Investigational New Drugs 10: 23-24, 1992. 9 1992KluwerAcademicPublishers. Printedin the Netherlands.
Phase II trial of didemnin-B in advanced epithelial ovarian cancer A S o u t h w e s t Oncology G r o u p S t u d y
Joanna M. Cain 1, P.Y. Liu 2, David E. Alberts 3, Holly H. Gallion 4, Leslie Laufman 5, Janet O'Sullivan 2, Geoffrey Weiss 6 and John N. Bickers 7
1Puget Sound Oncology Consortium, Seattle, WA, USA; 2Southwest Oncology Group Statistical Center, Seattle, WA, USA; 3University of Arizona Cancer Center, Tucson, AZ, USA; 4University of Kentucky Medical Center, Lexington, KY, USA; 5Columbus CCOP, Columbus, OH, USA; 6University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; 7Louisiana State University Medical Center, New Orleans, LA, USA Key words: Didemnin-B, ovarian cancer
Summary A Phase II study of Didemnin-B, a marine cyclic depsipeptide, was undertaken in patients with progressive epithelial ovarian cancer. The starting dose was 2.6 m g / m 2. Fifteen patients received the drug, of whom twelve were evaluable. There were no responses observed in the twelve patients. The two most frequent toxicities were nausea and vomiting and anemia. On the basis of this trial, Didemnin-B is not felt to have significant effect with epithelial ovarian cancer.
Didemnin-B (NSC 325319) represents a class of marine compounds with a novel cyclic depsipeptide structure [1]. It showed in vitro and in vivo antitumor activity against B-16 melanoma, M5076 sarcoma, and P388 leukemia cell lines [2,3]. The mechanism of cytotoxicity is unknown. Inhibition of protein synthesis has been observed with correlation to inhibition of L1210 cell growth and a lesser inhibition of DNA [2]. Significant schedule dependency was not demonstrated in the B-16 melanoma model with day 1-5-9 versus day 1 to 9 or day 1 only slightly superior. Six of nine ovarian cancer cell lines showed a response in a human tumor cloning system [4]. Phase I clinical trials revealed dose limiting toxicity of nausea and vomiting with concurrent malaise, and liver enzyme abnormalities. Because of its activity in vitro, the Southwest Oncology Group (SWOG) performed a phase II trial to determine clinical response and toxicity of Didemnin-B in patients with advanced ovarian carcinoma. Patients entering the trial were randomized to two arms, amonafide or Didemnin-B.
Eligibility criteria included: pathologically verified diagnosis of incurable, metastatic or recurrent epithelial ovarian cancer; bidimensionally measurable disease; SWOG performance statues of 0 - 2 ; failed cisplatin or a cisplatin analogue based regimen; no more than one prior chemotherapy regimen; no concurrent radiation, chemotherapy, hormonal or immunotherapy; previous radiation or chemotherapy must be > four weeks prior to entry; adequate organ function with polymorphonuclear leukocytes (PMN) > 1,500//A and platelets > 100,000//xl, serum bilirubin _< 1.5 mg/dL, serum creatinine __ 1.5 mg/dL; institutional review board approval and informed consent. Didemnin-B was given as an IV infusion in 150 ml normal saline over 30 minutes once every 28 days. The starting dose was 2.6 m g / m 2 with dose escalation or deescalation based on observed interval toxicity. Decreasing dose levels based on 25% decrements from the highest escalation level of 3.5 m g / m 2 were based on the presence of SWOG grade III gastrointestinal toxicity or SWOG grade I-II
24 Table 1. Toxicity: Didemnin-B Type
Grade (SWOG)
Number
Nausea & Vomiting Anemia Leukopenia Bilirubin (increase) Transaminase (increase) Diarrhea Facial Flushing
II-III II-III I-II IV II
7 5 3 1 1 3 2
hepatic toxicity. No dosage increases were allowed after prior dosage decreases. Responses were classified by the standard SWOG definitions [5]. Fifteen patients from 15 SWOG institutions entered this study on the Didemnin-B arm. Two were found to have ineligible pathology and one refused to participate after enrollment leaving 12 evaluable patients. The patients were equally divided between FIGO Stage III/IV 6/6 and refractory/relapse status 6/6. Refractory includes patients with no response to previous therapy and relapse includes patients with recurrent or persistent disease after a partial or complete response to previous therapy. The median age was 62.5 (r 49-73). There were no responses observed in the 12 evaluable patients for an estimated response rate of 0% with a confidence interval of 0 % - 2 6 % . The median survival is estimated at 6.6 months. The most common toxicities were nausea and vomiting, grade II-III in 7 patients and anemia (SWOG Grade II-III) in 5 patients. Other toxicity included diarrhea (3 patients), facial flushing (2 patients) and leukopenia (Grade I-II) in three patients. One patient had a grade IV bilirubin increase, one a grade II transaminase increase, and one a grade II alkaline phosphatase increase. One patient developed mild disorientation and headache after infusion which resolved with conservative measures. Toxicity is summarized in Table 1. On the basis of this trial, Didemnin-B is not felt to have significant antitumor activity in ovarian cancer at the doses used in this phase II randomized
study. The discrepancy between the in vitro results and the findings of this study may represent an inability to achieve tolerable serum concentrations correlating to those achieved in vitro. On this basis, further clinical trials are not indicated in patients with this tumor type.
