Early Clinical Study of an Intermittent Schedule for Maytansine (NSC-153858): Brief
`Communication 1.2
`
`R. T. Eagan, M.D., 3 J. N. Ingle, M.D., 3 J. Rubin, M.D., 3 S. Frytak, M.D., 3 and C. G. Moertel, M.D. 3
`
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`
` by Kelley Martin on November 13, 2014
`
`ABSTRACT-Maytansine, an ansa macrolide, was evaluated in
`an early clinical
`trial
`in 40 adult patients with various solid
`tumors. Severe nausea and vomiting, sometimes associated
`with watery diarrhea and abdominal cramps, and Iiver function
`abnormalities, mainly elevation of serum glutamic-oxaloacetic
`transaminase levels, together constituted what we considered
`dose-Iimiting toxicity. Mild hematologic toxicity (mainly thrombo(cid:173)
`cytopenia), neurotoxicity, and possibly cardiac toxicity were also
`noted. No antitumor effect was seen. An iv dose of 0.750 mg/m 2
`on days 1, 3, and 5 (total dose, 2.25 mg/m 2
`) repeated every 4
`weeks is recommended for Phase 11 trials.-J Natl Cancer Inst
`60: 93-96, 1978.
`
`MA YT (NSC-153858) is a naturally occurring ansa
`macrolide originally isolated from the East African
`shrub Maytenus ovatus (l). MA YT belongs to a new class
`of compounds characterized by the presence of a large
`macrocyclic lactone ring, frequently N-heterocyclic, and
`incorporating within it an m- or p-bridged aromatic
`moiety.
`MA YT possesses stathmokinetic (mitosis-inhibiting)
`properties including metaphase arrest, an action similar
`to the vinca alkaloids vincristine and vinblastine (2).
`DNA synthesis is inhibited more than RNA or protein
`synthesis. DNA-dependent RNA polymerase is also not
`greatly affected. MA YT is active against a variety of in
`vivo tumor systems including P388 Ieukernia, B16 mela(cid:173)
`noma, and Lewis lung carcinoma as weIl as against KB,
`L1210, L51784, and P388 tumors in vitro (1).
`Drug-related toxicities in dogs and monkeys include
`enteritis and degeneration of intestinal mucosa, deple(cid:173)
`tion of lymphoid organs, e mesis , blood diarrhea, bone
`marrow hypoplasia , and liver disorder manifested by
`increased SeOT, serum glutamic-pyruvic transami(cid:173)
`nase
`and bromsulphalein-rctention levels. The inci(cid:173)
`dence and severity of toxicities were dose related in
`dogs and monkeys. Five-day pulses of drug with int~r­
`mittent 9-day rest periods suggest lack of cumulative
`toxicity. The reported toxicities were reversible with
`the exception of some histopathologic liver lesions (3).
`Rarer toxicities included hindlimb paralysis in MA YT(cid:173)
`treated mice. N eurotoxicity was not seen in other ani(cid:173)
`mals , but, because of the similarity of the drug's action
`to that of the vinca alkaloids, e.g., its effect on the size
`of the mitotic spindie believed to be secondary to the
`inhibition of the polymerization of tubulin (4), neuro(cid:173)
`toxicity was also a possibility. Also, 1 dog and 1 monkey
`treated with lethai doses showed degenerative myocar(cid:173)
`dial changes of questionable significance according to
`the authors.
`Our early clinical toxicity trial began with a dosage of
`
`0.045 mg MA YT/m 2 given as 0.015 rng/rn" on days 1, 3,
`and 5 with repeat cycles at 4-week intervals. That
`starting dose had already been studied at the NCI and
`represented one-fifth the highest nontoxic dose in the
`monkey.
`
`MATERIALS AND METHODS
`
`Eligible patients had to have histologic or cytologic
`evidence of unresectable or metastatic cancer beyond
`any reasonable hope of eure or significant palliation by
`more conventional
`therapy. Patients were excluded
`from study for any of the following reasons:
`recent
`major
`surgery,
`radiation therapy or chemothera~y
`within 4 weeks (8 wk for any nitrosourea), leukopema
`«4,100 cells/mrn"), thrombocytopenia «130,000 cells/
`mrn"), any elevation of the direct-reading serum biliru(cid:173)
`bin levels , aserum creatinine level greater than 1.5 mg/
`dl, or an Ecoe performance score of 4 (total disability).
