Targeted Radiation Therapy for Ovarian Cancer: Intraperitoneal Treatment With 211-astatine-MX35 F(ab')2

Study Overview
=================
Brief Summary
-----------------
In this alpha-radioimmunotherapy study groups of 3 patients with recurring epithelial ovarian cancer treated by salvage chemo-therapy and being in complete or good partial remission will receive one intra peritoneal infusion of 211 astatine (211At)-MX35 F(ab')2 . Patients will receive a single dose of MX35 F(ab')2 radiolabeled with increasing activity concentration of 211At in 1.0 - 2 L Extraneal® solution starting at an activity concentration of 50 megabecquerel per litre (MBq/L).

Detailed Description
-----------------
Five days prior to therapy the patient is provided with a central intra venous line and an abdominal catheter will be introduced during laparoscopy. To investigate the access to the whole abdominal cavity and possible catheter leakage, a 99mTc-colloid, will be infused intra peritoneally (IP) within 1.0 L of a gluco-polymer (Extraneal®). At the day of treatment vital signs will be measured prior to and after the 30 min infusion and at least every second hour during the first 6 hours after infusion, daily for the remainder of the in-hospital stay and at a minimum at 2, 3, 4 and 8 weeks after the IP infusion. Blood samples will be obtained for pharmacokinetic analyses every hour after completion of the IP infusion for 8 hours, then every 6 hours, together with sampling from the i.p. catheter. SPECT imaging of the whole abdominal cavity and thorax including the thyroid may be performed following completion of the IP infusion and at approx 8 or 20hrs post infusion. Physical examination and electrocardiogram will be done prior to and 4 weeks after the IP infusion. Clinical biochemical and hematological parameters will be monitored weekly after treatment. Blood samples to evaluate immunogenicity as well as cancer antigen-125 (CA-125) will also be taken at 2 and 8 weeks after treatment. The first patient will be observed for at least 4 weeks with any observed toxicity is Grade 2 or less, before the additional patient is accrued at the dose level. Dosimetry safety criteria: Based upon published data on maximal tolerated absorbed dose (Gy) recalculated to equivalent dose (Sv) with the assumption that the relative biological effectiveness (RBE) = 5, a limit for organ doses is defined. If any organ would reach the defined limit the study will be stopped.

Official Title
-----------------
Targeted Radiation Therapy for Ovarian Cancer: Intraperitoneal Treatment With 211-astatine-MX35 F(ab')2

Conditions
-----------------
Ovarian Cancer

Intervention / Treatment
-----------------
* Combination Product: 211-astatine MX35 F(ab')2


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically confirmed ovarian or tubal or primary peritoneal adenocarcinoma. Patients must have a recurrent intraperitoneal cancer and treated by a salvage chemotherapy to complete or good partial remission The following laboratory and clinical results within 2 weeks prior to first study day: Absolute neutrophil count (ANC) > 1.5 x 109/L Platelet count > 100 x 109/L Serum bilirubin < upper limit of normal(ULN) Aspartate aminotransaminase (ASAT) < 1.5 x ULN Serum aminotransferase (ALAT) < 1.5 x ULN Serum creatinine < 1.5 x upper limit of normal Thyreoglobulin baseline information Thyroid-stimulating hormone (TSH) baseline information T4 baseline information Karnofsky performance status > 70. Must understand written and spoken Swedish Before any trial-specific procedures or treatment can be performed, the patient must give written informed consent for participation in the trial. Exclusion Criteria: Active parenchymal disease (distant metastasis) (i.e. stage IV International Federation of Gynecology and Obstetrics (FIGO) classification. Presence of diagnosed extra abdominal metastasis Clinically significant heart disease. Electrocardiographic demonstrating clinically significant arrhythmias. Other serious illnesses, e.g. serious infections requiring antibiotics, coagulation disorders. Chronic inflammatory bowel disease. Chemotherapy, biologic therapy, or immunotherapy within 4 weeks prior Advanced abdominal adherences.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: To investigate the pharmacokinetics of the conjugate 211At-MX35 F(ab') 2. Groups of 3 patients will be treated at increasing activity concentrations starting at 50 MBq/L
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intraperitoneal Radioimmunotherapy boost<br>Four groups of 3 patients with recurring ovarian cancer treated by salvage chemo-therapy and being in complete or good partial remission will receive one IP dose of 211astatine-MX35 F(ab'2). Starting at 50 MBq/L. Dose escalation 100 Mbq/L, 200 MBq/L and finally 300 MBq/L. | Combination Product: 211-astatine MX35 F(ab')2<br>* Alpha emitting radionuclide 211At conjugated to monoclonal antibody MX35 F(ab')2. Targeting the sodium phosphate transporter (NaPi2b).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) of Astatine 211 | Decay corrected activity concentration in serum, intraperitoneal fluid and urine. | Sampled from +1 hour to +48 hrs post infusion. | 
| Area under the curve (AUC) of astatine 211 from time of dosing to 48 hrs after dosing | Decay corrected activity concentration in serum, intraperitoneal fluid and urine, including actual imaging quantification on gamma-Camera scintigraphy. | Sampled from +1 hour to +48 hrs post infusion. | 
| Toxicity: hematology, liver, kidney, thyroid function | As defined by NCI Common Toxicity Criteria v2.0 | From procedure start (implantation of catheter) to 8 weeks after infusion |