Page 1
`
`Lilly Research Laboratories
`A Division of Eli Lilly an0 Company
`
`Lilty Corporate Cenler
`Indiana.|is, Indiana 46285
`(3~ 7} 276-2000
`
`December 3, 1999
`
`IND Safety Report Follow-Up and
`Request for FDA Input
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Oncologic Drug Products, HFD-150
`Attn: Mr. Alvis Dunson
`1451 Rockville Pike
`Rockville, MD 20852-1448
`
`Subject: IND 40,061, I~ITA (LY231514) - Sedal no. 195
`Supplementation with Folic Acid and Vitamin B~2 To Reduce
`Toxicity in Patients Receiving LY231514
`
`Recently, Lilly sent a letter to investigators informing them to exclude patients
`with high baseline homocysteine levels from participation in LY231514 clinical
`trials (see submission serial number 194 to IND # 40,061 dated November 24,
`1999). This letter was sent to all LY231514 investigators except for investigators
`in two studies (H3E-MC-JMAF and H3E-MC-JMAS) where patients are currently
`receiving folic acid supplementation. In the interest of patient safety, this action
`was taken preceeding formal protocol amendments.
`
`In the cover letter to the FDA accompanying the November 24 letter Lilly stated
`that the exclusion of patients with high baseline homocysteine levels was a
`preliminary action, Lilly also indicated that a further communication would be
`sent to the FDA with details of the updated safety anafysis together with a plan
`for an intervention to lessen serious toxic effects in patients with high baseline
`homocysteine levels. The updated safety analysis (see attachment) again
`reinforces the relationship between high baseline homocysteine levels and the
`potential for serious toxicity after treatment with LY231514 as shown by the
`following:
`
`L
`
`I TRIAL EXHIBIT
`
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`

`
`Food and Drug Administration
`December 3, 1999
`
`Page 2
`
`Elevated homocysteine level at baseline is highly correlated with severe
`toxicity (e.g. neutropenia, neutropenia accompanied by infection,
`diarrhea).
`
`Drug-related death is highly correlated with severe toxicity.
`
`Preliminary data from an ongoing siudy in gastdc cancer (H3E-MC-
`JMAF) in a small number of patients has shown that at standard doses
`(500 mg/mZ), LY231514 has demonstrated activity in the presence of folic
`acid supplementation.
`
`LY231514 may be escalated as high as 925 mg/m2 when accompanied
`by folic acid supplementation at a schedule of 5 mg orally daily for two
`days before, the day of, and two days after LY231514 administration
`(Study H3E--MC-JMAS). Data from this study shows that in patients with
`elevated homocysteine levets, this amount of supplementation causes
`homocysteine levels to drop below 10 !~M and causes no change in
`patients that do not exhibit an elevated baseline homocysteine level.
`
`It is well known that elevated homocysteine levels are an indicator of
`poor nutritional status, and recently, elevated homocysteine levels have
`also been shown to be a predictor of mortality in cardiovascular disease.
`A study of homocysteine levels in 1788 middle-aged and elderly.
`volunteers has shown that an elevated homocysteine level of 14 I~M or
`greater puts a patient at increased risk for death caused by
`cardiovascular disease [Annals Internal Medicine 131:321-330, 1999].
`
`Folic acid supplementation of 400 ~g daily in elderly patients with
`elevated homocysteine levels has been shown to substantially reduce
`plasma homocysteine levels .within two weeks. The level continues to
`drop slightly for another two weeks, and then plateaus [International
`Journal for Vitamin and Nutrition Research 69:187-93, 1999]. Brouwer
`and coworkers showed that low dose folic acid (250 p.g - 500 l~g)
`intervention significantly decreases homocysteine levels. An eight week
`washout period was not sufficient for blood folate and plasma
`homccysteine levels to return to baseline. [American Journal of Clinical
`Nutrition 69:99-104, 1999] Niyikiza et al have shown that in patients.who
`are not supplemented, homocysteine levels do not change over the
`course of treatment with LY231514 [Annals of Oncology, Supplement 4,
`9: Abstract 609, 1998].
`
`Based on this analysis, we have concluded that the following interventions are
`appropriate for ongoing trials.
