' .
`
`ANNUAL REPORT
`
`TO THE
`
`FOOD AND DRUG ADMINISTRATION
`
`MAYTANSINE
`
`NSC 153858
`
`IND 11857
`
`February 1984
`
`Drug Sponsor:
`
`Investigational Drug Branch
`Cancer Therapy Evaluation Program
`Division of Cancer Treatment
`National Cancer Institute
`
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`I
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`" I
`
`INTRODUCTION
`
`This annual report to the Food and Drug Administration is a summary of
`the status of clinical trials with Maytansine (NSC 153858,
`IND 11857).
`Maytansine, and ansa macrolide antibiotic, was first isolated f~om alcoholic
`extracts of the East African shrub Maytenus serrata (formerly known as M.
`ovatus) and later from the wood and bark of Maytenus buchanii (1,2). Bec.ause
`it was found to have high antitumor activity against P388 lymphocytic leukemia,_
`B16 melanoma and Walker 256 carcinosarcoma, it was developed for clinical
`trials (2,3). The results of these trials will be summarized and evaluated in
`this report.
`
`MECHANISM OF ACTION
`
`Maytansine resembles the vinca alkaloids and other tubulin-binding agents
`in its antitumor activity (4). Histological examination of Ll210 cells fixed
`1n alcohol and stained with Giemsa after 24 hours exposure to Maytansine
`showed 30% mitotic figures compared to 3% mitotic figures in control cells
`indicating that Maytansine is primarily a mitotic inhibitor (4,5). As a
`mitotic inhibitor, Maytansine is effective over a wide range of concentrations
`(6).
`In Hela cells, the lowest effective concentration of Maytansine (10.5nm)
`was 200 times smaller than that for Colcemid (1.37 x 10- 7 M), another mitotic
`inhibitor.
`In experiments with sea urchin eggs, Maytansine was 100 fold more
`potent than Vincristine, a vinca alkaloid, in blocking mitosis (7).
`
`Studies with synchronized Hela cells have shown that (a) cells 1n mitosis
`are the most sensitive to Maytansine, (b) cells in G1 are the most resistant,
`and (c) cells in S phase are intermediate in their resistance ( 6) .
`Consequently, it can be concluded that the closer a cell is to mitosis, the
`more sensitive it is to Maytansine ( 6) .
`
`At the beginning of mitosis, cells usually contain peak concentrations of
`spindle protein (tubulin). Mitosis is inhibited by depolymerization and
`inhibition of polymerization of tubulin by oxidation of the sulfhydryl groups
`in tubulin (8). This maytansine-induced metaphase arrest of dividing cells is
`the mechanism of action for maytansine's cytotoxicity.
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`ANTITUMOR ACTIVITY
`
`Kupchan initially reported Maytansine activity in KB cell cultures (human
`epidermoid carcinoma of the nasopharnyx), sarcoma 180, Lewis lung carcinoma,
`Ll210 leukemia, P388 leukemia, and Walker 256 (i .m.) carcinosarcoma (2,3).
`
`~vitro studies with Maytansine showed L5178Y and P388 leukemias to be
`inhibited at concentrations in the nanomolar range, with P388 cells being ·the
`most sensitive (4). Maytansine was also tested against P388 leukemia cells
`resistant to Vincristine.
`It was found that the Vincristine resistant cells
`were cross resistant to Maytansine (9).
`
`NCI testing revealed significant activity against P388 leukemia, Bl6
`melanocarcinoma, and Lewis lung carcinoma in mice, and marginal activity in
`the L1210 system. The drug is effective at doses in the meg/kg/day range
`( 10).
`
`PRECLINICAL TOXICOLOGY
`
`Preclinical toxicity studies were conducted in B602F/1 m1ce, F344 rats,
`beagle dogs and rhesus monkeys. Histopathologic evaluation of mice revealed
`lymphoid depletion of spleenic follicles, fatty changes and mild degeneration
`of hepatocytes (10) while rats showed necrotizing lesions in the gastro(cid:173)
`intestinal tract mucosa, thymus, spleen, bone marrow and testes (11). Also
`reported in rats was the observation of hemorrhagic lesions of the brain,
`mononuclear infiltration in the meninges and chromatolysis and vacuolation of
`dorsal and ventral root ganglion cells (11).
`
`Multiple dose and more chronic treatment schedules in the beagle dog and
`rhesus monkey resulted in pancreatic acinar cell degeneration, enteritis and
`degeneration of intestinal mucosa, lymphocyte depletion of lymphoid organs,
`emesis, bloody diarrhea, bone marrow hypoplasia, abnormal BSP retention levels
`and nephrosis (10).
`Increased mitotic activity was observed in the pancreas,
`esophagus, stomach, small and large intestines, adrenal cortex, renal pelvis,
`ureter, urinary bladder, and skin. The results from these studies suggested
`that toxicity was dose-related, reversible (except for histopathologic liver
`lesions) and noncumulative.
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`Pregnant m1ce were treated with single injections of Maytansine on days
`6, 7 and 8 of gestation and their fetuses examined for malformation on day 17
`of gestation (9). Both embryotoxic and teratogenic effects which appeared to
`be dose-related were demonstrated. They were most marked when Maytansine was
`administ~red on day 7 of gestation.
