1-lfAL TH SCIENCES USRAR'f
`University of Wis-cOO'Jin
`1305 Linden Dr., Madison, Wis. 53706
`
`cancer
`treatment
`reports
`
`1)
`
`u. . kt lUI I !. Ut
`·con
`MAR 11978
`
`U.S DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
`
`Publ1c Health Service
`
`National Institutes of Health
`
`IMMUNOGEN 2044, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`..
`
`Phase I Study of Maytansine Using a 3-Day Schedule 1•2 •3
`
`Fernando Cabanillas,* Victoria Rodriguez, Stephen W. Hall, Michael A. Burgess, Gerald P. Bodey,
`and Emil J Freireich 4
`
`SUMMARY
`
`Maytansine, a new ansa macrolide antitumor antibiotic, was administered to 60
`patients as part of a phase I study. The doses given ranged from 0.01 (starting level)
`to 0.9 mg/m 2 for 3 days. The toxic effects encountered consisted principally of
`nausea, vomiti~g, diarrhea, and occasionally, stomatitis and alopecia. Superficial
`phlebitis was also encountered and occurred when the drug was diluted in a volume
`of < 250 mi. Myelosuppression occurred infrequently; it was almost regularly
`associated with abnormal liver function tests. Antitumor activity was detected in one
`patient each with melanoma, breast carcinoma, and head and neck clear cell
`carcinoma. Further studies are indicated with this compound since it has shown
`evidence of activity with little or no myelosuppression.
`
`[Cancer Treat Rep 62:425-428, 1978]
`
`Maytansine is a natural compound originally iso(cid:173)
`-lated by Kupchan from the stem bark of an East
`African shrub, Maytenus ovatus (1). It belongs to
`the ansa macrolide class of antibiotics which are
`currently the subject of intense investigation as
`possible anticancer agents. Maytansine has shown
`· antitumor activity in the P388 leukemia model and
`B16 melanoma. 5 No significant activity has been
`detected against L1210 leukemia, and it is only
`marginally active against Lewis lung carcinoma. 5
`The compound produces stathmokinetic effects at
`ext remely low doses (2,3). One of the interesting
`aspects of this compound is that it has shown
`activity in experimental animal tumors at micro(cid:173)
`gram/kilogram dose levels while most antitumor
`
`'Received Sept 6, 1977; revised Nov 11, 1977; accepted Nov 21,
`1977.
`' Supported in part by contract N01-CM-43801 from the Divi(cid:173)
`sion of Cancer Treatment (DCT), National Cancer Institute
`(NCI), National Institutes of Health, Department of Health,
`Education, and Welfare.
`3 Maytansine was supplied by the DCT, NCI, Bethesda, Md.
`'Department of Developmental Therapeutics, The University
`of Texas System Cancer Center, M. D. Anderson Hospital and
`Tumor Institute, Houston.
`' Helman L, Henney J , and Slavik M. Clinical brochure: may(cid:173)
`tansine. Prepared by the NCI, Bethesda, Md, 1976.
`*Reprint requests to: Fernando Cabanillas, MD, Department
`of Developmental Therapeutics, The University of Texas System
`Cancer Center, M. D. Anderson Hospital and Tumor Institute,
`6723 Bertner Ave, Houston, Tex 77030.
`
`agents are active at the milligram/kilogram dose
`level. While most drugs lose their antitumor activity
`after a two- to three-fold reduction below the opti(cid:173)
`mal dose, maytansine has been shown to retain its
`activity against P388 leukemia over a 50-100-fold
`dosage reduction. 6
`Toxicology studies in beagle dogs showed the
`highest nontoxic dose to be 0.15 mg/m 2/day x 1
`while the lethal dose was 2.4 mg/m 2/day x 1. In
`mice, dogs, and monkeys, the most frequently ob(cid:173)
`served toxic effects were related to the gastrointes(cid:173)
`tinal tract, liver, and hematopoietic systems. 5 Gas(cid:173)
`trointestinal tract toxicity was one of the most
`prominent side effects observed and consisted of
`anorexia, emesis, and bloody diarrhea. The liver
`was also consistently affected at the higher doses as
`manifested by elevations of the liver enzymes and
`fatty changes. A consistent effect was also observed
`in the bone marrow manifested by hypoplasia which
`did not appear to be cumulative. Other side effects
`observed were phlebitis at the injection site and
`reversible elevations of BUN levels.
`We elected to conduct phase I trials of maytansine
`in patients with advanced malignancies. We report
`the initial results of our clinical experience with
`this compound.