`Entered into the study were 42 patients. Only 1 was a
`pediatric patient, a 3-year-old with an advanc~d ne~ro­
`blastoma treated at
`the initial dose level. This panent
`developed thrombocytopenia with a platelet nadir of
`52,000 cells/rnrn" on day 18. One adult
`treated with
`1.350 mg MAYT/m2 total dose died of tumor-related
`ca uses 1 day after her first injection. These 2 patien ts
`were not
`included in the subsequent analysis, which
`consisted of 40 adult patients with solid tumors. The
`clinical characteristics of these 40 patients were as fol(cid:173)
`lows: median age, 59 years (range, 23-78 yr); 65%
`males; 65% ECOG performance score of 2 or 3; 92%
`prior chemotherapy; 42% prior radiation therapy; and
`the lung (32%) and the colorectum (28%) being the
`most common primary tumor sites.
`Pretreatment (within 72 hr) and retreatment (day 29
`and every 4 wk thereafter) tests included a hemoglobin
`test: WBC count; PL T count and differential test; a 12(cid:173)
`test' chemistry group including electrolytes , creatinine,
`bilirubin, alkaline phosphatase , SeOT, calcium, phos(cid:173)
`phorus, uric acid, and total serum protein: an electro(cid:173)
`cardiogram; an electromyogram (first pauent at each
`
`ABBREVIATIONS USED: MAYT = maytansine; SGOT = serum glu(cid:173)
`tarnic-oxaloacetic transaminase; NCI = National Cancer Institute;
`ECOG = Eastern Cooperative Oncology Group; WBC = white blood
`cells; PL T = platelet(s).
`
`1 Received May 11, 1977; accepted August 23,1977.
`2 Supported by Public Health Service Phase I c~ntract N01(cid:173)
`CM53838 from the Division of Cancer Treatment, National Cancer
`Institute.
`3 Mayo Clinic, Rochester, Minn. 55901.
`
`VOL. 60, NO. 1, JANUARY 1978
`
`93
`
`J NATL CANCER INST
`
`IMMUNOGEN 2042, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
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`

`

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`
` by Kelley Martin on November 13, 2014
`
`94
`
`EAGAN,
`
`INGLE, RUBIN, FRYTAK, AND MOERTEL
`
`total
`new dose level); urinalysis; 12-hour urine for
`protein; a short
`iothalamate renal clearance; anel a
`ehest X-ray. WBC anel PLT counts were also obtained
`on days 3 and 5 or 6 as well as once per week thereafter
`for PLT and twice per week for WBC. A repeat ehern(cid:173)
`istry group test was obtaineel on elay 5 or 6, anel serum
`creatinine or blood urea nitrogen anel SGOT were
`measured once per week for 3 weeks.
`MAYT was administereel by rapiel iv infusion over 3(cid:173)
`10 minutes into the siele arm of a freely floating infusion
`set-up on da ys 1, 3, anel 5 anel repeateel every 4 weeks
`from day 1. MA YT was supplied in l O-rnl Flint vials
`containing a white lyophilized powder consisting of 0.2.5
`mg MAYT and 100 mg mannitol. When reconstituted
`with 4.9 ml sodium chloride, each milliliter contained
`0.05 mg MA YT and 20 mg rnannitol. The reconstituted
`vials were eliscarded after 8 hours. The initial dose level
`was 0.015 mg MA YT/m 2 on days 1, 3, and 5 for an
`total elose of 0.045 mg/rn". Subsequent elosage
`initial
`escalations are shown in table 1. A slightly modifieel
`
`TABLE l.-Dosage escalation scheme [or MAYT
`
`Dose on days 1, 3, 5
`mg/rn"
`0.015
`0.030
`0.045
`0.090
`0.135
`
`0.300
`0.450
`0.600
`0.750
`0.900
`
`Total dose per course
`mg/rn"
`0.045
`0.090
`0.135
`0.270
`0.405
`Phase I meeting
`0.900
`1.350
`1.800
`2.250
`2.700
`
`Multiples ofthe
`starting dose
`1
`2
`3
`6
`9
`
`20
`30
`40
`50
`60
`
`Fibonacci escalation scheme (5) was employed initially
`up to the 0.405 mg/rn'' total-dose level. At that point, a
`discussion among the MAYT Phase I investigators and
`the NCI investigators resulted in a direct escalation to
`0.900 mg/rn" total dose.
