Radioimmunotherapy of Small Cell Lung Carcinoma with The

Vol. 5, 3259s-3267s, October 1999 (Suppl.) Clinical Cancer Research 3259s

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

Jean-Philippe Vuillez, 2 Fran~oise Kraeber-Bod~r~, mated tumor dose was 2.6-32.2 cGy/mCi. Among the 12 pa- Denis Moro, Manuel Bardi~s, tients evaluated to date, we have observed 9 progressions, 2 partial responses (one almost complete for 3 months), and 1 Jean-Yves Douillard, Emmanuel Gautherot, stabilization of more than 24 months. Efficiency and toxicity Eric Rouvier, Jacques Barbet, Frederic Garban, were dose-related. The maximal tolerable dose without hema- Philippe Moreau, and Jean-Francois Chatal tological rescue was 150 mCi. These preliminary results are Nuclear Medicine Department [J. P. V.], Pneumology Department encouraging, and dose escalation is currently continuing to [D. M.], and Hematology Department [F. G.], University Hospital, reach 300 mCi. RIT should prove to be an interesting thera- 38000 Grenoble; Nuclear Medicine Department IF. K-B., M. B., peutic method for SCLC, although repeated injections and J-F. C.], Oncology Department [J-Y. D.], and Hematology Department [P. M.], Cancer Center and University Hospital, 4400 Nantes; and hematological rescue will probably be required, as well as Immunotech Co., 13276 Marseille [E. G., E. R., J. B.], France combination with other treatment modalities.

Introduction Abstract SCLC 3 represents 15-20% of all bronchogenic carcinoma As small cell lung carcinoma (SCLC) is frequently a diagnosed in France (1) and the United States (2). Over the past widespread disease at diagnosis, highly radiosensitive and 15 years, multimodality treatment, including multiagent chemo- often only partially responsive to chemotherapy, radioim- therapy, has led to an improvement in survival, but the efficacy munotherapy (RIT) would appear to be a promising tech- of SCLC treatment remains limited despite high response rates nique for treatment. We report the preliminary results of a to chemotherapy and radiotherapy. The use of combined chem- Phase I/II trial of RIT in SCLC using a two-step method and otherapy and thoracic radiation therapy for limited SCLC en- a myeloablative protocol with circulating stem cells trans- hances local control and improves survival (3); prophylactic plantation. Fourteen patients with proved SCLC relapse cranial irradiation reduces the frequency of clinically significant after chemotherapy were treated with RIT. They were first brain metastases and should be proposed to patients achieving a injected i.v. with a bispecific (anti-carcinoembryonic anti- complete response (4), whereas surgery may benefit a small gen/anti-diethylenetriaminepentaacetic acid) monoclonal number of patients with stage 1 tumor (5). However, 2-year antibody (20-80 mg in 100 ml of saline solution) and then survival is usually less than 25%, even in limited disease, and 4 days later with di-(In-diethylenetriaminepentaacetic acid)- fewer than 10% of patients are alive and tree of disease at 5 tyrosyl-lysine hapten labeled with 1.48-6.66 GBq (40-180 years (6-8). mCi) of 1-131 and diluted in 100 ml of saline solution. In RIT is an internal radiotherapy approach in which radio- patients receiving 150 mCi or more, circulating stem cells were nuclide-labeled monoclonal antibodies recognizing tumor-asso- harvested before treatment and reinfused 10-15 days later. ciated antigens are administered systemically for selective tar- Treatment response was evaluated by CT and biochemical geting of radioactivity to tumor cells. Very encouraging results data during the month before and 1, 3, 6, and 12 months after have already been obtained in NHML with or without myeloa- treatment. All patients received the scheduled dose without blation with iodine-13 I-labeled anti-CD20 monoclonal antibod- immediate adverse reactions to bispecific antibody or 1-131 ies (9-12). hapten. Toxicity was mainly hematological, with two cases of However, some well-known limitations of RIT are mostly grade 2 leukopenia and three cases of grade 3 or 4 thrombope- problematic for solid tumor. In particular, nonspecific activity in nia. Body scanning 8 days after injection of the radiolabeled normal tissues is usually too high compared to tumor uptake, hapten generally showed good uptake at the tumor sites. Esti- 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

1 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 3 The abbreviations used are: SCLC, small cell lung carcinoma; RIT, Clinique" 1996 conducted by the French Ministry of Health. radioimmunotherapy; AES, affinity enhancement system; Bs, bispecific; 2 To whom requests for reprints should be addressed, at Laboratoire Ab, antibody; MAb, monoclonal Ab; HAMA, human antimouse anti- d'Etude de Radiopharmaceutiques Unite Propre de Recherche de bodies; CEA, carcinoembryonic antigen; BMT, bone marrow transplan- l'Enseignement Superieur Associ6. Centre National de la Recherche tation; NHML, non-Hodgkin malignant lymphoma; DTPA, diethylene- Scientifique 5077, Facult6 de M6decine, 38700 La Tronche, France. triaminepentaacetic acid; CT, computed tomography.