`
`'Plants yield chemicals active against tumors. Chern EnJC
`News, Feb 28, 1972, pp 58-59.
`
`Cancer Treatment Reports Vol. 62, No.3, March 1978
`
`425
`
`IMMUNOGEN 2044, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`MATERIALS AND METHODS
`
`Studies with this compound were initiated in the
`Department of Developmental Therapeutics, M. D.
`Anderson Hospital and Tumor Institute, in April
`1976. Only patients > 15 years old were entered into
`this study. All had evidence of metastatic malig(cid:173)
`nancy refractory to standard treatment. A 3-day
`schedule beginning at a dose of 0.01 mg/m 2 iv was
`selected as the starting dose level. Dose escalations
`proceeded at 50% increments initially and later at
`100% when it was realized that the starting dose
`selected was very low (table 1). A total of 60 patients
`entered in this study received 108 courses of treat(cid:173)
`ment. The number of courses given as the initial
`dose at each level and the number of subsequent
`courses are shown in table 1. The drug was admin(cid:173)
`istered initially in 50 ml of dextrose solution and
`infused over 15 minutes. Later in the study, the
`drug was diluted in 250-500 ml of fluid and infused
`over 30 minutes to avoid superficial phlebitis.
`Courses of treatment were repeated every 2-8
`weeks, depending on toxicity.
`Pretreatment studies included an SMA-12 profile,
`cbc, differential, and platelet counts, and a bone
`marrow aspiration. Other laboratory and radiologic
`studies were performed when indicated. During
`treatment, the patients had cbc, differential, and
`platelet counts taken at least twice a week and an
`SMA-12 profile prior to every course of treatment.
`Patients were followed closely for any evidence of
`toxicity or any other biologic effect; all roentgeno(cid:173)
`graphic and laboratory studies were repeated after
`two courses of treatment to assess response.
`A partial remission (PR) was classified as a > 50%
`reduction in the sum of the product of tt._~ diameters
`
`TABLE 1.-No. of courses of maytansine at each dose level
`
`Dose level
`(mg/m' x 3 days)
`
`No. of courses given-
`
`As 1st
`dose
`
`Subsequently
`
`0.01
`0.015
`0.025
`0.037
`0.05
`0.075 _
`0.15
`0.3
`0.4
`0.5
`0.6
`0.7
`0.9
`
`Total
`
`6
`3
`3
`3
`5
`6
`1
`1
`2
`15
`0
`5
`4
`
`54
`
`2
`2
`2
`4
`3
`5
`5
`4
`4
`8
`4
`6
`5
`
`54
`
`of measurable lesions. Any objective response of
`< 50% reduction in the product of the diameters of
`a lesion was considered less than a PR. Myelo(cid:173)
`suppression was defined as any decrease in wbc
`count to < 3000/mma or a decrease in platelet count
`to < 150,000/mma in a patient with no tumor in(cid:173)
`volvement of the bone marrow. For the purpose of
`correlating drug toxicity to pre-existing liver dys(cid:173)
`function, we have considered liver enzymes to be
`significantly abnormal when any elevation more
`than twice the normal value for any single liver
`enzyme occurred in a patient with known or sus(cid:173)
`pected liver disease. Also, any simultaneous eleva(cid:173)
`tion of the three liver enzymes of at least 25% was
`considered to represent significant liver dysfunc(cid:173)
`tion.
`Informed consent was obtained from the patients
`prior to instituting therapy according to institu(cid:173)
`tional policies.
`
`RESULTS
`
`Nonmyelosuppressive Toxicity
`
`Of the 108 courses administered, 102 were evalu(cid:173)
`able for nonmyelosuppressive toxicity. The earliest
`evidence of toxicity was seen at doses of 0.15/m 2 and
`consisted of superficial phlebitis (table 2). This side
`effect was eliminated by diluting the drug in larger
`volumes (250-500 ml) of fluid. Gastrointestinal tox(cid:173)
`icity was first seen at the dose of 0.4 mg/m 2 and
`consisted of vomiting and diarrhea which became
`progressively more severe at higher dose levels (0_.7
`and 0.9 mg/m 2
`) leading to severe dehydration within
`a few hours. Fewer episodes of diarrhea were ob(cid:173)
`served at 0.5 mg/m 2 than at higher doses, and the
`severity was also considerably less. Deterioration of
`liver function tests (bilirubin, SGOT, and alkaline
`phosphatase) was also observed at doses between
`0.6 and 0.9 mg/m 2 as shown in table 2. These
`instances of possible hepatic toxicity occurred in
`three patients whose liver function studies were
`abnormal before treatment was instituted. In each
`case, rapid deterioration of liver function occurred
`during therapy associated with the onset of jaun(cid:173)
`dice. All three patients died with liver dysfunction,
`although the cause of death was probably directly
`related to hepatic toxicity in only one. An autopsy
`performed in one of these patients showed fatty
`infiltration of the liver and early cirrhosis. Moderate
`stomatitis and mild alopecia were also observed at
`doses between 0.6 and 0.9 mg/m 2 in three patients.
