InvestigationalNew Drugs9: 339-342, 1991. 9 1991 KluwerAcademic Publishers. Printedin the Netherlands.
Phase II trial of indicine N-oxide in relapsed pediatric solid tumors A report f r o m the Childrens Cancer S t u d y Group*
James S. Miser 1, William A. Smithson 1, William Krivit 2, Carla Hughes 3, Dianne Davis 3, Mark Krailo 4 and Denman H a m m o n d 4
1Department of Pediatrics, Mayo Clinic Foundation, Rochester, Minnesota; 2Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; 3Children's Hospital of Columbus, Columbus, Ohio; 4University of Southern California, Los Angeles, California Pasadena, California, USA Key words: indicine N-oxide, pediatric solid tumors, osteosarcoma, neuroblastoma, pediatric brain tumors
Abstract
We used indicine N-oxide to treat 46 children with malignant solid tumors: 17 with osteosarcoma, 12 with neuroblastoma, 13 with a brain tumor, and 4 with other miscellaneous tumors. The efficacy and toxicity of the drug was assessed at the dose of 2000 mg/m2/day for five consecutive days. None of the 39 patients evaluable for response achieved a complete or partial response. Hepatotoxicity was experienced by 13 patients: 11 patients developed asymptomatic elevations of transaminases, 1 patient developed hyperbilirubinemia, and 1 developed ascites. Indicine N-oxide appears to be ineffective in the treatment of osteosarcoma, neuroblastoma, and pediatric brain tumors at this dose and schedule. Because higher doses are associated with an unacceptably high incidence of severe, irreversible hepatotoxicity, we do not recommend further study of this agent in pediatric solid tumors.
Introduction
Indicine N-oxide is a pyrrolizidine alkaloid isolated from Heliotropium indicum, a flower used as a herbal medicine in Asia, Africa, and South America [1,2]. The alkaloids produce both antimitotic activity, as well as chromosomal breakage, suggesting that these agents may be of benefit in the treatment of malignant tumors [3,4]. The mechanism of action of indicine N-oxide is presently unknown; however, the toxicity may be due to interference with the purine metabolic pathway or to the drug's action as an oxygenating agent [5]. Because of its activity in experimental animal tumor systems (intraperitoneal murine leukemia P388, murine B16 melanoma, murine L1210 leukemia, and rat
Walker carcinoma 256), this agent was chosen for study in phase I and phase II trials in humans.
Materials and methods
Indicine N-oxide was administered to patients with relapsed solid tumors at the dose of 2000 mg/m2/day for 5 consecutive days (CCG 084). This dose was the maximally tolerated dose (MTD) in a phase I study of a five-day schedule of administration in children with solid tumors [6]. The doselimiting toxicity was myelosuppression, both thrombocytopenia and neutropenia; higher doses were also associated with severe hepatotoxicity. Patients whose surface area was less than 0.8 m 2 had
* Contributing Childrens Cancer Study Group Investigators, Institutions, and Grant Numbers are given in the Appendix.
