obturator subregions bilaterally as well as in any other pelvic location. The readers were blinded to all clinical information except for the history of prostate cancer prior to definitive treatment. Extrapelvic sites and the prostate gland itself were not analyzed in this study. For each patient, gallium Ga 68 gozetotide PET results and reference standard histopathology obtained from dissected pelvic lymph nodes were compared by region (left hemipelvis, right hemipelvis, and other).

For the 123 evaluable patients, the mean age was 65 years (range 45 to 76 years), and 89% were white. The median serum PSA was 11.8 ng/mL. The summed Gleason score was 7 for 44%, 8 for 20%, and 9 for 31% of the patients, with the remainder of the patients having Gleason scores of 6 or 10.

Table 7 compares majority PET reads to pelvic lymph node histopathology results at the patient-level with region matching, such that at least one true positive region defines a true positive patient. As shown, approximately 24% of subjects studied were found to have pelvic nodal metastases based on histopathology (95% confidence interval: 17%, 32%).

Table 7: Patient-Level Performance of Gallium Ga 68 Gozetotide PET for Detection of Pelvic Lymph Node Metastasis* in the PSMA-PreRP Study (n=123)

		Histopathology		Predictive value** (95% CI)
		Positive	Negative
PET scan	Positive	14	9	PPV 61% (41%, 81%)
	Negative	16	84	NPV 84% (79%, 91%)
Total		30	93
Diagnostic performance (95% CI)		Sensitivity 47% (29%, 65%)	Specificity 90% (84%, 96%)

*with region matching where at least one true positive region defines a true positive patient
**PPV: positive predictive value, NPV: negative predictive value

Among the pool of six readers, sensitivity ranged from 36% to 60%, specificity from 83% to 96%, positive predictive value from 38% to 80%, and negative predictive value from 80% to 88%. In an exploratory subgroup analysis based on summed Gleason score, there was a numerical trend toward more true positives in patients with Gleason score of 8 or higher compared to those with Gleason score of 7 or lower.

An exploratory analysis was performed to estimate the sensitivity and specificity for pelvic nodal metastasis detection in all scanned patients, including the patients who were lacking histopathology reference standard. An imputation method was used based on patient-specific factors. This exploratory analysis resulted in an imputed sensitivity of 47%, with a 95% confidence interval ranging from 38% to 55%, and an imputed specificity of 74%, with a 95% confidence interval ranging from 68% to 80% for all patients imaged with gallium Ga 68 gozetotide PET.

Imaging Prior to Suspected Recurrence Therapy

The efficacy of GOZELLIX for PET of PSMA-positive lesions in men with prostate cancer with suspected recurrence based on elevated serum PSA level has been established based on a study of another formulation of gallium Ga 68 gozetotide. Below is a display of the results of the prospective, open label study PSMA-BCR (NCT02940262 and NCT02918357).

This two-center study enrolled 635 patients with biochemical evidence of recurrent prostate cancer after definitive therapy, defined by serum PSA of >0.2 ng/mL more than 6 weeks after prostatectomy or by an increase in serum PSA of at least 2 ng/mL above nadir after definitive radiotherapy. All patients received a single gallium Ga 68 gozetotide PET/CT or PET/MR from mid-thigh to skull base. Three members of a pool of nine independent central readers evaluated each scan for the presence and regional location (20 subregions grouped into four regions) of abnormal gallium Ga 68 gozetotide uptake suggestive of recurrent prostate cancer. The readers were blinded to all clinical information other than type of primary therapy and most recent serum PSA level.

A total of 469 patients (74%) had at least one positive region detected by gallium Ga 68 gozetotide PET majority read. The distribution of gallium Ga 68 gozetotide PET positive regions was 34% bone, 25% prostate bed, 25% pelvic lymph node, and 17% extrapelvic soft tissue. Two hundred and ten patients had composite reference standard information collected in a PET positive region (evaluable patients), consisting of at least one of the following: histopathology, imaging (bone scintigraphy, CT, or MRI) acquired at baseline or within 12 months after gallium Ga 68 gozetotide PET, or serial serum PSA.

Composite reference standard information for gallium Ga 68 gozetotide PET negative regions was not systematically collected in this study.

In the 210 evaluable patients, the mean age was 70 years (range 49 to 88 years) and 82% were 65 years of age or older. White patients made up 90% of the group. The median serum PSA was 3.6 ng/mL. Prior treatment included radical prostatectomy in 64% and radiotherapy in 73%.

Of the 210 evaluable patients, 192 patients (91%) were found to be true positive in one or more regions against the composite reference standard (95% confidence interval: 88%, 95%). Among the pool of nine readers used in the study, the proportion of patients who were true positive in one or more regions ranged from 82% to 97%. The prostate bed had the lowest proportion of true positive results at the region-level (76% versus 96% for non-prostate regions).

An exploratory analysis was also performed in which gallium Ga 68 gozetotide PET positive patients who lacked reference standard information were imputed using an estimated likelihood that at least one location-matched PET positive lesion was reference standard positive based on patient-specific factors. In this exploratory analysis, 340 of 475 patients (72%) were imputed as true positive in one or more regions (95% confidence interval: 68%, 76%).

In another exploratory analysis using the same imputation approach for PET positive patients who lacked reference standard information, 340 of 635 patients (54%) were correctly detected as true positive (95% confidence interval: 50%, 57%) among all BCR patients who received a PET scan, whether it was read as positive or negative.

The likelihood of identifying a gallium Ga 68 gozetotide PET positive lesion in this study increased with higher serum PSA level. Table 8 shows the patient-level gallium Ga 68 gozetotide PET results stratified by serum PSA level. The mean time between PSA measurement and PET scan was 40 days with a range of 0 to 367 days. Percent PET positivity was calculated as the proportion of patients with a positive gallium Ga 68 gozetotide PET out of all patients scanned. Percent PET positivity includes patients determined to be either true positive or false positive as well as those in whom such determination was not made due to the absence of composite reference standard data.

Table 8: Patient-Level Gallium Ga 68 Gozetotide PET Results and Percent PET Positivity Stratified by Serum PSA Level in the PSMA-BCR Study (n=628)*

PSA (ng/mL)	PET positive patients				PET negative patients	Percent PET positivity*** (95% CI)
	Total	TP**	FP**	Without reference standard
		With reference standard
<0.5	48	11	1	36	87	36% (27%, 44%)
		12
≥0.5 and <1	44	15	3	26	35	56% (45%, 67%)
		18
≥1 and <2	71	29	1	41	15	83% (75%, 91%)
		30
≥2	299	137	13	149	29	91% (88%, 94%)
		150
Total	462	192	18	252	166	74% (70%, 77%)
		210

*7 patients were excluded from this table due to protocol deviations
**TP: true positive, FP: false positive
***Percent PET positivity = PET positive patients/total patients scanned

Patient Information for Gozellix

Adequate Hydration

Instruct patients to drink a sufficient amount of water to ensure adequate hydration before their PET study and urge them to drink and urinate as often as possible during the first hours following the administration of Gallium Ga 68 Gozetotide Injection, in order to reduce radiation exposure [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)] .