`No evidence of neurotoxicity was observed with the
`dose levels used.
`
`426
`
`Cancer Treatment Reports
`
`IMMUNOGEN 2044, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`TABLE 2.-Maytansine nonmyelosuppressive toxicitj in 102 courses
`
`Dose
`(mg/m' x 3 days)
`
`No. of evaluable
`courses/
`No. of evaluable
`patients
`
`0.01-0.1
`
`0.15-0.5
`
`0.6-0.9
`
`49/45
`
`30/22
`
`23/20
`
`% toxicity (courses/patients)
`
`Vomiting
`
`Diarrhea
`
`Hepatotoxicity
`
`Other
`
`0/0
`
`16/15
`
`60170
`
`0/0
`
`33/21
`
`65/70
`
`0/0
`
`0/0
`
`13/15
`
`0/0
`
`14/9
`(phlebitis)
`
`13/15
`(stomatitis)
`13/15
`(alopecia)
`
`I
`I
`
`TABLE 3.-Lowest blood cell counts in all patients as related to
`dose of maytansine
`
`No. of
`evaluable
`courses/
`No. with
`myelo-
`suppression
`
`40/-
`
`28/4
`
`20/5
`
`88/9
`
`Dose
`(mg/m2
`x 3 days)
`
`0.01-0.075
`
`0.15-0.5
`
`0.6-0.9
`-- Total
`
`Median (cells x 10"/mm")
`
`Lowest
`wbcs
`(range)
`
`Lowest
`platelets
`(range)
`
`6.5(3.9-22.0)
`
`300(132--442)
`
`5.7(2.8-15.9)
`
`220(110--456)
`
`4.9(0.7-16.2)
`
`204(11-690)
`
`Myelosuppressive Toxicity
`
`A total of 88 courses administered to 60 patients
`were considered evaluable for myelosuppression.
`The myelosuppressive toxicity is shown in table 3.
`In only nine courses administered to five patients
`was some degree of myelosuppression observed (ta(cid:173)
`ble 4). Eight of these courses of therapy were
`administered to patients with significant abnormal(cid:173)
`ities in liver function tests prior to or immediately
`after therapy (table 4). The most frequently ob(cid:173)
`served liver function abnormality was an elevated
`alkaline phosphatase. In all patients except one (a
`patient who died with sepsis), myelosuppression was
`reversible and usually of brief duration. The median
`day of the lowest wbc count in the patients who
`showed myelosuppression was Day 8. The counts
`usually recovered completely within 1 week.
`
`Therapeutic Response
`
`Of the 60 patients entered, 42 were evaluable for
`response. Eighteen patients were inevaluable for
`response (nine early deaths, three protocol viola(cid:173)
`tions, and six patients who did not return for
`further therapy). Antitumor activity with this com-
`
`pound was related to dosage as shown in table 5. No
`responses were observed with doses< 0.3 mg/m 2• Of
`19 patients receiving doses > 0.3 mg/m 2, three had
`an objective response. The diagnoses of these 19
`patients are shown in table 6. The patient with
`melanoma who responded achieved PR of multiple
`metastatic lung and skin lesions which has lasted
`for 5+ months. Another patient achieving PR had
`breast carcinoma with soft tissue involvement of
`the chest wall and an axillary mass; her response
`was of brief duration (1 month). The patient with
`head and neck clear cell carcinoma had objective
`evidence of response in multiple skin lesions but the
`reduction in size was not enough to classify it as a
`PR.
`
`DISCUSSION
`
`The results of this study indicate that in patients
`with normal liver function maytansine has tolerable
`toxicity and can be given safely at a dose of 0.5 mg/
`m 2 daily for 3 days. Side effects at that dose level
`include nausea, vomiting, diarrhea, and phlebitis.
