Ga-68-DOTATOC (Page 3 of 4)

11.2 Physical Characteristics

Table 3 and Table 4 display the principal radiation emission data and physical decay of Ga 68.

Gallium-68 (Ga 68) decays with a half-life of 68 minutes to stable Zn 68:

• 89% through positron emission with a mean energy of 836 keV followed by emission of two 511 keV annihilation photons (178%),
• 10% through orbital electron capture (with associated X-ray or Auger emissions), and
• 3% through 13 gamma transitions from 5 excited levels of the daughter Zn 68 nucleus. The most probable prompt gamma emission is a 1088 keV gamma with a 3.2% per decay probability.

Table 3: Principal Radiation Emission Data (>1%)

Radiation/Emission	% Disintegration	Mean Energy (MeV)
beta+	88%	0.8360
beta+	1.1%	0.3526
gamma	178%	0.5110
gamma	3%	1.0770
X-ray	2.8%	0.0086
X-ray	1.4%	0.0086

Table 4: Physical Decay Chart for Gallium Ga-68

Minutes	Fraction Remaining
0	1.000
15	0.858
30	0.736
60	0.541
90	0.398
120	0.293
180	0.158
360	0.025

11.3 External Radiation

Gamma constant: 1.8 × 10^-4 mSv/hr per MBq at 1 meter [0.67 mrem/hr per mCi at 1 meter] Table 5 displays the radiation attenuation by lead shielding of Ga 68.

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ga 68 DOTATOC binds to somatostatin receptors, with highest affinity (K_i = 2.5± 0.5 nanomolar) for subtype 2 receptors (sstr2). Ga 68 DOTATOC binds to cells that express somatostatin receptors including malignant neuroendocrine cells, which overexpress sstr2 receptors. Gallium 68 is a β+ emitting radionuclide with associated 511 keV annihilation photons that allow positron emission tomography (PET) imaging.

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

Distribution

Ga 68 DOTATOC distributes to all sstr2-expressing organs such as pituitary, thyroid, spleen, adrenals, kidney, pancreas, prostate, liver, and salivary glands. Uptake in the lung and lymph nodes are lower as compared to other sstr-2 expressing organs.

Elimination

Radiotracer elimination is exclusively via urine. Approximately 16% of the injected dose is excreted in urine in the first two to four hours post-injection.

14 CLINICAL STUDIES

The safety and efficacy of Ga-68 DOTATOC Injection were established in two single-center, open-label studies (Study A and Study B) in which 282 patients with known or suspected SSTR-positive NETs received a single dose of Ga-68 DOTATOC. A total of 238 of the 282 patients (84%) had a history of neoplasm at the time of Ga-68 DOTATOC imaging. Among the 282 patients, 59% were female and 95% white; the mean age was 54 years (range from 4 to 82 years).

The Ga-68 DOTATOC images were rated by two independent readers blinded to clinical information as either positive or negative for NET within each patient. The imaging results were compared to a composite reference consisting of histopathology and imaging (MR, CT, or In-111 pentetreotide imaging) acquired within 1 year of the Ga-68 DOTATOC imaging, as well as chromogranin A and pancreastatin levels. The proportion of patients positive for NET per composite reference who were identified as positive by the Ga-68 DOTATOC image was used to quantify positive percent agreement. The proportion of patients without NET per composite reference who were identified as negative by the Ga-68 DOTATOC image was used to quantify negative percent agreement.

Study A (NCT: 01619865) included 220 subjects with known or suspected SSTR positive tumors referred for diagnosis or evaluation of disease extension before or after treatment. A total of 178 of the 220 patients (81%) had a history of neoplasm at the time of Ga-68 DOTATOC imaging. In 177 of the 220 patients, sufficient data to establish NET status per composite reference was available for efficacy evaluation. Table 6 shows the performance of Ga-68 DOTATOC in the detection of NETs for Study A.

Table 6: Study A. Performance of Ga-68 DOTATOC in the detection of NET by reader

N = 177	NET status as identified by reader	Reference
		Positive	Negative
N: number of patients, CI: confidence interval,
* Percent reader agreement with reference; † Exact method
Reader 1	Positive	121	5
	Negative	12	39
	Agreement (%)* (95% CI)†	91 (85, 95)	89 (75, 96)
Reader 2	Positive	120	6
	Negative	13	38
	Agreement (%)* (95% CI)†	90 (84, 95)	86 (73, 95)

Study B (NCT: 01869725) included 62 patients with histologically positive NET or other SSTR positive tumor referred for evaluation of disease before or after treatment. In 59 of the 62 patients, sufficient data to establish NET status per composite reference was available for efficacy evaluation. The estimated positive and negative percent agreements were 92% and 75% for reader 1 and 90% and 75% for reader 2, respectively.