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A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer

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A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer
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  PHASE II STUDIES A pilot phase II trial of all- trans  retinoic acid (Vesanoid)and paclitaxel (Taxol) in patients with recurrentor metastatic breast cancer Margarette Bryan  &  E. Dianne Pulte  & Kathleen C. Toomey  &  Lillian Pliner  &  Anna C. Pavlick   & Tracie Saunders  &  Robert Wieder Received: 5 March 2010 /Accepted: 15 June 2010 /Published online: 2 July 2010 # Springer Science+Business Media, LLC 2010 Summary  Purpose : We investigated a combination thera- py with weekly paclitaxel and all  trans -retinoic acid(ATRA) for tolerability, response to treatment, time to progression and survival in previously treated patients withmetastatic or recurrent breast cancer. Our rationale was based on preclinical studies demonstrating potentiation of the cytotoxic effects of taxanes and induction of differen-tiation by ATRA.  Patients and methods : Seventeen patientswith previously treated metastatic or recurrent breast cancer were enrolled to a regimen of all- trans  retinoic acid(Vesanoid, tretinoin, Hoffman-La Roche, Inc.) 45 mg/m 2 PO daily for 4 days starting 2 days before a 1 h treatment with paclitaxel (Taxol, Bristol-Myers Squibb, Plainsboro, NJ) 80 mg/m 2 IV administered weekly for 3 weeks,repeated in 28 day cycles until disease progression or untilno longer tolerated. Patients were evaluated for toxicity,response, time to progression and survival. Patients were primarily African American and Latino, representative of the population served by our Cancer Center.  Results : Theregimen was relatively well tolerated. There were ninegrade 3 and one grade 4 toxic events. We administered 162treatment cycles with a mean of 7.5 per patient (range 1  –  22,median 5). Three patients had a partial response (17.6%)and ten patients had stable disease (58.8%), with an overallclinical benefit of 76.4%. Median time to progression was6.0 months (range 1  –  21, mean 7.7 months). Fourteenevaluable patients had a median survival of 16 months(range 1  –  68 months, mean 25.2 months).  Conclusions : Thedata suggest this is a well tolerated regimen with modest response rates but with time to progression and survivalrates similar to those reported for paclitaxel alone andrelatively high rates of stable disease in this sample of  patients. Keywords  All trans retinoic acid.Taxol.Metastatic breast cancer .Potentiation Introduction Advances in the adjuvant and neoadjuvant therapy of  breast cancer have resulted in decreased rates of recur-rence, which translated to higher cure rates in patientswith localized disease. However, despite these advances,metastatic or recurrent breast cancer remains incurable [1].The current treatment goals in patients with metastatic or  Support  The study was partially supported by a research grant fromBristol-Myers Squibb, Plainsboro, NJ (RW) and study drug suppliedfrom Hoffman-La Roche, Inc.M. Bryan : E. D. Pulte : L. Pliner  : T. Saunders : R. Wieder Department of Medicine, UMDNJ-New Jersey MedicalSchool/University Hospital Cancer Center, Newark, NJ, USAK. C. ToomeyThe Steeplechase Cancer Center at Somerset Medical Center,Somerville, NJ, USAA. C. Pavlick  New York University Cancer Institute, New York, NY, USAR. Wieder ( * )UMDNJ-New Jersey Medical School,185 South Orange Avenue, Cancer Center H1216, Newark, NJ 07103, USAe-mail: wiederro@umdnj.eduInvest New Drugs (2011) 29:1482 – 1487DOI 10.1007/s10637-010-9478-3  recurrent breast cancer are prolongation and maintenance of the quality of life. Many therapeutic options for treatingwomen with metastatic or recurrent breast cancer areavailable. These include chemotherapy agents as well as biologicals.Of the available agents, taxanes are among the most effective and commonly used in the metastatic setting [2].Regimens that contain taxanes result in superior tumor response, time to progression and overall survival com- pared with regimens that do not contain taxanes [3]. Nevertheless, time to progression, even with taxane-containing regimens, is relatively short and overall survivaldifferences are measured in months [4]. Patients inevitablyrelapse and become resistant to therapy. In addition,administration of paclitaxel every-3-weeks is limited bythe relatively