Cancer Chemother Pharmacol (2008) 61:453–458
`DOI 10.1007/s00280-007-0489-5
`
`ORIGINAL ARTICLE
`
`A phase II study of milataxel: a novel taxane analogue
`in previously treated patients with advanced colorectal cancer
`
`Ramesh K. Ramanathan · Joel Picus · Haralambos Raftopoulos · Stephen Bernard ·
`A. Craig Lockhart · Gary Frenette · John Macdonald · Susan Melin · Daniel Berg ·
`Frank Brescia · Howard Hochster · Allen Cohn
`
`Received: 26 January 2007 / Accepted: 30 April 2007 / Published online: 22 May 2007
` Springer-Verlag 2007
`
`Abstract
`Background Milataxel is a novel taxane analog, with evi-
`dence of enhanced preclinical activity compared to paclit-
`axel and docetaxel, especially in cell lines that over express
`P-glycoprotein. Based on preclinical data that milataxel
`may be active in colorectal cancer (CRC), a phase II study
`was performed in patients with advanced previously treated
`CRC.
`Patients and results Forty-four eligible patients were
`entered. Milataxel was administered intravenously every
`
`Supported by a grant from Wyeth Research, Philadelphia, PA.
`
`R. K. Ramanathan
`Division of Hematology/Oncology,
`Department of Medicine, University of Pittsburgh
`School of Medicine, Pittsburgh, PA 15213, USA
`
`J. Picus
`Washington School of Medicine,
`Saint Louis, MO 63110, USA
`
`H. Raftopoulos
`Columbia University Medical Center,
`New York, NY 10032, USA
`
`S. Bernard
`University of North Carolina,
`Chapel Hill, Chapel Hill, NC 27599, USA
`
`A. C. Lockhart
`Vanderbilt University Medical Center,
`Nashville, TN 37232, USA
`
`G. Frenette
`Carolinas Hematology–Oncology Associates,
`Charlotte, NC 28203, USA
`
`J. Macdonald
`Saint Vincent’s Comprehensive Cancer Center,
`New York, NY 10011, USA
`
`3 weeks at the dose of 35 mg/m2. No objective responses
`were noted, stable disease was seen in three patients. The
`median time to progression was 1.4 months (95% CI of
`1.2–2.4 months). Three subjects developed neutropenic
`sepsis and two died. The most frequent grade 3/4 adverse
`events were neutropenia (57%), leukopenia (27%), dehy-
`dration (14%), neuropathy (16%), diarrhea (14%) and
`thrombocytopenia (14%). The pharmacokinetics of milat-
`axel was assessed in Wve subjects. The mean milataxel
`elimination half-life was 64 h and the mean area under the
`plasma concentration-time curve was 1,708 ng·h/ml.
`
`J. Macdonald
`Aptium Oncology, Los Angeles, CA 90048, USA
`
`S. Melin
`Wake Forest University, Winston–Salem,
`NC 27157, USA
`
`D. Berg
`Department of Internal Medicine,
`Division of Hematology/Oncology,
`University of Iowa, Iowa City, IA 52242, USA
`
`F. Brescia
`Medical University of South Carolina,
`Charleston, SC 29425, USA
`
`H. Hochster
`New York University School of Medicine,
`New York, NY 10016, USA
`
`A. Cohn
`Rocky Mountain Cancer Center,
`Denver, CO 80218, USA
`
`R. K. Ramanathan (&)
`UPMC Cancer Pavilion, #562 5150 Centre Avenue,
`Pittsburgh, PA 15232, USA
`e-mail: ramanathanrk@upmc.edu
`
`123
`
`AVENTIS EXHIBIT 2038
`Mylan v. Aventis
`IPR2016-00627
`
`©
`

`
`454
`
`Cancer Chemother Pharmacol (2008) 61:453–458
`
`Conclusions A syndrome of neutropenic sepsis and diar-
`rhea can be life threatening and close surveillance is needed
`in patients treated with milataxel at the dose of 35 mg/m2
`every 3 weeks. Clinical activity was not demonstrated in
`patients with advanced previously treated CRC.
