Investigational New Drugs 23: 79–84, 2005.
`C(cid:1) 2005 Springer Science + Business Media, Inc. Manufactured in The Netherlands.
`
`79
`
`Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum
`(IV) (JM-216, BMS-182751) given daily x 5 inhormone refractory prostate
`cancer (HRPC)
`
`Tahir Latif1, Laura Wood1, Cindy Connell2, David C. Smith3, David Vaughn4,
`David Lebwohl5 and David Peereboom1
`1Department of Hematology and Medical Oncology, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland
`OH 44195; 2University Hospitals of Cleveland, Cleveland OH 44106; 3The University of Michigan, Ann Arbor MI
`481090; 4Abramson Cancer Center at the University of Pennsylvania, Philadelphia PA 19104; 5Novartis Oncology,
`Florham Park, NJ
`
`Key words: Hormone refractory prostate cancer (HRPC), JM-216 (BMS-18751, Satraplatin), Phase II Open-label study,
`Prostate-specific antigen (PSA)
`
`Summary
`
`JM-216 is an orally bioavailable platinum compound with activity against many tumor models. The objective of this
`study was to determine the safety profile and anti-tumor activity of JM-216 in patients with hormone refractory prostate
`cancer (HRPC) when given orally daily × 5 days. In this open label phase II study JM-216 was administered orally
`at the dose of 120 mg/m2/d for 5 days every 4 weeks. Patients continued on the therapy until evidence of disease
`progression or intolerable toxicity developed. Dose escalation and de-escalation were allowed according to patient’s
`tolerance. Thirty-nine patients were enrolled onto the study and received a total of 155 courses (median 2, range 1–16)
`of JM-216. Dose delays (77% of courses) and dose reductions (31% of courses) were common and were mainly due
`to myelosupression. Treatment was discontinued in 5 patients due to treatment related toxicities. One patient developed
`myelodysplastic syndrome 11 months after the start of treatment. The most frequent grade III or higher adverse events
`included thrombocytopenia (54%), neutropenia (52%), anemia (24%) nausea (13%), vomiting (16%) and diarrhea (28%).
`PSA response was assessed in 32 patients, 10 (26%) had partial response, 14 (36%) had stable disease while PSA
`progression was seen in 8 (21%) patients. Of 20 (54%) patients with measurable disease two patients had a documented
`partial response. Although JM-216 had moderate activity in HRPC when given on daily basis for 5 days, it is associated
`with significant treatment related toxicities in this patient population.
`
`Introduction
`
`Metastatic prostate cancer remains the second leading
`cause of male cancer deaths in the United States of Amer-
`ica with estimated 28, 900 deaths in the year 2003 [1].
`Although androgen deprivation is the mainstay of treat-
`ment in metastatic prostate cancer it is generally consid-
`ered palliative and all patients eventually become resis-
`tant to hormonal therapy. Once prostate cancer becomes
`hormone refractory, the prognosis is dismal with a me-
`dian overall survival generally demonstrated to be less
`than one year [2]. To date none of the several clinical
`trails evaluating experimental chemotherapeutic and or
`hormonal regimens in hormone refractory prostate can-
`cer (HRPC) patients had demonstrated a definite survival
`
`benefit [2]. Due to the use of differing response and entry
`criteria the comparison of objective advantage obtained
`from the use of these cytotoxic agents is difficult to assess
`[3, 4]. Nonetheless objective response rate (i.e. reduc-
`tion in measurable disease including complete and partial
`response) remains less than 10% with most of these reg-
`imens [5]. Although no evidence was available in favor
`of chemotherapy improving the survival in HRPC recent
`trials have demonstrated encouraging results in symptom
`palliation, response rate and quality of life [6].