`Myelosuppression was not observed as a frequent
`side effect at the doses used in this study. The few
`instances of myelosuppression occurred almost ex(cid:173)
`clusively in patients with abnormal liver function
`tests. This suggests that there is either impaired
`metabolism or a decrease in biliary excretion of the
`drug in these patients. Pharmacology studies are in
`progress to clarify this hypothesis. When myelo(cid:173)
`suppression took place, it usually occurred early,
`around Days 7-10, and its duration was usually
`brief, allowing us to administer the drug every 2
`weeks in many instances.
`The dose-limiting toxic effect of maytansine in the
`3-day schedule administered to our patients was
`diarrhea which in 'several cases led to rapid and
`severe dehydration. The diarrhea usually started on
`the second or third day of therapy, but it has not
`been a regular toxic effect even at doses of 0.6-0.9
`
`Vol. 62, No.3, March 1978
`
`427
`
`IMMUNOGEN 2044, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`TABLE 4.-Liver function tests in 9 courses of maytansine associated with- myelosuppression •
`
`Alkaline
`phosphatase
`(N = 30-80)
`
`SGOT
`(N = 7-40)
`
`LDH
`(N = 100-225)
`
`Bilirubin
`(N = < 1.0)
`
`Lowest
`wbcs/mm"
`
`Lowest
`platelets/mm"
`
`193
`180
`147
`231
`117
`195
`176
`315
`142
`• N = normal range.
`
`78
`64
`62
`27
`26
`40
`90
`34
`40
`
`> 600
`296
`332
`171
`146
`220
`240
`200
`230
`
`1.0
`0.6
`0.8
`0.9
`0.6
`1.0
`1.1
`0.9
`0.9
`
`2800
`2800
`3100
`1700
`2100
`4000
`1600
`700
`2700
`
`110,000
`118,000
`102,000
`123,000
`251,000
`96,000
`215,000
`11,000
`300,000
`
`TABLE 5.-Antitumor activity of maytansine related to dosage
`
`Dose
`(mg/m 2 x 3 days)
`
`No. of evaluable
`patients/
`No. responding
`
`0.01-41.05
`
`0.075-41.15
`
`0.3-0.9
`
`Total
`
`17/0
`
`610
`
`19/3
`
`42/3
`
`TABLE 6.-Diagnoses and response of patients with advanced
`cancer treated with maytansine at doses> 0.3 mg/m 2 *
`
`Tumor type
`
`Melanoma
`
`Breast carcinoma
`
`Head and neck clear cell carcinoma
`
`Lung carcinoma
`
`Renal cell carcinoma
`
`Adenocarcinoma, unknown primary
`
`Total
`
`No. of
`patients
`
`7
`
`7
`
`2
`
`19
`
`Response
`
`1 PR
`
`1 PR
`1 < PR
`
`0
`
`0
`
`0
`
`• Includes only patients who have received at least 2 courses
`of the drug.
`
`mg/m 2• However, at the higher doses (O.(H).9 mg/
`m 2), most of the patients did develop this side effect.
`
`The severity of the diarrheal episodes was also more
`pronounced at high doses.
`Since myelosuppressive toxicity from maytansine
`appears to be more severe in patients with elevated
`bilirubin or with elevation of liver enzymes more
`than twice the normal levels, we recommend an
`initial dosage of 0.25 mg/m 2/day for 3 days; this may
`need to be modified in light of pending results of
`pharmacology tests. In patients with normal liver
`function tests, the recommended dose for phase II
`studies is 0.5 mg/m 2 for 3 days.
`At this dose, maytansine appears to be nonmyelo(cid:173)
`suppressive in patients with normal liver function.
`This makes it a very attractive compound to use in
`combination with other myelosuppressive drugs.
`Other schedules that will allow delivery of a higher
`dose with less gastrointestinal toxicity need to be
`investigated. Further phase II studies are indicated
`since activity in tumors such as melanoma, breast
`carcinoma, and head and neck clear cell carcinoma
`has been observed.
`
`REFERENCES
`
`1. KUPCHAN SM, and KOMODA Y. Maytansine, a novel antileu(cid:173)
`kemic ansa macrolide from Maytenus ovatus. J Am Chern Soc
`94:1354-1356, 1972.
`2. REMILLARD S, REBHUN LI, HOWIE GA, ET AL. Antimitotic
`activity of the potent tumor inhibitor, maytansine. Science
`189:1002-1005, 1975.
`3. WOLPERT-DEFILIPPES MK. Initial studies on the cytotoxic
`action of maytansine, a novel ansa macrolide. Biochem Phar·
`macol 24:751-753, 1975.
`
`428
`
`IMMUNOGEN 2044, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`