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`I400-
`
`I200-
`
`I216
`
`914
`
`772
`
`652
`
`
`
`Over the 14 years surveyed, an average of 569 pa-
`tients were entered on phase I trials each year. The
`drugs studied each year are detailed in Table 1. The
`average number of different drugs studied per year
`was 13 (range 2-26).
`The number of responses, as well as the number
`of patients with stable disease, recorded each year
`are listed in Table 2. Overall, for the 7,960 patients
`treated, there were 75 complete responses and 432
`partial responses for an overall objective response
`rate of 6.3%. If the 228 marginal responses are in-
`cluded, the overall response rate is 9.8%. As noted
`in Table 2, the yearly percent complete plus partial
`response ranged from 2% to 31%. Table 3 details
`the duration of the responses. The duration for
`complete and partial responses was quite respecta-
`ble in these patients with advanced disease.
`
`116
`
`which included trials with 113 different agents.
`
`The following parameters were collected for each
`study:
`(1) number of patients entered into each
`study; (2) the maximum tolerated dose; (3) the dose
`recommended for phase II studies; (4) the number
`of complete, partial, and marginal responses and
`the number of patients with stable disease;
`(5)
`the dose of drug at which the responses for each
`patient occurred; (6) the type of tumor the respond-
`ing patients had; and (7) the duration of the re-
`sponses.
`
`As definitions of response for solid tumor pa-
`tients, we utilized standard Southwest Oncology
`
`Group criteria which included:
`1. Complete remission, defined as disappearance
`of all clinical evidence of active tumor for at least
`
`four weeks. The patient must be free of any
`symptoms related to the malignancy.
`2. Partial remission, defined as 50% or greater
`
`decrease in the sum of the products of the dia-
`meters of the measured lesions for at least three
`
`months. No simultaneous increase in size or ap-
`
`pearance of new lesions may occur.
`3. Stable disease, defined as steady state or with a
`decrease in disease of <25%, or an increase in
`
`disease that is less than progression. There may
`
`be no appearance of new lesions and no worsen-
`ing of symptoms. This state must be maintained
`for a minimum of three months.
`
`4. Progression, defined as unequivocal increase of
`at least 50% in the size of any measurable lesion,
`
`the appearance of new lesions, uncontrolled
`hypercalcemia or increasing skeletal
`involve-
`ment as manifested by an increasing number of
`lytic lesions or lesions on bone scan.
`5. A final category which is included in standard
`Southwest Oncology Group Criteria is the cate-
`gory of a marginal response. Marginal response
`is defined as any decrease in tumor size of from
`25-49% in the sum of the products of the dia-
`meters of the measured lesions for at least three
`
`months. This is not usually utilized as any mean-
`ingful measurement of response and is often in-
`cluded in the definitions of stable disease. How-
`
`ever, many phase I investigators reporting their
`data have used this category so the information
`was collected.
`
`Iooo4
`
`(DO‘P
`
`600--
`
`NumberofPatients 400-
`2ooJ
`
`70 7: 72 73 74 75 7e 77 78 79 so an 32 83
`Year
`
`Fig. 1. Number of patients in published phase I trials each year
`from 1970-1983.
`
`For definitions of response for patients with-
`leukemia, standard Southwest Oncology Group
`criteria were also utilized.
`
`Results
`
`Overview
`
`A total of 7,960 patients were treated in the 228
`phase I studies examined. Figure 1 details the num-
`ber of patients entered on phase I trials each year.
`A maximum of 1,216 were reported on phase I trials
`in 1980. This number has decreased since then.
