S em a
`Oncology '
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`
`Seminars in
`Oncology
`
`EDITORS
`
`john W. Yarbro, MD, PhD
`Richard S..Borr15tein, MD
`
`Michael ]. Mastrangelo, MD
`
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`
`Overview of Phase II Trials of MTA in Solid Tumors
`
`Peter J. O’Dwyer, Katrina Nelson, and Donald E. Thornton
`
`MTA (LY23l5l4, multitargeted antifolate) represents
`a new class of folate antimetabolites and inhibits mul-
`tiple enzymes in the purine and thymidine biosynthetic
`pathways, including thymidylate synthase, dihydrofo-
`late reductase, and glycinamide ribonucleotide formyl
`transferase. Based on the results of phase I Investlga-
`tion, the dose and schedule of 600 mglml administered
`intravenously every 2| days was selected to carry into
`the phase II setting. A number of phase II studies are
`completed or ongoing in a wide range of tumor types,
`and encouraging results have been observed in colorec-
`tal, breast, non-small cell lung, head and neck, bladder,
`and cervical cancers.
`
`Semin Oncol 26 (suppl 6):99-I04. Copyright © I999 by
`W.B. Saunders Company.
`
`TA (LYZ3l5l4, multitargeted antifolare), is
`a pyrrolo-pyrimidine analog of folic acid
`that inhibits thymidylate synthase, dihydrofolate
`reductasc, and glycinamide ribonucleotide formyl
`transfcrase.‘-2 The antitumor activity of MTA re-
`sults from the inhibition of these folate-requiring
`enzymes, which are components of purine and
`thymidine synthesis. MTA enters the cell via the
`reduced folate carrier and, once there, rapidly un-
`dergoes polyglutaiiiylation. The more extensively
`polyglutaiiiated species exhibit greater affinity for
`the target enzymes and greater in vitro activity.‘
`
`RATIONALE ron PHASE II nose AND
`
`SCI-lEDULE
`
`Three dosing schedules have been investigated
`in phase I studies. In one study, patients were
`treated on a once-every-21 days schedule (see
`Rinaldi, elsewhere in this supplement); in a sec-
`ond study, patients received drug once weekly for
`4 weeks every 6 weeks‘ and in a third, patients
`were treated using a schedule of daily X5 every 21
`days.‘
`Based on the toxicity profile, the ability to give
`repeat doses, and the ease of administration, the
`every-Z1-days schedule was selected for further
`development of MTA in clinical phase II studies.
`In the phase I
`trial
`investigating this dose, 37
`patients were treated at doses ranging from 50 to
`700 mg/ml. Dose escalation proceeded by the
`Modified Continual Reassessment Method in this
`
`study, limiting the number of patients exposed to
`lower, potentially less-effective doses of drug.“
`Dose-limiting toxicities on this schedule were neu-
`
`Seminars in Oncology, Vol 26. No 2. Suppl 6 (April). I999: pp 99-I04
`
`thrombocytopenia, and fatigue. The
`tropenia,
`maximum tolerated dose on this schedule was de-
`termined to be 600 mg/m2, and of the 20 patients
`treated at
`this dose, National Cancer Institute
`Common Toxicity Criteria grade 4 neutropenia
`and grade 4 tlirombocytopenia occurred in four
`and one patient, respectively,
`in the first cycle.
`National Cancer Institute Common Toxicity Cri-
`teria grade 2 toxicities included rash, mucositis,
`nausea, vomiting, fatigue, anorexia, and elevations
`of liver transaminases. Patients who experienced
`rash and were treated in subsequent cycles with 4
`mg of dexamethasone twice daily for 3 days start-
`ing the day before MTA therapy experienced a
`decrease in severity or even prevention of the rash.
`The phase I experience is summarized in Table 1.
`Pharmacokinetic calculations based on non-
`
`compartmental methods were performed in 20 pa-
`tients who were treated at the maximum tolerated
`dose (600 mg/mz). A mean maximum plasma con-
`centration of 137 ttg/mL was attained. with an
`effective harmonic mean half-life of 3.1 hours
`
`(range, 2.2 to 7.2 hours). Mean clearance and
`steady—state volume of distribution values of 40
`mL/min/ml (24% coefficient of variance) and 7.0
`L/m2 (20% coefficient of variance) were also cal-
`culated. This mean clearance value is similar to
`
`that of creatinine clearance in the age range of the
`patients enrolled (approximately 45 to 55 mL/min/
`ml) and the volume of distribution reflects limited
`distribution outside the blood stream.7 The clear-
`ance was invariant with dose over the entire dose
`range (0.2 to 700 mg/ml). The clearance of the
`drug is primarily renal, with 280% of the dose
`recovered unchanged in the urine during the first
`24 hours after dosing. The disposition of MTA
`does not change after multiple doses and no accu-
`
`Fmm the University of Pmnsyloania, Philadelphia. PA and Lilly
`Research Laboratories. lndianapolis, lN.
