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Clinical Cancer Research Vol. 10, 1299-1305, February 2004
© 2004 American Association for Cancer Research

Clinical Trials

Clinical Efficacy, Tolerability, and Safety of SAM486A, a Novel Polyamine Biosynthesis Inhibitor, in Patients with Relapsed or Refractory Non-Hodgkin’s Lymphoma

Results from a Phase II Multicenter Study

Miklos Pless1, Karim Belhadj2, Hans D. Menssen3, Wolfgang Kern4, Bertrand Coiffier5, Jürgen Wolf6, Richard Herrmann1, Eckhard Thiel3, Doug Bootle7, Ivo Sklenar7, Christian Müller7, Les Choi8, Carl Porter9 and Renaud Capdeville7

1 University Hospital of Basel, Switzerland;2 Hôpital Henri Mondor, Créteil, France;3 Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany;4 Klinikum Grosshadern, Munich, Germany;5 Centre Hospitalier Lyon Sud, France;6 Universitätsklinik Köln, Germany;7 Novartis Pharma AG, Basel, Switzerland;8 Novartis Corp., East Hanover, New Jersey; and9 Grace Cancer Drug Center, Roswell Park Cancer Institute, New York, New York


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: SAM486A is a new inhibitor of S-adenosyl-methionine-decarboxylase, a key enzyme for polyamine biosynthesis. It is more potent than the first generation S-adenosyl-methionine-decarboxylase inhibitor methylglyoxal bis-guanylhydrazone. This Phase IIa study reports the findings of SAM486A monotherapy in patients with refractory or relapsed non-Hodgkin’s lymphoma (NHL).

Patients and Methods: Forty-one previously treated patients with either diffuse large cell, follicular, or peripheral T-cell NHL were treated i.v. with 100 mg/m2 SAM486A as a daily 1-h infusion for 5 days repeated every 3 weeks. Treatment was continued for a total of eight cycles or until disease progression.

Results: Two patients, both with large B-cell lymphoma, showed a complete response at cycle 3 that was maintained for >=13 and >=28 months. Five patients had a partial response, and 3 had stable disease at last follow-up. The overall response rate (complete response plus partial response) was 18.9% for evaluable patients (7 patients). Anemia was the primary hematological toxicity and observed in 7 (17.1%) patients. Five patients experienced grade 3/4 anemia. Four patients (9.8%) experienced grade 3/4 febrile neutropenia and grade 3/4 thrombocytopenia, respectively. Nonhematological toxicities were mild to moderate in intensity. The most frequent side effects were nausea (39%), vomiting (22%), diarrhea (19.5%), asthenia (17.1%), abdominal pain (14.6%), and flushing (9.8%).

Conclusion: SAM486A has a promising clinical activity in patients with poor prognosis NHL and manageable safety profile. To further define the role of SAM486A, in the treatment of NHL, additional studies are warranted.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The polyamines spermidine and spermine are of vital importance for cell proliferation, although their precise mechanism of action is unclear. Tumor cells have an altered polyamine homeostasis reflected by increased activity of biosynthetic enzymes and elevated polyamine pools (1) . The essential enzymatic step in the biosynthesis of polyamines is the conversion of putrescine to spermidine and spermine in which S-adenosyl-methionine-decarboxylase (SAMDC) is the rate-limiting enzyme. SAMDC is therefore a potential therapeutic target for cancer chemotherapy (2, 3, 4, 5) .

Methylglyoxal bis-guanylhydrazone (MGBG) was the first SAMDC inhibitor extensively studied both in preclinical and clinical investigations. In clinical studies, MGBG was shown to be efficacious as a treatment for a broad spectrum of malignant diseases, including acute leukemia, lymphoma, and multiple myeloma. MGBG yielded response rates between 30 and 50% in heavily pretreated or refractory non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease patients (4 , 6, 7, 8) . Response rates in patients with acute myeloid leukemia were also substantial (30–44%; Ref. 4 ). More recently, activity in AIDS-related lymphomas has been reported (9) . However, despite its activity, the development of MGBG had to be stopped because of its significant toxicity, mucositis, muscle weakness, hypoglycemia, and malaise (4 , 10) .

To reduce the toxicity of MGBG, a series of sterically hindered molecules related to MGBG were synthesized with the goal of increasing selectivity and potency at the enzyme level. SAM486A possesses these characteristics and has good efficacy against cancer cell lines and solid tumors in animal models, with potential for an increased therapeutic window compared with MGBG. Studies in L1210 leukemia-bearing nude mice indicated a dose-dependent activity of SAM486A, which was paralleled with a decrease in spermidine and spermine and elevation of putrescine pools (11 , 12) .

