EAP 177Lu-DOTA0-Tyr3-Octreotate for Inoperable, SSR+, NETs, Progressive Under SSA Tx

Advanced Accelerator Applications activated in 2012 a multicenter, stratified, open,
randomized, comparator-controlled, parallel-group Phase III study comparing treatment with
177Lu-DOTA0-Tyr3-Octreotate to 60 mg Octreotide LAR in patients with inoperable, progressive,
somatostatin receptor positive, midgut carcinoid tumors (NETTER-1 trial, EudraCT number
2011-005049-11, IND number 77219).

Clinical studies, including NETTER-1 for which the primary analysis has been conducted,
showed clinical evidence of safety and effectiveness to support the expanded access use
without any unreasonable potential risks for the patients in the context of the disease to be
treated.

In July 2016, the first patient was treated under an Expanded Access Program (EAP) for
inoperable, progressive, somatostatin receptor positive, midgut carcinoid tumors.

Compassionate use programs in Europe include pulmonary NETs. In the US, there were many
centers with patients with NETs who did not meet the inclusion criteria for the original EAP.
In May 2017, Advanced Accelerator Applications inquired with the FDA if amending the
inclusion criteria of the original protocol to include all NETs would be permissible.

In June 2017, Advanced Accelerator Applications was able to submit a revision to the original
Expanded Access Program's protocol for 177Lu-DOTA0-Tyr3-Octreotate to include neuroendocrine
tumors arising from sites other than midgut.

The locations listed below that are participating in the EAP may have received IRB approval
for either the original protocol or the new protocol or both. Please, inquire with the
Facility Contact as to which protocol is active at their site.

Inclusion Criteria:

- Presence of metastasized or locally advanced neuroendocrine tumor, inoperable
(curative intent) at enrollment time, and regardless of the origin of the tumor.

- Ki67 index ≤ 20%

- Patients progressive under SSA (any dose) at the time of enrollment

- Target lesions over-expressing somatostatin receptors according to an appropriate
imaging method (e.g. 111In-pentetreotide (Octreoscan) imaging or
68Ga-DOTA0-Tyr3-Octreotate (or 68Ga-edotreotide) imaging)

Exclusion Criteria:

- Either serum creatinine >150 μmol/L (>1.7 mg/dL), or creatinine clearance <50 mL/min
calculated by the Cockroft Gault method, eventually confirmed by measured creatinine
clearance (or measured glomerular filtration rate (GFR) using plasma clearance
methods, not gamma camera-based) <50 mL/min (the measured creatinine clearance / GFR
is required only as confirmatory exam).

- Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3); platelets <75x109/L
(75x103/mm3).

- Total bilirubin >3 x ULN.

- Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.

- Pregnancy or lactation.

- For female patients of childbearing potential (defined as < 2 years after last
menstruation and not surgically sterile) and male patients, who are not surgically
sterile or with female partners of childbearing potential: absence of effective,
non-hormonal means of contraception (intrauterine contraceptive device, barrier method
of contraception in conjunction with spermicidal gel).

- Any surgery, radioembolization, chemoembolization, chemotherapy and radiofrequency
ablation within 12 weeks prior to enrollment.

- Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks
prior to enrollment.

- Known brain metastases, unless these metastases have been treated and stabilized.

- Uncontrolled congestive heart failure (NYHA II, III, IV).

- Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN.

- Any patient receiving treatment with short-acting Octreotide, which cannot be
interrupted for 24 h before and 24 h after the administration of
177Lu-DOTA0-Tyr3-Octreotate, or any patient receiving treatment with Octreotide LAR,
which cannot be interrupted for at least 4 weeks before the administration of
177Lu-DOTA0-Tyr3-Octreotate, unless the tumor uptake on target lesions is at least as
high as normal liver uptake.

- Patients with any other significant medical, psychiatric, or surgical condition,
currently uncontrolled by treatment, which may pose a risk to the patient safety

- Prior external beam radiation therapy to more than 25% of the bone marrow.

- Current spontaneous urinary incontinence making impossible the safe administration of
the radioactive IMP.

- Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in
situ of the uterine cervix, unless definitively treated and with no evidence of
recurrence.

- Patients who have not provided a signed informed consent form to accept this
treatment.