`
`RESULTS
`
`in the 43 treatment courses
`Toxicity was minimal
`given to 26 patients at dosage levels up to and including
`the 1.350 mg/rn? total dose level. These 43 treatment
`courses consisted of 26 initial treatments with MA YT
`and 17 subsequent or escalation treatments after prior
`MA YT treatment at
`the same or a lower dose level.
`The most common side effects encountered in this
`group related to the gastrointestinal tract and consisted
`of mild nausea in 16% (7/43), vomiting in 9% (4/43),
`and eliarrhea in 9%. The next most common toxicity,
`which did not appear to be dose related, was thrombo(cid:173)
`cytopenia that occurred after 9% of the treatment
`courses. The PL T nadirs, day of nadir count, and
`dosage level were as follows: 99,000 on day 29 at 0.090
`mg/rn", 100,000 on day 13 at 0.270 mg/rn", 93,000 on
`day 17 at 0.900 mg/rn", and 90,000 on day 21 at 1.350
`
`mg/rn". All PLT counts returned to normal wit hi n 4-7
`elays. Leukopenia, with a WBC nadir of 3,900 on da}'
`14, was noteel
`in only 1 patient , Two par ients (5%)
`elevelopeel an increase in SGOT levels on day 5 (at least
`a 50% increase above pretreatrnent level), which had
`returneel
`to normal by day 29 in bot.h parients. Both
`patients were treated at the 1.350 mg/m" total-dose level
`(table 2). Two patients also eleveloped neurologie S\J1l p(cid:173)
`to ms. One eleveloped an agitated depression an d alter(cid:173)
`ation in sleep pattern at 1.350 mg/rn" afrer reeeiving
`two prior courses of 0.900 mg/rn". One month after his
`fourth MA YT treatment
`(at 1.800 mg/m"). he also
`complained of leg cramps and parest hesia involving the
`fingers. No further MAYT was given, and all neuro(cid:173)
`logic sym pto ms had lessened at reexamination 2 months
`later. This patient was a 78-year-old man with lung
`cancer. He also developed atrial fibrillation after his
`first course of 0.900 mg/rn". The rate of fibrillatio n was
`slowed with digitalization, but the r hyth m did not re(cid:173)
`turn to normal. No clinical congestive heart failure was
`apparent. The other patient with neurologic syrnpto ms
`become "light-headed" after his day-l treatment at the
`1.350 mg/rn'' total-dose level (i.e., after 0.450 mg MA YTI
`m"). Blood pressure was not altered . The light-headed(cid:173)
`ness remained stable during the day-3 anel day-5 injec(cid:173)
`tions and cleared up 1 week later. This patient did not
`receive further MAYT.
`Toxicity became more severe and consistent at total(cid:173)
`dose levels of 1.800 mg/rn" and higher (table 2). At the
`1.800-2.250 mg/rn''
`total-dose
`levels,
`14 treatment
`courses were given. Ten were initial
`treatments and
`foul' were subsequent or escalation treatments. In this
`group, nausea, vomiting, and diarrhea occurred in 29%
`(4/14),14% (2/14), and 29%, respectively. These symp(cid:173)
`toms generally began on days 3-5 and persisted for
`another 24-48 hours. One episode of diarrhea, associ(cid:173)
`ated with cramps, was severe but not bloody. It began
`on day 6 and persisted for 2 days. SGOT elevatio ns
`were t he most frequent
`toxicity noted, occurring in
`43% (6/14). All SGOT levels that had been elevatecl
`returned to or toward normal by day 29. The alkaline
`phosphatase levels became elevated (an increase in 25%
`or more above base line) in 2 patients on day-5 deterrni(cid:173)
`nations. One of the 2 patients had extensive liver
`metastases from a colon cancer
`that progressed Oll
`therapy. Two instances of leukopenia arid thromboey(cid:173)
`topenia oecurred at the 1.800 mg/rn" dose level resulting
`in WBC nadirs of 3,600 and 3,300 on days 15 a n d 14,
`respectively, and in PLT nadirs of 126,000 anel 121,000
`on days 13 and 19, respectively. Orie patient developed
`unilateral facial n umbness at the 2.25 mg/m 2 level. This
`patient had known central nervous system metastases .