Table 1 Eligibility of patients Inclusion criteria Exclusion criteria Histologically confirmed diagnosis of SCLC Known intercurrent cancer CEA expression by primary tumor ~>40% of tumor cells Psychiatric disorders Documented known recurrence(s) Previous injected murine monoclonal antibody with positive HAMA No alternative treatment External radiotherapy and chemotherapy within the last month Bone scan within the last 3 months Unstable condition not allowing isolation therapy Serum bilirubin and serum creatinine level < 1.5• normal value Pregnancy or breast-feeding Leukocyte count >4000/mm ~ No informed consent Platelet count > 100,000/mm 3 Age -> 18 years and --<75 years Karnofsky index >60% Life expectancy >9 weeks Signed informed consent form

method using a BsAb and a bivalent radiolabeled hapten (15, txSv at 1 m. To protect the thyroid gland from inappropriate 16). Dosimetric studies in patients have confirmed the possible irradiation, the patient received 30 drops of saturated solution of therapeutic benefit of this method (17). potassium iodine p.o. three times daily, beginning 3 days before The present Phase I/II dose escalation trial was undertaken injection of 131I -hapten and then for 14 days after therapy. to evaluate the feasibility and toxicity of the method. Response Toxicity Monitoring. Toxicity was assessed from clini- to treatment was evaluated as a secondary goal of the study. cal and biological data, i.e., blood cell count, liver enzyme level (aspartate aminotransferase, alanine aminotransferase, y glu- Patients and Methods tamyl transpeptidase, alkaline phosphatase, and lactate dehydro- Patients. Eligible patients were adults with histologically genase), blood biochemistry (urea, creatinine, glucose, total proved SCLC expressing the CEA antigen (at least 40% of bilirubin, total proteins, and albumin), and urine parameters tumor cells expressing CEA on a biopsy specimen), who had (protein, WBCs, and RBCs). failed at least on one prior chemotherapy regimen and had Hematological Rescue. During the first course of the assessable and measurable disease. Detailed patient selection protocol, it appeared that hematological toxicity was problem- criteria are indicated in Table 1. atic for injected activities above 5.55 GBq (150 mCi). Thus, the Reagents. A Bs anti-CEA/anti-DTPA-indium Ab protocol was modified, with the approval of the local ethics (BsMAb anti-CEA/anti-DTPA-In) designated F6-734 was ob- committee, to perform autologous BMT with peripheral stem tained by coupling an equimolar quantity of a Fab' fragment of cells. Stem cells obtained by cytapheresis after stimulation by anti-CEA MAb F6 (murine IgG1 K, specific for human CEA) to granulocyte macrophage colony-stimulating factor (10 txg/kg of a Fab fragment of anti-DTPA-In MAb 734 (murine IgG1M body weight for 5 days) were systematically harvested before specific for DTPA-In complexes) previously activated by o- RIT for doses of 150 mCi or more. RIT was then performed if phenylenedimaleimide. more than 1.5 • 106 stem cells (CD34+)/kg were obtained; if The bivalent DTPA hapten N-oL-DTPA-tyrosyl-n-e-DTPA- not, the injected activity was reduced to 100 mCi. When BMT lysine (di-DTPA) was obtained by reaction of DTPA dianhy- was scheduled, stem cells were reinjected as soon as blood dride with tyrosyl-lysine diacetate (18). 131I -bivalent hapten activity became lower than 1 bLCi/ml. (13JI -di-DTPA-In) was provided by Cis Bio-International Treatment Effectiveness. Response to treatment was (Saclay, France). Before labeling, DTPA bivalent hapten was evaluated by clinical data, morphological imaging (CT, ultra- saturated with indium in an indium chloride solution because sound, and sometimes magnetic resonance imaging), and bio- MAb 734 only recognizes the DTPA-In complex. logical data (CEA and neuron-specific enolase serum levels). AES Therapeutic Protocol and Dose Escalation Proto- Response categories were defined as follows. A complete re- col. The aim of this Phase I/II study was mainly to determine sponse (CR) was defined as the disappearance of all clinical and the maximal tolerated dose. For this purpose, dose escalation radiological evidence of disease, together with negative CEA was performed, starting from 1.85 GBq (50 mCi) of 131I -di- and neurone-specific enolase serum blood levels, lasting a min- DTPA-In and increasing by 1.85-GBq steps. imum of 1 month. A partial response (PR) was defined as a The two-step method has been described elsewhere (15). decrease of 50% or more in the size of all of the measurable Briefly, during the first step at day 0 (DO), nonlabeled Bs lesions lasting at least 1 month. A minor response (PR) was anti-CEA/anti-DTPA Ab was injected at a dose of 1 mg of Ab defined as a decrease of less than 50% and more than 25% in the for 4 nmol (74 MBq) of 131I-hapten in a 100 ml serum saline size of all of the measurable lesions, lasting for at least 1 month. infusion. Four days later (day 4), the second step consisted in Stable disease (SD) was defined as a less than 25% decrease or injecting di-DTPA-tyrosyl-lysine bivalent hapten labeled with a less than 25% increase in size lasting for at least 1 month. iodine-131. The 131I -hapten was injected in serum saline Disease progression (PD) was defined as an increase of greater through a radioprotected device (Perfucis, Cis Bio-Internation- than 25% of the cross-sectional area of one or more lesions or al). Infusion was performed inside a lead-protected room in the occurrence of new lesions irrespective of response else- which patients remained until the dose rate became less than 20 where.