common occurrence of severe neutropenia,leucopenia and hyperglycemia and less common occurrenceof neuropathy, pain and malaise [5]. Weekly paclitaxel has been evaluated for its capacity to decrease incidence of these adverse events and to increase dose density. Lower rates of some of these toxic events were observed withweekly administration, although higher rates of neuropathywith weekly administration were noted in one study [6].Response and time to progression were also greater with a weekly paclitaxel than with an every 3 week treatment regimen, establishing it as the preferred norm for paclitaxeladministration [6].One potential approach to increasing the efficacy of taxanes and potentially allow lower doses to be adminis-tered with equal or greater effects is to modulate their cytotoxicity using retinoids. In preclinical studies, we havedemonstrated that treatment of breast cancer cells with all trans -retinoic acid (ATRA) sensitizes cells to the effects of  paclitaxel [7]. Incubation of estrogen-dependent MCF-7and T-47D and estrogen-independent MDA-MB-231 breast cancer cells with ATRA for 3 days at concentrations of 10 − 8 M can decrease the ED 50  for cell death of paclitaxel byup to two logs in a synergistic manner. The mode of celldeath is apoptosis and is mediated by phosphorylation of Bcl-2 [7]. When used in a clinical trial, ATRA had modest in vivo effects in breast cancer patients by itself. In a phaseII trial in patients with metastatic breast cancer, all- trans retinoic acid induced a partial response in one patient andstable disease in three other patients out of 14 evaluable patients, a 26.8% clinical benefit [8]. Because retinoidshave been well-tolerated in patients in prior clinical trials[9  –  12] and specifically, ATRA has presented few sideeffects to patients in prior phase I and II studies [8, 13], we hypothesized that the combination of ATRA administeredto breast cancer patients receiving weekly paclitaxel (Taxol,Bristol-Myers Squibb, Plainsboro, NJ) would result in a high response rate with relatively low levels of toxicity. Weundertook this study to test this hypothesis. Study design and methods This was a non-randomized, open label, two-center, phaseII response and time to progression study of all- trans retinoic acid (Vesanoid, tretinoin, Hoffman-La Roche, Inc.)45 mg/m 2 PO daily for 4 days, starting 2 days before, theday of and 1 day after treatment with paclitaxel (Taxol,Bristol-Myers Squibb, Plainsboro, NJ) 80 mg/m 2 IV over 1 h administered weekly for 3 weeks, followed by 1 week off andrepeatedin28daycyclesuntildiseaseprogressionoruntilthe patient could no longer tolerate treatment. There were nodosereductionsplanned.Patientsreceivedpremedicationwithantiemetic regimens that included a 5-hydroxytriptamine 3 (5-HT 3 ) receptor antagonist, dexamethasone, lorazepam,diphenhydramine, famotidine and prochlorperazine. Antie-metics were included because of reported nausea with ATRAadministration and as a precaution for possible potentiationof nausea with paclitaxel, although paclitaxel by itself isminimally emetogenic. The use of filgrastim was permitted24 h after paclitaxel administration, as needed, if neutropenia with granulocytes below 1,000/mm 3 occurred in prior cycles.The protocol was approved by the institutional review boardsof both UMDNJ-University Hospital and the Somerset Medical Center and patients signed informed consent prior to enrollment.Eligibility criteria restricted entry topatients over 18yearsold with a histologic or cytologic diagnosis of carcinoma of the breast which had either recurred or was metastatic.Patients were required to have measurable disease and a Karnofsky performance status of   ≥ 50%. Entry criteria wereintentionally designed to provide an opportunity for previ-ously treated patients with less than optimum performance to participate in this relatively non-toxic protocol based on preclinical data that supported a rationale for a potential benefit. Adequate hematologic function as indicated bywhite blood cell count of   ≥ 2,000/mm 3 , absolute neutrophilcount of   ≥ 1,000/mm 3 , hemoglobin  ≥ 7.5 gm/dL and platelet count of   ≥ 50,000/mm 3 were required for entry. Adequaterenal function as indicated by a serum creatinine  ≤ 1.8 mg/ dL and hepatic function as indicated by serum aspartateaminotransferase (AST) and serum alanine aminotransfer-ase (ALT) levels <2× the upper limit of normal and total bilirubin levels of   ≤ 2.0 mg/dl were