Acknowledgements This investigation was supported in part by the following PHS Cooperative Agreement grant numbers and awarded by the National Cancer Institute DHHS: CA-20319, CA-37429, CA-12312 CA-46136, CA-35261, CA-22433, CA-12213 CA-35431, CA-46441, CA-46282, CA-35176 CA-35117, CA-37981, CA-45807, CA-35200 CA-35178, CA-32734, CA-35281, CA-35119 CA-35128, CA-45450, CA-03096, CA-45560. CA-36020, CA-32102.
References 1. Rhineart KL Jr., Grever JB, Hughes RG, Swynenberg EG, Stringfellow DA, Kuentzel SL, Li LH: Didemnins: antiviral and antitumor depsipeptides from a Caribbean Tunicate Science 212:933, 1981 2. Chun HG, Davies B, Hoth D, Suffness M, Yun S: Didemnin-B: The first marine compound entering clinical trials as an antineoplastic agent. Invest New Drugs 4(3): 279-84, 1986 3. Weiss GR, Arteaga C, Brown TD, Craig JB, Harman GS, Havlin KA, Koehler JH, Kuhu JG, Von Hoff DD: New anticancer agents. Ca Chemo Biol Res Modif 10:85-116, 1988 4. Ziang TL, Liu RL, Salman RF: Antitumor activity of didemnin-B in the human tumor stem cell assay. Cancer Chemotherapy Pharmacol 11:1, 1983 5. Miller A, Hoogstranten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47:207-214, 1981
Address for offprints: Southwest Oncology Group (SWOG8717), Operations Office, 5430 Fredricksburg Road, Suite #618, San Antonio, TX 78229-6197, USA
Phase II trial of didemnin-B in advanced epithelial ovarian cancer A S o u t h w e s t Oncology G r o u p S t u d y
Joanna M. Cain 1, P.Y. Liu 2, David E. Alberts 3, Holly H. Gallion 4, Leslie Laufman 5, Janet O'Sullivan 2, Geoffrey Weiss 6 and John N. Bickers 7
1Puget Sound Oncology Consortium, Seattle, WA, USA; 2Southwest Oncology Group Statistical Center, Seattle, WA, USA; 3University of Arizona Cancer Center, Tucson, AZ, USA; 4University of Kentucky Medical Center, Lexington, KY, USA; 5Columbus CCOP, Columbus, OH, USA; 6University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; 7Louisiana State University Medical Center, New Orleans, LA, USA Key words: Didemnin-B, ovarian cancer
Summary A Phase II study of Didemnin-B, a marine cyclic depsipeptide, was undertaken in patients with progressive epithelial ovarian cancer. The starting dose was 2.6 m g / m 2. Fifteen patients received the drug, of whom twelve were evaluable. There were no responses observed in the twelve patients. The two most frequent toxicities were nausea and vomiting and anemia. On the basis of this trial, Didemnin-B is not felt to have significant effect with epithelial ovarian cancer.
Didemnin-B (NSC 325319) represents a class of marine compounds with a novel cyclic depsipeptide structure [1]. It showed in vitro and in vivo antitumor activity against B-16 melanoma, M5076 sarcoma, and P388 leukemia cell lines [2,3]. The mechanism of cytotoxicity is unknown. Inhibition of protein synthesis has been observed with correlation to inhibition of L1210 cell growth and a lesser inhibition of DNA [2]. Significant schedule dependency was not demonstrated in the B-16 melanoma model with day 1-5-9 versus day 1 to 9 or day 1 only slightly superior. Six of nine ovarian cancer cell lines showed a response in a human tumor cloning system [4]. Phase I clinical trials revealed dose limiting toxicity of nausea and vomiting with concurrent malaise, and liver enzyme abnormalities. Because of its activity in vitro, the Southwest Oncology Group (SWOG) performed a phase II trial to determine clinical response and toxicity of Didemnin-B in patients with advanced ovarian carcinoma. Patients entering the trial were randomized to two arms, amonafide or Didemnin-B.