`Sponsored by Eli Lilly and Company.
`I} O'Dwyer is a consultant for and has received honoraria and
`research support from Eli Lilly and Company. Dr Tlimviton is an
`employee and a stockholder of Eli Lilly and Company.
`Address reprint requests to l’etcr_l. O'Dwyer, MD, University of
`Pennsylvania, 5i N 39tll Sr. MAB—l03. Phihdclpliia. PA
`l9l04.
`Copyright © 1999 by WB. Saunders Company
`0093-7754/99/Z602-06l 6$l 0.00/0
`
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`

`
`MTA PHASE ll OVERVIEW
`
`Table I. Single Agent Phase I Experience
`
`Every 3 Weeks
`
`Weekly
`
`'33“)!
`
`-1
`
`Daily X5. every 1|
`33
`0.2-5.2
`
`Neutropenia
`Minor responses in
`colorectal cancer (I) and
`NSCLC (I)
`
`Once every 2| d
`37
`50-700
`
`600
`
`Neutrcpenia, rnutcsitis, fatigue
`
`Par-rial responses in pancreas (2)
`and colorectal [2) cancer
`
`Weekiy X4, every 6 wk
`24
`I040
`
`30
`Myelosuppression. particulariy
`granuiocytopenia
`
`Minor responses in coioractai
`(2) cancer
`
`J
`
`I-
`i:
`
`Schedule (all doses administered
`as a I0-min infusion}
`No. of patients treated
`Dose range (mgfmz)
`Recommended phase ii dose
`(me/m‘)
`
`DLT
`
`|
`
`|_
`
`Responses
`Abbreviations: DLT, dose-limiting toxicity: NSCLC, non-smil tell iung cancer.
`
`mulation appears to occur with multiple courses.
`Initial clinical data indicated that an element of
`cumulative toxicity may have been present (see
`Rinaldi, this supplement), but so far this has not
`been borne out in subsequent clinical experience.
`MTA clearance does appear to decrease with age,
`although this decrease is most
`likely related to
`decreasing renal function.7
`
`PHASE II EXPERIENCE
`
`Gastrointestinal Cancers
`
`Clinical activity in metastatic colorectal carci-
`noma has been demonstrated in two multicenter
`trials performed in the United States and Canada.
`Because MTA was initially believed to be primar-
`ily a thymidylate synthase inhibitor, early phase II
`trials were designed to require a 1-year interval
`from prior treatment with drugs that also inhibit
`thymidylate synthase. For this reason, prior adju-
`vant chemotherapy was allowed if completed at
`least 1 year before study entry. In the Canadian
`study, the starting dose of 600 mg/ml was reduced
`to 500 mg/m2 after close reductions were required
`in five of the first eight patients. Toxicities leading
`to these reductions included rash, mucositis, neu-
`tropenia, and febrile neutropenia. Responses have
`been seen at this reduced dose in six patients, for
`an overall response rate of 20%.“ In the US colo-
`rectal study, objective tumor responses have been
`seen in six of 39 patients for an overall response
`rate of 17%.” The median times to progressive
`disease in the two studies were 4.6 months and 3.3
`
`months, and the median survival times have been
`16.2 months and 15 months.
`Two additional studies were initiated to study
`the antitumor effects of MTA in colorectal cancer
`in patients who had received prior therapy. In
`each of these two trials, 31 patients were evaluated
`for tumor response. In the first, patients must have
`been refractory to both 5-fluorouracil and irinote-
`can, defined as having disease progression on or
`within 6 months of prior therapy containing 5-flu-
`orouracil and disease progression on or within 6
`months of prior irinotecan therapy. In the second,
`patients must have progressed within 6 months of
`therapy containing 5-fluorouracil. Although sev-
`eral patients in these studies have maintained sta-
`ble disease for longer than 4 months, objective
`tumor responses have not been observed. Median
`survival times on these studies will be closely mon-
`
`itored_as these data mature.