`
`PHASE I STUDIES
`
`Phase I studies (Table I) with Maytansine found the ma x1mum tolerated
`2.1 mg/m2 every 3 weeks when given as a single
`dose (MTD) to be from 1.8
`dose or 0.6 - 0.9 mg/m 2/d x 3 every three weeks. The M.D. Anderson study
`established the MTD of Maytansine to be 0.75 - 1.25 mg/m2 when given as a
`single dose every week. The dose-limiting toxicity in all studies was
`determined to be gastrointestinal toxicities consisting primarily of nausea,
`vomiting and diarrhea (often followed by constipation). These toxicities
`appeared to be dose-related but not schedule-dependent with toxicity first
`appearing at doses of 1.2 mg/m 2 and generally becoming severe at doses of 1.8
`mg/m2 and higher.
`
`Maytansine also caused significant central nervous system toxicities
`consisting of profound weakness, lethargy, dysphoria and insomnia on the
`single bolus studies but not on the d x 3 study by M.D. Anderson or the d1, 3,
`5, study by Mayo. These central nervous system toxicities seemed to be
`distinct from peripheral nervous system toxicities and were not related to
`metabolic or electrolytic abnormalities. Dose-limiting Vincristine-like
`peripheral neuropathies were reported by Sidney Farber after Maytansine
`treatment on a d x 5 dose schedule. Patients complained of jaw pain and
`paresthesia as well as severe myalgia. The loss of deep tendon reflexes and
`marked prolongation of nerve conduction times was also noted. Patients with
`prior neuropathy either secondary to malignancy or Vincristine treatment
`demonstrated further neurologic toxicity from Maytansine. Transient
`paresthesia for 24 hours following drug administration on a single dose
`schedule, was also reported in four patients on the NCI-MB study.
`
`Transient elevations of serum transaminase, alkaline phosphatase and
`bilirubin have been reported in all Phase I studies.
`In patients without
`initial liver impairment these elevations returned to normal by day 29.
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`Recommended Phase II doses were:
`1. Single dose of 2 mg/m2 i . v. every 3 weeks
`2. Weekly dose of 0.75 mg/m 2 i . v.
`3. Course of 3 days: 0.6 mg/m 2/day ~ . v. for 3 days, every 2, 3, or 4
`weeks
`
`In patients with hepatic dysfunction, the weekly dose was recommended to
`be reduced to 0.6 mg/m2 and the 3 day schedule to 0.4 mg/m 2/dx3.
`
`PHASE II STUDIES
`
`Phase II studies are listed 1n Table II. Only single agent trials have
`been performed. Trials by tumor site are described below. Except for the
`Mayo W82-989 study in islet cell carcinoma, all studies with Maytansine are
`now closed.
`
`ISLET CELL
`
`There is one protocol, W82-989, being conducted at the Mayo Clinic for
`islet cell carcinoma. Two patients have been evaluated in this study. No
`responses have been seen. This protocol was activated because of a near(cid:173)
`complete response seen in a single patient treated with Maytansine at the Mayo
`Clinic. The patient was assumed to have ductal adenocarcinoma of the pancreas
`with hepatic metastasis and was entered on GITSG 9376. The patient's response
`lasted for over three years, during which time the patient was restored from
`disability to full activity. Although the patient showed progression after
`voluntarily discontinuing Maytansine therapy, he remains alive at over five
`years. A pathologic review of the tissue was conducted and the patient was
`rediagnosed as having a typical islet cell carcinoma.
`
`PANCREATIC
`
`GITSG 9376 and SEG 78 ST 222 have both treated patients with pancreatic
`cancer on a dx3 schedule. Between the two studies, a total of 46 patients are
`evaluable for response. Besides the near complete response in the one patient
`with islet cell carcinoma (see islet cell section), there were no responses
`reported.
`
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`GASTROINTESTINAL
`
`The SEG 78 ST 222 trial treated several gastrointestinal tumor types with
`Maytansine on a dx3 schedule and saw no responses in two patients with gastric
`cancer, one with esophageal, one with bile duct, one with abdominal and three
`with gastrointestinal tumors of unknown primary site.
`
`COLON
`
`Three studies were conducted us1ng two different dose schedules for colon
`cancer.
`SEG 78 ST 222 a;d Mayo (C77-196) both used a dx3 schedule and
`reported 1 PR in 53 evaluable patients. Wayne State (C77 205), us1ng a weekly
`schedule, reported no responses in 22 evaluable patients.
`
`SMALL CELL LUNG
`
`Three studies have evaluated Maytansine in small cell lung cancer. The
`first study, ECOG 2578, was a randomized trial of Maytansine (using a q3w
`schedule) versus Cisplatin versus Chlorozotocin. There were 19 evaluable
`patients on the Maytansine arm and no responses were reported. The median
`survival of all patients in this study was 9.7 weeks.
`
`SEG 78 ST 222 and Mayo (C77-195) treated 12 patients on a dx3 schedule
`and reported no responses. The median survival for all patients treated on
`the Mayo study (all lung histologies) was 82 days.
`
`NON-SMALL CELL LUNG
`
`Large Cell Lung
`
`SEG 78 ST 222 and the Mayo Clinic (C77-195) treated 15 patients with
`large cell lung cancer. One PR was reported in a patient with no prior
`chemotherapy. The duration of response was 73 days.
`
`Adenocarcinoma-Lung
`
`Three studies were conducted us1ng Maytansine in adenocarcinoma of the
`lung.