also required. Theinclusion criteria also required triglyceride levels to be  ≤ 2×the upper limit of normal. Patients had to be able to swallow,or have a nasogastric or gastric tube, although all patients onstudy were able to swallow. Patients who had brainmetastases must have received definitive whole brainradiation therapy prior to consideration for protocol entry.Patients were excluded it they were pregnant or lactating if  premenopausal, were HIV positive or had surgery less than3 weeks prior to study entry. Exclusion criteria did not include extent or type of prior therapy. Invest New Drugs (2011) 29:1482 – 1487 1483  Pre-entry patient evaluations included a history, includ-ing history of prior therapy regimens, surgery or radiation, a  physical exam and performance status evaluation. Hemato-logic and serum chemistry evaluations, a serum pregnancytest if they were premenopausal and an HIV test were performed. Patients underwent extent of disease evaluationincluding physical measurement of palpable lesions, CTscans or MRIs within 1 month prior to initiating therapy.Patientshadcompletebloodcount,serumchemistrypanelandtriglyceride evaluations on the day of each paclitaxeladministration, as well as during the fourth week of the cycle.During the off week after the last paclitaxel administration ineach cycle, patients were also evaluated by their physician byahistoryandphysicalexam,measurementofcutaneoustumor sizes, if present, and for toxicity.After completion of two cycles, a complete extent of disease evaluation by CT scan or MRI was performed.Bidimensional tumor measurements were compared with pre-study measurements by a radiologist and were used toanalyze response by World Health Organization objectiveresponse criteria. Patients were taken off study if they haddisease progression, if they no longer wished to participate,if they could not tolerate treatment for any reason, if their  performance status dropped to <50%, if they became pregnant or lactating, if they developed grade 3 toxicity, if renal or liver function fell to below eligibility criteria or if triglyceride levels rose to above eligibility criteria. After terminating protocol therapy, patients were evaluatedmonthly with a history and physical examination, cutane-ous tumor measurement, complete blood counts and serumchemistries. The primary objective of the study was tumor response and secondary objectives were time to progres-sion, survival and toxicity. Results Patient and tumor characteristicsSeventeen patients were enrolled on the study. They wereall women with a median age of 54 (range 44  –  66) and a mean age of 55.6 (Table 1). There were 10 (58.8%) AfricanAmericans, 3 (17.6%) Hispanics, 2 (11.8%) Asians and 2(11.8%) Caucasians, reflective of the primarily minorityethnic distribution of the patients treated at UniversityHospital, where the majority of the patients on study wereenrolled (14, 82.4%). Three of the patients were enrolled at the Steeplechase Cancer Center (17.6%). Twelve (70.6%)of the patients were postmenopausal, two (11.8%) were premenopausal and the status of three (17.6%) is unknown.The median Karnofsky performance status was 90% (range70  –  100%). Nine of the patients had prior therapy for recurrent or metastatic disease (52.9%). The patients previously treated had a mean number of 1.6 prior linesof therapy (range 1  –  7) and a median of 1. Three patientshad prior taxane therapy. Additional chemotherapy treat-ments included gemcitabine, liposomal doxorubicin, cape-citabine, navelbine and unknown regimens. Ten patientsalso received hormone ablative therapy and six received bisphosphonates.Eight (47.1%) of the patients were initially diagnosedwith stage IV disease while the rest were stage III or less at initial diagnosis and were being treated for recurrent disease(Table 2). Eleven (64.7%) of the patients tumors ’  wereestrogen receptor (ER) positive, 5 (29.4%) were ER negative and the hormone receptor status of one (5.9%)was unknown. The Her2 status of the tumors was positivein 5 (29.4%) patients, negative in 9 (53.0%) patients andunknown in 3 (17.6%) patients. Fifteen (88.2%) of the patients had bony metastases and fifteen (88.2%) patientsalso had visceral metastases.Safety and toxicityThe treatment regimen was relatively well tolerated(Table 3). There were six grade 3 adverse events, includingone anemia, two nausea and vomiting, two pain and oneataxia. There were three serious adverse events that