Investigational New Drugs 8: 325-328, 1990. 9 1990KluwerAcademic Publishers. Printed in the Netherlands.
Phase II study of tallysomycin Slob in patients with advanced head and neck cancer Claude Nicaise 1, W.K. Hong 2, W. Dimery3, J. Usakewicz4, M. Rozencweig5 and I. Krakoff6 1,4,SBristol-Myers Company, Pharmaceutical Research and Development Division, 5 Research Parkway, P.O. Box 5100, Wallingford, C T 06492-7660; 2,3,6University o f Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, T X 77030, USA
Key words: tallysomycin S10b, head and neck cancer
Summary Twenty patients with advanced head and neck tumors were entered in a phase II trial of tallysomycin $10b given intravenously at weekly doses of 2.5 mg/mL All patients had received prior chemotherapy +_ radiotherapy. Sixteen patients were evaluable for response. Two had stable disease for 15 and 22 weeks respectively. None exhibited tumor shrinkage. Non-hematologic toxicities primarily consisted of gastrointestinal intolerance. Mild fever was noted in about half of the patients and increase in serum creatinine was observed in four. Other side effects consisted of decrease in pulmonary diffusion capacity and skin changes. In conclusion, tallysomycin S10b has no activity in previously treated head and neck cancer patients and has a toxicity spectrum similar to that of bleomycin.
Introduction Chemotherapy has been widely used in the treatment of recurrent and metastatic head and neck tumors. Cisplatin, methotrexate and bleomycin are the most active compounds in these diseases and currently form the basis of a variety of combination regimens. In a review of 298 patients, single-agent bleomycin yielded an 18 % response rate [1]. Despite definite activity, its use has been limited by undesirable side-effects, primarily cumulative pulmonary toxicity, fever and local toxicity. The search for analogs with better therapeutic index led to the development of tallysomycin S10b. In experimental tumor systems, tallysomycin S10b has a somewhat broader spectrum of activity than bleomycin [2]. Both compounds were active in vivo against a variety of murine tumors including the P388 leukemia, B16 melanoma, Lewis lung carcinoma, Sarcoma 180 and Madison 109 lung carcinoma. In the subrenal capsule assay, tallysomycin
S10b produced ninety percent growth inhibition of human, colon, and lung tumor xenograft. Toxicology studies suggested that the pulmonary toxicity induced by tallysomycin S10b was less severe than that of the parent compound [3]. Two phase I studies were conducted using weekly and twice weekly schedules [4-5]. In both trials pulmonary toxicity consisting of decreases in pulmonary diffusion capacity and chest x-ray abnormalities were noted. Other adverse reactions included skin toxicity comparable to that produced by bleomycin, mild nausea/vomiting, fever, chills and fatigue. With both schedules, the recommended dose for phase II trials was 2.5 mg/m 2. This phase II study was designed to evaluate the efficacy and safety of tallysomycin S10b in patients with squamous cell carcinoma of the head and neck not previously exposed to bleomycin.
326 Materials and methods
The study was open to patients with histologically confirmed squamous cell carcinoma of the head and neck not or no longer suitable for surgery a n d / o r radiotherapy. Eligibility criteria included: age greater than 18 years, W H O performance status of less than 3 and a life expectancy of at least 8 weeks. Patients had to have measurable indicator lesions preferably located outside previously irradiated areas. Absolute granulocyte count > 1,500/tzl and platelet count > 75,000//zl were required as well as BUN < 20 mg/dl, serum creatinine < 1.5 mg/dl, creatinine clearance greater than 60 ml/min and bilirubin < 1.2 mg/dl, normal spirometry and DLCO above 60~ of predictive value. Patients with prior bleomycin and those with a history of COPD or prior lung irradiation were not eligible. Tallysomycin S10b was administered weekly as an i.v. push injection at a dose of 2.5 mg/mL Treatment was discontinued when tumor progression was documented or after a maximum cumulative dose of 60 m g / m 2. Chemotherapy was held if at the time of retreatment the absolute granulocyte count was < 1,500//A a n d / o r the platelet count < 25,000/#1 a n d / o r bilirubin > 1.2 mg/dl). If recovery did not occur within four weeks, they were taken off study. Creatinine clearance below 60 ml/min as well as evidence of pulmonary toxicity (abnormal chest x-rays or 30~ reduction in pulmonary function test a n d / o r diffusion capacity) resulted in treatment discontinuation. Prior to entry, each patient had a complete history and physical examination. Prestudy tests included CBC with differential and platelet count, serum chemistries (SGOT, total bilirubin, alkaline phosphatase BUN, creatinine, glucose, CO 2, Na, K and C1) creatinine clearance and urinalysis. Pulmonary function was measured by pulmonary diffusion capacity (DLCO) and spirometry. Chest x-rays and CT scans were performed as clinically indicated. Interval history, physical examination with tumor measurement if applicable, as well as CBC and platelet counts were repeated weekly. Chest x-ray, CT scan, serum chemistries, urinalysis, and pulmonary function tests were performed monthly. An-
titumor activity was evaluated according to W H O criteria and toxicities were graded according to the M.D. Anderson scale [6, 7].