340 their doses calculated on the basis of weight (60 m g / kg). Subsequent courses of therapy were administered at 28-day intervals. The drug was supplied by the National Cancer Institute as an off-white powder and administered by slow intravenous injection over 15 rain after reconstitution of the 1 g vials with 9.2 ml of sterile water. All patients were required to have disease that had relapsed and was refractory to standard therapy. All patients were required not to have received any anticancer therapy in the 4 weeks prior to study entry. Requirements for entry onto the study included adequate renal function and normal hepatic function. At least one measurable lesion was identified for the assessment of response to indicine Noxide. The index lesion(s) were reevaluated no later than 28 days after study entry. The following criteria for response were used: (1) Complete Remission (CR) - complete tumor regression and disappearance of all symptoms associated with the disease; (2) Partial Remission (PR) - 50 percent to 99 percent reduction in the sum of the products of the two greatest perpendicular diameters of all measurable tumor masses without the appearance of any new lesions; (3) Stable Disease (SD) - 0 percent to 49 percent reduction in the sum of the products of the two greatest perpendicular diameters of all measurable tumor masses without the appearance of any new lesions; and (4) Progressive Disease (PD) - occurrence of any new lesion or increase of any single measurable lesion by 25 percent as measured by the product of the two greatest perpendicular diameters. Therapy was continued until a patient demonstrated progression of disease, irreversible grade III toxicity or grade IV toxicity of any organ system. Toxicities were rated grade I (mild) to grade IV (life-threatening) based on specific limits for each organ system (schedule of toxicity measures available on request from Childrens Cancer Study Group). Hepatotoxicity was defined using the following criteria: grade 0 (enzymes and bilirubin within normal limits); grade 1 (enzymes elevated but _< 2.5 • normal); grade 2 (enzymes 2 . 6 - 5 . 0 x normal, bilirubin < 1.5 x normal); grade 3 (en-
zymes 5 . 1 - 2 0 . 0 x normal or bilirubin 1.5-3.0 x normal); grade 4 (enzymes > 20 x normal or bilirubin > 3 x normal). Myelosuppressive toxicity was defined as: grade 0 (white blood count (WBC) > 4,000/ml, absolute neutrophil count (ANC) _> 2,000/ml and platelet count (PLT) within normal limits); grade 1 (WBC 3,000-3,999/ml, ANC 1,500-1,999/ml, or P L T 7 5 , 0 0 0 / m l - n o r mal); grade 2 (WBC 2,000-2,999/ml, ANC 1,000-1,499/ml, or P L T 50,000-74,999/ml); grade 3 (WBC 1,000-1,999/ml, ANC 5 0 0 - 9 9 9 / ml, or P L T 25,000-49,999/ml); grade 4 (WBC < 1,000/ml, ANC < 500/ml, P L T < 25,000/ml). Patients receiving at least one course of therapy were considered evaluable for response. Patients who had progressive disease at any time after administration of the first course of therapy were considered as treatment failures.
Results
Forty-six patients were entered onto the study from December 1981 to April i986. The median age was 16 years (range, 4 to 23 years); 20 patients were female and 26 were male. Seventeen patients had histologically documented osteosarcoma: 16 had overt metastatic disease in the lungs documented by chest radiographs or computed tomography; the remaining patient had an unresectable osteosarcoma in an irradiated field. Twelve had neuroblastomas. Thirteen had a brain tumor: 2 brainstem gliomas, 7 supratentorial gliomas, and 4 other brain tumors. All patients had b e e n previously treated with chemotherapy and were judged to be refractory to standard chemotherapy; the patients had received a median of two previous chemotherapy regimens (range 1-4). Twenty-six had previously received radiation therapy. Thirty-nine o f the 46 patients had an adequate trial of therapy, defined as having received at least one 5-day course of treatment, with adequate documentation of response: 16 with osteosarcoma, 10 with neuroblastoma, 12 with brain tumors, and one with an epithelioid sarcoma. The remaining 7 patients did not receive the prescribed 5 days of therapy and were not analyzed for response. None
341 tial response in 16 evaluable patients with osteosarcoma, 12 with brain tumors (9 with glioma), and 10 with neuroblastoma provides significant evidence to contradict the hypothesis that this agent evokes a response in: (1) at least 20 percent of patients with osteosarcoma (1-sided p = 0.01, upper 95 percent confidence limit = 17 percent); (2) at least 30 percent of patients with glioma (1-sided p = 0.04, upper 95 percent confidence limit = 28 percent); (3) and at least 30 percent of patients with neuroblastoma (1-sided p = 0.03, upper 95 percent confidence limit = 26 percent). Thus, indicine N-oxide appears to be ineffective in the treatment of heavily pretreated patients with osteosarcoma, neuroblastoma, and pediatric brain tumors at this dose and schedule.
of the 39 evaluable patients achieved a complete or partial response. No patient received more than one course of therapy. Because prior experience with this drug in a phase I setting demonstrated that hepatotoxicity was the most significant toxicity, this toxicity was evaluated in the present study. Thirteen patients developed hepatotoxicity manifested by asymptomatic elevations of transaminases in 11 patients, hyperbilirubinemia in 1 patient, and ascites in 1 patient. No patient had renal toxicity. Grade 3 or 4 thrombocytopenia occurred in 11 patients, and 5 patients experienced grade 3 or 4 neutropenia. There was one death due to sepsis. Twelve patients were not completely evaluable for toxicity because the data were incomplete.
