Intraperitoneal α-Particle Radioimmunotherapy of Ovarian Cancer Patients: Pharmacokinetics and Dosimetry of ²¹¹At-MX35 F(ab′)₂—A Phase I Study

Abstract

The a-emitter 211 At labeled to a monoclonal antibody has proven safe and effective in treating microscopic ovarian cancer in the abdominal cavity of mice. Women in complete clinical remission after second-line chemotherapy for recurrent ovarian carcinoma were enrolled in a phase I study. The aim was to determine the pharmacokinetics for assessing absorbed dose to normal tissues and investigating toxicity. Methods: Nine patients underwent laparoscopy 2-5 d before the therapy; a peritoneal catheter was inserted, and the abdominal cavity was inspected to exclude the presence of macroscopic tumor growth or major adhesions. 211 At was labeled to MX35 F(ab9) 2 using the reagent N-succinimidyl-3-(trimethylstannyl)-benzoate. Patients were infused with 211 At-MX35 F(ab9) 2 (22.4-101 MBq/L) in dialysis solution via the peritoneal catheter. g-camera scans were acquired on 3-5 occasions after infusion, and a SPECT scan was acquired at 6 h. Samples of blood, urine, and peritoneal fluid were collected at 1-48 h. Hematology and renal and thyroid function were followed for a median of 23 mo. Results: Pharmacokinetics and dosimetric results were related to the initial activity concentration (IC) of the infused solution. The decay-corrected activity concentration decreased with time in the peritoneal fluid to 50% IC at 24 h, increased in serum to 6% IC at 45 h, and increased in the thyroid to 127% 6 63% IC at 20 h without blocking and less than 20% IC with blocking. No other organ uptakes could be detected. The cumulative urinary excretion was 40 kBq/(MBq/L) at 24 h. The estimated absorbed dose to the peritoneum was 15.6 6 1.0 mGy/(MBq/L), to red bone marrow it was 0.14 6 0.04 mGy/(MBq/L), to the urinary bladder wall it was 0.77 6 0.19 mGy/(MBq/L), to the unblocked thyroid it was 24.7 6 11.1 mGy/(MBq/L), and to the blocked thyroid it was 1.4 6 1.6 mGy/(MBq/L) (mean 6 SD). No adverse effects were observed either subjectively or in laboratory parameters. Conclusion: This study indicates that by intraperitoneal administration of 211 At-MX35 F(ab9) 2 it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity. The lifetime risk of ovarian cancer is 1%22% in European and U.S. women. Despite seemingly successful cytoreductive surgery, followed by systemic chemotherapy, most patients will relapse and succumb. The relapse is most frequently localized in the abdominal cavity. New systemic chemotherapy regimens have not improved the outcome over the past decade, which prompted experimental intraperitoneal treatments, including radioimmunotherapy.Radioimmunotherapy with b-emitters has displayed promising results, although an international randomized phase III study of 90 Y-HMFG1 showed no improvement in survival or time to relapse (1). This disappointing result could be partly explained by the choice of radionuclide. The long range of this b-emitter results in poor irradiation of small tumor clusters, likely insufficient to eradicate peritoneal micrometastases. Furthermore, the relativel...

Pharmacokinetics and Imaging of212Pb-TCMC-Trastuzumab After Intraperitoneal Administration in Ovarian Cancer Patients

“…[13][14][15][16][17] The starting dose level for this first cohort in a Phase I trial was low compared to theoretical tolerance and experience in other species but was consistent with the starting dose for another a particle radioimmunotherapy trial using 211 At. 20 This dose allowed monitoring of blood, urine, and imaging with minimal exposure to laboratory personnel. Subsequent dose groups will also be followed for toxicity but will have less quantitative pharmacokinetics/dosimetry data collection.…”

“…[6][7][8][9][10]22 IP therapy using another a-emitting conjugate, 211 At-MX35F(ab¢) 2 , has shown promise as an adjuvant therapy for ovarian cancer in patients with no evidence of gross disease. 20 Based on clinical experience and preclinical data, it is reasonable to expect that treatment at the time when disease deposits are only microscopic should provide the maximum therapeutic benefit. 7,8,10,20 212 Pb-TCMC-trastuzumab may have beneficial activity against a number of malignancies that have HER-2 expression.…”

“…The amount of radioactivity detected in the blood and urinary loss is consistent with that of other radiolabeled antibody conjugates. 9,10,[20][21][22] As a precaution to possible localization to organs/tissues outside the peritoneal cavity that might have HER-2 expression, a standard loading dose of 4 mg/kg trastuzumab was given intravenously within 4 hours prior to the IP injection of 212 Pb-TCMC-trastuzumab.…”

Radio-immunothérapie alpha

“…At-MX35-F(ab') 2 Cancer des ovaires 9 patients traités ; aucune toxicité significative [31] 213 Bi-Substance P Glioblastome 5 patients traités ; 2 améliorations de l'index de Barthel [32,33] TIRÉS À PART J. Ménager …”

Emerging Trends for Radioimmunotherapy in Solid Tumors

“…Several studies have been undertaken to identify the most suitable radionuclides (b-, a-or auger-emitters), antibody formats [F(ab¢) 2 IgG, IgM] and types (internalizing vs. noninternalizing), and evaluating the toxicity of radionuclides on the peritoneal membrane. [18][19][20][21][22][23][24] In the context of intraperitoneal RIT involving a-particle emitters, recent studies have also explored their utility in several ways: multiple administrations 25 and the impact of using variable specific activities 26 ; compared the efficacy of intraperitoneal RIT with pretargeted intraperitoneal RIT 27 ; and investigated the impact of antibody glycosylation on efficacy. 28 …”