Table 2 Patient characteristics Patient Disease [ACE] [NSE] no. Sex Age spread ng/ml ng/ml Previous treatments Residual disease 01 M 65 D a 135.1 19.5 (Cisplatin-VP 16) • 6 Right lung, mediastinal mass and (Adria-cyclophosphamide-vincristine)• 2 lymphnodes 02 F 61 D 1.7 20 (Cisplatin-VP 16) • 6 Left lung, mediastinum, liver (Adria-cyclophosphamide-vincristine)X4 VPl6peros • 4 03 M 46 D 1.6 8.5 (Cisplatin-VP16) • 3 Mediastinum, lungs, liver (Epirubicin-ifosfamide-vepeside) • 4 04 M 59 D 4.5 74.7 (Adria-cisplatin-VP16-cyclophosphamide) x 6 Mediastinum (ifosfamide-uromitexan) • 3 Neck lymphnodes Radiotherapy Liver, bone metastases 05 F 67 D 4.3 9.6 (Adria-cisplatin-VP16-cyclophosphamide) • 5 Right lung mass (Ifosfamide-uromitexan) • 3 Bone metastases Radiotherapy 06 M 66 L 19.4 18.2 (Adria-cisplatin-VP16-cyclophosphamide) • 6 Left lung mass Radiotherapy 07 M 56 L 0.8 5.8 (Adria-cisplatin-VP16-cyclophosphamide) X 6 Left lung mass Radiotherapy 08 M 50 D 264. l 16.7 (Cisplatin-VP16) • 6 Bone, neck and mediastinal mass Radiotherapy 09 M 60 D 4.4 19.5 (Cisplatin-VP16) X 6 Liver metastases 10 M 71 D 6.4 12 (Cisplatin-VP16) X 6 Mediastinal lymphnodes, liver 11 M 63 L 1,015 5.3 (Adria-cisplatin-VP16) • 12 Mediastinal lymphnodes and tumor mass Radiotherapy 12 F 50 D 1,280 137.9 (Farmorubicin-cisplatin-VP16- Mediastinum and lung tumor mass cyclophosphamide) • 6 Liver and bone metastases 13 M 64 L 3 28.1 (Adria-cyclophosphamide-VP16) • 6 Mediastinum and lung tumor mass 14 M 48 L 3.5 7 (Cisplatin-VP16) • 6 Neck lymph nodes Taxotere X 3 Radiotherapy D, diffuse; L, localized disease, limited to the thorax.

Dosimetric Studies. The radiation dose delivered to tu- lives of 131I -labeled hapten in the regions defined and then the mor sites and normal organs was estimated by daily serial cumulative activity. whole-body scanning. Cumulative activity in whole-body, tu- The doses absorbed by tumor targets and normal tissues mor, liver, and kidneys was determined by whole-body quanti- after injection of 13 ~I -labeled hapten were calculated according tative scintigraphy performed with a double-headed Sopha Med- to the medical internal radiation dose scheme (20). ical camera (DHD Body Track) equipped with a high-energy Dosimetry was performed on scintigraphically visualized collimator, as proposed by DeNardo et al. (19). Whole-body tumors for which it was possible to define a target volume (and scintigraphic images (anterior and posterior views) were re- thus estimate the mass) from CT scan sections. Regions of corded 5 min after injection of 131I -labeled hapten and then at interest were defined on the liver and left kidney of each patient days 1, 2, 3, 4, and 7, using a 20% window set on the ~3~I to estimate the doses delivered to these organs. photopeak (364 keV). The positioning of the patient was done in The calculation of the bone-marrow dose was performed a reproducible manner using a system based on laser sources. according to the technique of DeNardo et al. (21) by summing The attenuation correction factor was determined from a a "whole-body" component of the bone-marrow dose (only transmission image. A collimated linear source perpendicular to penetrating radiations were taken into account) and a blood the direction of scanning movement was attached to the lower component (only nonpenetrating radiations were taken into ac- camera head. To define the geometrical parameters for record- count). ings, acquisition was performed in the presence and then the Bioethical Considerations. All patients received de- absence of the patient on the day of nonradiolabeled F6-734 tailed information and gave their signed written consent before BsMAb injection. being included. The protocol was approved by the local ethics The geometrical mean of each acquisition was calculated committee, according to European regulations. and multiplied by the attenuation correction factor to obtain the resulting image. During each acquisition, a known activity standard was placed on the examination table at the level of the Results patient's feet to determine the calibration factor for the camera Fourteen patients were included and completed the treat- (in counts per MBq in the air). The activities calculated at the ment. All patients had previously received at least one course of different time points were transferred to a pharmacokinetic chemotherapy and were in relapse of the disease. Patient char- study program (Siphar, Simed) to determine the effective half- acteristics are shown in Table 2.