`
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`
`Food and Drug Administration
`December 3, 1999
`
`Page 3
`
`For the ongoing phase I trials of LY231514 in combination with another cytotoxic
`agent where the top dose level has been reached:
`
`Any patient with a baseline homocysteine level _>12 ~M will be excluded
`from enrollment. For these tdals, this is a continuation of the policy
`mentioned in the November 24, 1999 letter to investigators (IND
`submission 194).
`
`In all other trials, the following actions are being implemented. The initial action
`to exclude patients with high baseline homocysteine levels was taken to prevent
`serious toxicity to a sub-set of potential patients. Further analyses and
`discussions with a number of external consultants led to the conclusion that an
`overall safety benefit to patients might be better served through the addition of
`dietary supplementation to patients-receiving LY231514 rather than exclusion of
`certain high-risk patients. Thus the following actions are being implemented.
`
`Because there is a strong link between severe toxicity and elevated
`homocysteine levels as well as severe toxicity and drug-related death, the
`strategy of reducing homocysteine levels prior to treatment with LY231514 in
`these trials is being implemented. The following actions are being taken via
`another =letter to investigator= to promote the immediate interest of patient
`safety. Formal protocol amendments will be submitted as soon as possible. The
`implementation schema is as follows: ’
`
`1) Each patient will have a blood sample drawn for the measurement of a
`baseline homocysteine level.
`
`2) Each patient will begin a daily supplement of 350 - 1000 l~g folic acid with
`500 p.g being the recommended dose. In countries where folic acid is not
`available, a multivitamin contain(ng 350 - 1000 p.g folic acid will be an
`acceptable substitute. This supplementation will continue daily as long as
`the patient is on study.
`
`3)
`
`4)
`
`5)
`
`At this time, each patient will receive 1000 ~g vitamin B12 as an
`intramuscular injection. (As mentioned in the introduction of the attached
`safety analysis, elevated homocysteine may also be caused by vitamin
`B12 deficierlcy in a small percentage of patients.) This will be repeated
`after every nine weeks cycle as long as the patient"remains on study.
`
`After at le~.~ sever~ days of folic acid supplementation, patients may
`begin to r~.~eive treatment with LY23151a~
`
`It is recommended that any patient currently on study begin folic acid and
`B12 supplementation as well. Any pat’..~falling into this category may
`receive his or her next regularly sche~]~,ti~d dose of LY231514 providing
`
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`
`Food and Drug Administration
`December 3, 1999
`
`Page4
`
`he or she has had at least two days of folic acid supplementation and one
`B 12 injection.
`
`For purposes of safety and study integrity, these steps will be implemented
`immediately in the ongoing randomized phase Ill study in malignant
`mesothelioma (H3E-MC-JMCH, A Single-blind Randomized Phase 3 Tdal of
`MTA plus Cisplatin versus Cisplatin in Patients with Malignant Pieural
`Mesothelioma; see attachment for the letter being sent to the JMCH
`investigators). This will provide a unique opportunity to study the effects of folic
`acid and B12 supplementation on toxicity and efficacy in a homogenous patient
`population. The implementation steps for all other studies will be addressed
`immediately following completion of modifications in this randomized trial.
`
`Re-evaluation of the prevalence of toxicity wil! be performed after 100 - 150
`patients receiving the proposed supplementation of folicacid and B12 have
`been enrolled and have received at least two cycles of treatment.
`
`Possible alternative methods to supplement folic acid and B12 will be evaluated
`and may be proposed for’future trials.
`
`Therefore Lilly asks DODP for a prompt review of these proposals to supplement
`LY231514 patients with folic acid and vitamin B~=. We believe that these actions
`will promote patient safety and not adversely effect the primary and secondary
`outcomes of the LY231514 registration trial for mesothelioma where
`approximately 40°/; of patients have high baseline homocysteine levels. In the
`JMCH study (the mesothelioma registration study), we are implementing the
`administration of fotic acid and vitamin B12 to all patients in the LY231514 plus
`cisplatin arm as well as the cisplatin alone arm to preserve the integrity of this
`single-blind study. At the present time almost half of the planned number of
`patients (280) are enrolled in study JMCH. At the end of the study, we intend to
`compare the toxicity and other outcomes of those patients supplemented with
`folic acid and vitamin Blzversus those patients who did not receive this
`supplementation
`
`Because of the implications for patient safety and also because of tire
`potential effects on a registration trial, Ully respectfully requests that we ’
`be notif’md by December 10 regarding DODP concurrence with these
`actions. We are available any time for a teleconference should DODP want
`to discuss these actions, Lilly is in the process of amending protocols for
`the LY231514 studies and await DODP comments before these protocol
`amendments are finalized.