Results
Twenty patients with recurrent squamous cell carcinoma of the head and neck were entered, of whom, 16 were adequately treated. Due to supply problems the study was temporarily discontinued during a period of 4 months. At that time, a total of four patients had received less than four weekly administrations of tallysomycin S10b without evidence of progressive disease. These four patients were not considered evaluable for response. Patients were predominantly male and their age ranged from 53 to 81 years (Table 1). Most had a favorable performance status and primary tumor sites were predominantly in the oral cavity. All patients were previously treated with chemotherapy which consisted of Platinol + 5FU with or without methotrexate. One patient also received bleomycin for a total cumulative dose of 180 mg/mL Although not eligible for the study, this patient received 3 weekly doses of tallysomycin Sa0b before being taken off study due to supply problem. All but one patient received radiation therapy to the primary tumor as well as cervical nodes. Two patients had elevated serum creatinine (1.6 mg/dl) at entry. N o n e of the patients had evaluable disease in areas that had not been previously irradiated. A total of 137 weekly doses were administered and the median number of doses per patient was 7. Overall, only four patients received a cumulative dose of tallysomycin S10b above 20 m g / m 2. No complete or partial responses were noted. One patient remained on-study for a total of 22 weeks without showing evidence of progression. This patient had an ill-defined lesion at the base of the skull which retrospectively could have been considered as scar tissue from previous surgery. She also had a small cervical adenopathy which remained unchanged during the entire duration of follow-up. Another patient with local recurrence of
327 Table 2. Non-hematologic toxicities
Table 1. Pretreatment characteristics
No. patients Sex: Male/female Age median: Range Performance status (WHO): 1 2 3 Unknown Primary tumor site: Tongue Palate Pharynx Tonsil Unknown Floor of the mouth Larynx Nasal cavity Ear Prior therapy: Chemotherapy Chemo- & radiotherapy
20 17/3 61 53-81 14 4 1 1 6 3 3 2 2 1 1 1 1 1 19
a tumor of the pharynx and bilateral lymph node metastases, had stable disease for a total of 15 weeks. Gastrointestinal intolerance was the most frequent non-hematologic toxicity. It consisted of mild to moderate nausea and/or vomiting in eleven patients and diarrhea in two. Transient fever was noted in nine patients. It was usually asymptomatic with a body temperature not exceeding 38~ In three patients, however, it was associated with chills and required symptomatic treatment. Skin toxicities were noted in six patients. They consisted of dryness, erythema, rash, edema, peeling palms and cracking nails. They usually occurred during the first weeks of treatment and there was no clear relationship with the cumulative dose of tallysomycin S10b. Five patients had dyspnea or minimal reduction of their pulmonary diffusion capacity which in most cases could not be clearly ascribed to the drug. Elevated serum creatinine was reported in four patients, two of whom had already elevated baseline value. The maximum serum creatinine values ranged from 1.7 mg/dl to 2.2 mg/dl. In one patient, a concomitant decrease of creatinine clearance was
No. of patients Evaluable Nausea and vomiting Fever Skin Pulmonary Renal Malaise Diarrhea Infection
20 11 9 6 5 4 (2) 4 2 2
( ) = severe toxicity
also noted. Four patients experienced malaise and general weakness. No hepatic nor hematologic toxicity was noted.