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`Table 1. Drugs studied in phase I trials each year
`
`Table 1. Continued
`
`117
`
`Compounds studied in phase I
`trials during year
`
`Year
`
`Compounds studied in phase I
`trials during year
`
`
`
`Year
`
`1970
`
`197 1
`
`1972
`
`1973
`
`1974
`
`1975
`
`1976
`
`1977
`
`1978
`
`Adriarrlycin
`Emetine
`DTIC
`CCNU
`Dibromodulcitol
`
`Pseudourea
`4 ’ -demethylepipodophyllotoxin
`DTIC
`
`5-Azacytidine
`Thiosemicarbazone
`Bleomycin
`Camptothecin
`Methyl CCNU
`Porfiromycin
`TEPA 132
`Chromomycin A3
`Cisplatinum
`lCRF—l59
`Tilerone
`
`4 ’ demethylepipodophyllotoxin
`5—Azacytidine
`BCNU
`Cisplatinum
`ICRF-159
`
`Lapachol
`Vitamin A
`5-Azacytidine
`C. Parvum
`Cyclocytidine
`Ftorafur
`Guanazole
`
`lnosine dialdehyde
`lsophosphamide
`L—asparagirlase
`Porfiromycin
`Thalicarpine
`Yoshi 864
`Dianhydrogalacitol
`Anhydro-ara—5-fluorocytidine
`Bakers Antifol
`
`Chromomycin A3
`Cytembena
`DTIC
`Levamisole
`Maytansine
`Mitomycin-C (oral)
`VP16-213
`Carmimomycin
`Cisplatinum
`MER-BCG
`Pyrazofurirl
`Aclacinomycin A
`
`1979
`
`1980
`
`AMSA
`Anguidine
`Chlorozotocin
`C. Parvum
`Gallium nitrate
`
`Hycanthone
`Levamisole
`AMSA
`
`Maytansine
`Methotrexate
`Misonidazole
`N-Benzyladenosine-5 ’ -monophosphate
`Neocarzinostatirl
`Pseudomonous Vaccine
`Pyrazofurin
`Quelamycin
`4’epi-adriamycin A
`Aclacinomycin A
`Glutaminase
`
`Aminopterin
`Anguidine
`Bruceantin
`Chlorozotocin
`Gallium nitrate
`
`Hycanthone
`IMPY
`AMSA
`Maytansine
`MER-BCG
`PALA
`Neocarzinostatin
`
`Piperazinedione
`Quelamycin
`Streptozotocin
`Thymidine
`Vincristine
`VPI6
`HCFU
`3-deazauridirle
`SFU
`
`DON
`Aclacinomycin A
`AMSA
`Glutaminase
`Carminomycin
`Chlorozotocin
`Cisplatinum
`C. Parvum
`Mitoxantrorle
`Fibroblast interferon
`IMPY
`AMSA
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`a diversity in histologic types of tumors which
`responded in these studies.
`The next question was whether or not a response
`in phase I trials was of prognostic significance for
`the drug to be successful (i.e., make it to the mar-
`ket). Figure 2 details the number of responses in
`phase I trials for drugs that made it to the market
`(or will be on the market within the next year) ver-
`sus those drugs which will definitely not be market-
`ed versus those in which the marketing strategy is
`not yet clear (i.e., still under active investigation).
`As noted in Fig. 2, the range of number of re-
`sponses in phase I trials is quite great for both
`marketed and non-marketed drugs. The median
`number of responses is higher (six total responses)
`
`1981
`
`Malanotoplatinum
`Metoprine
`M. Smegmatis cell wall
`PALA
`PCNU
`
`Pentamethylmelamine
`Pseudoisocytidine
`Quelamycin
`Glutaminase
`
`Spirogermanium
`Vinblastine
`Vindestine
`WR2721
`
`2-deoxycoformycin
`5-aza-2 ’ deoxcytidine
`SFU
`
`Aclacinomycin A
`AD32
`Ametantrone
`
`AZQ
`Bisantrene
`Bruceantin
`Nocardia rubra cell wall
`Chlorozotocin
`Mitoxantrone
`DON
`ICRF-187
`IMPY
`Misonidazole
`PCNU
`
`Pentamethylelamine
`Rubidazione
`Vincristine
`Vindesine
`VP16
`Immune RNA
`
`1982
`
`Carboxyphtalatoplatinum
`4-demethoxydaunorubicin
`5 ’ -deoxy-5—fluororidine
`13—cisretinoic acid
`DON
`
`9—hydroxy-2Nmethyl-ellipticinium acid
`Acivicin
`Aclacinomycin A
`Adriamycin
`Bisantrene
`Carminomycin
`Cisplatinum
`Doxorubicin-DNA-complex
`Human lyrnphoblastoid interferon
`Indicine-N-oxide
`L-Alanosine
`
`118
`
`Table 1. Continued
`
`Table 1. Continued
`
`Year
`
`Compounds studied in phase I
`trials during year
`
`Year
`
`Compounds studied in phase I
`trials during year
`
`1983
`
`Methy GAG
`Mitomycin
`Mitoxantrone
`Pentamethylmelamine
`SOAZ
`
`Spirogermanium
`StaphAureus
`VP16
`
`l0-deazoaminopterin
`4 ’ -O-tetrahydropyranyl
`4—demethoxydaunorubicin
`Aclacinomycin A
`Aclarubicin
`
`AZQ
`Indicine-N-oxide
`L—Alanosine
`Marcellomycin
`Mitoxantrone
`MVE—2
`
`Pepleomycin
`Alpha 2 interferon
`Retinal
`Semustine
`SOAZ
`
`Spirogermanium
`Tegafur
`Tricyclic nucleoside phosphate
`
`Table 4 details the types of tumors patients had