`
`Lilly is closely monitoring patient safety and attempting to find potential
`predictors that may identify patients at increased risk. The identification of
`
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`
`Food and Drug Administration
`December 3, 1999
`
`Page 5
`
`elevated baseline homocysteine lever as a predictor for toxicity and the steps
`taken to prevent this are a potential advance for chemotherapy with LY231514.
`We thank DODP with their continuing assistance regarding the development of
`LY231514.
`
`PIease call Mr. John Worzalla at (317) 276-5052 or myself at (317) 277-3799 if
`there are any questions.
`
`Sincerely,
`
`ELI LILLY AND COMPANY
`
`Brophy, PhD.
`
`Gre
`Director
`U.S. Regulatory Affairs
`
`Enclosures (2)
`LY231514 (MTA) Safety Analysis
`Copy of =Letter to Investigator’ for JMCH
`
`COPY
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`

`
`LY231514 (MTA) Safety
`Analysis
`
`03 December 1999
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`Page 1 of 20
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`

`
`1. Introduction
`
`1. I. Objective
`
`A prelirninary analysis on the relationship between homocysteine levels and toxicity in
`patients treated with LY231514 (MTA), has been presented by Niyildza et al. [1]. The
`current document will provide additional information in the form of a more thorough
`analysis and will serve as the basis for discussion of a number of recommendations for
`increasing the safety of patients treated with LY231514. A number of retrospective,
`exploratory analyses have been performed in an attempt to identify factors which may put
`certain patients at risk of experiencing severe toxicity or death caused by treatment with
`LY231514o These include multivariate, descriptive, and contingency analyses. The
`dataset used for each analysis will be described.
`
`1.2. Background Information
`Given the toxicity associated with the administration of anticancer drags, the ability to
`predict those patients at risk of developing serious toxicity would represent an important
`therapeutic advance in this area. This safety analysis has been undertaken in order to
`identify potential prognostic factors which may predispose patients to experience severe
`toxicity or even dea~ secondary to treatment with LY231514, a multitargeted antifolate.
`Historical data on the toxicity of lometrexol (another antifolate) and the efforts to
`modulate its toxicity, have been examined to more precisely define a starting point for the
`analysis of current LY231514 data.
`
`As might b~ predicted with an antifolate, phase I studies of LY231514 identified
`myelosuppression as the principal dose limiting toxicity, with other toxicities including
`stomatitis, fatigue and rash. A broad-spectrum phase 1I program with a Q3 week schedule
`of administration began in 1995 [reviewed.in 2, 3, 4]. The safety profile in 209 patients
`treated in this setting is consistent with the phase I experience and is reviewed in [2].
`Consistent with the toxicity profile of other antifolates, the most severe and dose-limiting
`toxicity is m. yelosuppression, while nonhematologie toxicities including mucositis,
`diarrhea, vomiting mad infection can also occur. The incidence of CTC grade llI and IV
`neutropenia is approximately 50% [2] and the rate of possibly or probably drug-reIated
`death to date is approximately 3.8%.
`
`Measures which affect plasma folate levels would also be expected to modulate the
`pharmacology of an antifolate. Indeed, the in vivo toxicity of lometrexol (LMTX), a pure
`pufine biosynthesis inhibitor is profoundly affected by supplemental folic acid. Mice fed a
`folate-depleted diet are very sensitive to the toxicity of lometrexol whereas under folate
`replete conditions toxicity is reduced. Careful control of folate levels allows preservation
`of antimmor activity, but if sufficient excess folate is provided, antitumor activity is
`ablated [5, 6].