Fig. 1 Patient 8. Whole-body scan at day 7 after RIT (50 mCi of ~31I -hapten), showing excellent targeting in all tumor sites in this very widespread recurrence of SCLC.

ANT POST

D 7 (50 mCi)

Tumor Targeting and Dosimetry. Tumor targeting was mass and tumor uptake, but also on the biological half-life of generally excellent, all tumoral sites being visualized with high radioactivity in the tumor. The maximum dose (32.2 cGy/mCi) contrast, even in case of very widespread disease (Fig. 1). The delivered to the tumor in terms of cGy/mCi was obtained with retention time of radioactivity in the tumor was good and, in the first level of activity in patient 5, who received 1.55 GBq (42 some cases, excellent; indeed, the biological half-life of radio- mCi) of hapten, producing a calculated total tumor dose of only activity in the tumor was between 4.5 and 22 days. Tumor:blood 13.5 Gy. ratios ranged between 0.64 and 5.8, and tumor:liver ratios For other tissues, greater doses were given to kidneys, ranged between 0.46 and 6.6 at day 7. according to the elimination of the radiolabeled hapten, and to Dosimetric data were available for six patients. Mean do- red bone marrow, which accounted for the toxicity. simetric values are indicated in Table 3. The estimated tumor Toxicity. Limiting toxicity was hematological (Table 4). dose was between 1.81 and 32.19 cGy/mCi, depending on tumor We observed four cases of grade III or IV leukopenia and 7

Table 3 Toxicity Grade 3 or 4 Injected activity, Bone marrow Red marrow Nadir duration Patient no. GBq (mCi) transplant dose (cGy) Myelotoxicity grade (days) (days) 02 1.18 (32) - NA a 1 (Plat.) 3O 04 1.61 (43.6) - 19 0 05 1.55 (42) - 73 1 (Plat.) 3O 08 1.86 (50.3) - NA 0 01 3.58 (96.8) - NA 0 03 3.64 (98.3) - NA 2 (Plat.) 30 06 3.90 (105.5) - 123 3 (Plat.), 2 (WBC) 33, 46 07 4.76 (128.8) - 117 0 09 5.03 (136) + NA 4 (Plat.), 3 (WBC) 19, 23 40, 5 10 4.62 (125) + NA 4 (Plat.), 4 (WBC) 24, 32 31, 32 11 5.91 (159.7) + 264 4 (Plat.), 3 (WBC) 25, 24 28, 7 12 2.78 (75.1) - NA 4 (Plat.), 3 (WBC) 14, 26 ND 13 5.74 (155.2) + NA 4 (Plat.), 3 (WBC) 21, 24 20 14 6.66 (180) + 3 (Plat.), 2 (WBC) 23, 30 2,2 a NA, not applicable; plat., platelet count.

Table 4 Dosimetry Dose (cGy) Dose/activity (cGy/mCi) Patient no. Injected activity, GBq (mCi) Tumor Total body Red marrow Liver Kidney 04 1.61 (44) 79/469 13 19 182 ND" 1.8/10.8 0.3 0.4 4.2 05 1.55 (42) 1352 41 73 210 ND 32.2 0.97 1.7 5.0 06 3.90 (106) 274 65 123 ND ND 2.6 0.62 1.2 07 4.76 (129) 2283 68 117 227 501 17.7 0.5 0.9 1.8 3.9 11 5.91 (160) 3655 140 161 258 ND 22.9 0.9 1.0 1.6 13 5.74 (155) 1706/2181 171 251 320 767 11/14 1.1 1.6 2.1 5.0 a ND, not determined.