`
`Keywords Colorectal cancer · Phase II · Milataxel ·
`MAC-321 · Taxanes
`
`Introduction
`
`Colorectal cancer (CRC) is a common disease worldwide,
`and in the United States about 146,000 new cases are
`expected in 2006 [1]. There have been rapid advances in
`the development of new chemotherapeutic drugs for CRC
`in the last decade. These changes have improved the out-
`come especially for patients with untreated advanced CRC
`[2]. In this group, the standard of care, at this time, is 5-
`Xuorouracil (5-FU) combined with other drugs, such as iri-
`notecan, oxaliplatin and bevacizumab [2–4]. However, the
`outcome for patients who have failed a Wrst line, multiagent
`regimen are still poor. Response rates to single agent sal-
`vage chemotherapy is in the range of 4–12% and median
`survival times are still less than 1 year [5–9].
`Milataxel [MAC-321, TL139, (microtubule/apoptosis/
`cytotoxic: 5beta, 20-epoxy-1, 2♡-, 4-, 7♢-, 10♢-, 13♡-hexa-
`hydroxytax-11-en-9-one 4 acetate 2 benzoate 7-propionate
`13-ester with (2R,3S)-N-tertbutoxycarbonyl-3-(2-furyl)iso-
`serine)] is a novel taxane analog of docetaxel. Milataxel is
`similar to the taxanes and enhances the rate of tubulin poly-
`merization [10, 11]. A major advantage of milataxel is the
`ability to overcome P-glycoprotein mediated resistance to
`paclitaxel and docetaxel. Preclinical studies of milataxel in
`a number of cell lines including colon (HCT-116, HT29),
`reveled signiWcant inhibition both with an oral and IV for-
`mulation [10]. Unlike paclitaxel and docetaxel, the IC (50)
`of milataxel did not vary in cells that expressed low to mod-
`erate levels of P-glycoprotein [10]. In KB-V1 cells, which
`highly over express P-glycoprotein, milataxel was more
`active compared to paclitaxel and docetaxel [10].
`Resistance to paclitaxel may also be mediated by a muta-
`tion in the paclitaxel binding region of beta tubulin [11–
`13]. In cell lines that contain such distinct point mutations,
`milataxel showed similar or less resistance compared to
`paclitaxel and docetaxel [10].
`Unlike the paclitaxel and docetaxel, milataxel does not
`require formulation with polysorbate 80 or cremophor,
`which can result in hypersensitivity reactions. Both paclit-
`axel and docetaxel have poor oral bioavailability, most
`likely due to high levels of P-glycoprotein in the gut [14].
`In addition, metabolism of docetaxel by cytochrome P450
`(CYP) 3A4 in gut and liver may also contribute to poor
`
`123
`
`bioavailability. Milataxel, however, has shown good oral
`bioavailability in early trials. Based on these promising pre-
`clinical data, phase I studies were conducted both with an
`oral and IV formulation.
`In the Wrst human study, milataxel was administered as
`an IV infusion over 4 h every 3 weeks to 26 patients. The
`starting dose was 1.25 mg/m2 and doses were escalated
`using a two-stage accelerated schema [15]. Dose limiting
`toxicity (DLT) was seen at the dose of 45 mg/m2 and con-
`sisted of myalgias, dyspnea, and neutropenia. Based on this
`study the dose of 35 mg/m2 every 3 weeks was chosen for
`subsequent phase II studies. An oral formulation of milat-
`axel has also been evaluated. Milataxel was administered
`orally once every 21 days up to a dose of 60 mg/m2, and
`DLT was neutropenic fever in this study [16].