`
`These preclinical observations of the importance of folic acid in modulating the toxicity
`of lometrexol in animals were subsequently confirmed in phase I clinical trims. Without
`
`L
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`folio acid supplementafion, the dose-lira/ring toxicity is myelosuppression, but toxicity is
`cumulative. Consistent with the in vivo observations, supplementing patients with oral
`folic acid improves tolerance to LMTX. On a Q3 week schedule in the absence of folio
`acid, the MTD is less than 12 mg/m2 [7]. However, the same schedule with 14 days of
`supplemental oral folio acid at 5 mg/day has a recommended phase 11 dose of at least 130
`mg/mz [8].
`
`As with lometrexol, in vivo experiments with LY231514 have suggested that
`supplemental folic acid modulates its toxicity profile and antitumor activity. The LD50 of
`LY231514 occurred at 60- and 250-fold lower doses of LY231514 in DBA/2 and CD1
`nu/nu mice maintained on a low rotate diet compared with those fed standard diets. In
`these experiments, the antimmor activity of LY231514 was preserved [9].
`
`Ongoing LY231514 trials include a phase I study of LY2315t4 and folic acid. An interim
`report suggests that fulie acid supplementation in this study permits dose escalation by
`ameliorating toxicity since heavily and minimally pretreated patients tolerate LY231514
`at doses ofT00 and 925 rag/m2 respectively [I0]. In a phase II trial in gastric cancer, a
`small set of patients has also received folic acid supplementation. This trial will be
`discussed in further detail in Section 3.
`
`Given the relevance of folic acid to the pharmacology of antifolates, it is reasonable to
`postulate that functional folate status could be an important predictor of toxicity. Recent
`studies have suggested that plasma homocysteine is a much more sensitive measure of
`functional folate status than is serum folate or red blood cell folate. [11, 12] Methionine
`synthase is a highly folate dependent enzyme that converts homocysteine to methionine.
`Thus, under conditions.of folate deprivation, levels of plasma homocysteine increase.
`Elevated serum homocysteine can also result from cobalamin (vitamin Bt2) or vitamin
`B6 deficiency. This is because cobalamin is a required cofactor for methionine synthase
`and the enzyme cystathionine synthase,.in converting homoeysteine to cystathiortine, uses
`vitamin B6 as a cofactor. Serum methylmalonic acid levels are elevated in cobalamin
`deficiency, but not in folate deficiency and therefore it is important to measure levels of
`methylmalonic acid to distinguish between cobalamin and folate deficiency.
`Cystathionine levels are markedly elevated in vitamin B6 deficiency a~ld are elevated to a
`lesser extent in both cobalarnin and rotate deficiency.
`
`As the findings which linked folate status to toxicity with lometrexol were coming to
`light, the development of LY231514 was well into the decision phase, ie, early phase II
`studies were taking place in a variety of solid tumors for the purposes of evaluating
`antitumor activity. In response to this information, the protocols for these ongoing studies
`were amended to collect vitamin metabolite levels at baseline and at various timepoints
`throughout the study. As such, within the entire LY231514 patient database, only a subset
`of patients have data on vitamin metabolite levels.
`
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`
`1.2.1. Initial Multivariate Analysis
`In late 1997, an analysis was conducted to assess the relationship of vitamin metabolites,
`drug exposure, and other pre-specified baseline padent characteristics to toxicity
`following therapy with LY231514. [1] Data was examined from 139 phase II patients
`with tumors of the colon, breast, pancreas, and esophagus who had been treated with
`LY231514 at 600 rag/m~ IV over 10 minutes onceevery 21 days. These patients had
`homocysteine (Hcys), cystathionine, and methytmalonic acid levels measured at baseline
`and once each cycle thereafter. Stepwise regression modeling, multivariate analysis of
`variance, and discriminant analysis were implementedto determine which predictors
`might correlate with severe toxicity, and to predict which patients are at high risk of
`experiencing such toxicity. Prognostic factors considered were age, gender, prior therapy,
`baseline albumin, liver enzymes, ANC, platelets, vitamin metabolites, and AUC.
`
`Statistically significant predictors of Grade 4 neutropertia (n:21 pts) were albumin
`(p<0.0001) and Hcys (p--0.0020). Grade 4 thrombocytopenia (n=8) was predicted by
`Hcys (p<0.0001) and Albumin (.19=0.0237). Heys was also found to be the only significant
`(p=0.0014) predictor of Grade 3/4 mucositis, diarrhea, rash, or fatigue following one
`course of therapy with LY231514. Hcys ~ 10/.dVl predicted Grade 4 neutropenia in cycle
`one 75% of the time. I-Icys alone in 71% of eases predicted grade 4 neutropenia_ Hcys and
`albumin levels did not appear to change from baseline during therapy with LY231514.