Discussion Acknowledgements
Although indicine N-oxide has had activity in acute leukemia and has in vitro activity in solid tumors, this limited study of indicine N-oxide in pediatric solid t u m o r s ; d e m o n s t r a t e d no evidence of antitumor activity in the treatment of heavily pretreated patients with osteogenic sarcoma, brain tumors, and neuroblastoma. Lack of any complete or par-
Grant support from the Division o f Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and H u m a n Services.
Appendix Principal investigators Childrens Cancer Study Group Institution
Investigator
Grant no.
Group Operations Office University of Southern California Comprehensive Cancer Center Los Angeles, California
Denman Hammond, M.D. John Weiner, Dr. P.H. Harland Sather,.Ph.D. Mark Krailo, Ph.D. Jonathan Buckley, M.B.B.S., Ph.D. Madelin Bauer, Ph.D. Raymond Hutchinson
CA 13539
Arthur Ablin, M.D.
CA17829
Paul Gaynon, M.D.
CA05436
Ronald Chard, M.D.
CA10382
Susan Shurin, M.D.
CA20320
University of Michigan Medical Center Ann Arbor, Michigan University of California Medical Center San Francisco, California University of Wisconsin Hospital Madison, Wisconsin Children's Hospital and Medical Center Seattle, Washington Rainbow Babies and Children's Hospital Cleveland, Ohio
CA02971
342
Principal investigators Childrens Cancer Study Group Institution
Investigator
Grant no.
Children's National Medical Center Washington, D.C. Childrens Memorial Hospital Chicago, Illinois Children's Hospital of Los Angeles Los Angeles, California Children's Hospital of Columbus Columbus, Ohio Babies Hospital New York, New Yorl~ Vanderbilt University School of Medicine Nashville, Tennessee Doernbecher Memorial Hospital for Children Portland, Oregon University of Minnesota Medical Center Minneapolis, Minnesota University of Texas Health Sciences Center San Antonio, Texas Children's Hospital of Philadelphia Philadelphia, Pennsylvania Memorial Sloan-Kettering Cancer Center New York, New York University of British Columbia Vancouver, British Columbia, Canada Children's Hospital Medical Center Cincinnati, Ohio Harbor/UCLA & Miller Children's Medical Center Torrance and Long Beach, California Children's Hospital of Denver Denver, Colorado Mayo Clinic Rochester, Minnesota
Gregory Reaman, M.D.
CA 03888
Edward Baum, M.D.
CA 07431
Jorge Ortega, M.D.
CA 02649
Frederick Ruymann, M.D.
CA 03750
Sergio Piomelli, M.D.
CA 03526
John Lukens, M.D.
CA 26270
Robert Neerhout, M.D.
CA 26044
William Woods, M.D.
CA 07306
Thomas Williams, M.D.
CA 36004
Anna Meadows, M.D.
CA 11796
References 1. Mattocks AR, Schoentel R, Crowley HC, Culvenor CCJ: Indicine, the major alkaloid of Heliotropium indicum. L J Chem Soc (London) 161:5400-5403, 1961 2. Schoentel R: Toxicology and carcinogenic action of pyrrolizidine alkaloids. Cancer Res 28:2237-2246, 1968 3. Bull LB, Culvenor CC, Dick AT: The pyrrolizidine alkaloids: their chemistry, pathogenicity and other biological properties. In: Neuberger A, Tatum EL (eds). Frontiers of Biology, Volume 9. John Wiley & Sons, New York, 1968 pp. 1-284
Peter Steinherz, M.D. Paul Rogers, M.D.
CA 29013
Robert Wells, M.D.
CA 26126
Jerry Finklestein, M.D.
CA 14560
David Tubergen, M.D.
CA 28851
Gerald Gilchrist, M.D.