`JM-216, (BMS-182751, Satraplatin), {bis (aceto) am-
`mine dichloro (cyclohexamine) platinum (IV)}, is a novel
`platinum analog that can be administered orally on a daily
`basis [7]. JM-216 has shown antitumor activity compara-
`ble to that of cisplatin or carboplatin in human ovarian
`
`AVENTIS EXHIBIT 2110
`Mylan v. Aventis, IPR2016-00712
`
`

`
`80
`
`carcinoma xenograft and murine sarcoma models [8]. It
`has also shown antitumor selectivity far superior to that
`observed for cisplatin or carboplatin against murine plas-
`macytoma in the in vivo preclinical studies [9]. Although
`phase I studies of JM-216 as a single agent have evalu-
`ated three administration schedules, daily dose for 5 con-
`secutive days, every three weeks was the recommended
`schedule for further studies due to ease of administration
`and best tolerability [10]. Utilizing this schedule the dose-
`limiting toxicities included thrombocytopenia, and diar-
`rhea and the maximum tolerated dose (MTD) was 100–
`140 mg/m2/d. The most frequent reasons for treatment
`discontinuations due to an adverse effect were hemato-
`logic and/or gastrointestinal toxicities. The recommended
`phase II dose using the daily times 5 days schedule was
`100–120 mg/m2/d every three to four weeks [10, 11]. Mul-
`tiple phase I/II trials have evaluated the role of cisplatin
`and carboplatin, either as single agent or in combination
`with other cytotoxic agents, in HRPC [12–18]. The ob-
`jective response rate to single agent cisplatin ranged 0 to
`19% in these trials and was comparable to that seen with
`other chemotherapeutic agents in HRPC [14–18]. Car-
`boplatin in combination with pactlitaxel and estramustine
`phosphate (TEC) has shown significant antitumor activity
`(45% response rate in patients with measurable disease)
`[12, 13]. Based on these results, ease of daily oral admin-
`istration and the need for improved therapy for HRPC a
`phase II study of JM-216 in the treatment of HRPC was
`undertaken. The objectives of the study were to deter-
`mine the anti-tumor activity of JM-216 in the treatment
`of HRPC, and to evaluate the safety profile of this unique
`agent in this patient population and schedule proposed.
`
`Patients and methods
`
`Patient eligibility and evaluation
`
`From December 1995 to October 1998 patients with histo-
`logically confirmed metastatic prostatic adenocarcinoma,
`who had disease progression despite one or more hor-
`monal therapies, and after anti-androgen withdrawal were
`enrolled in the study. Both measurable and evaluable pa-
`tients were eligible for the study provided progression of
`disease could be objectively established. Progression was
`demonstrated by worsening disease on bone scan or other
`objective measures including bone X-ray, CAT scan and
`magnetic resonance imaging (MRI). Isolated increase in
`Prostate Specific Antigen (PSA) was not considered suf-
`ficient evidence of disease progression. Patients were re-
`quired to have ECOG performance status of 0–2, and a
`life expectancy of at least 6 months. No prior cytotoxic
`chemotherapy (including suramin) or large field radiation
`(greater than 30% of marrow bearing area) was allowed.
`
`Patients were required to have adequate bone marrow re-
`serve, renal and hepatic function. Sexually active, fertile
`patients were required to use effective birth control meth-
`ods while receiving study drug. Individuals were excluded
`if they were diagnosed with a serious concurrent uncon-
`trolled medical disorder; a history of major gastrointesti-
`nal surgery or pathology likely to influence absorption;
`and a history or prior malignancy except appropriately
`treated localized epithelial skin cancer.
`Pretreatment evaluation included a history and physical
`examination including height, weight, performance sta-
`tus, and symptom review. Pretreatment testing included
`an EKG, chest X-ray, pain assessment, and tumor assess-
`ment. Laboratory tests required within 14 days of initial
`treatment included the following: complete blood count
`(CBC), blood chemistry profile, urinalysis, PSA and cre-
`atinine clearance in case of abnormal serum creatinine.
`While receiving treatment, weekly CBC was obtained.
`History and physical examination, pain assessment, blood
`chemistry profile, urinalysis and PSA were required prior
`to each treatment cycle. Repeat creatinine clearance val-
`ues were obtained if the serum creatinine rose to above
`the upper normal limit. Chest X-ray and EKG were re-
`peated as clinically indicated. Toxicity assessment was
`performed at every clinic visit using National Cancer In-
`stitute common toxicity criteria (version 1). Tumor re-
`assessment was required prior to every other course and
`as clinically indicated.
