Radioimmunotherapy of Small Cell Lung Carcinoma with the Two- Step Method Using a Bispecific Anti-Carcinoembryonic Antigen/ Anti-Diethylenetriaminepentaacetic Acid (DTPA) Antibody and Iodine-131 Di-DTPA Hapten: Results of a Phase I/II Trial 1

As small cell lung carcinoma (SCLC) is frequently a widespread disease at diagnosis, highly radiosensitive and often only partially responsive to chemotherapy, radioimmunotherapy (RIT) would appear to be a promising technique for treatment. We report the preliminary results of a Phase I/II trial of RIT in SCLC using a two-step method and a myeloablative protocol with circulating stem cells transplantation. Fourteen patients with proved SCLC relapse after chemotherapy were treated with RIT. They were first injected i.v. with a bispecific (anti-carcinoembryonic antigen/anti-diethylenetriaminepentaacetic acid) monoclonal antibody (20-80 mg in 100 ml of saline solution) and then 4 days later with di-(In-diethylenetriaminepentaacetic acid)tyrosyl-lysine hapten labeled with 1.48-6.66 GBq (40-180 mCi) of 1-131 and diluted in 100 ml of saline solution. In patients receiving 150 mCi or more, circulating stem cells were harvested before treatment and reinfused 10-15 days later. Treatment response was evaluated by CT and biochemical data during the month before and 1, 3, 6, and 12 months after treatment. All patients received the scheduled dose without immediate adverse reactions to bispecific antibody or 1-131 hapten. Toxicity was mainly hematological, with two cases of grade 2 leukopenia and three cases of grade 3 or 4 thrombopenia. Body scanning 8 days after injection of the radiolabeled hapten generally showed good uptake at the tumor sites. Esti1 Presented at the "Seventh Conference on Radioimmunodetection and Radioimmunotherapy of Cancer," October 15-17, 1998, Princeton, NJ. Supported by a grant from the "Program Hospitatier de Recherche Clinique" 1996 conducted by the French Ministry of Health. 2 To whom requests for reprints should be addressed, at Laboratoire d'Etude de Radiopharmaceutiques Unite Propre de Recherche de l'Enseignement Superieur Associ6. Centre National de la Recherche Scientifique 5077, Facult6 de M6decine, 38700 La Tronche, France. mated tumor dose was 2.6-32.2 cGy/mCi. Among the 12 patients evaluated to date, we have observed 9 progressions, 2 partial responses (one almost complete for 3 months), and 1 stabilization of more than 24 months. Efficiency and toxicity were dose-related. The maximal tolerable dose without hematological rescue was 150 mCi. These preliminary results are encouraging, and dose escalation is currently continuing to reach 300 mCi. RIT should prove to be an interesting therapeutic method for SCLC, although repeated injections and hematological rescue will probably be required, as well as combination with other treatment modalities. Introduction SCLC 3 represents 15-20% of all bronchogenic carcinoma diagnosed in France (1) and the United States (2). Over the past 15 years, multimodality treatment, including multiagent chemotherapy, has led to an improvement in survival, but the efficacy of SCLC treatment remains limited despite high response rates to chemotherapy and radiotherapy. The use of combined chemotherapy and thoracic radiation therapy for limited SCLC enhances local control and improves survival (3); prophylactic cranial irradiation reduces the frequency of clinically significant brain metastases and should be proposed to patients achieving a complete response (4), whereas surgery may benefit a small number of patients with stage 1 tumor (5). However, 2-year survival is usually less than 25%, even in limited disease, and fewer than 10% of patients are alive and tree of disease at 5 years (6-8) . RIT is an internal radiotherapy approach in which radionuclide-labeled monoclonal antibodies recognizing tumor-associated antigens are administered systemically for selective targeting of radioactivity to tumor cells. Very encouraging results have already been obtained in N H M L with or without myeloablation with iodine-13 I-labeled anti-CD20 monoclonal antibodies (9-12). However, some well-known limitations of RIT are mostly problematic for solid tumor. In particular, nonspecific activity in normal tissues is usually too high compared to tumor uptake, providing an inadequate tumor:nontumor ratio that limits the rate of injected activity (13, 14). The AES has been proposed to increase the tumor:nontumor ratios. AES consists in a two-step 3 The abbreviations used are: SCLC, small cell lung carcinoma; RIT, radioimmunotherapy; AES, affinity enhancement system; Bs, bispecific; Ab, antibody; MAb, monoclonal Ab; HAMA, human antimouse antibodies; CEA, carcinoembryonic antigen; BMT, bone marrow transplantation; NHML, non-Hodgkin malignant lymphoma; DTPA, diethylenetriaminepentaacetic acid; CT, computed tomography. Research. on November 1, 2017. © 1999 American Association for Cancer clincancerres.aacrjournals.org Downloaded from 3260s Two-Step Radioimmunotherapy for SCLC Table 1 Eligibility of patients Inclusion criteria Exclusion criteria Histologically confirmed diagnosis of SCLC CEA expression by primary tumor ~>40% of tumor cells Documented known recurrence(s) No alternative treatment Bone scan within the last 3 months Serum bilirubin and serum creatinine level < 1.5• normal value Leukocyte count >4000/mm ~ Platelet count > 100,000/mm 3 Age -> 18 years and --<75 years Karnofsky