Discussion
This study failed to demonstrate any acitivity of tallysomycin S10b in refractory head and neck tumors. Most patients included in this trial were heavily pretreated and indicator lesions were located in previously irradiated areas. These unfavorable characteristics may have contributed to the negative results. Although a direct comparison with bleomycin cannot be established, these data suggest that tallysomycin S10b has lower antitumor activity than its parent compound. Side effects were usually mild to moderate and primarily consisted of gastrointestinal intolerance, fever and cutaneous toxicities. They were comparable in incidence and severity to those produced by bleomycin. Based on these data, no further trials of tallysomycin S10b are warranted in this tumor type.
References 1. Hong WK, Bromer R: Chemotherapy in head and neck cancer. N Eng J Med 308: 75-79, 1983 2. Schurig JE, Rose WC, Hirth RS, Schlein A, Huftalen JB, Florczyk AP, Bradner WT: Tallysomycin S10b: Experimental antitumor activity and toxicity. Cancer Chemother Pharmacol 13: 164-170, 1984 3. Buroker RA, Comereski CR, Barnett D, Hirth RS, Madissoo
328 H, Hottendorf GH: The toxicological evaluation of tallysomycin S10b biosynthetic tallysomycin derivative. Drug Chem Toxicol 7: 259-272, 1984 4. Sorensen PG, Pedersen H, Clausen HV, Hansen HH: Tallysomycin Sl0b. A Phase I Study. Cancer Chemother Pharmacol 24: 113-116, 1989 5. Paolozzi FP, Gaver RC, Newman NB, Poiesz BJ, DeFino S, Louie A, Comis RL: Phase I trial of Tallysomycin S10b, a Bleomycin analogue. Invest New Drug (in press, 1989) 6. WHO handbook for reporting results of cancer treatment. Geneva, WHO 1979
7. Ajani JA, Welch SR, Raber MN, Fields WS, Krakoff IH: Comprehensive criteria for therapy-induced toxicity. Cancer Invest (in press, 1989)
Address for offprints: C. Nicaise, Bristol-Myers Company, Pharmaceutical Research and Development Division, 5 Research Parkway, P.O. Box 5100, Wallingford, CT 06492-7660, USA
Phase II study of tallysomycin Slob in patients with advanced head and neck cancer Claude Nicaise 1, W.K. Hong 2, W. Dimery3, J. Usakewicz4, M. Rozencweig5 and I. Krakoff6 1,4,SBristol-Myers Company, Pharmaceutical Research and Development Division, 5 Research Parkway, P.O. Box 5100, Wallingford, C T 06492-7660; 2,3,6University o f Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, T X 77030, USA
Key words: tallysomycin S10b, head and neck cancer
Summary Twenty patients with advanced head and neck tumors were entered in a phase II trial of tallysomycin $10b given intravenously at weekly doses of 2.5 mg/mL All patients had received prior chemotherapy +_ radiotherapy. Sixteen patients were evaluable for response. Two had stable disease for 15 and 22 weeks respectively. None exhibited tumor shrinkage. Non-hematologic toxicities primarily consisted of gastrointestinal intolerance. Mild fever was noted in about half of the patients and increase in serum creatinine was observed in four. Other side effects consisted of decrease in pulmonary diffusion capacity and skin changes. In conclusion, tallysomycin S10b has no activity in previously treated head and neck cancer patients and has a toxicity spectrum similar to that of bleomycin.
Introduction Chemotherapy has been widely used in the treatment of recurrent and metastatic head and neck tumors. Cisplatin, methotrexate and bleomycin are the most active compounds in these diseases and currently form the basis of a variety of combination regimens. In a review of 298 patients, single-agent bleomycin yielded an 18 % response rate [1]. Despite definite activity, its use has been limited by undesirable side-effects, primarily cumulative pulmonary toxicity, fever and local toxicity. The search for analogs with better therapeutic index led to the development of tallysomycin S10b. In experimental tumor systems, tallysomycin S10b has a somewhat broader spectrum of activity than bleomycin [2]. Both compounds were active in vivo against a variety of murine tumors including the P388 leukemia, B16 melanoma, Lewis lung carcinoma, Sarcoma 180 and Madison 109 lung carcinoma. In the subrenal capsule assay, tallysomycin
S10b produced ninety percent growth inhibition of human, colon, and lung tumor xenograft. Toxicology studies suggested that the pulmonary toxicity induced by tallysomycin S10b was less severe than that of the parent compound [3]. Two phase I studies were conducted using weekly and twice weekly schedules [4-5]. In both trials pulmonary toxicity consisting of decreases in pulmonary diffusion capacity and chest x-ray abnormalities were noted. Other adverse reactions included skin toxicity comparable to that produced by bleomycin, mild nausea/vomiting, fever, chills and fatigue. With both schedules, the recommended dose for phase II trials was 2.5 mg/m 2. This phase II study was designed to evaluate the efficacy and safety of tallysomycin S10b in patients with squamous cell carcinoma of the head and neck not previously exposed to bleomycin.