`
`Treatment
`
`JM-216 was provided by Bristol-Myers Squibb Pharma-
`ceutical Research Institute in capsules of 10 mg, 50 mg,
`and 200 mg. JM-216 was initiated at 120 mg/m2/d for five
`days, repeated every three weeks. The dose interval was
`amended to every four weeks after the first five patients
`experienced delayed hematologic recovery. Dose escala-
`tion or de-escalation was allowed according to preplanned
`dose adjustment schema that is shown in Table 1. Patients
`were allowed to continue treatment as long as clinical
`benefit was observed, in the absence of disease progres-
`sion and/or intolerable toxicities. Reasons for termination
`
`Table 1. Schema for planned dose adjustments
`
`Dose adjustmenta
`
`Toxicity
`≤Grade 1 hematological toxicityb
`Equal to grade II hematological toxicity
`≥Grade II hematological toxicity
`or 25–50% reduction in creatinine clearance
`aDose levels:− 2= 80 mg/m2/d,− 1= 100 mg/m2/d,0= 120 mg/m2/d,
`+ 1= 140 mg/m2/d,+ 2= Do not exceed 140 mg/m2/d.
`bAccording to CTC version 1.
`
`Escalate to next level
`No change
`Reduce one level
`
`

`
`included toxicity, disease progression, patient request,
`non-compliance, or physician decision.
`
`Evaluation
`
`Evaluation for progression of disease or response to
`chemotherapy was performed using physical examina-
`tion, bone scans, bone X-rays, and other appropriate imag-
`ing techniques and PSA levels. Measurable disease was
`defined as lesions measurable in two perpendicular diam-
`eters. A complete response (CR) in patients with measur-
`able disease consisted of complete disappearance of all
`tumor lesions and of all signs and symptoms of disease
`for at least four weeks from the date of documentation
`of the complete response. A partial response (PR) among
`patients with measurable disease consisted of a decrease
`by more than 50% in the sum of the products of the two
`largest perpendicular diameters of all measurable lesions
`as determined by two consecutive observations, at least
`four weeks apart. Stable disease was defined as failure to
`observe either a CR or PR, in the absence of progressive
`disease (PD), as determined by two consecutive observa-
`tions at least four weeks apart. Progressive disease was
`determined by an increase in size by at least 25% of any
`measurable or evaluable lesion, and/or the appearance of
`new lesions or the occurrence of malignant pleural effu-
`sion or ascites.
`A complete PSA response was defined as PSA values
`within institutional normal range provided there was no
`disease progression during or before the response period.
`Partial PSA response consisted of PSA values that had
`decreased by at least 50% of their baseline values, without
`disease progression during or before the response period.
`A stable PSA response was defined as PSA values that are
`less than 50% from the baseline value, provided there is no
`CR, PR or PD, during or before the response period. PSA
`progression was determined by PSA values with atleast
`a 50% increase from the nadir value. Assessment of PSA
`response required two consecutive PSA values at least
`28 days apart for each of the circumstances (CR, PR, and
`PD)
`
`Statistical methods
`
`The original study incorporated a two-stage accrual de-
`sign to allow early termination should preliminary results
`indicates that treatment has minimal activity or unaccept-
`able toxicity in this population. Objective response rate
`was the primary endpoint of the study. However, the de-
`cision to continue the trial was based on overall evidence
`of response including both objective response and PSA
`response. Fifteen evaluable patients were to enter into
`the study initially; if 2–4 responses were observed, then
`
`81
`
`stage two would begin with the accrual of 15 additional
`patients to estimate the effectiveness of JM-216 in this pa-
`tient population. If more than 7 responses were observed,
`the regimen was concluded to be promising. Tabulations
`and descriptive statistics were used to analyze patient
`characteristics, drug efficacy, drug safety and laboratory
`observations.
`
`Results
`
`The pretreatment characteristics of patients entered into
`this trial are listed in Table 1. Thirty-nine patients were
`registered from December 1995 to October 1998. All pa-
`tients initiated treatment at a dose of 120 mg/m2/day and
`received a total of 155 courses of JM-216 (median 2, range
`1–16). The original protocol required that the chemother-
`apy be given for five consecutive days every 21 days.
`The protocol was amended in July 1996, to reflect the
`discovery of late hematologic nadirs occurring at approx-
`imately day 21 of each course. The cycle length was then
`changed to every 28 days. Dose delays were common
`and occurred in 88 (77%) of 116 courses delivered sub-
`sequent to the first course and the median number of days
`between courses was 38 (range 21–72 days). The ma-
`jority of courses were delayed due to the late recovery
`from hematologic toxicity. Dose reductions occurred fre-
`quently and reasons for dose reduction included cytopenia
`in 23 patients and an increase in creatinine in 2 patients. Of
`37 patients who received a minimum of two courses, 22
`(59%) patients required at least one dose reduction during
`their treatment. Dose reductions occurred in 36 (31%) of
`116 courses administered subsequent to the first course.