`A study in pancreatic cancer is complete; there
`was one complete and one partial response in 35
`evaluable patients, for an overall response rate of
`6%. importantly, the median time to progression
`to date is 3.9 months with a median survival of 6.5
`months, and 13 additional patients have main-
`tained a status of stable disease for longer than 6
`months of treatment, suggesting a clinical benefit
`not
`immediately apparent from objective tumor
`measurements. 10
`
`A study in patients with esophageal cancer was
`conducted in the United Kingdom and South Af-
`rica. Paticnts had inoperable,
`locally advanced,
`recurrent, or metastatic esophageal cancer and had
`
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`
`ODWYER. NELSON. AND THORNTON
`
`Table '2. Phase II Activity of HTA in Gastrointestinal Cancers
`
`Coiorectai
`
`Cofiorectal
`
`Colorectal
`
`Cc-lc-rectal
`
`Tumor
`
`No. of evaluable patients
`CR
`PR
`Overall RR
`Median survival. mo (36 Cans)
`Median TTP, mo 1% Cans)
`
`15
`I61 (54%)
`4.5 (I 5%)
`
`5.5 (34%)
`319 (I let)
`
`Abbreviations: CR. complete response: PR, partial response: RR. response rate; Cans. censored: '|'|'P. time no progression.
`—. Data not available at this time.
`
`not received prior therapy. All patients received a
`dose of 600 ing/ml MTA. This study was designed
`with two stages, with an early stopping rule in the
`event of poor antitumor activity, and in fact closed
`after no objective tumor responses were noted in
`the first 20 patients. Although this study was not
`designed to quantify clinical benefit. investigators
`reported some instances of decreased pain and
`improved swallowing. The incidence of toxicity in
`this study was high, with grade 3 and 4 neutrope-
`nia experienced by 33% and 23% of patients and
`grade 3 and 4 thrombocytopenia experienced by
`30% and 55% of patients.
`Table 2 illustrates the activity of MTA in gas-
`trointestinal cancers.
`
`Breast Cancer
`
`A study of MTA in locally advanced or meta-
`static breast cancer is complete and involved a
`heterogenous population, with five of 38 patients
`having received no prior chemotherapy, 15 of 38
`having received prior adjuvant therapy, and 12 of
`38 who had received prior therapy in the meta-
`static setting (additionally. five patients had re-
`ceived therapy both in the adjuvant and the met-
`astatic setting}. Of the 36 patients evaluable for
`response, one complete and 10 partial responses
`have been documented, for an overall response
`rate of 31%. Responses have been seen following
`prior therapy for metastatic disease with a variety
`of treatments,
`including epirubicin,
`ifosfamide,
`paclitaxel, gemcitabine, and doceraxel. Neutrope—
`nia was the major hematologic toxicity observed.
`with grade 3 seen in 24% of patients and grade 4
`seen in 29% of patients."
`An additional study of MTA in metastatic
`
`breast cancer is ongoing in Europe. Patients par—
`ticipating in this study must have been previously
`treated with an anthracycline- or anthracenedi-
`one—containing regimen and are classified as hav-
`ing failed prior therapy (ie, having disease progresv
`sion beyond one cycle length of the final dose of
`this therapy) or as being refractory to prior therapy
`(ie, having disease progression during or within
`one cycle length of the final dose of this therapy).
`While this data set is quite immature at this point.
`two partial responses have been noted within the
`group of 12 evaluable patients in the anthracy-
`ciineqefractory group and two compiete responses
`and four partial responses have been noted within
`the group of 16 patients in the anthracycline fini-
`ure group.
`
`Table 3 illustrates the activity of MTA in breast
`cancer.
`
`Tabie 3. Phase II Activity of HTA in Breast Cancer
`
`Ongoing
`B (Anthra
`Failures)
`
`A {Anthra
`Refrtcto ry)
`
`Complete
`
`No. of evaluable
`patients
`CR
`PR
`
`Abbreviations: CR. complete response; PR. partial response:
`RR. response rate.
`—. Data not available at this time.
`
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`
`IO’).
`
`MTA PHASE II OVERVIEW‘
`
`N on—Small Cell Lung Cancer
`
`A study of MTA in patients with locally ad—
`vanced or metastatic non—small cell lung cancer
`was carried out by the National Cancer Institute of
`Canada Clinical Trials Group. Patients participat-
`ing in this study had not received prior chemo—
`therapy. The original starting dose of MTA of 600
`mg/ml was decreased to 500 mgfrnl after initial
`patients on this study as well as a study of MTA in
`colorectal cancer experienced toxicity leading to
`dose reductions. Of 30 patients evaluable for tu-
`mor response, seven partial responses were seen.