CA 28882
4. Mattocks AR: Toxicity of pyrrolizidine alkaloids. Nature 21:723-728, 1968 5. Culvenor CC: Tumor inhibitory activity of pyrrolizidine alkaloids. J Pharm Sci 57:112-117, 1968 6. Miser JS: Final report of the phase I trial of indicine N-oxide to the Investigational Drug Branch, National Cancer Institute, 1981
Address for offprints: Childrens Cancer Study Group, Operations Office, 440 East Huntingtort Drive, Suite 300, P.O. Box 60012, Arcadia, CA 91066-6012, USA
Phase II trial of indicine N-oxide in relapsed pediatric solid tumors A report f r o m the Childrens Cancer S t u d y Group*
James S. Miser 1, William A. Smithson 1, William Krivit 2, Carla Hughes 3, Dianne Davis 3, Mark Krailo 4 and Denman H a m m o n d 4
1Department of Pediatrics, Mayo Clinic Foundation, Rochester, Minnesota; 2Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; 3Children's Hospital of Columbus, Columbus, Ohio; 4University of Southern California, Los Angeles, California Pasadena, California, USA Key words: indicine N-oxide, pediatric solid tumors, osteosarcoma, neuroblastoma, pediatric brain tumors
Abstract
We used indicine N-oxide to treat 46 children with malignant solid tumors: 17 with osteosarcoma, 12 with neuroblastoma, 13 with a brain tumor, and 4 with other miscellaneous tumors. The efficacy and toxicity of the drug was assessed at the dose of 2000 mg/m2/day for five consecutive days. None of the 39 patients evaluable for response achieved a complete or partial response. Hepatotoxicity was experienced by 13 patients: 11 patients developed asymptomatic elevations of transaminases, 1 patient developed hyperbilirubinemia, and 1 developed ascites. Indicine N-oxide appears to be ineffective in the treatment of osteosarcoma, neuroblastoma, and pediatric brain tumors at this dose and schedule. Because higher doses are associated with an unacceptably high incidence of severe, irreversible hepatotoxicity, we do not recommend further study of this agent in pediatric solid tumors.
Introduction
Indicine N-oxide is a pyrrolizidine alkaloid isolated from Heliotropium indicum, a flower used as a herbal medicine in Asia, Africa, and South America [1,2]. The alkaloids produce both antimitotic activity, as well as chromosomal breakage, suggesting that these agents may be of benefit in the treatment of malignant tumors [3,4]. The mechanism of action of indicine N-oxide is presently unknown; however, the toxicity may be due to interference with the purine metabolic pathway or to the drug's action as an oxygenating agent [5]. Because of its activity in experimental animal tumor systems (intraperitoneal murine leukemia P388, murine B16 melanoma, murine L1210 leukemia, and rat
Walker carcinoma 256), this agent was chosen for study in phase I and phase II trials in humans.
Materials and methods
Indicine N-oxide was administered to patients with relapsed solid tumors at the dose of 2000 mg/m2/day for 5 consecutive days (CCG 084). This dose was the maximally tolerated dose (MTD) in a phase I study of a five-day schedule of administration in children with solid tumors [6]. The doselimiting toxicity was myelosuppression, both thrombocytopenia and neutropenia; higher doses were also associated with severe hepatotoxicity. Patients whose surface area was less than 0.8 m 2 had
* Contributing Childrens Cancer Study Group Investigators, Institutions, and Grant Numbers are given in the Appendix.
340 their doses calculated on the basis of weight (60 m g / kg). Subsequent courses of therapy were administered at 28-day intervals. The drug was supplied by the National Cancer Institute as an off-white powder and administered by slow intravenous injection over 15 rain after reconstitution of the 1 g vials with 9.2 ml of sterile water. All patients were required to have disease that had relapsed and was refractory to standard therapy. All patients were required not to have received any anticancer therapy in the 4 weeks prior to study entry. Requirements for entry onto the study included adequate renal function and normal hepatic function. At least one measurable lesion was identified for the assessment of response to indicine Noxide. The index lesion(s) were reevaluated no later than 28 days after study entry. The following criteria for response were used: (1) Complete Remission (CR) - complete tumor regression and disappearance of all symptoms associated with the disease; (2) Partial Remission (PR) - 50 percent to 99 percent reduction in the sum of the products of the two greatest perpendicular diameters of all measurable tumor masses without the