`However, 10 (26%) patients who received a minimum
`of two courses, were dose escalated to 140 mg/m2/day
`at some point in time during their therapy. Permanent
`dose discontinuation occurred in 5 patients. Three had el-
`evated liver function tests and one each had leukopenia
`and thrombocytopenia.
`Hematologic toxicities are summarized in Table 2. Me-
`dian time to hematologic nadir during evaluation of all
`courses was day 27 for hemoglobin (range 2–154); day 22
`for absolute neutrophil count (range 2–45) and day 24 for
`platelet count (range 2–108). Fourteen patients required
`transfusions for anemia or thrombocytopenia at some time
`during their course of treatment. Approximately 88% of
`patients had abnormal lymphocyte values at the initia-
`tion of the study with 95% of patients developing grade 3
`lymphopenia during the treatment phase. One patient de-
`veloped a latent myelodysplastic syndrome (MDS) with
`complex karyotype (including 7q-) on cytogenetic analy-
`sis approximately eleven months after his treatment.
`Non-hematological toxicities were mostly grade I or
`II and included nausea (95%), asthenia (90%), diarrhea
`
`

`
`82
`
`Table 2. Patient characteristics
`N = 39
`
`Characteristics
`
`Age
`Median (years)
`Range
`Performance status
`0
`1
`Not Reported
`PSA
`Median (ng/L)
`Range
`Time from diagnosis
`Median (months)
`Range
`Bone metastases
`Present
`Absent
`Prior therapy
`Radiation
`Hormone therapy
`Orchiectomy
`LHRH agonist
`Anti-androgen
`Estrogen
`
`69
`47–82
`
`16 (41%)
`22 (56%)
`1 (3%)
`
`117.7
`4.3–1497.8
`
`55
`<1–116
`
`33 (85%)
`6 (15%)
`
`24 (61%)
`39 (100%)
`12
`29
`35
`6
`
`(87%), anorexia (69%), vomiting (51%) constipation
`(44%), chills (38%), myalgia (36%), dysgeusia (33%),
`dizziness (33%), and headache (31%). As summarized in
`Table 2 Gastrointestinal toxicities were significant, with
`Grade 3 or higher nausea, vomiting and diarrhea noted
`in 13, 16 and 28% of the patients respectively. Approxi-
`mately one-third of patients had an elevation of ALT, AST,
`or total bilirubin from baseline at some point during treat-
`ment. Most elevations were grade 1or II, transient, tended
`to occur soon after the course of treatment and recurred
`in some cases upon re-challenge with JM-216. Grade 3
`or higher abnormalities of liver related enzymes occurred
`in 4 patients and treatment was discontinued in three pa-
`tients. Abnormalities of liver enzymes were uniformly re-
`versible in all cases on discontinuation of therapy. Renal
`toxicities were mild and infrequent with only two patients
`requiring dose delays and reductions secondary to renal
`function abnormalities. Seventeen patients reported a to-
`tal of 35 hospitalizations during the course of this study.
`Twelve of these hospitalizations were believed related to
`study drug toxicity. Treatment were discontinued due to
`progressive disease in 19 (49%) patients, treatment related
`toxicity in 13 (33%) patients and upon patient’s request
`in 5 (13%) cases.
`Twenty patients (54%) had measurable disease. Two
`patients, one with liver metastasis had a documented par-
`tial response. The remaining 18 patients did not have any
`measurable response to treatment, in 7 patients the disease
`
`Table 3. Grade 3 or higher toxicities according to
`CTC version 1
`
`Toxicity
`
`% of Patients, N = 39
`
`Hematologic
`Anemia
`Leukopenia
`Neutropenia
`Lymphopenia
`Thrombocytopenia
`Gastrointestinal
`Diarrhea
`Vomiting
`Nausea
`Elevated Liver enzymes
`Renal
`
`24
`41
`52
`95
`54
`
`28
`13
`16
`10
`0
`
`remained stable for the duration of treatment. PSA values
`were measured at the time of each chemotherapy admin-
`istration. Thirty-two patients had all PSA values available
`for response assessment. A complete PSA response or a
`partial PSA response was measured in 10 (26%) patients,
`stable disease was noted in 14 (36%) patients while PSA
`progression occurred in 8 (20%) patients. PSA response
`could not be evaluated in 7 (18%) patients due to the miss-
`ing values. Treatment was discontinued in many patients
`before the documentation of PSA progression due to tox-
`icity and other reasons, 14 (35%) patients enrolled in the
`study had documented PSA progression during the treat-
`ment period. The median survival for the whole cohort is
`16.7 months (95% confidence interval 9.3–19.2 months).