`for an overall response rate of 23% (95% confi-
`dence interval, 9.9% to 42.3%). Four of these
`responses were in patients with stage lllb disease
`(of eight patients with stage Illb disease) and three
`were in patients with stage IV disease (of 25 pa-
`tients with stage IV disease). Principal nonhema-
`tologie toxicities seen in this study included grade
`3 lethargy (21% of patients) and grade 3 skin rash
`(39% of patients). Subsequent studies have incorr
`porated prophylactic administration of dexameth—
`asone, which has served to ameliorate or prevent
`this type of rash. Principal hematologic toxicities
`included grade 3 and 4- neutropenia in 27% and
`12% of patients and grade 4 thrombocytopenia in
`3% of patients. Grade 3 febrile neutropenia was
`experienced by 12% of patients.”
`A similar study of MTA in previously untreated
`non—small cell lung cancer was carried out jointly
`between Australia and South Africa. All patients
`in this study received a starting dose of MTA of
`600 mg,r'm2. Of the 42 patients evaluable for re-
`sponse. seven partial responses (six in patients
`with stage IV disease and one in a patient with
`
`stage lllb disease) were noted for an overall re-
`sponse rate of 17%. The median survival to date is
`9.8 months, median time to disease progression is
`4.5 months, and 42% of patients were alive after 1
`year. As these data mature.
`the time to event
`intervals are expected to increase. Hematologic
`toxicity seen on this study included grades 3 and 4
`neutropenia in 24% and 8% of patients. Rash was
`the most common nonhematologic toxicity, expe-
`rienced by 21% (grade 3) and 11% (grade 4) of
`patients. Other grade 4 nonhematologic toxicities
`included vomiting (2% of patients) and diarrhea
`(4% of patients).”
`Additionally, a study of MTA in second—line
`non-small cell lung cancer is currently ongoing in
`Europe. All patients in this study are receiving a
`starting dose of 500 mgimz. Patients are classified
`into two groups according to whether prior che—
`motherapy did (group A) or did not (group B)
`contain a platinum agent. Of the 27 patients en-
`rolled to date,‘15 are currently evaluable for re—
`sponse. Four patients have experienced a partial
`response, for a preliminary response rate of 27%.
`No responses have been seen in the group of
`patients who had received prior platinum therapy,
`but
`this is most
`likely a function of the small
`sample size, as response to MTA following plati-
`num failure has been noted in other tumor types.
`Grade 3 or 4 neutropenia occurred in 27% of
`cycles and grade 3 or 4 thrombocytopenia occurred
`in 4% of cycles. Grade 3 or 4 infection occurred in
`8% of cycles. Skin rash was frequent. although
`mostly mild, with moderate to severe rash occur—
`ring in only 2% of cycles.
`
`Table 4. Phase II llcfivity of MTA In Non-Small Cell Lung Cancer
`
`No. of evaluable patients
`
`CR
`PR
`Overall RR
`Median survival (% Cans)
`Median TIP ($8 Cans}
`
`First-Line Canada.
`Complete
`
`30
`
`0
`T
`23
`9.6 (33%)
`3.8
`
`1
`First-Line Australia.’
`
`South Africa,
`Complete
`
`42
`
`Cl
`?
`I7
`9.? {6|%)
`4.4 (|8%)
`
`Abbreviations: CR. complete response; PR. partial response; RR. response rate; Cens
`#. Data not available at this time.
`
`5"°°"""""°' °"3°“"9
`
`A (Prior Treatrnent
`Not With Platinum)
`
`IO
`
`0
`3
`—
`-—
`
`. censored; TTP,timeto progression.
`
`B (Prior Treatrnent
`Wrdi Platinum)
`
`7
`I
`
`|
`
`l
`
`9
`
`0
`0
`—
`—
`
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`
`O‘DW'YEP.. NELSON. AND THORNTON
`
`Table 4 illustrates the activity of MTA in non-
`small cell lung cancer.
`
`Head and Neck Cancer
`
`A phase II study of MTA in advanced or recur-
`rent squamous cell carcinoma of the head and
`neck is ongoing in France. Patients may have
`received chemotherapy in the neoadjuvant or ad-
`juvant setting and the minimum chemotherapy-
`free interval is 6 months. All patients are receiving
`a starting dose of 500 mg/ml, although 17% of 51
`total courses have been reduced or delayed. To
`date, there have been seven responses to MTA in
`19 patients treated. Although these data are pre-
`liminary, this is an encouraging level of activity.