appearance of any new lesions; (3) Stable Disease (SD) - 0 percent to 49 percent reduction in the sum of the products of the two greatest perpendicular diameters of all measurable tumor masses without the appearance of any new lesions; and (4) Progressive Disease (PD) - occurrence of any new lesion or increase of any single measurable lesion by 25 percent as measured by the product of the two greatest perpendicular diameters. Therapy was continued until a patient demonstrated progression of disease, irreversible grade III toxicity or grade IV toxicity of any organ system. Toxicities were rated grade I (mild) to grade IV (life-threatening) based on specific limits for each organ system (schedule of toxicity measures available on request from Childrens Cancer Study Group). Hepatotoxicity was defined using the following criteria: grade 0 (enzymes and bilirubin within normal limits); grade 1 (enzymes elevated but _< 2.5 • normal); grade 2 (enzymes 2 . 6 - 5 . 0 x normal, bilirubin < 1.5 x normal); grade 3 (en-
zymes 5 . 1 - 2 0 . 0 x normal or bilirubin 1.5-3.0 x normal); grade 4 (enzymes > 20 x normal or bilirubin > 3 x normal). Myelosuppressive toxicity was defined as: grade 0 (white blood count (WBC) > 4,000/ml, absolute neutrophil count (ANC) _> 2,000/ml and platelet count (PLT) within normal limits); grade 1 (WBC 3,000-3,999/ml, ANC 1,500-1,999/ml, or P L T 7 5 , 0 0 0 / m l - n o r mal); grade 2 (WBC 2,000-2,999/ml, ANC 1,000-1,499/ml, or P L T 50,000-74,999/ml); grade 3 (WBC 1,000-1,999/ml, ANC 5 0 0 - 9 9 9 / ml, or P L T 25,000-49,999/ml); grade 4 (WBC < 1,000/ml, ANC < 500/ml, P L T < 25,000/ml). Patients receiving at least one course of therapy were considered evaluable for response. Patients who had progressive disease at any time after administration of the first course of therapy were considered as treatment failures.
Results
Forty-six patients were entered onto the study from December 1981 to April i986. The median age was 16 years (range, 4 to 23 years); 20 patients were female and 26 were male. Seventeen patients had histologically documented osteosarcoma: 16 had overt metastatic disease in the lungs documented by chest radiographs or computed tomography; the remaining patient had an unresectable osteosarcoma in an irradiated field. Twelve had neuroblastomas. Thirteen had a brain tumor: 2 brainstem gliomas, 7 supratentorial gliomas, and 4 other brain tumors. All patients had b e e n previously treated with chemotherapy and were judged to be refractory to standard chemotherapy; the patients had received a median of two previous chemotherapy regimens (range 1-4). Twenty-six had previously received radiation therapy. Thirty-nine o f the 46 patients had an adequate trial of therapy, defined as having received at least one 5-day course of treatment, with adequate documentation of response: 16 with osteosarcoma, 10 with neuroblastoma, 12 with brain tumors, and one with an epithelioid sarcoma. The remaining 7 patients did not receive the prescribed 5 days of therapy and were not analyzed for response. None
341 tial response in 16 evaluable patients with osteosarcoma, 12 with brain tumors (9 with glioma), and 10 with neuroblastoma provides significant evidence to contradict the hypothesis that this agent evokes a response in: (1) at least 20 percent of patients with osteosarcoma (1-sided p = 0.01, upper 95 percent confidence limit = 17 percent); (2) at least 30 percent of patients with glioma (1-sided p = 0.04, upper 95 percent confidence limit = 28 percent); (3) and at least 30 percent of patients with neuroblastoma (1-sided p = 0.03, upper 95 percent confidence limit = 26 percent). Thus, indicine N-oxide appears to be ineffective in the treatment of heavily pretreated patients with osteosarcoma, neuroblastoma, and pediatric brain tumors at this dose and schedule.
of the 39 evaluable patients achieved a complete or partial response. No patient received more than one course of therapy. Because prior experience with this drug in a phase I setting demonstrated that hepatotoxicity was the most significant toxicity, this toxicity was evaluated in the present study. Thirteen patients developed hepatotoxicity manifested by asymptomatic elevations of transaminases in 11 patients, hyperbilirubinemia in 1 patient, and ascites in 1 patient. No patient had renal toxicity. Grade 3 or 4 thrombocytopenia occurred in 11 patients, and 5 patients experienced grade 3 or 4 neutropenia. There was one death due to sepsis. Twelve patients were not completely evaluable for toxicity because the data were incomplete.
