Phase II 177Lu-DOTATATE Study in Metastatic NPC With a Safety Run-in

This study is the first phase II study of 177Lu-DOTA0-Tyr3-Octreotate in metastatic NPC. Patients whom have failed 2 or more lines of therapy or exhausted standard therapy and are avid on 68Ga-DOTATATE imaging will be eligible to receive up to 4 cycles of 177Lu-DOTA0-Tyr3-Octreotate. The primary outcome will be progression free survival at 6 months.

This would be an open label, single arm, single centre, phase II study designed to evaluate the efficacy of 177Lu-DOTA0-Tyr3-Octreotate in Metastatic NPC.

Patients will first need to go for a 68Ga-DOTATATE scan to determine if they are suitable for 177Lu-DOTA0-Tyr3-Octreotate therapy. A'Hern single stage phase II design (A'Hern, 2001) will be used for conducting the trial. The null hypothesis that the true PFS rate at 6 months is 10% will be tested against the alternate hypothesis of 25%. A total number of 25 patients will be recruited. If there are 5 or more patients who are alive and progression free among these 25 patients at 6 months, we reject the null hypothesis and claim that the treatment is promising.

The design controls the type I error rate at 9.8% and yields a power of 78.6% when the true PFS rate at 6 months is 25%. The first 5 patients will receive 180mCi of 177Lu-DOTA0-Tyr3-Octreotate for the first cycle followed by 200mCi for the remaining 3 cycles if there are no \> Grade 2 toxicities after the first cycle. If there are \>G2 toxicities, the remaining cycles will proceed at 180mCi. A safety review will be done after the first 5 patients. If there are no significant toxicities, the remaining patients will receive 200mCi for 4 cycles. If there are significant toxicities in patients receiving 200mCi for the 2nd to 4th cycle, the remaining patients will receive 180mCi for 4 cycles. If there are significant toxicities in patients receiving 180mCi for the 2nd to 4th cycle, the remaining patients will receive 160mCi for 4 cycles. Dosimetry scans will be done after each cycle of 177Lu-DOTA0-Tyr3-Octreotate at 1h and 96h. Safety and tolerability of 177LuDOTA0-Tyr3-Octreotate will be assessed for the duration of study treatment.

FDG PET/CT scan and 68Ga-DOTATATE scan will be performed at baseline and after cycle 1 (week 4) and cycle 4 (week 28). CT scans will be done at week 12, 24, then 3-monthly starting from week 40. 177Lu-DOTA0-Tyr3-Octreotate treatment will be continued until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, dose adjustment is permitted. A treatment cycle is eight weeks (56 days) and will be repeated without therapy interruption for 4 cycles unless there is dose limiting toxicities.

Eligibility Criteria:
Inclusion Criteria:

* a histologically confirmed diagnosis of NPC
* metastatic NPC that has failed two or more lines of therapy or exhausted standard therapy
* an Eastern Cooperative Oncology Group performance status of 0-2
* age 21-75 years, a life expectancy of more than 3 months
* no prior use of radionuclide therapy
* no prior radiotherapy to more than 25% of bone marrow
* less than 50% of bone marrow involved on 68Ga-DOTATATE scan
* Krenning score ≥ 3 and at least 75% concordance between 68Ga-DOTATATE scan and 18F-FDG PET scan
* at least 1 bidimensionally measurable (2 cm) site of disease.
* A wash-out period of at least 3 weeks from the last dose of prior chemotherapy is required before the administration of the first dose of 177Lu-DOTATATE.
* adequate hematologic, renal, and liver function using standard laboratory measurements
* no history of other malignancy, except treated basal cell and squamous cell skin carcinomas

Exclusion Criteria:

* Serum creatinine \>120 μmol/L or 1.2 mg/dL, or a measured creatinine clearance (or measured glomerular filtration rate (GFR) using plasma clearance methods, not gamma camera-based) of \<50 mL/min.
* Hb concentration \<5.0 mmol/L (\<8.0 g/dL); WBC \<3x10\^9/L (3000/mm3); platelets \<75x10\^9/L (75x10\^3/mm3).
* Total bilirubin \>3 x ULN.
* Serum albumin \<3.0 g/dL unless prothrombin time is within the normal range.
* Pregnancy (see protocol Appendix 6).
* 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) as defined in Appendix 6.
* Peptide receptor radionuclide therapy (PRRT) at any time prior to enrolment in the study.
* Targeted surgery, radiotherapy (external beam), chemotherapy, embolization, interferons, mTOR-inhibitors or other investigational therapy within 3 weeks prior to enrolment in the study.
* Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrolment in the study. Patients with a history of brain metastases should have a head CT/MRI to document stable disease prior to enrolment in the study.
* 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 or long acting somatostatin analogs.
* Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study.
* Urinary incontinence.
* Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
* Patients who have not provided a signed an informed consent form to participate in the study, obtained prior to the start of any protocol related activities.
* Patients who are unable to comply with relevant contact precautions post Lutetium therapy.
* Patients with a synchronous local nasopharyngeal recurrence, with prior high-dose irradiation to the primary tumour.
* Patients with active Hepatitis B (HBsAg positive) or Hepatitis C (HCV Ab positive) infection will be excluded.
* Patients with known history of Human Immunodeficiency Virus (HIV) will be excluded.