`Based on the excellent preclinical data showing activity
`in cell lines including colon cancer, and the ability to over-
`come the multi drug resistant (MDR) phenotype [17], we
`conducted a phase II study of milataxel in patients with pre-
`viously treated advanced CRC. The objectives of this study
`were to evaluate the response rate and safety proWle of mil-
`ataxel in patients with advanced CRC. The pharmacokinet-
`ics (PK) of milataxel was also evaluated in a subset of
`patients.
`
`Patients and methods
`
`Patient selection
`Eligible patients (>18 years old) had failed ¸1 prior
`approved chemotherapy regimen for metastatic disease. All
`patients had histologically conWrmed adenocarcinoma of
`colon or rectum, and were required to have measurable dis-
`ease. Patients had Eastern Cooperative Oncology Group
`(ECOG) performance status of 0–2; Adequate organ func-
`tion was required [serum aspartate aminotransferase (AST)
`and alanine aminotransferase (ALT) ·2.5 times the upper
`limit of normal (ULN), serum bilirubin ·1.5 £ ULN]. In
`the presence of liver metastasis AST, ALT ·5 £ ULN and
`serum bilirubin ·3 £ ULN was allowed. Patients were
`required to have serum triglycerides ·750 mg/dl, absolute
`neutrophil count (ANC) >1,500cells/mm3 and platelet
`>100,000 cells/mm3. Life expectancy of ¸12 weeks was
`also required.
`Pertinent exclusion criteria were: prior therapy with mil-
`ataxel; >4 treatment regimens (including adjuvant therapy);
`Grade ¸2 peripheral neuropathy, radiation therapy to >25%
`of bone marrow; brain metastasis; known hypersensitivity
`to taxanes, and pregnant or nursing women. All patients
`signed an informed consent prior to therapy, according to
`institutional and federal guidelines. The study was carried
`out at 12 sites in the United States.
`
`

`
`Cancer Chemother Pharmacol (2008) 61:453–458
`
`455
`
`Study assessments and requirements
`
`Prior to the start of treatment, a history and physical exam
`(H&P) including a detailed neurological exam, complete
`blood count (CBC), chemistries including liver function
`tests, urine analysis, ECG and radiological scans to deWne
`extent of tumor were performed. Patients were followed
`with weekly CBC and chemistries. Toxicity assessment
`was performed weekly by telephone and an H&P was done
`every 3 weeks. Radiological scans were performed every
`6 weeks. Toxicity was graded according to the common
`toxicity criteria (CTC) version 2.0.
`
`Drug therapy
`
`Milataxel (Wyeth Research, Philadelphia, PA) was sup-
`plied as a powder in 10-ml amber vials each containing
`40 mg of drug. USP anhydrous ethanol (10.5 ml) was
`added to reconstitute. Once dissolved, the solution was
`added to prelabeled EVA IV administration bag. The Lipo-
`syn (200 ml) was then transferred to the EVA administra-
`tion bag. For the Wrst dose, the drug was administered at the
`rate of 0.5 ml/min over 15 min. If no reaction occurred, the
`remaining milataxel was given over 3 h and 45 min. All
`subsequent infusions were given over 4 h at a constant rate.
`The duration of one cycle of therapy was 3 weeks. Antie-
`metic therapy was at the discretion of the investigator
`according to institutional guidelines.
`
`Dose modiWcations
`
`A maximum of two-dose reductions and a 2-week delay for
`drug administration in case of toxicity was were permitted.
`Dose reductions were done in 25% decrements. Patients
`were required to meet pre-study laboratory requirements
`prior to dosing on each subsequent cycle.
`
`Hematologic toxicity
`
`If platelet count was <100,000 cells/mm3 on day of treat-
`ment or grade 4 thrombocytopenia was seen at any time, a
`25% dose reduction was mandated. If ANC was
`<1,500 cells/mm3 on day of treatment or grade 4 neutrope-
`nia >5 days or any grade neutropenia with fever was docu-
`mented, then patients were treated with a 25% dose
`reduction on recovery.