`While AUC was not found to be a predictor of toxicity, little variability was observed in
`AUC. Maximum values were still below AUC values related to hematological toxicity in
`phas61 studies. These findings led to the following conclusions:
`
`¯ Toxicity resulting from therapy with LY231514 appears to be higher in patients with
`elevated pretherapy homocysteine levels.
`¯ Elevated baseline homocysteine levels (>10p_M, for the 139 patients included in this
`analysis) highly correlate with severe hematological and nonhematologic toxicity
`following therapy with LY231514.
`¯ Homocysteine was found to be better than albumin at predicting toxicity and was not
`altered with LY231514 therapy.
`
`1,3. Overview of L Y231514 Databaae
`Approximately 1127 patients have been treated with LY231514 to date. This number
`includes:
`
`850 patients treated in "in-house" studies with full safety data available
`
`~ Multivariate analyses on predictors for drug-related death have been performed
`using data from these 880 patients. (34 drug related deaths in this group.)
`
`~ Of these 880 patients, a subgroup of 305 patients have data on homocysteine
`levels. Multivariate analyses on predictors for toxicity have been performed using
`data from these 305 patients.
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`
`r
`
`=> In addition to the analyses using multivariate methods, a number of contingency
`analyses (ie, 2 x 2 tables) have been undertaken for the purposes of corroborating the
`multivariate findings.
`
`247 patients treated in "external" studies with limited data available. (9 drug-related
`deaths in this group.)
`~ Although no multivariate analyses can be mn over these patients, they will be
`included in descriptive analyses.
`
`Patient distribution by tumor type is shown in Table 1. I.
`
`Table 1.1
`
`Patient Disposition: Distribution of Patients by Tumor Type
`
`Tumor Type
`
`Phase ] Single Agent
`
`Bladder
`
`Breast.
`
`Cervix
`
`CRC
`
`H&N
`
`JMAS~iJMAW2
`
`NSCLC, front line
`
`NSCLC, second line
`
`Other GI
`
`Pancreas
`
`Ph 1 Combination
`
`Renal
`
`Total*
`
`Number of Patients
`
`100
`
`29
`
`123
`
`35
`
`203
`
`35
`
`40/24
`
`160
`
`81
`
`29
`
`42
`
`187
`
`39
`
`1127
`
`*Note: Mesothelioma trials are not included in this number.
`1: l~olic acid supplementation study
`2: Renal impairment ~tudy
`
`Because the trials in mesothelioma have recently started and the data are immature, they
`have not been included in the overall safety analysis.
`
`2.
`
`Updated Multivariate Analyses
`
`2. I. Analysis for Drug-related Death
`A total of 43 deaths in 1127 patients have been reported as possibly or probably related to
`LY231514, giving an overall death rote of 3.8%. In describing any on-study death,
`
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`
`investigators select a designation of probably, possibly, or not related to treatment with.
`LY231514. The 43 deaths discussed represent the most conservative approach to
`designation of causa!ity, and include all deaths that have been designated as possibly or
`probably related to treatment. An internal review has indicated that four of these (patients
`403-4089. 403-4102, 403-4103, and 720-7003) may be attributed to other causes such as
`disease progression and/or underlying medical conditions. When these patients are
`excluded from the total, the rate of drag-related death is 3.5%. Nevertheless, we have
`performed all analyses discussed here using all deaths designated by the investigator as
`possibly or probably drug-related. The prevalence of drug-related death by tumor type is
`shown in Table 2.1.