cases of grade III or IV thrombopenia. Typically, thrombopenia The patient who exhibited almost complete response for 3 occurred earlier and persisted longer than leukopenia. No other months (patient 9) had residual disease consisting only in sev- significant adverse events were observed. eral small liver metastases (less than 1 cm in diameter). Most of Response to Treatment. Twelve patients were fully these lesions had disappeared 6 weeks after RIT (Fig. 4). Un- evaluated (for the other 2 patients, follow-up was less than 3 fortunately, reccurrences were detected after 3 months in liver months). Among these 12 patients, we observed 9 progressions, and brain. 2 partial responses (1 almost complete, but unfortunately lasting HAMA Response. In most cases, survival was too short only 3 months), and 1 stabilization of more than 24 months. One to allow a good evaluation of HAMA occurrence. Among five patient (patient 12) was enrolled on a compassionate basis and complete evaluations, one patient showed significant HAMA thus was not taken into account for evaluation of efficacy. levels after 2 months, which persisted at 12 months. The patient who presented disease stabilization for more than 24 months (patient 3, Fig. 2) was a 46-year-old male. Pulmonary and mediastinal lesions, which were in progression Discussion before RIT, as compared to previous CT, were unchanged 1 year RIT is a new potentially useful method of treating dissem- after RIT was performed. inated, radiosensitive tumors for which chemotherapy, despite In the first patient who presented a partial response (patient significant responses, cannot provide a complete cure. Impres- 7, Fig. 3), lesions had decreased by more than 60% 3 and 6 sive results have been obtained in NHMLs using anti-CD20 months after RIT. This effect occurred quite late, differing from antibodies labeled with iodine-131 (9-11). An overall and com- effects usually obtained with conventional radiotherapy, and plete response rate of respectively 79 and 50% was obtained persisted after 17 months, at which time the patient died from with nonmyeloablative activities of 1311 -labeled anti-CD20 Ab. heart failure without evidence of disease progression. SCLC is another type of cancer for which RIT could

Table 5 Response to treatment and clinical outcome Survival after Patient Injected activity, Estimated RIT no. GBq (mCi) tumor dose Tumor response and clinical outcome (days) 01 3.58 (96.8) NA" Progression: death 109 02 1.18 (32) NA Progression: death 63 03 3.64 (98.3) NA Stable (>24 months) >800 04 1.61 (43.6) 80/473 Progression: death 48 05 1.55 (42) 1352 Progression: death 92 06 3.90 (105.5) 274 Progression: death 193 07 4.76 (128.8) 2286 Partial response: 60% decrease of tumor size (20 months) 583 08 1.86 (50.3) NA Progression: death 34 09 5.03 (136) NA D30: partial response (>50%) of multiple liver metastases; occurrence of brain 165 metastases M3: partial response (liver metastases); external beam radiation of brain; death 10 4.62 (125) NA Progression: death 78 11 5.91 (159.7) 3664 Rapidly growing tumor before inclusion; progression: death 127 12 2.78 (75.1) NA Enrolled on a compassionate basis (life expectancy <9 weeks); progression: death 30 13 5.74 (155.2) NA Progression >60 14 6.66 (180) NA D30: minimal response (-20%) >50 a NA, not applicable.

provide beneficial additional treatment. Despite a high response rate since the introduction of platinum and multidrug regimens, chemotherapy has led to durable complete remission in less than 20% of cases, even in localized intrathoracic forms (22). Preliminary studies have been conducted with various antibodies, such as anti-GD2 ganglioside MAb 3F8 (23), MOC-31 (24), and anti-neural cell adhesion molecule antibodies (25, 26). However, no clinical results appear to have been reported with RIT for SCLC. Toxicity. The AES method provided high tumor:whole- body, tumor:liver, and tumor:blood ratios, as well as a favorable tumor:red marrow ratio, whereas limiting toxicity was hemato- July 29, 1996 - Month 2 PRE-RIT logical with severe leukopenia and thrombopenia occurring when injected activity was greater than 5.55 GBq (150 mCi), which required autologous BMT. This hematological toxicity could be partially explained by bone marrow tumor involve- ment, which is frequent at advanced stages of the disease. Dosimetry and Clinical Response. Three significant responses were obtained in 12 evaluable patients. The total tumor dose, which depended on injected activity as well as tumor uptake and the retention time of radiolabeled hapten, was significant, but probably not sufficient for a tumoricidal effect (the March 19, 1997 - Month 6 POST-RIT maximum calculated dose was 36 Gy). At least three parameters may account for the dose received by the tumor, i.e., tumor uptake and the tumor:nontumor ratio, retention time of radioactivity in the tumor, and injected activity. In solid tumors (with the exception of lymphoma), RIT is generally limited by a low tumor:tissue uptake ratio, which reduces injected activity and the dose delivered to tumor to spare other tissues from excessive toxicity. Moreover, in many cases, the retention time of radiolabeled antibodies in tumor is of short duration. The AES method improves both of these limiting September 22, 1997 - Month 12 POST-tilT parameters (15). The tumor:nontumor tissue ratio is increased, mainly because nonspecific activity is reduced, which has been Fig. 2 Patient 3. This patient experienced disease stabilization for demonstrated with radioimmunodetection using l~In-labeled more than 12 months. Lesions that were in progression before RIT, as bivalent hapten for immunoscintigraphy of medullary thyroid compared to previous CT, were unchanged in subsequent examinations after RIT was performed. After 24 months, the clinical status of this carcinoma (27) and non-SCLC (28), and in animal studies (29). patient was unchanged. In addition, the retention time in tumor is increased, which, in