`SEG 78 ST 222 and Mayo (C77-195) treated a total of 24 patients using a
`dx3 schedule. One PR was reported in a patient who had received prior chemo(cid:173)
`therapy. This response lasted 53 days.
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`Wayne State (C77-205) used both a low (0.5- 0.75 mg/m 2/w) and high (0.75
`- 1.0 mg/m 2/w) dose of Maytansine on a weekly schedule. Three patients were
`treated with the low dose, with one PR reported. Twelve patients received the
`high dose with no responses reported.
`
`Squamous Cell Lung
`
`Four studies were conducted using Maytansine in squamous cell lung
`carc1noma.
`SEG 78 ST 222, Mayo (C77-195), and Intramural Protocol N77-204
`used a dx3 schedule in squamous cell lung cancer patients. A total of 27
`patients were evaluable. One PR was reported by Mayo, which lasted 78 days.
`
`Wayne State (C77-205) reported one PR in one patient entered on a low
`dose (0.5 - 0.75 mg/m 2/w) of Maytansine and no responses in 14 patients
`treated with high dose (0.75 - 1.0 mg/m 2/w) Maytansine using a weekly
`schedule.
`
`MELANOMA/SARCOMA
`
`The Mayo Clinic (C77-207) conducted a randomized study of Maytansine and
`Chlorozotocin in melanoma patients. All patients were pretreated.
`Initially,
`16 patients received Maytansine with no responses. An additional 7 patients
`were crossed over from Chlorozotocin therapy and no responses were reported.
`
`SEG 78 ST 222 treated 22 melanoma/sarcoma (unspecified) patients using a
`dx3 schedule and reported no responses.
`
`M.D. Anderson (113-820), conducted a Phase II single agent study in
`melanoma. They used 2 dose levels of Maytansine--0.4-0.6 mg/m2 and 0.75
`mg/m 2, on a dx3 schedule. Thirty-three patients were treated at the lower
`dose level and twelve were treated on the higher. No responses were reported.
`
`ECOG 3377 and SWOG 7820 both conducted studies of Maytansine in
`sarcoma. The ECOG study was a randomized study of Maytansine (1.5 mg/m2 q3w)
`vs. Dibromodulcitol vs. ICRF-159. Forty-seven patients were treated with
`Maytansine with no responses.
`SWOG, employing a weekly x4 schedule, reported
`no responses in 17 evaluable patients.
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`THYMOMA
`
`Mt. Sinai (C77-229) performed a study of Maytansine in patients with
`malignant thymoma. Patients first underwent surgical resection and then
`radiation to the mediastinum and/or to other sites of relapse. Three patients
`then received Maytansine. Two PRs were achieved, one in a patient who
`received 18 weeks of therapy before relapsing.
`
`LYMPHOMA
`
`Using a weekly schedule, SWOG 7821 treated 3 patients with Hodgkin 1 s
`disease and 23 with non-Hodgkin 1 s lymphoma. One PR was reported in a patient
`with non-Hodgkin 1 s. This response lasted 4 weeks.
`
`ECOG PA 477 used a dx3 schedule for lymphoma patients. There were 9
`patients with Hodgkin 1 s disease and 22 with non-Hodgkin 1 s lymphoma on this
`study. Three PRs were reported, one in Hodgkin 1 s disease with a duration of
`13 months, and 2 in non-Hodgkin 1 S, both of 4 months 1 duration.
`
`BREAST
`
`Three trials, M.D. Anderson (113-820), SEG 78 ST 222 and Mayo (C77-225),
`used a dx3 schedule of Maytansine for treating patients with breast cancer.
`SEG and M.D. Anderson evaluated a total of 39 patients. One PR was reported
`by M.D. Anderson with a duration of 4 months. The Mayo study was a randomized
`study of Maytansine versus Chlorozotocin. Fifteen patients were evaluable on
`the Maytansine arm.
`No responses were reported.
`In addition, M.D. Anderson
`(113-820) treated three patients on a weekly schedule and reported no
`responses.
`
`Using a dx5 schedule, SWOG 7809 reported one patient who had partial
`regression of pulmonary disease (duration 7 weeks) during Maytansine
`therapy. A total of 29 patients were treated in this study.
`
`Sidney Farber (C77-203) reported no responses in 14 evaluable patients
`treated with Maytansine using a single bolus q3w schedule.
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`GYNECOLOGICAL MALIGNANCIES
`
`GOG 26H, using a q3w schedule, has treated 29 patients with cervical
`cancer and 29 with ovarian carcinoma. One PR was seen in a patient with
`cervical cancer who had not been previously treated with chemotherapy.
`No
`responses were reported in patients with ovarian carcinoma.
`
`SEG 78 ST 222 reported no responses in 6 evaluable ovarian carcinoma ·
`patients treated with Maytansine on a dx3 schedule.
`
`GENITOURINARY
`
`SEG 78 ST 222 treated a total of 28 patients using a dx3 schedule. One
`PR was reported out of 25 patients with renal cancer, and no responses were
`reported in 3 other patients with genitourinary malignancies (2 bladder, 1
`testicular).
`
`HEAD AND NECK
`
`SEG 78 ST 222 treated 8 patients with head and neck cancer on a dx3
`schedule. One PR was reported. The duration of response is unknown.