werenot treatment related, including one each of a grade 3gastrointestinal bleed from a Mallory-Weiss tear, a supra-ventricular tachycardia and one grade 4 pulmonary embolusthat was associated with an ataxia that affected ambulation. Table 1  Patient characteristicsCharacteristicAge (years) Range 46  –  66Median 54Mean 55.6Race (number of patients) AfricanAmerican10Hispanic 3Asian 2Caucasian 2Menopausal status (number of patients)Postmenopausal 12Premenopausal 2Unknown 3KPS Median 90Range 70  –  100 Number of patients who had prior therapyYes 9 No 8 Number of prior treatments for relapsed or metastatic diseaseRange 1  –  7Median 1Mean 1.6Previous taxane 31484 Invest New Drugs (2011) 29:1482 – 1487  There was also one serious adverse event, a seizure, that was possibly related to study medication modifying theserum levels of the patient  ’ s anti-epileptic medication.ResponsePatients received a total of 162 treatment cycles. There wereno dose reductions. The mean number of treatment cycles perpatientwas7.5(range1  –  22)withamedianof5(Table4).The mean number of ATRA doses administered per cyclewas 10.8 (range 1  –  12) and the mean number of paclitaxeldoses per cycle was 2.7 (range 0  –  3). Three patients had a  partial response (17.6%) and ten patients had stable diseaseafter at least one extent of disease evaluation (58.8%), for an overall clinical benefit of 76.4%. One patient progressedand three patients were unevaluable. Of the unevaluable patients, one withdrew consent when she developed grade 1nausea during the first treatment cycle, one had a seizureduring the first cycle and one had pain, neuropathy, andheadache after one cycle. These patients were taken off study and did not undergo post treatment imaging.The duration of stable disease ranged from 2  –  12 months.One patient had stable disease for 2 months while on study andwastakenofffortoxicitywhilestillexperiencingstabledisease.The shortest duration of stable disease among the other nine patients was 4 months. The median duration of stable diseasewas 5.0 months and the mean was 6.8 months. Five patientsweretakenoffstudyfortoxicityorwithdrawalofconsent.Theyranged in age from 50 to 61. Three had had no prior treatment for metastatic disease and two had had 2  –  3 prior therapies,includingtaxanesinonecase.Thereasonsforcomingoffstudywere withdrawal of consent for grade 1 nausea and vomiting inone patient, seizure in one patient, grade 2 edema andneuropathy in one patient, grade 3 pain with neuropathy inone patient and grade 3 ataxia in one patient.Time to progression was evaluated for all 17 patients.For the five patients that came off study, the time fromstudy enrollment to the point they were taken off study wasused to calculate time to progression. The median time to progression was 6.0 months (range 1  –  21) with a mean of 7.7 months. We tabulated survival in eligible patients. One patient was alive at the time of data tabulation for a periodof 54 months. Two patients, who were lost to follow up,and the one who was alive at the time the data was Table 2  Tumor characteristicsStage at diagnosis III 7IV 8other 2ER status Positive 11 Negative 5Unknown 1PR status Positive 9 Negative 7Unknown 1HER-2 status Positive 5 Negative 9Unknown 3Bony metastases Yes 15 No 2Visceral metastases Yes 15 No 2Grade 1 Grade 2 Grade 3 Grade 4 Adverse events Alopecia 4 2Anemia 4 3 1Constipation 5 0 0Edema 4 1 0Fatigue 3 3 0Leukopenia/neutropenia 2 1 0 Nausea and vomiting 3 1 2 Neuropathy 3 2 0Pain 3 2 2Other 7 1 1 Serious adverse events Gastrointestinal bleed 1Pulmonary embolus 1Seizure 1Supreventricular tachycardia 1 Table 3  Adverse eventsInvest New Drugs (2011) 29:1482 – 1487 1485  tabulated were censored. The 14 evaluable patients had a median survival of 16.0 months (range 1  –  68 months) with a mean of 25.2 months. The data suggest this is a relativelywell tolerated regimen in previously treated patients withrecurrent/metastatic breast cancer. The response rate was at the low end of the range reported in prior studies with paclitaxel but the time to progression and survival rateswere similar to those with paclitaxel alone as administeredweekly for recurrent or metastatic disease. The clinicalefficacy was higher than previously reported, however, possibly related to the presence of ATRA in the regimen. Discussion This small pilot study demonstrated that a combination of all- trans  retinoic acid and paclitaxel administered as a weekly regimen 