`which responded (in which the tumor types were
`detailed). It is clear that although no denominators
`are known for most of the studies, there is indeed
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`Table 2. Number of responses each year in phase I clinical trial
`
`119
`
`Total patients
`treated
`
`#CR
`
`#PR
`
`#MR
`
`#Stable
`
`%CR + °7oPR
`
`174
`229
`414
`207
`369
`422
`603
`264
`842
`882
`1216
`914
`772
`652
`
`7960
`
`7
`4
`8
`12
`3
`2
`1
`1
`4
`5
`6
`15
`2
`5
`
`75
`
`47
`27
`64
`14
`4
`19
`19
`19
`33
`32
`64
`35
`29
`26
`
`17
`0
`8
`7
`17
`5
`17
`12
`14
`40
`64
`29
`31
`17
`
`2
`60
`15
`1
`14
`0
`19
`2
`33
`59
`67
`25
`53
`42
`
`432
`
`278
`
`393
`
`31
`14
`17
`13
`2
`5
`3
`8
`4
`4
`6
`5
`4
`5
`
`-
`
`
`
`gories. It is clear from that diagram that the greatest
`percentage of responses (complete, partial or mar-
`ginal) were noted in the category of 80-120% of
`the recommended dose for phase II trials. How-
`ever, the stable disease patients exhibited no such
`distribution of responses.
`
`Year
`
`1970
`1971
`1972
`1973
`1974
`1975
`1976
`1977
`1978
`1979
`1980
`1981
`1982
`1983
`
`Totals
`
`Table 3. Duration of responses in phase I studies
`
`Type of response
`
`Duration of response (months)
`
`Complete
`Partial
`Marginal
`Stable
`
`Median
`
`Range
`
`6
`3
`3
`4
`
`1-18
`1- 17
`1-18
`1-36
`
`mended phase II dose, the better the chances of
`
`or marginal
`partial,
`complete,
`a
`achieving
`response. Patients with stable disease received less
`
`of a dose (on the median).
`Figure 4 examines the data in another way. In
`that figure, the distribution of response, according
`to percent of recommended phase 11 doses is plotted
`for each of the response and stable disease cate-
`
`for those compounds which eventually were mar-
`keted versus those that were not marketed (one to-
`tal response). To date, there has not been one com-
`pound which has made it to market which did not
`have at least one response in phase I trials.
`Another major question in phase I
`trials is
`whether a patient must receive a dose near the dose
`
`recommended for phase II trials with the agent in
`order to have a response. Figure 3 details the per-
`cent of the recommended phase II dose at which the
`responses in phase I
`trials occurred. From this
`figure, it is quite clear that there is considerable var-
`iation in the percent of the recommended dose at
`
`which responses or stable disease occur. Complete
`and partial responses were noted even at doses as
`low as 3-5 "70 of the recommended dose. It is of in-
`
`terest that when the medians are examined, it does
`appear that the closer one is to 100% of the recom-
`
`Discussion
`
`The first finding of this study is that in the 228
`phase I studies conducted in 7,960 patients over the
`
`the overall percent of objective
`14 year-period,
`responses was 6% (1% complete response and 5%
`
`partial response). The 6% response is higher than
`the 2% response rate noted by Estey and colleagues
`[1] when they examined the response rate in a
`
`smaller number of patients (1,248) in phase I clini-
`cal trials. If we examine the response rate by year,
`there is no indication that the response rate is im-
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`
`TotalNumberofResponsesinPhaseITrial
`
`
`
`the NCI changes its screen [2,3]. In addition, with
`the very low response rates in phase I trials, it ap-
`pears that there may be room for the addition of a
`screening method for the patients. Perhaps as the
`methodology for in vitro sensitivity testing becomes
`more refined, patients with tumors sensitive in vitro
`can be selected for entrance into phase I studies
`with an attendant improvement in response rate
`
`120
`
`Table 4. Types of tumors in which objective responses occured
`
`Tumor type
`
`Number of Number of
`completed
`partial
`responses
`responses
`
`Acute lymphocytic leukemia
`Acute non-lymphocytic leukemia
`Adrenal
`Anus-squamous
`Brain
`Breast
`Bladder