`She had disease progression and clid not return for
`subsequent
`reevaluation; no further
`information is
`available on the facial weakness.
`t he
`Toxicity was severe in the 4 patients treatecl at
`2.700 mg/rn'' total-dose level. All 4 patien ts received t his
`dose level as their first exposure to MA YT. Severe
`nausea and vomiting occurred in 3 of the 4 patients
`beginning on day 3. Two of these patients, who also
`had abdominal cramps, were eventually hospitalized
`
`J NATL CANCER INST
`
`VaL. 60, NO. 1, JANUARY 1978
`
`IMMUNOGEN 2042, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

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`
` by Kelley Martin on November 13, 2014
`
`TABLE 2.-Nature and frequency of toxicities" from MAYT based on total dosage of drug (in rnglmi) administered per course
`
`EARLY CLINICAL STUDY OF MAYTANSINE
`
`95
`
`Dose level
`mg/rn"
`
`No. of initial
`treatment
`courses
`
`No. of subse-
`quent esca-
`lation
`courses
`
`Toxic effects b
`
`Nausea Vomiting Diarrhea
`
`t SGOTc
`
`t Alka-
`line phos-
`phatase
`
`0.045
`0.090
`0.135
`0.270
`0.405
`0.900
`1.350
`
`1.800
`2.250
`2.700
`
`Total
`
`~1.350;
`
`1.8-2.25
`
`2.7
`
`3
`4
`4
`3
`5
`3
`4
`
`5
`5
`4
`
`40
`
`26
`
`10
`
`4
`
`0
`1
`2
`3
`1
`7
`3
`
`3
`1
`0
`
`21
`
`17
`
`4
`
`0
`
`0
`2
`1
`3
`0
`0
`1
`
`4
`0
`3
`
`14/61
`(23)
`
`7/43
`(16)
`4/14
`(29)
`3/4
`(75)
`
`0
`0
`1
`2
`0
`0
`1
`
`2
`0
`3
`
`9/61
`(15)
`
`4/43
`(9)
`2/14
`(14)
`3/4
`(75)
`
`0
`0
`0
`0
`0
`2
`2
`
`3
`1
`0
`
`8/61
`(13)
`
`4/43
`(9)
`4/14
`(29)
`0/4
`
`0
`0
`0
`0
`0
`0
`2
`
`3
`3
`3
`
`11/61
`(18)
`
`2/43
`(5)
`6/14
`(43)
`3/4
`75
`
`0
`0
`0
`0
`0
`0
`0
`
`2
`0
`0
`
`2/61
`(3)
`
`0/43
`
`2/14
`(14)
`0/4
`
`Neuro-
`logic
`symp-
`toms
`0
`0
`0
`0
`0
`1
`1
`
`0
`1
`0
`
`3/61
`(5)
`
`2/43
`(5)
`1/14
`
`0/4
`
`t WBCd
`
`t PLTe
`
`~-~-"----_.-
`
`0
`0
`0
`0
`0
`0
`1
`
`2
`0
`0
`
`3/61
`(5)
`
`1/43
`(2)
`2/14
`(14)
`0/4
`
`0
`1
`0
`1
`0
`1
`1
`
`2
`0
`0
`
`6/61
`(10)
`
`4/43
`(9)
`2/14
`(14)
`0/4
`
`gressed after one course, 4 (10%) after two courses, 2
`three courses, and 1 (2.5%) after
`four
`(5%) after
`courses; 5 (12.5%) currently are stable.
`
`DISCUSSION
`
`The major clinical dose-limiting toxicity from MA YT
`was severe nausea and vomiting, generally beginning
`about day 4 or 5 and persisting for 1-5 days. This was
`sometimes accompanied by stornach cramps and waterv
`diarrhea. These toxicities became most apparent start(cid:173)
`ing at the 1.80 mg/m" dose level. At 2.7 mg/rn", 2 of 4
`patients had to be hospitalized for intraetable nausea,
`vomiting, and dehydration. The other major toxicity
`was liver dysfunction as evideneed by increases in SGOT
`levels and, occasionally, alkaline phosphatase levels.