Discussion Acknowledgements
Although indicine N-oxide has had activity in acute leukemia and has in vitro activity in solid tumors, this limited study of indicine N-oxide in pediatric solid t u m o r s ; d e m o n s t r a t e d no evidence of antitumor activity in the treatment of heavily pretreated patients with osteogenic sarcoma, brain tumors, and neuroblastoma. Lack of any complete or par-
Grant support from the Division o f Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and H u m a n Services.
Appendix Principal investigators Childrens Cancer Study Group Institution
Investigator
Grant no.
Group Operations Office University of Southern California Comprehensive Cancer Center Los Angeles, California
Denman Hammond, M.D. John Weiner, Dr. P.H. Harland Sather,.Ph.D. Mark Krailo, Ph.D. Jonathan Buckley, M.B.B.S., Ph.D. Madelin Bauer, Ph.D. Raymond Hutchinson
CA 13539
Arthur Ablin, M.D.
CA17829
Paul Gaynon, M.D.
CA05436
Ronald Chard, M.D.
CA10382
Susan Shurin, M.D.
CA20320
University of Michigan Medical Center Ann Arbor, Michigan University of California Medical Center San Francisco, California University of Wisconsin Hospital Madison, Wisconsin Children's Hospital and Medical Center Seattle, Washington Rainbow Babies and Children's Hospital Cleveland, Ohio
CA02971
342
Principal investigators Childrens Cancer Study Group Institution
Investigator
Grant no.
Children's National Medical Center Washington, D.C. Childrens Memorial Hospital Chicago, Illinois Children's Hospital of Los Angeles Los Angeles, California Children's Hospital of Columbus Columbus, Ohio Babies Hospital New York, New Yorl~ Vanderbilt University School of Medicine Nashville, Tennessee Doernbecher Memorial Hospital for Children Portland, Oregon University of Minnesota Medical Center Minneapolis, Minnesota University of Texas Health Sciences Center San Antonio, Texas Children's Hospital of Philadelphia Philadelphia, Pennsylvania Memorial Sloan-Kettering Cancer Center New York, New York University of British Columbia Vancouver, British Columbia, Canada Children's Hospital Medical Center Cincinnati, Ohio Harbor/UCLA & Miller Children's Medical Center Torrance and Long Beach, California Children's Hospital of Denver Denver, Colorado Mayo Clinic Rochester, Minnesota
Gregory Reaman, M.D.
CA 03888
Edward Baum, M.D.
CA 07431
Jorge Ortega, M.D.
CA 02649
Frederick Ruymann, M.D.
CA 03750
Sergio Piomelli, M.D.
CA 03526
John Lukens, M.D.
CA 26270
Robert Neerhout, M.D.
CA 26044
William Woods, M.D.
CA 07306
Thomas Williams, M.D.
CA 36004
Anna Meadows, M.D.
CA 11796
References 1. Mattocks AR, Schoentel R, Crowley HC, Culvenor CCJ: Indicine, the major alkaloid of Heliotropium indicum. L J Chem Soc (London) 161:5400-5403, 1961 2. Schoentel R: Toxicology and carcinogenic action of pyrrolizidine alkaloids. Cancer Res 28:2237-2246, 1968 3. Bull LB, Culvenor CC, Dick AT: The pyrrolizidine alkaloids: their chemistry, pathogenicity and other biological properties. In: Neuberger A, Tatum EL (eds). Frontiers of Biology, Volume 9. John Wiley & Sons, New York, 1968 pp. 1-284
Peter Steinherz, M.D. Paul Rogers, M.D.
CA 29013
Robert Wells, M.D.
CA 26126
Jerry Finklestein, M.D.
CA 14560
David Tubergen, M.D.
CA 28851
Gerald Gilchrist, M.D.
CA 28882
4. Mattocks AR: Toxicity of pyrrolizidine alkaloids. Nature 21:723-728, 1968 5. Culvenor CC: Tumor inhibitory activity of pyrrolizidine alkaloids. J Pharm Sci 57:112-117, 1968 6. Miser JS: Final report of the phase I trial of indicine N-oxide to the Investigational Drug Branch, National Cancer Institute, 1981
Address for offprints: Childrens Cancer Study Group, Operations Office, 440 East Huntingtort Drive, Suite 300, P.O. Box 60012, Arcadia, CA 91066-6012, USA