`The median PSA response duration was 3.8 months while
`median progression-free survival was 7.7 months in 32 as-
`sessable patients.
`
`Discussion
`
`JM-216 (BMS-182751, Satraplatin) is a novel orally
`bioavalible platinum analog that had demonstrated anti-
`tumor activity comparable with parentrally administered
`cisplatin or carboplatin in both in vitro and in vivo stud-
`ies. Although phase II studies in small cell lung cancer
`JM-216 has shown considerable promise as first line ther-
`apy [19], its antitumor activity in refractory cervical and
`non-small cell lung cancers is at best modest [20, 21].
`Its role as a radiation sensitizer and in combination with
`other drugs has been evaluated in small studies [22, 23].
`The overall response rate including objective and PSA re-
`sponse (excluding stable disease) was 26% in this study.
`Stable disease was observed in another 36% of the patients
`demonstrating modest anti-tumor activity of JM-216 in
`HRPC comparable to that observed for other cytotoxic
`agents in this setting.
`
`

`
`Despite JM-216 showing modest activity within this
`patient group, frequent dose modification and delays sec-
`ondary to treatment-related toxicity complicated man-
`agement considerably. The most common and signifi-
`cant grade 3 or higher toxicities were myelosupression
`(54%) and gastrointestinal (28%) as noted in previous
`studies. The unexpected finding noted in this study was
`the unusually late recovery of neutropenia and thrombo-
`cytopenia as reflected by prolonged cycle interval (me-
`dian 38 days) between subsequent courses. This result
`could be explained partly by older age of the patients
`and the fact that 61% of patients had received prior radi-
`ation therapy that can potentially damage bone marrow
`reserves [24]. It is more likely that the late nadir repre-
`sents toxicity to stem cells, which has become evident
`in this patient population. Development of MDS in one
`patient eleven months after the therapy, the first noted
`case of possible treatment related leukemia following JM-
`216 therapy, supports the hypothesis of stem cell damage.
`Presence of complex karyotype (including 7q-, an abnor-
`mality typically associated with prior chemotherapy re-
`lated leukemia/MDS) in our patient and existence of re-
`ports describing higher incidence of secondary leukemia
`following cisplatin and carboplatin therapy in ovarian
`cancer favors this conclusion [25, 26]. The cause and
`significance of lymphopenia in majority of patients dur-
`ing the treatment phase is also not clear even though
`it has been reported in other studies evaluating estro-
`gen, corticosteroids, suramin and mitoxantrone in HRPC
`[27–29].
`Non hematological toxicities were mainly gastroin-
`testinal with grade 3 or higher nausea, vomiting and diar-
`rhea occurring in 13–28% of patients. Three patients were
`hospitalized due to refractory gastrointestinal toxicities.
`Elevation of the liver enzymes and bilirubin was noted
`in approximately one third of the patients treated with
`JM-216 at some point during their treatment. Although
`these abnormalities were mild and transient in majority
`of patients, contrary to previous studies treatment had to
`be discontinued in three patients a finding that could also
`be related to older age and higher dose of JM-216 in our
`patients.
`In conclusion although this study had demonstrated
`a modest antitumor activity of JM-216, comparable to
`other currently available chemotherapeutic agents for
`HRPC, we believe that toxicities associated with this
`dose and schedule significantly complicate the manage-
`ment of these patients. As evident by frequent dose
`delays and dose reductions starting dose in this trial
`seems to be too high for prostate cancer patients. Fu-
`ture studies should design to evaluate lower starting doses
`with longer cycle duration especially if used in com-
`bination with any other myelotoxic chemotherapeutic
`agents.
`
`83
`
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