`These abnormalities tended to improve or to disappear
`with time. Most patients reeeived only one course of
`treatment so that eumulative neurotoxicity as seen with
`the vinca alkaloids is hard to assess, but the development
`of paresthesia, leg eramps, agitation, and sleep abnor(cid:173)
`malities in a patient who received four courses of
`treatment seems to indicate that neurotoxieity does
`oeeur with MAYT. None ofthe 3 patients who devel(cid:173)
`oped apparent neurotoxicity had electromyograms
`done. Only 1 patient, who was 78 years old, developed
`a eardiac arrhythmia; it cannot be definitely aseribed to
`MA YT. Hematologic toxieity was seen infrequently,
`was mild, and usually presented as a transient throrn-
`
`a Toxicities are included in this table only if noted in > 1 patient.
`b Numbers in parentheses indicate percent.
`C 50% increase above pretreatment level.
`dA WBC nadir of <4,100 cells/mm".
`e A platelet nadir of <130,000 cells/mm".
`
`because the nausea and vorrntmg became intractable
`and led to dehydration. Three of these 4 patients also
`developed elevations of SGOT above their base line
`levels , two of which were elevated initially. However,
`by day 29, the SGOT levels had returned to normal in
`1 patient with the normal initial value and to a lower
`but still elevated level in 1 of the other 2 patients with
`initially elevated values on whom follow-up data are
`available.
`No objective tumors were noted in the 40 patients
`treated (table 3). Twenty-eight
`(70%) patients pro-
`
`TABLE 3.-Tumor site or histology in the 40 evaluable patients
`
`Tumor site or histology
`
`No.ofpatients
`
`13
`
`6331
`
`11
`
`332221111
`
`40
`
`Lung
`Large cell
`Adenocarcinoma
`Squamous cell
`Small cell
`Colorectal area
`Melanoma
`Adenocarcinoma-unknown primary
`Stomach
`Prostate gland
`Leiomyosarcoma
`Breast
`Liver
`Pancreas
`Thymoma
`Total
`
`VaL. 60, NO. 1, JANUARY 1978
`
`J NATL CANCER INST
`
`IMMUNOGEN 2042, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

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`
`http://jnci.oxfordjournals.org/
`
` by Kelley Martin on November 13, 2014
`
`96
`
`EAGAN,
`
`INGLE, RUBIN, FRYTAK, AND MOERTEL
`
`bocytopenia occurring most frequently between days 14
`and 21 post treatment.
`No tumor responses were seen. Most treated tumors,
`colorectal and lung, are relatively drug resistant
`to
`single-agent chemotherapy, particularly when the single
`agent
`is given after prior chemotherapy. All but 3
`patients had received prior chemotherapy.
`The recommended starting dosage for Phase 11 stud(cid:173)
`ies is 2.25 mg/m" total dose per course. Whether or not
`transient liver dysfunction, as noted in this stud y, would
`progress to permanent hepatic parenchymal damage is
`unknown at present, since no patient in this current
`study received suffieient drug over a long enough time
`to develop persistent liver function abnormalities not
`associated with liver metastases. There was no clear
`relationship between the frequency or severity of toxic-
`
`ity and preexisting liver disease In the form of hepatic
`metastases .
`
`REFERENCES
`(1) KUPCHAN SM, KOMODA Y, COURT WA, et al: Maytansine, a
`novel antileukemic ansa macrolide from Maytenus ouatus . J Am
`Chem Soc 94: 1354-1356, 1972
`(2) WOLPERT-DEFILLIPES MK, BONO VH JR, DION RL, et al: Initial
`studies on maytansine-induced metaphase arrest
`in L1210
`murine leukemia cells. Biochem PharmacoI24:1735-1738, 1975
`(3) HOLMAN LJ, SLAVIK M: Clinical brochure on maytansirie (NSC
`153858)
`from the Investigational Drug Branch, Division of
`Cancer Teatrnent, National Cancer Institute, 1976
`(4) REMILLARDS S, REBHUN LI: Antimitotic activity of t.he potent
`tumor in hibitor , maytansine. Science 189:1002-1005, 1975
`(5) GOLDSMITH MA, SLAVIK M, CARTER SK: Quantitative prediction
`of drug toxicity in humans from toxicology in small and large
`animals. Cancer Res 35: 1354-1364, 1975
`
`J NATL CANCER INST
`
`VOL. 60, NO. 1, JANUARY 1978
`
`IMMUNOGEN 2042, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`