Fig. 3 a, left, this patient (patient 7) had a left pulmonary residual tumor before RIT (arrow). Right, after RIT, a significant decrease (greater than 50%) in the tumor mass December 20, 1996 dune 22, 1998 was observed, and the case was considered as a partial response. PRE-RIT Month 17 POST-RIT This effect occurred late, reached 60% of decrease at 6 months, and persisted after 17 months (arrow). b, control scan performed 3 days after injection of the labeled hapten, showing the good targeting of the tumoral site, providing a dose of 17.7 cGy/mCi. This patient received 129 mCi; thus, the total dose to the tumor could be estimated as 22.8 Gy

ANT POST

the present study, was especially favorable in some cases, reach- Such results are satisfactory in a Phase I/II trial and justify ing 32.2 days. the continuation of this therapeutic approach, to improve the In the present Phase I/II trial, treatment efficiency was not dose delivered to tumor. If sufficient dose levels are obtained, the main objective, and only three responses were obtained, the therapeutic benefit of internal irradiation could be extrapo- probably because of the low injected activities. In terms of lated from that of external beam radiation on the thorax, which cGy/mCi, the maximum dose delivered to tumor was obtained provides an increase of 5-15% in relapse-free survival in local- with 1.55 GBq (42 mCi) of hapten, providing a total tumor dose ized forms (3, 22). For this purpose, two complementary strat- of only 13.5 Gy, which probably accounted at least in part tor egies may be proposed. First, injected activity could be in- the observed progression of disease in this patient. Conversely, creased. Our study shows that in cases in which circulating stem the three significant responses we observed were all obtained for cells could be harvested (in fact, bone marrow is often impaired injected activities greater than 3.7 GBq (100 mCi). If only after chemotherapy), more than 200 mCi could be given without patients injected with a dose of 3.7 GBq or more are considered, significant nonhematological adverse effects. Thus, dose esca- the response rate was three of seven evaluable patients (42.8%). lation studies are continuing to reach a level of 300 mCi.