`
`The Mayo Clinic (C77-248) conducted a study of Maytansine versus a combi(cid:173)
`nation of Cytoxan, Adriamycin, and Cisplatin. Patients with active renal or
`cardiac disease were to receive Maytansine and those without received the
`combination. Thirty-one patients were entered on the Maytansine arm. One PR
`was reported which had a duration of 73 days.
`
`BROAD STUDIES
`
`SEG 78 ST 222 treated nine patients with several tumor types using a dx3
`schedule. One PR was reported in a patient with neuroblastoma (out of two
`evaluated) and in one patient with multiple myeloma (2 evaluable patients on
`the study). No responses were seen in one patient with NLPD, one with cancer
`of the thymus, one with Hodgkin 1 s disease, and one patient with tumor of
`unknown origin.
`
`Sidney Farber (C77-203) evaluated a total of 55 patients with various
`tumors using a q3w schedule. One PR was reported in four evaluable patients
`with bladder cancer.
`No responses were seen in six patients with colon
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`cancer, four with non-small cell lung, four with melanoma, four with soft(cid:173)
`tissue sarcoma, four with ovarian, three with small cell lung, one with ALL,
`four with renal, two with head and neck, one with CLL,
`two with pancreatic,
`and two with Ewing 1 s sarcoma.
`
`Wayne State (C77-205) used two different doses of Maytansine on a weekly
`dose schedule. The low dose was 0.5-0.75 mg/m 2 and the high dose was 0.75 7
`1.0 mg/m 2. Two PRs were reported on the low dose schedule. One PR was
`reported in three evaluable patients with squamous cell lung (duration was 3.7
`weeks) and one PR was reported in the only patient entered with adenocarcinoma
`of the lung (duration was 4.1 weeks) (see section for adenocarcinoma and
`squamous cell lung). No responses were reported in six patients with breast
`cancer, one with cervical, five with colon, one with small cell lung, eight
`with melanoma, one with ovarian, two with sarcoma, one with esophageal, and
`one with stomach cancer.
`
`On the high dose schedule, one PR (duration 13.5 weeks) was noted in s1x
`evaluable patients with melanoma.
`No responses were noted in one patient with
`prostatic cancer, one with sarcoma, four with stomach, two with liver, seven
`with breast, two with pancreatic, one with bladder, one with ovarian cancer,
`two with head and neck, one with cervical, and one patient with lymphoma.
`
`PEDIATRIC ACUTE LEUKEMIA
`
`SWOG 7819 did the only pediatric study with Maytansine. Seventeen
`patients with ALL were treated with Maytansine (0.6 mg/m 2/dx3) and no
`responses were observed.
`
`SUMMARY
`
`The response rates by tumor origin site are summarized in Table III.
`These do not take into account varying schedules.
`Some activity was seen 1n
`non-Hodgkins lymphoma (3 PRs/47), Hodgkins lymphoma (1 PR/13), NSCL (6 PRs/97)
`and head and neck carcinoma (2 PRs/43). Minimal activity was seen in renal (1
`PR/29), melanoma (1 PR/86), or cervical (1 PR/31) carcinoma. No activity was
`seen in SCLC, sarcoma, pancreas, colon or ovarian carcinoma. All other
`diseases that have had sporadic responses have not had adequate numbers of
`patients evaluated to make the response rates (as stated) reliable.
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`TOXICITY
`
`The toxicities reported with Maytansine have generally been grade I to
`II. The most commonly observed toxicities were gastrointestinal, especially
`nausea and vomiting, the incidence of which as observed in 557 patients was
`grade I-II--30%, grade III--6.5%, and grade IV--1%. Other less frequently
`observed gastrointestinal toxicities were diarrhea, constipation and, rarely,
`oral toxicities (mucositis/stomatitis).
`
`Hematologic toxicities were seen mainly as leukopenia, grade I-II--5%,
`grade III--0.5% and thrombocytopenia, grade I-II--7.4%, grade III--1.8% and
`grade IV--0.7%. Anemia was rarely observed.
`
`Hepatic toxicities characterized by elevated levels of SGOT, tglutamyl
`transpeptidase and alkaline phosphatase, were seen with incidence rates of
`grade I-II--7.0% and grade III--0.4%
`
`Peripheral neuropathy was also a commonly observed toxicity with
`Maytansine therapy.
`It occurred as paresthesia, myalgia, weakness and jaw
`pain. The incidence of grade I and II neuropathy was 7%, and grade III--2%.
`There was also one reported grade III case of paralytic ileus.
`
`CNS toxicities consisted of encephalopathy, somnolence, lethargy,
`insomnia, confusion and dysphoria. The grade I to II incidence was 8%, grade
`III was 4%, and there were two reported cases of grade IV CNS toxicities.
`
`Less commonly observed toxicities were GU, fever, cellulitis, alopecia,
`skin/hair, and cardiovascular (undefined).
`
`A summary of Maytansine toxicities can be found 1n Table IV.
`
`PLANS
`
`The ON Committee had voted to close the INO of Maytansine. Due to the CR
`which was reported in one patient with islet cell tumor, however, the NCI
`decided to keep the INO open to better evaluate the drug in this tumor.
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`REFERENCES
`
`1. K u p c h an , S . M . , K o mo d a , Y . , B r a n t man , A . R . , 0 a i l e y , R . G . , J r . , an d
`Zimmerly, V.A. Novel maytansoids. Structural interrelations and
`requirements for antileukemic activity. ~Am Chem Soc 96:3706-3708, 1974.