326 Materials and methods
The study was open to patients with histologically confirmed squamous cell carcinoma of the head and neck not or no longer suitable for surgery a n d / o r radiotherapy. Eligibility criteria included: age greater than 18 years, W H O performance status of less than 3 and a life expectancy of at least 8 weeks. Patients had to have measurable indicator lesions preferably located outside previously irradiated areas. Absolute granulocyte count > 1,500/tzl and platelet count > 75,000//zl were required as well as BUN < 20 mg/dl, serum creatinine < 1.5 mg/dl, creatinine clearance greater than 60 ml/min and bilirubin < 1.2 mg/dl, normal spirometry and DLCO above 60~ of predictive value. Patients with prior bleomycin and those with a history of COPD or prior lung irradiation were not eligible. Tallysomycin S10b was administered weekly as an i.v. push injection at a dose of 2.5 mg/mL Treatment was discontinued when tumor progression was documented or after a maximum cumulative dose of 60 m g / m 2. Chemotherapy was held if at the time of retreatment the absolute granulocyte count was < 1,500//A a n d / o r the platelet count < 25,000/#1 a n d / o r bilirubin > 1.2 mg/dl). If recovery did not occur within four weeks, they were taken off study. Creatinine clearance below 60 ml/min as well as evidence of pulmonary toxicity (abnormal chest x-rays or 30~ reduction in pulmonary function test a n d / o r diffusion capacity) resulted in treatment discontinuation. Prior to entry, each patient had a complete history and physical examination. Prestudy tests included CBC with differential and platelet count, serum chemistries (SGOT, total bilirubin, alkaline phosphatase BUN, creatinine, glucose, CO 2, Na, K and C1) creatinine clearance and urinalysis. Pulmonary function was measured by pulmonary diffusion capacity (DLCO) and spirometry. Chest x-rays and CT scans were performed as clinically indicated. Interval history, physical examination with tumor measurement if applicable, as well as CBC and platelet counts were repeated weekly. Chest x-ray, CT scan, serum chemistries, urinalysis, and pulmonary function tests were performed monthly. An-
titumor activity was evaluated according to W H O criteria and toxicities were graded according to the M.D. Anderson scale [6, 7].