References 1. Moro, D., Jacoulet, P., Quoix, E., Ranfang, E., Brambilla, E., Capron, F., Lagrange, J. L., Milleron, B., Lebeau, B., Ruffle, P., Riviere, A., Blanchon, F., Geraads, A., Depien'e, A., and the members of the "Groupe d'Oncologie de Langue Fran~aise." Small-cell lung cancer: patients surviving longer than thirty months. Anticancer Res., 14: 301- 304, 1994. 2. American Cancer Society. Cancer Statistics 1984. CA Cancer J. Clin., 34: 7-23, 1984. 3. Pignon, J. P., Arriagada, R., Ihde, D. C., Johnson, D. H., Perry, M. C., Souhami, R. L., Brodin, O., Joss, R., Kies, M. S., Lebeau, B., Onoshi, T., Osterlind, K., Tattersall, M. H. N., and Wagner, H. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N. Engl. J. Med., 327: 1618-1624, 1992. 4. Gregor, A., Cull, A., Stephens, R. J., Kirkpatrick, J. A., Yarnold, J. R., Girling, D. J., Macbeth, F. R., Stout, R., and Machin, D. Prophy- lactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. Eur. J. Cancer, 33: 1752-1758, 1997. 5. Shields, T. W., Higgins, G. A., and Matthews, M. S. Surgical resection in the management of small cell carcinoma of the lung. J. Thorac. Cardiovasc. Surg., 84: 481-488, 1982. 6. Ihde, D. C. Chemotherapy of lung cancer. N. Engl. J. Med., 327: 1434-1441, 1992. 7. Souhami, R. L., and Law, K. Longevity in small-cell lung cancer. A report of the United Kingdom Coorcinating Committee for Cancer Research. Br. J. Cancer, 61: 584-589, 1990. Before RIT 6 weeks after RIT 8. Lassen, U., Osterlind, K., Hansen, M., Dombernowsky, P., Bergman, B., and Hansen, H. Long-term survival in small-cell lung cancer: post- Fig. 4 Patient 9. Almost complete response for 3 months. Residual treatment characteristic in patients surviving 5 to 18+ years: an analysis disease in this patient consisted only small liver metastases (arrows), of 1,714 consecutive patients. J. Clin. Oncol. 13: 1215-1220, 1995. most of which disappeared 6 weeks after RIT. Unfortunately, recur- 9. Kaminski, M. S., Zasadny, K. R., Francis, I. R., Fenner, M. C., Ross, rences were detected after 3 months, in liver and brain. C. W., Milik, A. W., Estes, J., Tuck, M., Regan, D., Fisher, S., Glenn, S. D., and Wahl, R. L. Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J. Clin. Oncol., 14: 1974-1981, 1996. 10. Kaminski, M. S., Zasadny, K. R., Francis, I. R., Milik, A. W., Ross, Second, injections could be repeated, as in NHML. The possi- C. W., Moon, S. D., Crawford, S. M., Burgess, J. M., Petry, N. A., bility of repeating injections depends on the absence of HAMA. Butchko, G. M., Glenn, S. D., and Wahl, R. L. Radioimmunotherapy of However, in the present study, follow-up was too short in most B-cell lymphoma with [131I]anti-B1 (anti-CD20) antibody. N. Engl. cases to have a correct evaluation of the frequency of HAMA J. Med., 329: 459-465, 1993. occurrence. In another study concerning medullary thyroid car- 11. Wahl, R. L., Zasadny, K. R., MacFartane, D., Francis, I. R., Ross, C. W., Estes, J., Fisher, S., Regan, D., Kroll, S., and Kaminski, M. S. cinoma, HAMA was found in 9 of 17 patients (53%). In any Iodine-131 anti-B1 antibody for B-cell lymphoma: an update on the event, BsAb will be totally humanized in the near future, so that Michigan Phase I experience. J. Nucl. Med., 39 (Suppl.): 21S-27S, HAMA should no longer be a problem with repeated injections. 1998. RIT, like internal radiotherapy in general, is more efficient 12. Press, O. W., Eary, J. F., Applebaum, F. R., Martin, F., Nelp, W., when tumor targets are smaller, i.e., less than 1 cm in diameter Glenn, S., Fisher, D, Porter, B., Matthews, D., Gooley, T., and Bern- (13). For this reason, patients enrolled in the present Phase I stein, I. D. Phase II trial of 13~I -B1 (anti CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. study, who generally had a large tumor burden after proved Lancet, 346: 336-340, 1995. chemotherapy failure, did not represent the best population for 13. Chatal, J. F., Peltier, P., Bardies, M., Chetanneau, A., Thedrez, P., the RIT success. The method would probably be more efficient Faivre-Chauvet, A., and Gestin, J. F. Does immunoscintigraphy serve if applied together with chemotherapy (either at the same time clinical needs effectively? Is there a future for radioimmunotherapy? or immediately after), to eradicate microscopic or subclinical Eur. J. Nucl. Med., 19: 205-213, 1992. residual disease. Interestingly, the best response in our study 14. Behr, T. M., Goldenberg, D. M., and Becker, W. S. Radioimmu- notherapy of solid tumors: a review "of mice and men." Hybridoma, 16: was obtained for minimal residual lesions (liver metastases less 101-107, 1997. than 1 cm in diameter). Unfortunately, the patient who had no 15. Le Doussal, J. M., Chetanneau, A., Gruaz-Guyon, A., Martin, M., prophylactic brain irradiation died from brain metastases that Gautherot, E., Lehur, P. A., Chatal, J. F., Delaage, M., and Barber, J. appeared 1 month after RIT. Bispecific monoclonal antibody-mediated targeting of" an indium-11 I- Our study confirms the putative interest of RIT in SCLC labeled DTPA dimer to primary colorectal tumors: pharmacokinetics, and indicates that the AES method could contribute to better biodistribution, scintigraphy and immune response. J. Nucl. Med., 34: 1662-1671, 1993. efficacy by providing lower toxicity together with high tumor 16. Le Doussal, J. M., Gautherot, E., Martin, M., Barbet, J., and uptake, thereby allowing injection of activities that produce a Delaage, M. Enhanced in vivo targeting of an asymetric divalent hapten significant tumoricidal effect. The AES method will probably to double antigen-positive mouse B cells with monoclonal antibody prove useful in the future in association with other modalities. conjugate cocktails. J. Immunol., 146: 169-175, 1991.

