Am] Clin Oncol (CCT) 8: 148-150, 1985.
`
`© 1985 Raven Press, New York
`
`Phase II evaluation of maytansine (NSC 153858) in
`advanced cancer
`A Southeastern Cancer Study Group trial
`
`Mario]. R. Ravry, M.D."
`George A. Omura, M.D.''
`Robert Birch, Ph.D.b
`
`MAYTANSINE GIVEN IN A 3·DAY COURSE q3 WEEKS pro(cid:173)
`duced only five responses (3%) in 163 evaluable
`adults with advanced cancer. The dose schedule em(cid:173)
`ployed is not recommended for further study.
`
`• From Emory University, Atlanta, Georgia.
`b From the University of Alabama in Birmingham, Uni(cid:173)
`versity Station, Birmingham, Alabama.
`
`Write for reprints to: George Omura, M.D., South(cid:173)
`eastern Cancer Study Group, University of Alabama in
`Birmingham, LBW Tumor Institute, Room 225, Bir(cid:173)
`mingham, Alabama 35294.
`
`M aytansine is an ansa macrolide, isolated
`
`from the East African shrub Maytenus
`Ovatus Loes; in vivo tumor inhibitory activity
`was reported in various animal systems such as
`mouse L1210, P388 leukemia, Lewis lung car(cid:173)
`cinoma, and B16 melanoma; human phase I
`studies incidentally demonstrated activity for
`this drug in breast, head-and-neck, and ovarian
`cancers, melanoma, leukemia and lymphoma. 6
`Encouraged by the spectrum of antitumor ac(cid:173)
`tivity demonstrated during these trials, we un(cid:173)
`dertook a broad phase II study of maytan(cid:173)
`sine.
`
`Methods
`
`Patients with advanced solid tumors refrac(cid:173)
`tory to previous therapy, or untreated but with
`a poor prognosis, were eligible for study if
`they: (1) had a definite histologic diagnosis; (2)
`were considered incurable by existing surgical,
`radiotherapeutic, or chemotherapeutic ap(cid:173)
`proaches; (3) had at least one measurable lesion
`(bone lesions alone were not acceptable); (4)
`had a Karnofsky performance status of at least
`40%; (5) had recovered from previous myelo(cid:173)
`suppressive therapy; (6) were 18 years of age
`or older; (7) gave written informed consent.
`Pretreatment studies included: history and
`physical examination; measurement of tumor
`indicator
`lesions; complete blood counts;
`serum transaminase, bilirubin, alkaline phos(cid:173)
`phatase, electrolytes, and creatinine; chest
`roentgenogram and other roentgenograms and
`scans as appropriate; and electrocardiogram.
`After starting treatment, blood counts were
`
`IMMUNOGEN 2005, pg. 1
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`