`
`Table 2.1. Prevalence of Drug Related Death by Tumor Type
`
`Tumor Type
`
`Bladder
`
`Breast
`
`Cervix
`
`CRC
`
`Head and Neck
`
`NSCLC 1= Line
`
`NS(~LC 2~ Line
`
`JMAS (FA Supplement)
`
`JMAW (Renally impaired)
`
`Other GI*
`
`Pancreas
`
`Phase 1 Single Agent
`
`Phase 1 Combination
`
`Renal
`
`Overall Prevalence
`
`Number of Drug Related Deaths (% of
`Total Pts)
`2 (6.9%)
`
`2 (1.6%)
`1 (2.9%)
`
`3 (1.5%)
`
`4 (11.4%)
`
`2 (1.2%)
`
`8 (9.9%)
`
`0 (0%)
`
`1 (4.2%)
`
`6 (20,!%)
`
`0 (OP/o)
`
`6 (6%)
`4 (2.1%)
`
`4 (10.3%)
`
`43 ~3.8%~
`
`Total
`
`29
`
`123
`
`35
`
`203
`
`35
`
`160
`
`40
`
`24
`
`29
`
`42
`
`100
`
`187
`
`39
`
`1127
`
`This table demonstrates the observation that particular rumor types may have a higher
`death rate. Although the sample sizes are small, these tumors appear to be bladder, head
`and neck, esophageal, gastric, renal, and second-line non-small cell lung cancer. Patients
`with these tumors might be expoeted to be nutritionally or metabolically deficient,
`lending support to the theory that nutritional status may play a large role in the degree of
`toxicity or death attributable to LY231514. In a second cluster of tumors which includes
`breast, colorectal, front-line non-small cell lung, and pancreas cancers, the rate of death is
`approximately 1.6%.
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`2.1.1. Definition of Patient Population
`Of the patients treated with LY231514, 880 of these have been treated on "in-house"
`studies, and have complete data available. Within this dataset, there have been 34 drug-
`related deaths.
`
`The remaining patients (247) have been treated in studies performed by contract research
`organizations. Data from these studies have not been integrated into the main database,
`and therefore, these patients are not included in any multivariate analyses. For any
`descriptive statistics, the goup of 1127 patients will be used as the denominator.
`
`2.1.2. Methods
`Stepwise regression modeling, muhivariate analysis of variance, and diseriminant
`analysis were implemented to determine which predictors might correlate with drug-
`related death. Prognostic factors considered for LY231514-related deaths were age,
`gender, baseline alburrdn, liver enzymes, ANC, platelets, AUC, pro-treatment weight,
`prior treatment, tumor type, grade 4 neutropenia in conjunction with grade 3 or 4
`infection (a surrogate indicator of febrile neutr.openia), post baseline minimum platelet
`count, grade 3 or 4 diarrhea, and grade 3 or 4 mucositis.
`
`Note** Because of the small number of patients with data.(n = 11 of 34), vitamin
`metabolites (including homocystdne) were not included in the multivariate analysis
`for LY231514-related deaths.
`
`2.1.3. Results
`Results of these analyses are shown in Table 2.2, Those factors that are independent
`predictors for drug-related death ata statisdcally significant level are shown in bold.
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`Table 2.2. Prognostic Factors for LY231514 Related Deaths (n = 880)
`
`Variables
`
`Age
`
`Gender
`
`BLALB
`
`BL ALT
`
`BL ALK Phos
`
`BL PLT
`
`BL ANC
`
`AUC*
`
`WEIGHT
`
`Prior Treatment
`
`G3/4 IN + G4Neut
`Tumor Type
`
`O3/4 MUC
`
`G314 Diarrhea
`
`P
`
`0.1009
`
`0.6286
`
`0.1182
`
`0.4591
`
`0.9884
`
`0.5106
`
`0.3385
`
`0.0759
`
`0.9893
`
`0.4169
`
`<0.00001
`
`0.0019
`
`0.5164
`0.0016
`
`*calculated from population PK mode] [131)
`Abbreviations: BL ALB, baseline albumin; BL ALT, baseline alanine transaminase; BL ALK
`Phos, baseline alkaline phosphatase; BL PLT, baseline plat.l(cid:128)ts; BL ANC, baseline absolute
`neutrophil (cid:128)OUnt; AUC, area under the eurv~; IN, infection; Neut, neutropenia; MUC, mueositis.
`
`As expected, Grade 3/4 infection accompanied Grade 4 neutropenia, Grade 4 neutropenia,
`Grade 3/4 diarrhea and tumor type were all significandy associated with drug-related
`death.
`
`In continge.ney ana/yses designed to compare the rate of death in patients receiving a
`starting dose of 500 mg/m2 versus 600 mg/m2, it was found that there was no difference
`in the relationship between death and either starting dose.