17. Bardi6s, M., Bardet, S., Faivre-Chauvet, A., Peltier, P., Douillard, 24. Kosterink, J. G. W., de Jonge, M. W. A., Smit, E. F., Piers, D. A., J. Y., Mah6, M., Fiche, M., Lisbona, A., Giacalone, F., Meyer, P., Kengen, R. A. M., Postmus, P. E., Shochat, D., Groen, H. J. M., The, Gautherot, E., Rouvier, E., Barbet, J., and Chatal, J. F. Bispecific H. T., and de Leij, L. Pharmacokinetics and scintigraphy of indium- antibody and iodine-131-1abeled bivalent hapten dosimetry in patients 111-DTPA-MOC-31 in small-cell lung carcinoma. J. Nucl. Med., 36: with medullary thyroid or small-cell lung cancer. J. Nucl. Med., 37: 2356-2362, 1995. 1853-1859, 1996. 25. Mijnheere, E. P., Boerman, O. C., Poels, L. G., Slobbe, R. L., van 18. Le Doussal, J. M., Gruaz-Guyon, A., Martin, M., Gautherot, E., Eys, G. J. J. M., and Ramaekers, F. C. S. Pharmacokinetics, biodistri- Delaage, M., and Barbet, J. Targeting of indium 11 l-labeled divalent bution and dosimetry of anti-NCAM monoclonal antibody RNL-1 and hapten to human melanoma mediated by bispecific monoclonal antibody its fragments in experimental lung cancer. J. Exp. Clin. Cancer Res., 15: conjugates: imaging of tumors hosted in nude mice. Cancer Res., 50: 1118, 1996. 3445-3452, 1990. 26. Ordanel, D., Ledermann, J. A., Eagle, K., Pedley, R. B., Boxer, G., 19. DeNardo, G. L., DeNardo, S. J., Macey, D. J., and Mills, S. L. Ward, S. E., Olabiran, Y., and Bomanji, J. Biodistribution of a radio- Quantitative pharmacokinetics of radiolabeled monoclonal antibodies labelled monoclonal antibody NY3DI 1 recognizing the neural cell for imaging and therapy in patients. In: S. C. Srivastava (ed.), Radio- adhesion molecule in turnout xenografts and patients with small-cell labeled monoclonal antibodies for imaging and therapy, pp. 293-310. lung cancer. Br. J. Cancer, 77: 103-109, 1998. New York: Plenum Publishing Corp., 1988. 27. Peltier, P., Curtet, C., Chatal, J. F., Le Doussal, J. M., Daniel, G., 20. Loevinger, R., Budinger, T. F., and Watson, E. E. MIRD Primer for Aillet, G., Gruaz-Guyon, A., Barbet, J., and Delaage, M. Radioimmu- Absorbed Dose Calculations. New York: The Society of Nuclear Med- nodetection of medullary thyroid cancer using a bispecific anti-CEA/ icine, 1988. anti-indium-DTPA antibody and an indium-11 l-labeled DTPA dimer. 21. DeNardo, G. L., Mah6, M. A., DeNardo, S. J., Macey, D., Mirick, J. Nucl. Med., 34: 1267-1273, 1993. G., Erwin, W., and Groch, M. Body and blood clearance and marrow 28. Vuillez, J. P., Moro, D., Brichon, P. Y., Rouvier, E., Brambilla, E., radiation dose of 131I -Lym-1 in patients with B-cell malignancies. Nucl. Barbet, J., Peltier, P., Meyer, P., Sarrazin, R., and Brambilla, C. Two- Med. Commun., 14: 587-595, 1993. step immunoscintigraphy for non-small-cell lung cancer staging using a 22. Hansen, H. H. Management of small-cell cancer of the lung. Lancet, bispecific anti-CEA/anti-indium-DTPA antibody and an indium-11 i- 339: 846-849, 1992. labeled DTPA dimer. J. Nucl. Med., 38: 507-511, 1997. 23. Grant, S. C., Kostakoglou, L., Kris, M. G., Yeh, S. D. J., Larson, 29. Gautherot, E., Le Doussal, J. M., Bouhou, J., Manetti, C., Martin, S. M., Finn, R. D., Oettgen, H. F., and Cheung, N. K. V. Targeting of M., Rouvier, E., and Barbet, J. Delivery of therapeutic doses of radio- small-cell lung cancer using the antiGD2 ganglioside monoclonal anti- iodine using bispecific antibody-targeted bivalent haptens. J. Nucl. body 3F8: a pilot trial. Eur. J. Nucl. Med., 23: 145-149, 1996. Med., 39:1937-1943, 1998.

Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 1999 American Association for Cancer Research. 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

Jean-Philippe Vuillez, Françoise Kraeber-Bodéré, Denis Moro, et al.

Clin Cancer Res 1999;5:3259s-3567s.

Updated version Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/5/10/3259s

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/5/10/3259s. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.