Eligibility criteria included: pathologically verified diagnosis of incurable, metastatic or recurrent epithelial ovarian cancer; bidimensionally measurable disease; SWOG performance statues of 0 - 2 ; failed cisplatin or a cisplatin analogue based regimen; no more than one prior chemotherapy regimen; no concurrent radiation, chemotherapy, hormonal or immunotherapy; previous radiation or chemotherapy must be > four weeks prior to entry; adequate organ function with polymorphonuclear leukocytes (PMN) > 1,500//A and platelets > 100,000//xl, serum bilirubin _< 1.5 mg/dL, serum creatinine __ 1.5 mg/dL; institutional review board approval and informed consent. Didemnin-B was given as an IV infusion in 150 ml normal saline over 30 minutes once every 28 days. The starting dose was 2.6 m g / m 2 with dose escalation or deescalation based on observed interval toxicity. Decreasing dose levels based on 25% decrements from the highest escalation level of 3.5 m g / m 2 were based on the presence of SWOG grade III gastrointestinal toxicity or SWOG grade I-II
24 Table 1. Toxicity: Didemnin-B Type
Grade (SWOG)
Number
Nausea & Vomiting Anemia Leukopenia Bilirubin (increase) Transaminase (increase) Diarrhea Facial Flushing
II-III II-III I-II IV II
7 5 3 1 1 3 2
hepatic toxicity. No dosage increases were allowed after prior dosage decreases. Responses were classified by the standard SWOG definitions [5]. Fifteen patients from 15 SWOG institutions entered this study on the Didemnin-B arm. Two were found to have ineligible pathology and one refused to participate after enrollment leaving 12 evaluable patients. The patients were equally divided between FIGO Stage III/IV 6/6 and refractory/relapse status 6/6. Refractory includes patients with no response to previous therapy and relapse includes patients with recurrent or persistent disease after a partial or complete response to previous therapy. The median age was 62.5 (r 49-73). There were no responses observed in the 12 evaluable patients for an estimated response rate of 0% with a confidence interval of 0 % - 2 6 % . The median survival is estimated at 6.6 months. The most common toxicities were nausea and vomiting, grade II-III in 7 patients and anemia (SWOG Grade II-III) in 5 patients. Other toxicity included diarrhea (3 patients), facial flushing (2 patients) and leukopenia (Grade I-II) in three patients. One patient had a grade IV bilirubin increase, one a grade II transaminase increase, and one a grade II alkaline phosphatase increase. One patient developed mild disorientation and headache after infusion which resolved with conservative measures. Toxicity is summarized in Table 1. On the basis of this trial, Didemnin-B is not felt to have significant antitumor activity in ovarian cancer at the doses used in this phase II randomized
study. The discrepancy between the in vitro results and the findings of this study may represent an inability to achieve tolerable serum concentrations correlating to those achieved in vitro. On this basis, further clinical trials are not indicated in patients with this tumor type.
Acknowledgements This investigation was supported in part by the following PHS Cooperative Agreement grant numbers and awarded by the National Cancer Institute DHHS: CA-20319, CA-37429, CA-12312 CA-46136, CA-35261, CA-22433, CA-12213 CA-35431, CA-46441, CA-46282, CA-35176 CA-35117, CA-37981, CA-45807, CA-35200 CA-35178, CA-32734, CA-35281, CA-35119 CA-35128, CA-45450, CA-03096, CA-45560. CA-36020, CA-32102.
References 1. Rhineart KL Jr., Grever JB, Hughes RG, Swynenberg EG, Stringfellow DA, Kuentzel SL, Li LH: Didemnins: antiviral and antitumor depsipeptides from a Caribbean Tunicate Science 212:933, 1981 2. Chun HG, Davies B, Hoth D, Suffness M, Yun S: Didemnin-B: The first marine compound entering clinical trials as an antineoplastic agent. Invest New Drugs 4(3): 279-84, 1986 3. Weiss GR, Arteaga C, Brown TD, Craig JB, Harman GS, Havlin KA, Koehler JH, Kuhu JG, Von Hoff DD: New anticancer agents. Ca Chemo Biol Res Modif 10:85-116, 1988 4. Ziang TL, Liu RL, Salman RF: Antitumor activity of didemnin-B in the human tumor stem cell assay. Cancer Chemotherapy Pharmacol 11:1, 1983 5. Miller A, Hoogstranten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47:207-214, 1981
Address for offprints: Southwest Oncology Group (SWOG8717), Operations Office, 5430 Fredricksburg Road, Suite #618, San Antonio, TX 78229-6197, USA
