phase ii 177lu-dotatate study in metastatic npc with a safety run-in

Conditions: Metastatic Nasopharyngeal Cancer

Summary: 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.

Keywords: peptide receptor radionuclide therapy (prrt) 177lu-dota0-tyr3-octreotate radionuclide therapy metastatic nasopharyngeal carcinoma theragnostics