Results
Twenty patients with recurrent squamous cell carcinoma of the head and neck were entered, of whom, 16 were adequately treated. Due to supply problems the study was temporarily discontinued during a period of 4 months. At that time, a total of four patients had received less than four weekly administrations of tallysomycin S10b without evidence of progressive disease. These four patients were not considered evaluable for response. Patients were predominantly male and their age ranged from 53 to 81 years (Table 1). Most had a favorable performance status and primary tumor sites were predominantly in the oral cavity. All patients were previously treated with chemotherapy which consisted of Platinol + 5FU with or without methotrexate. One patient also received bleomycin for a total cumulative dose of 180 mg/mL Although not eligible for the study, this patient received 3 weekly doses of tallysomycin Sa0b before being taken off study due to supply problem. All but one patient received radiation therapy to the primary tumor as well as cervical nodes. Two patients had elevated serum creatinine (1.6 mg/dl) at entry. N o n e of the patients had evaluable disease in areas that had not been previously irradiated. A total of 137 weekly doses were administered and the median number of doses per patient was 7. Overall, only four patients received a cumulative dose of tallysomycin S10b above 20 m g / m 2. No complete or partial responses were noted. One patient remained on-study for a total of 22 weeks without showing evidence of progression. This patient had an ill-defined lesion at the base of the skull which retrospectively could have been considered as scar tissue from previous surgery. She also had a small cervical adenopathy which remained unchanged during the entire duration of follow-up. Another patient with local recurrence of
327 Table 2. Non-hematologic toxicities
Table 1. Pretreatment characteristics
No. patients Sex: Male/female Age median: Range Performance status (WHO): 1 2 3 Unknown Primary tumor site: Tongue Palate Pharynx Tonsil Unknown Floor of the mouth Larynx Nasal cavity Ear Prior therapy: Chemotherapy Chemo- & radiotherapy
20 17/3 61 53-81 14 4 1 1 6 3 3 2 2 1 1 1 1 1 19
a tumor of the pharynx and bilateral lymph node metastases, had stable disease for a total of 15 weeks. Gastrointestinal intolerance was the most frequent non-hematologic toxicity. It consisted of mild to moderate nausea and/or vomiting in eleven patients and diarrhea in two. Transient fever was noted in nine patients. It was usually asymptomatic with a body temperature not exceeding 38~ In three patients, however, it was associated with chills and required symptomatic treatment. Skin toxicities were noted in six patients. They consisted of dryness, erythema, rash, edema, peeling palms and cracking nails. They usually occurred during the first weeks of treatment and there was no clear relationship with the cumulative dose of tallysomycin S10b. Five patients had dyspnea or minimal reduction of their pulmonary diffusion capacity which in most cases could not be clearly ascribed to the drug. Elevated serum creatinine was reported in four patients, two of whom had already elevated baseline value. The maximum serum creatinine values ranged from 1.7 mg/dl to 2.2 mg/dl. In one patient, a concomitant decrease of creatinine clearance was
No. of patients Evaluable Nausea and vomiting Fever Skin Pulmonary Renal Malaise Diarrhea Infection
20 11 9 6 5 4 (2) 4 2 2
( ) = severe toxicity
also noted. Four patients experienced malaise and general weakness. No hepatic nor hematologic toxicity was noted.
Discussion
This study failed to demonstrate any acitivity of tallysomycin S10b in refractory head and neck tumors. Most patients included in this trial were heavily pretreated and indicator lesions were located in previously irradiated areas. These unfavorable characteristics may have contributed to the negative results. Although a direct comparison with bleomycin cannot be established, these data suggest that tallysomycin S10b has lower antitumor activity than its parent compound. Side effects were usually mild to moderate and primarily consisted of gastrointestinal intolerance, fever and cutaneous toxicities. They were comparable in incidence and severity to those produced by bleomycin. Based on these data, no further trials of tallysomycin S10b are warranted in this tumor type.
References 1. Hong WK, Bromer R: Chemotherapy in head and neck cancer. N Eng J Med 308: 75-79, 1983 2. Schurig JE, Rose WC, Hirth RS, Schlein A, Huftalen JB, Florczyk AP, Bradner WT: Tallysomycin S10b: Experimental antitumor activity and toxicity. Cancer Chemother Pharmacol 13: 164-170, 1984 3. Buroker RA, Comereski CR, Barnett D, Hirth RS, Madissoo
328 H, Hottendorf GH: The toxicological evaluation of tallysomycin S10b biosynthetic tallysomycin derivative. Drug Chem Toxicol 7: 259-272, 1984 4. Sorensen PG, Pedersen H, Clausen HV, Hansen HH: Tallysomycin Sl0b. A Phase I Study. Cancer Chemother Pharmacol 24: 113-116, 1989 5. Paolozzi FP, Gaver RC, Newman NB, Poiesz BJ, DeFino S, Louie A, Comis RL: Phase I trial of Tallysomycin S10b, a Bleomycin analogue. Invest New Drug (in press, 1989) 6. WHO handbook for reporting results of cancer treatment. Geneva, WHO 1979
7. Ajani JA, Welch SR, Raber MN, Fields WS, Krakoff IH: Comprehensive criteria for therapy-induced toxicity. Cancer Invest (in press, 1989)
Address for offprints: C. Nicaise, Bristol-Myers Company, Pharmaceutical Research and Development Division, 5 Research Parkway, P.O. Box 5100, Wallingford, CT 06492-7660, USA