`
`Non-hematologic toxicity
`
`then dose was also reduced by 25%. If a grade 4 toxicity
`occurred or for grade 3 neurotoxicity lasting more than
`5 days, patients were taken oV study.
`
`Evaluation of response
`
`Radiological tests were performed at baseline and every
`6 weeks to assess the response. The RECIST criteria were
`used to assess response [18].
`
`Trial design and statistics
`
`The study used a two-stage group sequential design [19]
`that had 80% probability to identify as eVective a drug with
`a response rate of 15 and 95% probability to reject as
`ineVective a drug with a response rate of 6%. If less than
`three responses were to occur in the Wrst 31 patients
`enrolled, the trial would end, and the treatment would be
`rejected. If at least three patients responded, then 51 addi-
`tional patients were to be enrolled for a total of 82. If ·7
`patients out of 82 responded, the drug would be declared
`ineVective; otherwise the agent would be declared suY-
`ciently eVective to warrant further study. An interim analy-
`ses for response was performed when 31 patients were
`accrued, accrual continued during this time till analysis was
`complete.
`
`Pharmacokinetic analysis
`
`Plasma samples were collected at selected clinical sites for
`bioanalysis and subsequent PK analysis. Blood (5 ml) sam-
`ples were collected in sodium EDTA Vacutainer tubes dur-
`ing cycle 1, prior to infusion and at the following times
`points from start of infusion, 2, 4, 4.25, 4.5, 5, 6, 8, 24, 48,
`72, 96, 120 and 168 h. These samples were centrifuged to
`separate and isolate plasma and stored at ¡70°C. Milataxel
`concentrations were determined using a validated HPLC
`mass spectrometry method (Xenobiotic Laboratories, Inc.
`Plainsboro, NJ) that utilized a typical solvent extraction
`technique. The mean area under the curve (AUC) of milat-
`axel was determined using standard model independent
`methods. The elimination half-life (T1/2) was estimated dur-
`ing the log-linear portion of the plasma concentration time
`proWle.
`
`Results
`
`Patient population
`
`If grade 2 or 3 toxicity (excluding nausea, vomiting, alope-
`cia, or diarrhea based on investigator discretion) was seen
`on day of treatment, then on recovery doses were reduced
`by 25%. If grade 2 neurotoxicity lasted more than 5 days,
`
`Forty-Wve (45) subjects were enrolled in the study from
`March 2003 to August 2003, 44 patients were evaluable
`and received at least one dose of drug. A total of 188 cycles
`
`123
`
`

`
`456
`
`Cancer Chemother Pharmacol (2008) 61:453–458
`
`were administered, range 1–6 cycles and median 2 cycles/
`patient. Patient characteristics are presented in Table 1. All
`patients had prior exposure to 5-Xurouracil or capecitabine,
`and the majority had prior exposure to irinotecan and oxa-
`liplatin. Only one patient had prior therapy with bev-
`acizumab and no patients had prior cetuximab therapy. The
`majority (87%) of the patients had liver metastasis at pre-
`sentation. Interim analysis for response was performed
`when 31 patients were accrued. Due to rapid accrual, 44
`evaluable patients were entered prior to terminating the
`study due to inactivity.
`
`EYcacy
`
`For the intent-to-treat population, all 45 subjects enrolled
`were included in the eYcacy analysis. There were no objec-
`tive responses, 3 subjects had conWrmed stable disease. The
`median time to progression was 1.4 months (95% conW-
`dence interval of 1.2–2.4 months).