`
`2. Kupchan, S.M., Komoda, Y., Court, W.A., Thomas, G. J., Smith, R.M., Karim,
`A., Gilmore, C.G., Haltiwanger, R.C., and Bryan, R.F. Maytansine, a novel
`antileukemia ansa macrolide from Maytenus ovatus. ~Am Chem Soc 94:13-54-
`1356, 1972.
`
`3. Yang, S.S. Rifamycin antibiotics:
`Inhibitors of Rauscher murine leukemia
`virus reverse transcriptase and of purified DNA polymerases from human
`normal and leukemic lymphoblasts. ~ Natl Cancer Inst 49:7-25, 1972.
`
`4. Wolpert-DeFilippes, M.K., Adamson, R.H., Cysyk, R.L. and Johns, D.G.
`Initial studies on the cytotoxic action of Maytansine, a novel ansa
`macrolide. Biochem Pharmacal 24:751-753, 1975.
`
`5. Wolpert-DeFilippes, M.K., Bono, V.H., Jr., Dion, R.L., and Johns, D.G.
`Initial studies on Maytansine-induced metaphase arrest in L1210 murine
`leukemia cells. Biochem Pharmacal 24:1735-1738, 1975.
`
`6. Rao, P.N., Freireich, E.J., Smith, M.L., and Lao, T.I. Cell cycle phase(cid:173)
`specific cytotoxicity of the antitumor agent Maytansine. Cancer Res
`39:3152-3155, 1979.
`
`7. Lawrence, J.H., and Wheatley, D.N. Synthesis of microtubule protein 1n
`Hela cells approaching division. Cytobros 13:167-179, 1975.
`
`8. Remillard, S., and Rebhun, L.I., Howe, G.A., et al. Antimitotic activity
`of the potent tumor inhibitor Maytansine. Science 189:1002-1005, 1975.
`
`9. Sieber, S.M., Wolpert, M.K., Adamson, R.H., Cysyk, R.L., Bond, V.H., and
`Johns, D.G. Experimental studies with Maytansine--a new antitumor
`agent. Bibl Haematol 43:495-500, 1975.
`
`10. Clinical Brochure, Maytansine. Division of Cancer Treatment, 1976.
`
`11. Mugera, G.M., Ward, J.M. Acute toxicity of Maytansine 1n F344 rats.
`Cancer Treat Rep 61:1333-1338, 1977.
`
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`TABLE
`l
`PHASE I STUDIES
`
`Institution
`
`Schedule
`
`Mayo
`
`NC 1-MB
`
`M. D. Anderson
`
`Si dney Farber
`
`Oiv . dose
`d 1, 3, 5 q28d
`
`Si ngle dose
`dl q2ld
`
`Oiv . dose
`dx3 q2ld
`
`Oiv . dose
`dx3 qw
`
`Di v. dose
`dx3 q2w
`
`Div . dose
`dx5 q2ld
`
`MTO
`(mg/m2)
`
`2. 25
`
`DLT
`
`Reference
`
`Gastrointestinal
`Heakness
`
`J . Natl. Cancer Inst.
`60 :93-96 I 1978
`
`2. 0
`
`Gastrointestinal
`
`CTR 62 :429-433 , 1978
`
`1.8-2 . 1
`
`Gast roint estinal
`
`CTR 62:425-428, 1978
`
`0. 75-1. 25
`
`Gas troi ntes tina 1
`
`1.8
`
`Gast rointestinal
`
`AACR/ASCO 19:102,
`1978
`
`AACR/ASCO 19:102 ,
`1978
`
`2.0-2 . 5
`
`Gast r ointestinal
`
`CTR 62:435-438, 1978
`
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`I I
`TA~ .. -
`MAYTANSINE STUDIES
`
`'cse
`
`~t Cell
`
`Protocol
`
`Regimen
`
`Ev . !Entl
`
`Activity
`
`Toxicity
`
`Status/ Source
`
`W82- 989
`Mayo
`(82"- 44- 01)
`
`2
`0 . 6 mglm /dx3 q3w
`
`2 (2)
`
`No response
`
`None reported
`
`Open
`Pers . ccmm. 2/84
`
`:reatlc
`
`GITSG 9376
`
`0 . 5 mglm
`
`2
`
`/dx3 q3w
`
`36 1391
`
`trol ntest I n a l
`
`SEG 78
`ST 222
`
`0 . 25-0 . 50 mglm
`q3w
`
`2
`/dx3
`
`Total
`18 (201
`
`No r esponses except
`for one CR I n a pt .
`with I slet eel I ca .
`Duration of resp . was
`3+ yrs . P+ . was
`Ine l i gib l e for this
`protocol .
`
`No responses
`1 0 pancreas , 2
`stomach, 1 esoph ,
`b I I e duct ,
`I abdcm, 3
`other
`
`Gr . 1- 11 : NIV-4 ,
`plt-7
`
`leuk-12,
`
`Gr . Ill : N/V - 2, leuk- 1
`
`Closed
`9/82 GI TSG Stat
`Report
`
`Listed under lung disease
`
`Cl csed
`SEG Stat Report 1/82
`
`)0
`
`,.....