3 weeks out of 4 in 28 day cycles is welltolerated in women previously treated for their recurrent or metastatic disease. The patient profile consisted of womenwho were primarily post-menopausal with good perfor-mance status. Approximately 65% of the patients hadhormone-receptor positive disease. All patients had some prior chemotherapy and some had hormonal and bisphosph-onate treatment. The patient population was primarilyAfrican American and Hispanic, reflecting the patient  population served by the New Jersey Medical School-University Hospital Cancer Center.The treatment-related adverse event profile was unre-markable. There were five instances of grade 3 toxicityrepresenting common side effects of chemotherapy. Therewas one case of grade 3 ataxia that was not likely treatment related. There were four serious adverse events. Three werenottreatmentrelatedandonemayhavebeenduetostudydrugmodifying the pharmacokinetics of antiseizure medications. None of the severe toxicities previously reported with paclitaxel, particularly neuropathy [6] were observed. Therewere no instances of headache and dermatological toxicityobserved with higher doses of all- trans  retinoic acid [8, 13] or other retinoids [9  –  12], but two patients did experiencegrade 3 nausea and vomiting, previously associated with protracted all- trans  retinoic acid treatment [8].Response rates were rather modest at 17.6% whencompared response rates to weekly paclitaxel of 21.5% to42% in three large studies [6, 14, 15]. This suggests that the hypothesis of response potentiation in patients is likelyincorrect. However, 58.8% of patients had stable disease,which lasted at least 4 months in 9 out of ten of these patients.This clinical benefit of 76.4% is likely reflective of a different  paradigm in outcomes expected with biologic therapy, that of stable disease, and supports a rationale for further investigat-ing this regimen in a larger study [16]. The median time to progression of 6 months was comparable to the 4.7 to9 months reported in these large studies [6, 14]. The median survival of 16 months was also comparable to the 12.8 to24 months reported in these studies [6, 14]. The rationale for this study came from our preclinicalobservations that ATRA increased the cytotoxic effects of  paclitaxel in breast cancer cells in vitro. ATRA lowered theLD 50  of paclitaxel by up to one hundred-fold whenincubated with the cells for 3 days prior to paclitaxel [7].This effect was associated with enhanced phosphorylationand consequent inactivation of Bcl-2 [7]. Prior studiesdemonstrated that phosphorylation of Bcl-2 by paclitaxel isassociated with activation of jun N-terminal kinase (JNK)[17]. We demonstrated that a related taxane, docetaxel,induced apoptosis in MCF-7 cells by activating JNK, aneffect potentiated by ATRA and sustained for at least 3 daysafter docetaxel [18]. The regimen for ATRA administrationin this clinical study was based on these preclinical data. It considered that paclitaxel serum half life can be as high as12 h and tumor half life can be over 24 h and tried to ensureATRA ’ s chemosensitizing effects were active during pacli-taxel bioavailability.Since preclinical studies cannot predict clinical outcome,the lack of a high response rate was disappointing but not  predictable. The high rate of stable disease suggested that another effect of ATRA, that of a differentiation agent, wasmore relevant in patient tumors. Our preclinical data demonstrated an ATRA-induced cell cycle arrest in breast cancer cells through modulation on the cyclin dependent kinase inhibitors p21 WAF1 and p27 KIP1 that resulted indephosphrylation of Rb and partial redifferentiation of breast  Table 4  Treatment administered and response Number of cycles given Range 1 – 22Median 5Mean 7.5Response a  PR 3SD 10PD 1Unevaluable 3Time to progression (months)  b Range 1 – 21Median 6.0Mean 7.7Survival (months) c Range 1 – 68Median 16Mean 25.2 a   PR  partial response;  SD  stable disease;  PD  progression of disease  b Evaluated for all 17 patients. Five patients who were taken off study for toxicity or withdrawal of consent were included in the calculation. For these patients, the time the patient came off study was used for the time of  progression calculation c Date of death known for 14 patients. Two patients lost to follow up, onealive at data tabulation 1486 Invest New Drugs (2011) 29:1482 – 1487
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