`
`2.1.4. Homocysteine Levers in L¥231514-related Death
`Homocysteine levels are currently available in only i I patients of the 43 whose deaths
`were reported as possibly or probably related to MTA. Table 2.3 shows the baseline
`homocysteine levels in these patients.
`
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`
`Table 2.3.
`
`Baseline Homocysteine Levels in 11 Patients Who Experienced
`Possibly or Probably Drug-related Death
`
`Baseline Hpmocysteine
`Patient Number (tumor)
`22.5
`,,l- 1 (CR_C3
`13.3
`5,o5-29 (HkN)
`14.4
`802-19
`12.4
`S02-~6 (HAND
`31.9
`803-849 (breast) -,
`14.3
`5.2
`100-5002 (renal impairment) ....
`403-4102" (2"d line NSCLC)
`10
`3.7
`403~4103* (2"d line NSCLC)
`3.6
`801-8006 (ph I w/doeetaxel)
`12.8
`302-3035 (ph I w/oxaliplatin)
`*: An internal review has indicated that these deaths may have been due to disease progression and/or
`underlying m~dical conditions.
`
`2.2. Analyses for Drug-related Toxicity
`Because the initial multivariate analysis suggested that homocysteine levels were
`critically important in predicting toxicity, these updated analyses for toxicity have been
`performed on the set of 305 patients who have had their baseline homocysteine levels
`measured and recorded. All homocysteine levels were measured using a single laboratory.
`
`Tabld 2.4 shows the incidence of selected hematologic and nonhematologic toxicities
`according to tumor type.
`
`L
`
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`
`Table 2.4. Prevalence of Selected Hematologic and Nonhematologlc Toxlcifies by Tumor Type
`
`Tumor Type
`
`G3/4 Diarrhea
`(%)
`
`G4 Neut
`(%)
`
`G3/4 INF
`(%)
`
`Bladder
`
`Breast
`
`Cervix
`
`CRC
`
`H&N
`
`NSCLC P’
`
`3 (10.3%)
`
`4 (3.2%)
`
`2 (5.7%)
`
`9 (5.26%)
`
`0 (0.0%)
`
`3 (3,|%)
`
`7 (24%)
`
`35 (28.5%)
`
`I 1 (31.4%)
`
`31 (18.1%)
`
`14 (40%)
`
`I (3.5%)
`
`5 (4.1%)
`
`0 (0.0%)
`
`4 (2.3%)
`
`6 (17.1%)
`
`16 (16.7%)
`
`1 (1%)
`
`G3/4 INF +
`G4 Neut
`(%),
`
`i (3.5%)
`
`3 (2.4%)
`
`0 (0.0%)
`
`2 (1.2%)
`
`3 (8.6%)
`
`0 (0.0%)
`
`G4 PLT
`(%)
`
`0 (o.8%)
`
`12 (9.8%)
`
`2 (5.7%)
`
`11 (6,4%)
`
`4 (11.4%)
`
`3 (3.1%)
`
`G3/4 MUC
`(%)
`
`G2/3/4 MUC
`(%)
`
`0 (0.0%)
`
`9 (7.3%)
`
`4 (I 1.4%)
`
`2(1.2%)
`
`5 (14,3%)
`
`4 (4.29’0)
`
`8 (27.6%)
`
`29 (23.6%)
`
`10 (28.6%)
`
`15 (8,8%)
`
`12 (34.3%)
`
`19 (19.8%)
`
`NSCLC 2~d
`
`JMAS
`
`JMAW
`
`Other GI*
`
`Ph I Combo
`
`Renal
`
`To~l
`
`0 (0.0%)
`
`O (0.0%)
`
`0 (0.0%)
`
`5 (7.0%)
`
`8 (5.9%)
`
`3 (7.7%)
`
`37 (4.2%)
`
`*Pancreas, esophageal, gastric
`
`15 (18.5%)
`
`5 (12.5%)
`
`3 (12.5%)
`
`24 (33.8%)
`
`58 (42.5%)
`
`I 1 (2g.2%)
`
`z3o (26%)
`
`4 (5%)
`
`0 (0.0%)
`
`0 (0.0%)
`
`4 (5.6%)
`
`6 (4.4%)
`
`3 (7.7%)
`
`I (1.2%)
`
`O (0.0%)
`
`0 (0.0%)
`
`4 (5.6%)
`
`5 (3.7%)
`
`3 (7.7%)
`
`6 (7.4%)
`2 (5%)
`
`I (4.2%)
`
`12 (16.9%)
`
`4 (2.9%)
`
`6 (15.4%)
`
`0 (0.0%)
`0 (0.0%)
`
`I (4.2%)
`
`6 (8A%)
`
`3 (2.2%)
`
`1 (2.6%)
`
`3 (3.7%)
`3 (7.5%)
`
`3
`