`w
`
`•n
`
`•n
`
`SEG 78
`ST 222
`
`C77-196
`Mayo
`
`2
`0 . 25-0 . 50 mglm
`q3w
`
`/dx3
`
`22 1271
`
`1 PR
`
`Listed under l ung disease
`
`2
`o . 6 mglm /dx3 q3w
`
`31
`
`No responses
`
`Q- . 1- 11: N/V- 7, d i ar rhea-
`12, paresthesla-2,
`alopecl a-4
`
`Gr . 111: N/V- 3, dl arrhea-
`2, paresthesla- 2, myalglas-
`1, paral yt lc II eus- 1
`
`Closed
`SEG Stat Report 1/82
`
`Closed
`CTR 62: I 237 , 1978
`
`C77-205
`Wayne State
`
`2
`0 . 75-J . O mglm /w
`
`22
`
`No responses
`
`Under broad dl sease
`
`Closed
`Cancer 46:1104 , 1980
`
`IMMUNOGEN 2002, pg. 14
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`T~·
`
`II
`MAYTANSINE STUDIES
`
`1ase
`
`Protocol
`
`Reg I men
`
`Ev. !Entl
`
`Act i vity
`
`Tox i city
`
`Status/Source
`
`ECOG 2578
`
`2
`Mayt . 1. 5 mg/m q3w
`vs . 2
`DDP 75 mg/m q3w
`vs .
`2
`CZT 1 20 mgl m q6w
`
`19 1251
`
`21 1251
`
`No responses
`
`I PR
`
`18 1231 •
`
`No responses
`
`Severe: neuro-4 (myalgia ,
`paresthesia, disorienta(cid:173)
`tion, headache, jaw pa i n ,
`weakness>, hemat-1, GI-l
`
`C I osed 1 0/79
`CTR 66 : 14 17, 1982
`
`SEG 78
`ST 222
`
`2
`0.25-Q . 50 mg/m /dx3
`q3w
`
`Total
`25 1311
`
`L. c . 2
`s.c. 7
`Sq . 8
`Ad . 7
`Unk .
`I
`
`Med . surv . al l pts .
`= 9. 7 w
`
`No responses
`
`Broad study, tox data for
`160 pts .
`
`Closed
`SEG Stat Report I /82
`
`Gr. I-ll: hgb-20, gran-9,
`p l t-15, CV-3 , oral-2, Gl --50
`(mostly N/Vl , GU-7,
`hepat lc-1, CNS- 14,
`skln/halr-12
`
`Gr. Ill : hgb-1, p l t-5,
`Gl -3, GU - 1, CNS- 6
`
`Gr . IV: hgb-1 , p l t-1
`
`Mild: nause.:t-10,
`vomltlng-6, dlarrhea- 13,
`constipation- !,
`neurol og I c-4 , y gamma
`gl utcrnyl transpept ldase-7,
`1-SGOT-6, 1' alkaline
`phosphatase-3
`
`Moderate to severe :
`n au se.:t-6, vomIt I ng-4,
`dlarrhea-7, constipation-a,
`neurolog lc-2
`
`Cl osed
`CTR 62:1577-1579,
`1978
`
`......
`~
`
`C77-195
`<Mayo)
`
`2
`0 . 6 mg/m /dx3 q3w
`
`Adenocarc.
`PCT 12
`N PCT 5
`
`Large cell
`PCT 10
`N PCT 3
`
`Squam . eel I
`PCT 10
`N PCT 2
`
`Small cell
`PCT 4
`N PCT 1
`
`In a pt . with
`One RR
`PCT (53d)
`
`One PR In a pt . with
`N PCT (73dl
`
`In a pt . with
`One PR
`PCT <78dl
`
`No responses
`
`Med surv . all pts=82d
`
`mous cell
`
`N77-204
`
`mous Cell
`
`C77-205
`Wayne State
`
`=prior chemotherapy
`=no prior chemotherapy
`
`2
`0 . 5 mg/m /dx3 q3w
`
`2
`0 . 5-Q . 75 mg/m /W
`2
`o. 75-1 .o mg/m /w
`
`7 17 I
`
`No responses
`
`Not reported
`
`3
`
`14
`
`IPR
`
`No responses
`
`Under broad disease
`
`Closed
`Annual Report 1980
`
`Closed
`Cancer 46:1104, 1980
`
`IMMUNOGEN 2002, pg. 15
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`se
`
`• Lung
`
`Protocol
`
`C77-205
`Wayne State
`
`ana
`
`C77-207
`Mayo
`
`2
`0 . 5-0.75 mg/m /w
`2
`0. 75-1.0 mg/m /w
`
`2
`Mayt . o. 6 mglm /dx3
`q3-4w
`
`2
`vs .
`CZT 150 m g/rn q6w
`
`0116/
`na
`
`Ctnll
`
`1-'
`tn
`
`SEG 78
`ST 222
`
`2
`0.25--{) . 50 mglm /dx3
`q3w
`
`113-820
`MDA
`
`2
`0. 4-0 . 6 mg/m /dx3
`q2-3w
`
`vs .
`2
`o. 75 mg/m /w
`
`na
`
`ECOG 3377
`
`2
`l~ayt ansI ne I • 5 mg/m
`q3w
`
`vs . 2
`OODI80mglm POdx10
`q4w
`
`2
`vs.
