Invest New Drugs (2011) 29:1482–1487 DOI 10.1007/s10637-010-9478-3 PHASE II STUDIES A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or 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 therapy with weekly paclitaxel and all trans-retinoic acid (ATRA) for tolerability, response to treatment, time to progression and survival in previously treated patients with metastatic or recurrent breast cancer. Our rationale was based on preclinical studies demonstrating potentiation of the cytotoxic effects of taxanes and induction of differentiation by ATRA. Patients and methods: Seventeen patients with 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/m2 PO daily for 4 days starting 2 days before a 1 h treatment with paclitaxel (Taxol, Bristol-Myers Squibb, Plainsboro, Support The study was partially supported by a research grant from Bristol-Myers Squibb, Plainsboro, NJ (RW) and study drug supplied from Hoffman-La Roche, Inc. M. Bryan : E. D. Pulte : L. Pliner : T. Saunders : R. Wieder Department of Medicine, UMDNJ-New Jersey Medical School/University Hospital Cancer Center, Newark, NJ, USA K. C. Toomey The Steeplechase Cancer Center at Somerset Medical Center, Somerville, NJ, USA NJ) 80 mg/m2 IV administered weekly for 3 weeks, repeated in 28 day cycles until disease progression or until no 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: The regimen was relatively well tolerated. There were nine grade 3 and one grade 4 toxic events. We administered 162 treatment 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 overall clinical benefit of 76.4%. Median time to progression was 6.0 months (range 1–21, mean 7.7 months). Fourteen evaluable patients had a median survival of 16 months (range 1–68 months, mean 25.2 months). Conclusions: The data suggest this is a well tolerated regimen with modest response rates but with time to progression and survival rates similar to those reported for paclitaxel alone and relatively high rates of stable disease in this sample of patients. Keywords All trans retinoic acid . Taxol . Metastatic breast cancer . Potentiation Introduction A. C. Pavlick New York University Cancer Institute, New York, NY, USA R. Wieder (*) UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Cancer Center H1216, Newark, NJ 07103, USA e-mail: wiederro@umdnj.edu Advances in the adjuvant and neoadjuvant therapy of breast cancer have resulted in decreased rates of recurrence, which translated to higher cure rates in patients with localized disease. However, despite these advances, metastatic or recurrent breast cancer remains incurable [1]. The current treatment goals in patients with metastatic or Invest New Drugs (2011) 29:1482–1487 recurrent breast cancer are prolongation and maintenance of the quality of life. Many therapeutic options for treating women with metastatic or recurrent breast cancer are available. 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 compared with regimens that do not contain taxanes [3]. Nevertheless, time to progression, even with taxanecontaining regimens, is relatively short and overall survival differences are measured in months [4]. Patients inevitably relapse and become resistant to therapy. In addition, administration of paclitaxel every-3-weeks is limited by the relatively common occurrence of severe neutropenia, leucopenia and hyperglycemia and less common occurrence of 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 with weekly administration, although higher rates of neuropathy with 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 paclitaxel administration [6]. One potential approach to increasing the efficacy of taxanes and potentially allow lower doses to be administered with equal or greater effects is to modulate their cytotoxicity using retinoids. In preclinical studies, we have demonstrated 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-7 and 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 ED50 for cell death of paclitaxel by up to two logs in a synergistic manner. The mode of cell death 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 phase II trial in patients with metastatic breast cancer, all-trans retinoic acid induced a partial response in one patient and stable disease in three other patients out of 14 evaluable patients, a 26.8% clinical benefit [8]. Because retinoids have been well-tolerated in patients in prior clinical trials [9–12] and specifically, ATRA has presented few side effects to patients in prior phase I and II studies [8, 13], we hypothesized that the combination of ATRA administered to 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. We undertook this study to test this hypothesis. 1483 Study design and methods This was a non-randomized, open label, two-center, phase II response and time to progression study of all-trans retinoic acid (Vesanoid, tretinoin, Hoffman-La Roche, Inc.) 45 mg/m2 PO daily for 4 days, starting 2 days before, the day of and 1 day after treatment with paclitaxel (Taxol, Bristol-Myers Squibb, Plainsboro, NJ) 80 mg/m2 IV over 1 h administered weekly for 3 weeks, followed by 1 week off and repeated in 28 day cycles until disease progression or until the patient could no longer tolerate treatment. There were no dose reductions planned. Patients received premedication with antiemetic regimens that included a 5-hydroxytriptamine3 (5-HT3) receptor antagonist, dexamethasone, lorazepam, diphenhydramine, famotidine and prochlorperazine. Antiemetics were included because of reported nausea with ATRA administration and as a precaution for possible potentiation of nausea with paclitaxel, although paclitaxel by itself is minimally emetogenic. The use of filgrastim was permitted 24 h after paclitaxel administration, as needed, if neutropenia with granulocytes below 1,000/mm3 occurred in prior cycles. The protocol was approved by the institutional review boards of both UMDNJ-University Hospital and the Somerset