`tO (14A%)
`
`13 (9£%)
`
`5 (12.8%)
`
`34 (3.9%)
`
`2,2 (~%)
`
`63 (7,2,%)
`
`35 (4.0%)
`
`130 (14,8 %)
`
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`

`
`2.2.1. Definition of patient population
`Of the patients with solid tumors treated with LY231514, 305 had homocysteine (Hcys)
`Ievels measured at baseline. A sub~oup of these also had cystathionine and
`methylmalonic acid measured at baseline and once each cycle thereafter. To eliminate
`the complicating factor of the effect of folic acid supplementation on toxicity, any patient
`who received folic acid supplementation (n = 38 in Study IMAS) was removed from the
`analysis, leaving a final sample size of 267.
`
`2.2.2. Methods
`Stepwise regression modeling, multivariate analysis of variance, and discriminant
`analysis were implemented to determine which predictors might correlate with severe
`toxicity, and to predict which patients are at high risk of experiencing such toxicity.
`Prognostic factors considered were age, gender, baseline albumin, liver enzymes, ANC,
`platelets, vitamin metabolites, pre-treatment weight, and AUC, tumor type, and prior
`treatment. The B12 metabolite methyl malonie acid is highly correlated with
`homocysteine and was therefore removed from the analysis to eliminate issues of
`colinearity,
`
`2.2.3. Results
`Results of these analyses are shown in Table 2.5. Those factors which are significant
`predictors for toxicity are shown in bold.
`
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`
`Table 2.5.
`
`Variables
`
`Age
`
`Gender
`
`BL ALB
`
`BL ALT
`
`BL ALK Phos
`
`BL HCYS
`
`BL CYST
`
`BL PLT
`
`BL ANC
`
`AUC
`
`Weight
`
`Prior Treatment
`
`Tumor Type
`
`Prognostic Factors for Hematologic Toxicity
`(n = 267)
`
`G4 Neutropenia G4 Neutropenia Thrombocytopenia
`+ G3/4 Infection
`
`Grade 3/4
`Diarrhea
`
`0.9735
`
`0.2528
`
`0.6348
`
`0,6916
`
`0.3874
`
`<0.0O001
`
`0.8030
`
`0.5250
`
`0.6029
`
`0.7298
`
`0,6487
`
`0,5059
`
`0.4855
`
`0.8050
`
`0.5208
`
`0. ! 934
`
`0.6050
`
`0.0573
`
`0.0191
`
`0.5971
`
`0.8101
`
`0.2737
`
`0.6081
`
`0.3182
`
`0.8122
`
`0.0153
`
`0.6136
`
`0.1932
`
`0.3423
`
`0.2206
`
`0.9044
`
`0.5120
`
`0.8705
`
`0.5391
`
`0.7246
`
`0.0452
`
`<0.00001
`
`<0,00001
`
`0.3907
`
`0,4457
`
`0.0736
`
`0.9531
`
`0.0633
`
`0.4813
`
`O. 1315
`
`0.9454
`
`0.2066
`
`0.2345
`
`0.3204
`
`0.9918
`
`0.4788
`
`0,4305
`
`Results of this analysis show that baseline homocysteine level is a statistically significant
`predictor for febrile neutropenia, Grade 4 neutropenia, Grade 4 thrombocytopenia, and
`Grade 3 or 4 diarrhea.
`
`These results confirm the findings of the original multivariate analysis (discussed in the
`introduction), and support the conclusion that homoeysteine may provide an ideal
`prognostic variable for predicting toxicity during LY231514 therapy.
`
`2.3.4. Contingency Analysis for LY231514-related Toxicity
`In order to investigate the relatio