`
`Safety
`
`Toxicities were assessed as possibly, probably or deWnitely
`related to treatment (Table 2). Safety analysis includes 44
`
`Table 1 Patient demographics
`
`Parameter
`
`(n = 45)
`
`59
`38–80
`
`27 (60%)
`18 (40%)
`
`Sex
`Male
`Female
`Age (years)
`Median
`Range
`Ethnicity
`33 (73%)
`White
`Othera
`12 (27%)
`Performance status (ECOG)b
`0
`21 (48%)
`1
`22 (50%)
`2
`1 (2%)
`Prior therapy
`6 (13%)
`Radiation therapy
`44 (98%)
`Surgery
`Prior chemotherapy 100%
`1 Regimen
`7 (16%)
`2 Regimens
`28 (62%)
`3 Regimens
`9 (20%)
`4 Regimens
`1 (2%)
`Drug exposure
`5-FU/capecitabine 45 (100%)
`Irinotecan
`41 (92%)
`Oxaliplatin
`39 (87%)
`
`ECOG-Eastern Cooperative
`Oncology group
`a Other included African Amer-
`ican (5), Hispanic (4), and Asian
`(3)
`
`123
`
`Table 2 Selected treatment related treatment-adverse events
`
`Toxicity
`
`(Patients, n = 44)
`
`Grade 1/2
`
`Grade 3/4
`
`General
`Asthenia
`Dehydration
`Fever
`Infection
`Gastrointestinal
`Abdominal pain
`Anorexia
`Diarrhea
`Nausea
`Vomiting
`Hematological
`Anemia
`Leukopenia
`Neutropenia
`Thrombocytopenia
`Musculoskeletal
`Arthralgia
`Myalgia
`Neurological
`Neuropathy
`
`24 (55%)
`3 (7%)
`6 (14%)
`3 (7%)
`
`7 (16%)
`13 (30%)
`10 (23%)
`18 (41%)
`8 (18%)
`
`8 (18%)
`6 (14%)
`4 (7%)
`3 (7%)
`
`18 (41%)
`14 (32%)
`
`11 (25%)
`
`3 (7%)
`6 (14%)
`1 (2%)
`3 (7%)
`
`1 (2%)
`1 (2%)
`6 (14%)
`3 (7%)
`4 (9%)
`
`5 (11%)
`12 (27%)
`25 (57%)
`6 (14%)
`
`1 (2%)
`5 (11%)
`
`7 (16%)
`
`patients who received at least one dose of milataxel. The
`most common adverse events (all grades) were neutropenia
`(66%), asthenia (62%), nausea (48%), arthralgia (43%),
`myalgia (43%), leukopenia (41%), neuropathy (41%), anor-
`exia (32%), anemia (30%) and abdominal pain (18%).
`Eight (8) subjects discontinued treatment due to toxicity;
`the most commonly reported event leading to discontinua-
`tion was neuropathy, which occurred in Wve subjects. Dose
`reductions occurred in 8 subjects after cycle 1; the most
`common reasons for dose reductions were neutropenia
`(n = 4) and neuropathy (n = 3). Dose delays occurred in 6
`subjects; the most common reason for dose delays was neu-
`ropathy (n = 4). Six patients developed neutropenic sepsis
`and two died as a result. The two deaths occurred 13 and
`16 days after the Wrst dose of milataxel.
`
`Pharmacokinetic results
`
`The pharmacokinetics of milataxel was assessed in Wve
`subjects on cycle 1 (Table 3). The mean milataxel elimina-
`tion half-life was 64 h and the mean AUC was 1,708
`ng·h/ml following a dose of 35 mg/m2 given over 4 h. The
`maximum concentrations ranged from 70 to 156 ng/ml, T1/2
`ranged from 37 to 106 h (mean of 64 h). Milataxel AUC
`ranged from 865 to 2,122 ng·h/ml (mean 1,708 ng·h/ml).