Medical Center and patients signed informed consent prior to enrollment. Eligibility criteria restricted entry to patients over 18 years old 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 were intentionally designed to provide an opportunity for previously 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 by white blood cell count of ≥2,000/mm3, absolute neutrophil count of ≥1,000/mm3, hemoglobin ≥7.5 gm/dL and platelet count of ≥50,000/mm3 were required for entry. Adequate renal function as indicated by a serum creatinine ≤1.8 mg/ dL and hepatic function as indicated by serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) levels <2× the upper limit of normal and total bilirubin levels of ≤2.0 mg/dl were also required. The inclusion 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 on study were able to swallow. Patients who had brain metastases must have received definitive whole brain radiation 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 than 3 weeks prior to study entry. Exclusion criteria did not include extent or type of prior therapy. 1484 Pre-entry patient evaluations included a history, including history of prior therapy regimens, surgery or radiation, a physical exam and performance status evaluation. Hematologic and serum chemistry evaluations, a serum pregnancy test if they were premenopausal and an HIV test were performed. Patients underwent extent of disease evaluation including physical measurement of palpable lesions, CT scans or MRIs within 1 month prior to initiating therapy. Patients had complete blood count, serum chemistry panel and triglyceride evaluations on the day of each paclitaxel administration, as well as during the fourth week of the cycle. During the off week after the last paclitaxel administration in each cycle, patients were also evaluated by their physician by a history and physical exam, measurement of cutaneous tumor 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 to analyze response by World Health Organization objective response criteria. Patients were taken off study if they had disease 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 evaluated monthly with a history and physical examination, cutaneous tumor measurement, complete blood counts and serum chemistries. The primary objective of the study was tumor response and secondary objectives were time to progression, survival and toxicity. Results Patient and tumor characteristics Seventeen patients were enrolled on the study. They were all women with a median age of 54 (range 44–66) and a mean age of 55.6 (Table 1). There were 10 (58.8%) African Americans, 3 (17.6%) Hispanics, 2 (11.8%) Asians and 2 (11.8%) Caucasians, reflective of the primarily minority ethnic distribution of the patients treated at University Hospital, where the majority of the patients on study were enrolled (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% (range 70–100%). Nine of the patients had prior therapy for recurrent or metastatic disease (52.9%). The patients Invest New Drugs (2011) 29:1482–1487 Table 1 Patient characteristics Characteristic Age (years) Race (number of patients) Menopausal status (number of patients) KPS Number of patients who had prior therapy Number of prior treatments for relapsed or metastatic disease Range Median Mean African American Hispanic Asian Caucasian Postmenopausal Premenopausal Unknown Median Range Yes No Range Median Mean Previous taxane 46–66 54 55.6 10 3 2 2 12 2 3 90 70–100 9 8 1–7 1 1.6 3 previously treated had a mean number of 1.6 prior lines of therapy (range 1–7) and a median of 1. Three patients had prior taxane therapy. Additional chemotherapy treatments included gemcitabine, liposomal doxorubicin, capecitabine, navelbine and unknown regimens. Ten patients also received hormone ablative therapy and six received bisphosphonates. Eight (47.1%) of the patients were initially diagnosed with 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’ were estrogen 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 positive in 5 (29.4%) patients, negative in 9 (53.0%) patients and unknown in 3 (17.6%) patients. Fifteen (88.2%) of the patients had bony metastases and fifteen (88.2%) patients also had visceral metastases. Safety and toxicity The treatment regimen was relatively well tolerated (Table 3). There were six grade 3 adverse events, including one anemia, two nausea and vomiting, two pain and one ataxia. There were three serious adverse events that were not treatment related, including one each of a grade 3 gastrointestinal bleed from a Mallory-Weiss tear, a supraventricular tachycardia and one grade 4 pulmonary embolus that was associated with an ataxia that affected ambulation. Invest New Drugs (2011) 29:1482–1487 1485 Table 2 Tumor characteristics Stage at diagnosis ER status PR status HER-2 status Bony metastases Visceral metastases III IV other Positive Negative Unknown 7 8 2 11 5 1 Positive Negative Unknown Positive Negative Unknown Yes No Yes No 9 7 1 5 9 3 15 2 15 2 There was also one serious adverse event, a seizure, that was possibly related to study medication modifying the serum levels of the patient’s anti-epileptic medication. Response Patients received a total of 162 treatment cycles. There were no dose reductions. The mean number of treatment cycles per patient was 7.5 (range 1–22) with a median of 5 (Table 4). The mean number of ATRA doses administered per cycle was 10.8 (range 1–12) and the mean number of paclitaxel doses per cycle was 2.7 (range 0–3). Three patients had a Table 3 Adverse events partial response (17.6%) and ten patients had stable disease after at least one extent of disease evaluation (58.8%), for an overall clinical benefit of 76.4%. One patient progressed and three patients were unevaluable. Of the unevaluable patients, one withdrew consent when she developed grade 1 nausea during the first treatment cycle, one had a seizure during the first