index >60% Life expectancy >9 weeks Signed informed consent form Known intercurrent cancer Psychiatric disorders Previous injected murine monoclonal antibody with positive HAMA External radiotherapy and chemotherapy within the last month Unstable condition not allowing isolation therapy Pregnancy or breast-feeding No informed consent method using a BsAb and a bivalent radiolabeled hapten (15, 16). Dosimetric studies in patients have confirmed the possible therapeutic benefit of this method (17). The present Phase I/II dose escalation trial was undertaken to evaluate the feasibility and toxicity of the method. Response to treatment was evaluated as a secondary goal of the study. Patients and Methods Patients. Eligible patients were adults with histologically proved SCLC expressing the CEA antigen (at least 40% of tumor cells expressing CEA on a biopsy specimen), who had failed at least on one prior chemotherapy regimen and had assessable and measurable disease. Detailed patient selection criteria are indicated in Table 1. Reagents. A Bs anti-CEA/anti-DTPA-indium Ab (BsMAb anti-CEA/anti-DTPA-In) designated F6-734 was obtained by coupling an equimolar quantity of a Fab' fragment of anti-CEA MAb F6 (murine IgG1 K, specific for human CEA) to a Fab fragment of anti-DTPA-In MAb 734 (murine IgG1M specific for DTPA-In complexes) previously activated by ophenylenedimaleimide. The bivalent DTPA hapten N-oL-DTPA-tyrosyl-n-e-DTPAlysine (di-DTPA) was obtained by reaction of DTPA dianhydride with tyrosyl-lysine diacetate (18). 131I -bivalent hapten (13JI -di-DTPA-In) was provided by Cis Bio-International (Saclay, France). Before labeling, DTPA bivalent hapten was saturated with indium in an indium chloride solution because MAb 734 only recognizes the DTPA-In complex. AES Therapeutic Protocol and Dose Escalation Protocol. The aim of this Phase I/II study was mainly to determine the maximal tolerated dose. For this purpose, dose escalation was performed, starting from 1.85 GBq (50 mCi) of 131I -diDTPA-In and increasing by 1.85-GBq steps. The two-step method has been described elsewhere (15). Briefly, during the first step at day 0 (DO), nonlabeled Bs anti-CEA/anti-DTPA Ab was injected at a dose of 1 mg of Ab for 4 nmol (74 MBq) of 131I-hapten in a 100 ml serum saline infusion. Four days later (day 4), the second step consisted in injecting di-DTPA-tyrosyl-lysine bivalent hapten labeled with iodine-131. The 131I -hapten was injected in serum saline through a radioprotected device (Perfucis, Cis Bio-International). Infusion was performed inside a lead-protected room in which patients remained until the dose rate became less than 20 txSv at 1 m. To protect the thyroid gland from inappropriate irradiation, the patient received 30 drops of saturated solution of potassium iodine p.o. three times daily, beginning 3 days before injection of 131I -hapten and then for 14 days after therapy. Toxicity Monitoring. Toxicity was assessed from clinical and biological data, i.e., blood cell count, liver enzyme level (aspartate aminotransferase, alanine aminotransferase, y glutamyl transpeptidase, alkaline phosphatase, and lactate dehydrogenase), blood biochemistry (urea, creatinine, glucose, total bilirubin, total proteins, and albumin), and urine parameters (protein, WBCs, and RBCs). Hematological Rescue. During the first course of the protocol, it appeared that hematological toxicity was problematic for injected activities above 5.55 GBq (150 mCi). Thus, the protocol was modified, with the approval of the local ethics committee, to perform autologous BMT with peripheral stem cells. Stem cells obtained by cytapheresis after stimulation by granulocyte macrophage colony-stimulating factor (10 txg/kg of body weight for 5 days) were systematically harvested before RIT for doses of 150 mCi or more. RIT was then performed if more than 1.5 • 106 stem cells (CD34+)/kg were obtained; if not, the injected activity was reduced to 100 mCi. When BMT was scheduled, stem cells were reinjected as soon as blood activity became lower than 1 bLCi/ml. Treatment Effectiveness. Response to treatment was evaluated by clinical data, morphological imaging (CT, ultrasound, and sometimes magnetic resonance imaging), and biological data (CEA and neuron-specific enolase serum levels). Response categories were defined as follows. A complete response (CR) was defined as the disappearance of all clinical and radiological evidence of disease, together with negative CEA and neurone-specific enolase serum blood levels, lasting a minimum of 1 month. A partial response (PR) was defined as a decrease of 50% or more in the size of all of the measurable lesions lasting at least 1 month. A minor response (PR) was defined as a decrease of less than 50% and more than 25% in the size of all of the measurable lesions, lasting for at least 1 month. Stable disease (SD) was defined as a less than 25% decrease or a less than 25% increase in size lasting for at least 1 month. Disease progression (PD) was defined as an increase of greater than 25% of the cross-sectional area of one or more lesions or the occurrence of new lesions irrespective of response elsewhere. Research. on November 1, 2017. © 1999 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Clinical Cancer Research 3261s Patient Disease [ACE] [NSE] no. Sex Age spread ng/ml ng/ml Table 2 Patient characteristics Previous treatments Residual disease 01 M 65 D a 135.1 19.5