`Toxicity that has been observed to date includes
`grade 3f4 ncutropenia in 48% of courses, moderate
`and severe nausea in 22% of courses, and rash in
`13% of courses. Febrile neutropenia has also oc-
`curred in 5% of courses. The toxicity seen in this
`study is possibly related to nutritional status in this
`patient population. This hypothesis is supported
`by the work of Niyikiza et al,'4 who have shown
`that functional folate status is highly correlated to
`the incidence of hematologic toxicity in patients
`who receive MTA.
`
`Genitourinary Cancers
`
`A phase II study ongoing in Spain has enrolled
`25 patients with advanced transitional cell carci-
`noma of the urothelium. Six patients received the
`standard phase II dose of MTA, which was reduced
`to 500 mglmz in subsequent patients due to unac-
`ceptable toxicities. Twenty patients are currently
`evaluable for response and toxicity. There have
`been seven partial remissions. for a response rate of
`35%. National Cancer lnstitute Common Toxic-
`
`ity Criteria grade 3 or 4 neutropenia has been seen
`in 75% 0F patients, with five patients developing
`neutropenic fever. Nonhernatologic toxicities in-
`cluded grade 3 diarrhea in 10 of Patients and grade
`4 mucositis in 5% of patients.“ Although MTA
`has definitive activity in transitional cell carci-
`noma, toxicities appear to be severe and results
`from patients receiving the lower dose are awaited
`with interest.
`
`A phase II study ongoing in Germany has en-
`rolled 26 patients with renal cell carcinoma. All
`patients had stage IV disease and had not received
`prior therapy. Nephrectomized patients were re-
`quired to have evidence of disease progression
`
`Table 5. Phase I! Activity of HTA in Head and Neck.
`Genitourinary, and Gynecologic cancer:
`(All Ongoing Studies)
`
`Head and
`Neck
`
`Renal
`Biadder Cell Cervix
`
`No. of evaluable patients
`CR
`PR
`
`Abbreviations: CR, complete response: PR, partial response;
`RR. response rate.
`
`before study entry. Of 21 evaluable patients, there
`have been two durable partial responses, one last-
`ing for 15 months to date and the other lasting 6
`months to date, for a response rate of 9%. Disease
`stabilization has been experienced by 59% of pa-
`tients. In this study, MTA has been quite well-
`tolerated, with grades 3 and 4 thrombocytopenia
`seen in 12% and 8% of patients.
`
`Gynecologic Cancers
`
`A phase II study of MTA in patients with FIGO
`stage IIIB or IV cervical cancer is currently ongo-
`ing in South Africa. Patients in this study were not
`permitted to have received prior chemotherapy.
`Of the 24 patients who are evaluable for response,
`there have been six confirmed partial responses.
`Responses have been quite durable, lasting from 4
`to 17+ months. Toxicity in patients with cervical
`cancer has been greater than that experienced in
`other tumor types. Grade 3 or 4 neutropenia was
`seen in 63% of patients and grade 3 or 4 throm-
`bocytopenia in 8%. Nearly half of all patients
`ultimately were discontinued from the study be—
`cause of decreased creatinine clearance, presum-
`ably due to ureteral obstruction, which precluded
`further dosing. In an attempt to improve the tox-
`icity profile in patients with this tumor, the study
`protocol has been recently amended to lower the
`starting dose to 500 mgfmz (from 600 mg/ml).
`Table 5 shows the activity of MTA in head and
`neck, genitourinary, and gynecologic cancers.
`
`CONCLUSION
`
`MTA has shown a broad spectrum of clinical
`activity in multiple tumor types, including colo-
`rectal, breast, non—small cell
`lung, pancreatic.
`
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`
`

`
`I04
`
`MTA PHASE II OVERVIEW
`
`head and neck. bladder, and cervical cancers. The
`toxicity profile of MTA is typical of an antifolate,
`with rnyelosuppression being the most common
`toxicity and mucositis. rash, and fatigue occasion—
`ally being dose—limiting. While roughly half of all
`patients treated to date have experienced grade 3
`or 4 neutropenia, this toxicity has proven to be
`noncumulative and reversible. Work by Zervos et
`al“5 supports the position that toxicity may be
`increased in patients with poor nutritional status.
`Additional studies are under way to explore the
`relationship between folate status and toxicity.
`
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`
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