`Carcinoid
`Cervix adenocarcinoma
`Cervix-squamous
`Choriepothelioma-uterus
`Choriocarcinoma
`Clear cell — Vagina
`CLL
`Colorectal
`
`Esophagus
`Fallopian tube
`Gastric
`Head and neck
`Hepatoma
`Lung
`Small cell
`Non-small cell
`Lymphoma
`Hodgkin’s
`Non-Hodgkin’s
`Melanoma
`Mycosis fungoides
`Myeloma
`Neuroblastoma
`Ovary
`Pancreas
`Prostate
`Renal
`Sarcoma
`Teratoma-Mediastinum
`Testes
`Thymus
`Thyroid
`Unknown primary
`Uterus
`
`13
`10
`—
`1
`—
`1
`2
`1
`—
`1
`~
`—
`—
`2
`2
`
`——
`—
`2
`6
`—
`
`1
`2
`
`1
`7
`1
`1
`~
`—
`1
`—
`—
`3
`2
`—
`7
`I
`1
`1
`—
`
`15
`20
`1
`3
`15
`30
`4
`2
`1
`10
`1
`1
`1
`2
`29
`
`1
`1
`14
`21
`5
`
`8
`39
`
`20
`49
`3
`3
`1
`4
`13
`1
`1
`10
`35
`1
`13
`2
`3
`19
`1
`
`Not Marketed
`
`Market Status
`
`Under
`Investigation
`
`Fig. 2 Number of responses in phase I trials for marketed, non-
`marketed, and for drugs
`still under
`investigation. Lines
`represent median number of responses. These values are six total
`responses for marketed compounds, one for non-marketed com—
`pounds, and 1.5 responses for those still under investigation.
`
`and early 1980’s, make it possible to speculate that
`
`drugs may not have been selected as carefully for
`phase I trials. Keeping track of this trend is indeed
`important as this information can provide input
`into the screening programs utilized by the National
`Cancer Institute. This is particularly important as
`
`in 1972 with only two drugs
`In fact,
`proving.
`studied, the response rate in phase I trials was 31%
`
`(Adriamycin was in phase I trials that year), while
`in 1983, the phase I trial response rate was only 5%.
`This trend, plus the large inflation in number of pa-
`tients entered into phase I trials in the late l970’s
`
`[4,5,6]. If nothing else, the present study will serve
`as an historical benchmark against which to assess
`
`changes in the drug screen or changes in the patient
`screen.
`
`The overall clinical response rate of 6% in the
`
`phase I studies is of course not very encouraging,
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`
` (cid:12) (cid:12) (cid:12) (cid:12) (cid:12)
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`
`122
`
`Acknowledgement
`
`This research paper was supported in part by Con-
`tract NCI N01 CM- 57737.
`
`
`
`human tumor stem cells to anti-cancer drugs. N Engl J Med
`298:l32l—1327, 1978
`5. Alberts DS, Mackel C, Pocelinko R, Salmon SE: Phase I in-
`vestigation of 9,10-anthracenedicarboxaldelydbis
`[4,5-di-
`hydro-1H-imidazidfe-2-yl)hydrazone]dihydrochloride with
`correlative in vitro human tumor clonogenic assay. Cancer
`Res 42:1l70—1l75, 1982
`6. Von Hoff DD, Coltman Jr CA, Forseth B: Activity of mito-
`xantrone in a human tumor cloning system. Cancer Res
`41:l853—l855, 1981
`7. Moertel CG, Hanley JA: The effect of measuring error on the
`results of therapeutic trials in advanced cancer. Cancer
`382388-394, 1976
`8. Pazdur R, Samson M, Haas C, Schilches P, Baker L: Correla-
`tion of murine antitumor models in predicting clinical drug
`activity in non-small cell lung cancer: A six-year experience.
`Proc Am Soc Clin Oncol 3:219, 1984
`
`References
`
`1. Estey F, Hoth D, Leyland-J ones B, et al: Therapeutic results
`in phase I studies. Proc Am Soc Clin Oncol 3:35, 1984
`2. Staquet MJ, Byar DP, Green SB, Rozencweig M: Clinical
`predictivity of transplantable tumor systems in the selection
`of new drugs for solid tumors: Rationale for a three-stage
`strategy. Cancer Treat Rep 672753-765, 1983
`3. Vendetti JM: The National Cancer Institute Antitumor Drug
`Discovery Program, current and future perspectives: A com-
`mentary. Cancer Treat Rep 671767-772, 1983
`4. Salmon SE, Hamburger AW, Soehnlen B, Durie BGM, Al—
`berts DS, Moon TE: Quantitation of differential sensitivity of
`
`Address for offprints: D.D. Von Hoff, Division of Oncology/
`Department of Medicine, The University of Texas Health
`Science Center at San Antonio, San Antonio, TX 78284, USA
`
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