`

`AMERICAN jOURNAL OF CLINICAL ONCOLOGY: CANCER CLINICAL TRIALS
`
`April, 1985 149
`
`performed q 7 days. Every 21 days and just be(cid:173)
`fore each subsequent course of maytansine, the
`clinical and
`laboratory assessments were
`repeated.
`Maytansine was diluted in 500 cc of 5% dex(cid:173)
`trose in water and given by intravenous infu(cid:173)
`sion over 2 hours at a dose of 0.5 mg/m 2/day for
`3 consecutive days. In view of possible dose-re(cid:173)
`lated hepatic toxicity reported in other studies,
`patients who had abnormal liver function tests
`or detectable liver involvement received a half
`dose initially. Treatment was continued q 3
`weeks as long as there was no progression of
`cancer, and no significant drug toxicity. Esca(cid:173)
`lation of drug dosage, by 20% of the previous
`dose, was permitted only in patients receiving
`the lower dose schedule, if no further hepatic
`deterioration and no significant hematologic
`toxicity occurred during the previous 3 weeks.
`Toxicity was rated using standard cooperative
`group toxicity criteria. An adequate trial re(cid:173)
`quired at least two courses of maytansine, and
`2 weeks of follow-up after the last course. A
`complete response required disappearance of
`all objective evidence of cancer. A decrease of
`50% or more in the sum of the products of the
`diameters of measurable lesions was a partial
`response.
`
`Results
`
`Of the 194 patients entered into the study,
`31 were inevaluable (five were ineligible, nine
`had major protocol violations, and 17 had in(cid:173)
`adequate data).
`Of the 163 evaluable patients (86%), five
`(3%) achieved partial responses in the follow(cid:173)
`ing tumor categories (response duration): 1/22
`colorectal (28.1 weeks), 1/25 kidney cancer
`(92.9+ weeks), 1/8 head and neck (12 weeks),
`1/2 myeloma (48.7+ weeks), 1/8 other cancer
`(3.6 weeks). There were no responses of 26
`with lung cancer; 21 with breast cancer; 10
`with pancreatic cancer; eight with other GI
`cancers; three ovarian, two cervix, and two en(cid:173)
`dometrial cancers; two bladder; one testicular
`and one adrenal carcinomas; five with melano(cid:173)
`mas; 16 sarcomas; and one mesothelioma. The
`median age was 55 (range 20-81) and the me(cid:173)
`dian performance status was 70 (range 40-
`100). Forty-eight percent were male. Sixty-two
`of the evaluable patients began treatment with
`the low dose; only one of the responders was in
`that category. Sixteen patients (9.8%) had no
`
`TABLE 1
`Toxicity in 163 Evaluable Cases
`
`Mild
`
`Moderate
`
`Severe
`
`Life-Threatening
`
`Granulocytes
`Platelets
`Cardiovascular
`Oral
`Gl
`GU
`L1ver
`CNS
`
`8
`1t
`2
`2
`44
`7
`1
`
`8
`
`4
`
`17
`
`6
`
`5
`
`3
`
`6
`
`prior chemotherapy; of these, one with a colon
`primary had a partial response.
`
`Toxicity
`
`The side effects observed were mostly mild
`to moderate in severity and clinically tolerable.
`As the frequency and severity of toxicity were
`similar on the low dose and high dose, the re(cid:173)
`sults were combined (Table 1). Twenty-two pa(cid:173)
`tients had falls in hematocrit of uncertain rela(cid:173)
`tionship to treatment. Genitourinary effects
`attributed to the drug included increases in
`creatinine and/or BUN, and proteinuria in one
`case. An arrhythmia was reported in one case
`and nonspecific cardiac abnormalities in two
`other cases. Neurologic effects attributed to
`treatment included paresthesias, sensory neu(cid:173)
`ropathy, generalized weakness, hyporeflexia,
`lethargy, confusion, hallucinations, coma, and
`seizure; paresthesias and lethargy were the
`most common neurologic effects. Phlebitis and
`alopecia were occasionally reported.
`
`Discussion
`
`This study was prompted by the wide spec(cid:173)
`trum of antitumor activity in phase I studies of
`maytansine. Unfortunately, we observed no
`consistent antitumor activity. In this broad
`phase II trial, several categories did not have
`adequate numbers of patients and most had had
`prior chemotherapy; but we did not think fur(cid:173)
`ther accession was warranted.
`Toxicity was mostly mild to moderate and
`not unexpected, based on previous reports.
`Our results and other studies 1-s.7
`9 do not
`-
`suggest a major role for this drug in the treat(cid:173)
`ment of cancer.
`
`IMMUNOGEN 2005, pg. 2
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`IPR2014-00676
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`

`

`150
`
`Phase II trial of maytansine / Ravry. Omura, Birch
`
`ACKNOWLEDGMENTS
`This study was performed by the Southeastern Can(cid:173)
`cer Study Group and was supported by Public Health
`Service grants (CA) from the NCI. National Institutes of
`Health. Department of Health and Human Services.
`The following institutions participated in the study:
`University of Alabama in Birmingham (CA030 13,
`CA196.57. CA2H.56): Duke University, Durham, NC
`(CA03177): Durham V.A. Hospital (CAO.S6.34): Emory
`University. Atlanta, GA (CA03227); University of
`Miami, FL (CA0.5641): Washington University. St.
`Louis. MO (CA03376) : University of Puerto Rico, San
`Juan (CA1222.3): Rush Medical Center. Chicago, IL
`(CA12640): Case Western Reserve University, Cleve(cid:173)
`land. OH (CA1.'5.584): University of Tennessee, Mem(cid:173)
`phis (CA17027): St. Louis University, MO (CA17214);
`University of Kentucky, Lexington (CA202.5.5); Uni(cid:173)
`versity of Cincinnati, OH (CA28138): University of
`South Florida, Tampa; University of Florida, Gaines(cid:173)
`(CA28143); Vanderbilt University, Nashville
`ville
`(CA23909): University of Tennessee, Knoxville
`(CA13237); University of Louisville, Kentucky
`(CA16389): and New Jersey College of Medicine.
`Maytansine was supplied by the Division of Cancer
`Treatment, National Cancer Institute, Bethesda. MD .
`
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`IMMUNOGEN 2005, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
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