cycle and one had pain, neuropathy, and headache 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 and was taken off for toxicity while still experiencing stable disease. The shortest duration of stable disease among the other nine patients was 4 months. The median duration of stable disease was 5.0 months and the mean was 6.8 months. Five patients were taken off study for toxicity or withdrawal of consent. They ranged in age from 50 to 61. Three had had no prior treatment for metastatic disease and two had had 2–3 prior therapies, including taxanes in one case. The reasons for coming off study were withdrawal of consent for grade 1 nausea and vomiting in one patient, seizure in one patient, grade 2 edema and neuropathy in one patient, grade 3 pain with neuropathy in one 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 from study enrollment to the point they were taken off study was used 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 period of 54 months. Two patients, who were lost to follow up, and the one who was alive at the time the data was Grade 1 Grade 2 Grade 3 4 4 5 4 3 2 3 3 3 7 2 3 0 1 3 1 1 2 2 1 1 0 0 0 0 2 0 2 1 Grade 4 Adverse events Alopecia Anemia Constipation Edema Fatigue Leukopenia/neutropenia Nausea and vomiting Neuropathy Pain Other Serious adverse events Gastrointestinal bleed Pulmonary embolus Seizure Supreventricular tachycardia 1 1 1 1 1486 Invest New Drugs (2011) 29:1482–1487 Table 4 Treatment administered and response Number of cycles given Responsea Time to progression (months)b Survival (months)c a Range Median Mean PR SD PD 1–22 5 7.5 3 10 1 Unevaluable Range Median Mean Range Median Mean 3 1–21 6.0 7.7 1–68 16 25.2 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, one alive at data tabulation 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 relatively well tolerated regimen in previously treated patients with recurrent/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 rates were similar to those with paclitaxel alone as administered weekly for recurrent or metastatic disease. The clinical efficacy 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 well tolerated in women previously treated for their recurrent or metastatic disease. The patient profile consisted of women who were primarily post-menopausal with good performance status. Approximately 65% of the patients had hormone-receptor positive disease. All patients had some prior chemotherapy and some had hormonal and bisphosphonate treatment. The patient population was primarily African American and Hispanic, reflecting the patient population served by the New Jersey Medical SchoolUniversity Hospital Cancer Center. The treatment-related adverse event profile was unremarkable. There were five instances of grade 3 toxicity representing common side effects of chemotherapy. There was one case of grade 3 ataxia that was not likely treatment related. There were four serious adverse events. Three were not treatment related and one may have been due to study drug modifying the pharmacokinetics of antiseizure medications. None of the severe toxicities previously reported with paclitaxel, particularly neuropathy [6] were observed. There were no instances of headache and dermatological toxicity observed with higher doses of all-trans retinoic acid [8, 13] or other retinoids [9–12], but two patients did experience grade 3 nausea and vomiting, previously associated with protracted all-trans retinoic acid treatment [8]. Response rates were rather modest at 17.6% when compared response rates to weekly paclitaxel of 21.5% to 42% in three large studies [6, 14, 15]. This suggests that the hypothesis of response potentiation in patients is likely incorrect. 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 investigating this regimen in a larger study [16]. The median time to progression of 6 months was comparable to the 4.7 to 9 months reported in these large studies [6, 14]. The median survival of 16 months was also comparable to the 12.8 to 24 months reported in these studies [6, 14]. The rationale for this study came from our preclinical observations that ATRA increased the cytotoxic effects of paclitaxel in breast cancer cells in vitro. ATRA lowered the LD50 of paclitaxel by up to one hundred-fold when incubated with the cells for 3 days prior to paclitaxel [7]. This effect was associated with enhanced phosphorylation and consequent inactivation of Bcl-2 [7]. Prior studies demonstrated that phosphorylation of Bcl-2 by paclitaxel is associated 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, an effect potentiated by ATRA and sustained for at least 3 days after docetaxel [18]. The regimen for ATRA administration in this clinical study was based on these preclinical data. It considered that paclitaxel serum half life can be as high as 12 h and tumor half life can be over 24 h and tried to ensure ATRA’s chemosensitizing effects were active during paclitaxel 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, was more 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 p21WAF1 and p27KIP1 that resulted in dephosphrylation of Rb and partial redifferentiation of breast Invest New Drugs (2011) 29:1482–1487 cancer cell as demonstrated by induction of lipid droplet formation [19]. Treatment with all-trans retinoic acid in patients with locally advanced operable breast cancer influenced tumor grade, induced progesterone receptors and influenced expression of RAR beta and TGFbeta, in line with the differentiating effects observed in our preclinical study [20]. Our results demonstrated lower response rates but comparable time to progression and survival to those with weekly paclitaxel alone. The high rates of stable disease are consistent with the hypothesis that ATRA may be influencing tumor progression by affecting cancer cell proliferation rates and their states of differentiation. 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