`ICRF-159 300 mg/m
`PO dx3 q4w
`
`tid
`
`12
`
`No responses
`
`Pr !mary ~~ay
`
`16
`
`No responses
`
`Cx fran CZT
`
`7
`
`22 (24 I
`
`33
`
`12
`
`47
`
`45
`
`37
`
`No responses
`(Unspecified no. of
`melanana or sarcana
`pts . l
`
`No responses
`
`No responses
`
`No responses
`
`1 PR (osteol
`
`1 PR ( f l b rol
`
`na
`
`51'/0G 7820
`
`2
`0 . 50-Q. 75 mg/m qwx4
`
`17 1301
`
`No responses
`
`TABU. II
`MAYTANSINE STUDIES
`
`Regimen
`
`Ev . !Entl
`
`Act tv lty
`
`Toxicity
`
`Si" atu s/ Sour ce
`
`PR
`
`Under broad disease
`
`Closed
`Al
`l pts . pr lor
`chemot 1-.er apy
`Cancer 46: I 104, 1980
`
`Closed
`CTR 64:721, 1980
`
`N!V-1 0, d I ar rhe~l 0,
`stomatitis-!, neuro
`(myalglas , sensory
`changesl-7
`
`Ll sted under I ung dIsease
`
`Closed
`SEG Stat Report 1/82
`
`Closed
`CTR 63:507-509, 1979
`
`Tox for 33 mel anon a and 2•.
`breast pts .: myelosupp-7,
`N/V-36, dl e~rrhe~43,
`lieus-3, constlpatton-6
`
`Tox for 36 melanana and 8
`breast pts .: myelosupp -1 ,
`N/V-17, diarrhee-16,
`Ileus-!, constipation- !
`
`Severe neuro(cid:173)
`halluclnatlons, confusion,
`rna I a I se, burnIng sen sat Jon
`In jeg s, lower back paln-4
`
`Closed
`Am . J, Cll n . Oncol .
`5:417, 1982
`
`Closed
`SWCG Agenda
`
`I /82
`
`leukope n la-2,
`Q- 1-11:
`anemle~-1, constipation-!,
`dlarrhee-3, N/V-6,
`paresthesia-!, mucositis-!,
`encephal cpathy-1,
`·
`neuropathy-)
`
`Gr-Ill: somnolence-!,
`const I pat lon-1, he pat I c-1
`
`IMMUNOGEN 2002, pg. 16
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`. ! I
`TA ...
`MAYTANSINE STUDIES
`
`~ase
`
`nc:ma
`
`Protoco l
`
`C77-229
`Mt . Slna I
`
`Regimen
`
`Ev . !Entl
`
`Activ ity
`
`Toxicity
`
`Status/Source
`
`I Sur gery
`I l Rad l at Jon
`I II Mayians lne 0 . 7-
`1. 1 mg/m /w
`
`3
`
`2 PR
`
`Per I pher<l l neuropathy - I
`
`Cl osed
`Cancer 47:1752, 1981
`
`1hcma
`
`SWOG 782 1
`
`2
`0 . 5(}-0.75 mg/m qw
`
`H. D. 3
`NHL 23
`
`No responses
`1 PR ( 4wl
`
`Gr . Ill: mye l csupp-2 pts .,
`dl arrhea- 1 pt .
`
`Closed
`SWOG Agenda 9/80
`
`1hcrna
`
`ECOG PA477
`
`2
`o. 5 mglm /dx3 q3w
`
`H. D. 9
`NHL 22
`
`1 PR C 13 ml
`2 PR (4, 4ml
`
`Unk . severity : weakness/
`parasthes l a-3 pts .
`
`Gr .
`I I I: neurotox-2
`( parastheslasJ
`NIY -1
`
`Gr .
`
`I I: N/V- 8
`
`Cl osed 6/79
`ECOG Ml nutes 6n9
`
`Cl osed
`SEG Stat Report 1/82
`
`Cl osed
`CTR 63 : 507-509, 1979
`
`2 1 !291
`
`No responses
`
`L i sted under lung disease
`
`I PR
`
`(4 mos . )
`
`L l sted under melancrna study
`
`No responses
`
`No responses
`
`N/V -1 l, d I arrhea-8,
`constl pat lon-3,
`sto'nati tl s-3
`
`Cl osed
`ern 55 : 535 , 1981
`
`SEG 78
`ST 222
`
`113- 820
`MDA
`
`C77-225
`Mayo
`
`0. 25-o . 50 mglm
`q3w
`
`2
`
`/dx3
`
`2
`Q. 4- 0 . 6 mg/m /dx3
`q2-3w
`vs .
`o. 75 mglm2/wx6
`
`2
`Mayt . 0 . 6 mg/m /dxJ
`q3-4w
`
`v s . 2
`CZT 150 mg/m q6w
`
`18
`
`3
`
`Mayt .
`15 ( 161
`
`1St
`,_.