`
`

`
`Cancer Chemother Pharmacol (2008) 61:453–458
`
`457
`
`Table 3 Milataxel pharmacokinetic parameter in cycle 1
`
`Dose (mg/m2)
`
`Statistic
`
`Cmax (ng/m2)
`
`Tmax (h)
`
`AUCt (ng*h/ml)
`
`AUC (ng*h/ml)
`
`T1/2 (h)
`
`CL (L/h/m2)
`
`Vss (L)
`
`35
`
`No of patients
`Mean
`SD
`
`5
`112
`40.6
`
`5
`3.20
`1.8
`
`5
`1458.24
`486
`
`5
`1707.77
`492
`
`5
`63.87
`28.1
`
`5
`22.8
`10.0
`
`5
`1556.86
`728.2
`
`Cmax maximal concentration, Tmax time to maximal concentration, AUC area under the concentration versus time curve, CL clearance, Vss volume
`of distribution at steady-state, AUCt area under the concentration versus time curve to last observable concentration, SD standard deviation
`
`Discussion
`
`The primary objective of this study was to evaluate the clin-
`ical activity of milataxel in patients with advanced CRC.
`However objective response was not observed, and study
`was terminated after an interim analysis was performed.
`Due to termination of study, analysis of other secondary
`endpoints (quality of life and overall survival) were not
`evaluated. The median time to progression of 1.4 months is
`disappointing. Agents which are active in previously
`treated CRC include irinotecan, oxaliplatin (with 5-FU),
`cetuximab and panitumumab [5–9]. In general, a response
`rate of 10% is considered as the benchmark to evaluate sin-
`gle agents in the refractory setting. Despite encouraging
`preclinical activity, in particular eYcacy in cells overex-
`pressing P-glycoprotein, milataxel was not active in CRC.
`The mechanism of taxane resistance, especially for second-
`generation taxanes in colon cancer remains unclear. It may
`be that preclinical and xenograft models are poor predictors
`of clinical activity in colon cancer [20, 21]. The PK proWle
`of milataxel in this study is similar to data previously pub-
`lished [15, 16].
`Milataxel administration resulted in neutropenic sepsis
`in 6 (14%) patients, and two deaths. A small number of
`subjects treated with milataxel among several studies have
`developed a fulminant syndrome within 1–2 weeks after
`initial exposure. The syndrome was characterized by severe
`neutropenia and diarrhea, resulting in sepsis, primarily with
`bowel and gastrointestinal organisms. Subjects at risk for
`this syndrome may include those with elevated serum alka-
`line phosphatase and/or total bilirubin. This syndrome was
`also associated with a rapid rise in serum bilirubin levels
`typically detected 1 to 2 weeks following initial treatment.
`Three (3) subjects in this study, including the two fatalities,
`may have been among the subjects manifesting this syn-
`drome. Data for all relevant subjects in milataxel clinical
`trials have been reviewed by an independent expert panel,
`which recommended continued clinical evaluation of milat-
`axel with appropriate monitoring. In this study hemopoietic
`growth factors were allowed if clinically indicated after two
`cycles of milataxel. Based on the degree of neutropenia and
`neutropenic fever, prophylactic hemopoietic growth factor
`support would be beneWcial if a dose of 35 mg/m2 of milat-
`axel is used in future studies. The PK proWle in patients
`
`with altered liver function also needs to be determined. The
`other adverse events seen in this study of neuropathy and
`myalgias are common to the taxanes. Hypersensitivity reac-
`tions were not observed with milataxel administration.
`In summary milataxel is inactive in patients with previ-
`ously treated advanced CRC. However, a phase II study in
`non-small cell lung cancer was conducted with four objec-
`tive responses (one complete and three partial responses) in
`32 evaluable patients for a 13% response rate. In this study,
`where milataxel was administered at the dose of 35 mg/m2
`every 3 weeks, responses were seen in patients who had
`previously been treated with platinum based chemotherapy
`regimens, as well as prior taxane therapy [22]. In addition,
`in a phase I weekly dosing study, there were two objective
`responses in ten evaluable breast cancer patients for a
`response rate of 20% [23]. Based on these observations,
`milataxel may be worth further evaluation in taxane sensi-
`tive diseases such as breast, lung and ovarian cancers. Fur-
`thermore, continued research is necessary to develop new
`agents and to understand the mechanisms of the MDR phe-
`notype in CRC.
`
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