`O"l
`
`>.ST
`
`>ST
`
`st
`
`1St
`
`SWOG 7809
`
`2
`0 . 3- 0 . 5 mg/m /dx5 q3w
`
`29 (41 J
`
`I partial regression
`of pu l rronary dl sease
`Dwl
`
`I ethargy-
`N/V - 9, II eus-1 1,
`14 C7 with confusion or
`psychosis) , a l t-ered
`mentat ion, p l t-4 , WBC- 5
`
`Cl osed
`CTR 64 : 675 , 1980
`
`C77 - 203
`SFCC
`
`2
`1. 0- 2 . 0 mg/m
`
`q3w
`
`14
`
`No responses
`
`See under broad dl sease
`
`Closed
`Annua l Report 1980
`
`IMMUNOGEN 2002, pg. 17
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`1 I
`TAl
`M~YTANSINE STUDIES
`
`ose
`
`lc
`gnancles
`
`Pr0tocol
`
`GOG 26- H
`
`Regimen
`
`Ev.
`
`lEnt]
`
`Act! vtty
`
`Toxicity
`
`Status/Source
`
`2
`1 .2 mg/m q3w
`
`Cervix
`29 (32)
`PCT:
`17
`NPCT:
`12
`
`PR In NPCT pt .
`
`leukopenl a-3,
`Gr I-ll :
`plt-3, N/V-13, azotemla- 3,
`weakness and paresthesla-5,
`thrombophlebltls-2,
`ce llu lltls-1
`
`Closed to oervlx,
`ovary 7/81
`GOG Stat Report 1/82
`Am . J . Clln . Oncol .
`6:427, 1983
`
`No responses
`
`Ovary
`29 (32)
`PCT: 28
`NPCT:
`1
`
`leukopenl a-1, p 1t-
`Gr Ill:
`2, weakness and
`paresthesia-!
`
`leukopenla- 7,
`Gr 1-1 1:
`plt-8, N/V-13, weakness and
`paresthes i a-!,
`cellulltls-1,
`
`GrIll : plt-1, N/V-1,
`phlebltls-1
`
`Am . J . Cltn. Oncol.
`6:273, 1983
`
`6 (81
`
`No responses
`
`Listed under lung disease
`
`Closed
`SEG Stat Report 1/82
`
`Tota l
`28 1331
`
`B 191
`
`1 PR/25 rena I
`No responses
`2 bladder, 1 testes
`
`1 PR (unknown tumor
`type>
`
`Listed under lung disease
`
`Closed
`SEG Stat Report 1/82
`
`Listed under lung disease
`
`Closed
`SEG Stat Report 1/82
`
`31
`
`1 PR 03 days!
`
`Overall: N/V-16 (6 sev> ,
`dlarrhea-14 {5 sevl,
`constlpatlon-6 , CNS-3,
`paresthesla- 3
`
`Closed
`CTR 63 : 2061, 1979
`
`I an
`
`,__.
`-.J
`
`'Ned<.
`
`Necl<.
`
`SEG 78
`ST 222
`
`SEG 78
`ST 222
`
`SEG 78
`ST 222
`
`C77-248
`(Mayo)
`
`' Prl or chemotherapy
`= No prior chemotherapy
`
`2
`0 . 25-0.50 mg/m /dx3
`q3w
`
`2
`0 . 25-0 . 50 mg/m /dx3
`q3w
`
`2
`0 . 25- 0 . 50 mg/m /dx3
`q3w
`
`Pts . with active renal
`or cardiac disease :
`2
`Mayt. 0 . 6 mg/m /dx3
`q3- 4w
`
`Pts . without above :
`2
`CTX 400 mg/~ q4w
`ADM 40 mg/m2 q4w
`DDP 40 mg/m
`q4w
`
`IMMUNOGEN 2002, pg. 18
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`II
`Th.
`MAYTANSINE STUDIES
`
`)ase
`
`xl
`
`)(j
`
`........
`00
`
`Protocol
`
`Reg i men
`
`SEG 78
`ST 222
`
`2
`0.25-0.50 mg/m /dx3
`q3w
`
`Ev .
`
`lE nt! --
`Myel
`2 121
`Neurb I 2 [3]
`NLPD
`1 121
`Thymus 2 121
`1 Ill
`Hodg
`1 111
`Unk
`
`C77- 203
`SFCC
`
`2
`1.0-2.0 mg/m q3w
`
`55 !701
`
`Act ivity
`
`Toxic ity
`
`Status/Source
`
`PR - neuroblastO'na
`PR - myelana
`
`Ll st ed under I ung dIsease
`
`Closed
`SEG Stat Report t/82
`
`Closed
`Annua l Report 1980
`
`I PR/4 bladder
`No responses
`col on-6 1 NSCL-4,
`melanoma-4, soft
`tIssue sarcona-4,
`ovary-4, SCLC-3,
`ALL-1, renal-4 ,
`head/neck-2 , CLL-1,
`pancreas-2, Ewing's
`sarcana- 2
`
`51 pts . eval . for tox .
`
`Gr. J-1 I: gastrolntest
`CNIV 1 dlarrheal - 31 1
`hepatlc- 19, CNS (lethargy ,
`InsomnIa, dysphorl al-15,
`perlph. neur . !jaw pain,
`muse Je weaknessl-27
`
`Gr . II t: gas trolntest-15 1
`CNS- 9, perlph . neur .-4
`
`IV: gas tro I ntest-5 1
`Gr .
`CNS-2
`
`Unknown seve rity:
`ph l eblt ls-6 1 stomatltls-4,
`illopecla-2
`
`IMMUNOGEN 2002, pg. 19
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`I I
`TAb._._
`~1AYTANSI NE STUDIES
`
`._
`
`Protoco l
`
`Reg !men
`
`Ev . lE