Phase I studies in patients with solid tumors have shown that SAM486A shows mild to moderate, and rarely severe, toxicity, such as nausea, vomiting, fatigue, somnolence, flushing of the skin, and neutropenia (13 , 14) . This Phase IIa study was designed to determine the response rate and toxicity of SAM486A as a single agent given to patients with relapsed or refractory NHL.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This was a Phase IIa, open-label multicenter, single arm study. The primary end point was to determine the objective response rate to treatment with SAM486A. Secondary end points were progression-free survival, safety, and tolerability.

Patient Selection.
Patients with a histologically confirmed diagnosis of follicular, diffuse large B-cell, or peripheral T-cell NHL (WHO classification) were eligible for the study if they had chemotherapy refractory disease or relapsed after at least two previous lines of systemic therapy. Presence of more than or equal to one measurable lesion was required. Additional eligibility criteria included: (a) Karnofsky performance status of >=60, a life expectancy of >=3 months, and age >=18 years; (b) no chemotherapy or other systemic cancer therapy or palliative radiotherapy in the previous 4 weeks; (c) no severe cardiac insufficiency (New York Heart Association classification III or IV) and baseline left ventricular ejection fraction >45%; (d) normal hepatic and renal function (liver function tests <= 2.5 times the upper limit of normal, serum creatinine <= 1.25 times the upper limit of normal); and (e) adequate bone marrow function (WBCs >= 3 x 109/liter, platelets >= 100 x 109/liter, and hemoglobin >= 10 grams/dl). Patients with chronic lymphocytic leukemia, Sézary syndrome, or mycosis fungoides, plasmacytoma, Waldenström’s macroglobulinemia, hairy cell leukemia, or small lymphocytic lymphoma were excluded. Patients were also excluded if they had another malignancy within 5 years before study entry, were HIV positive, had central nervous system or leptomeningeal involvement, or were pregnant or breast feeding.

Patients were recruited from six study centers throughout Switzerland, France, and Germany. The first patient enrolled October 16, 1998, and the final patient completed the study on June 21, 2000. The study protocol was approved by the independent ethics committees of each center, and written informed consent was obtained from all patients.

Treatment Regimen.
Treatment was administered i.v. at 100 mg/m2 as a daily 1-h infusion for 5 days repeated every 3 weeks. Treatment was continued for a total of eight cycles or until disease progression or withdrawal attributable to adverse events. The routine use of prophylactic antiemetics was not foreseen. Doses of SAM486A were modified according to toxicity assessed using the National Cancer Institute Common Toxicity Criteria. If a patient developed grade >= 3 hematological or nonhematological toxicity, the next cycle of SAM486A was delayed for a maximum of 14 days until toxicity resolved to baseline status. If toxicity did not resolve after this time, the patient was withdrawn from the study. If toxicity of grade >= 3 occurred in a given cycle but resolved within 14 days, the subsequent cycle was given at the full dose. However, if a profound neutropenia was observed (grade 4 neutropenia lasting >5 days or febrile neutropenia) or the severity of toxicity observed precluded rechallenge at full dose, then a dose reduction to 66% of the full dose was given in subsequent cycles. Recurrence of grade 4 neutropenia or other severe toxicity after dose reduction led to the termination of treatment with SAM486A. If toxicity occurred during the days of SAM486A administration, that cycle was interrupted, depending on the nature of the toxicity and at the discretion of the investigator. The patient could later continue treatment in a subsequent cycle. Appropriate treatment was used to ameliorate signs and symptoms of toxicity, including antiemetics, antidiarrheals, and antipyretics after toxicity grade was determined.

Pre and Post-treatment Assessments.
Within 14 days before treatment, patients were required to undergo a medical history and physical examination, evaluation of height, weight and body surface area, Karnofsky performance status, hematology/blood chemistry, urinalysis and pregnancy test, electrocardiogram and left ventricular ejection fraction, and bone marrow assessment. Baseline tumor assessments could be made as early as 28 days before treatment. Tumor assessments were made at the start of every other treatment cycle from cycle 3 onwards. Adverse events were monitored throughout the study, and hematology variables were assessed before infusion on days 1 and 5 and then on days 11, 15, and 18 of each cycle. An assessment of toxicity was determined according to the National Cancer Institute Common Toxicity Criteria.

Definition of Best Objective Response.
Tumor assessments were performed using the optimal imaging technique (computed tomography scan for all), as determined by the consulting radiologist at each center, at baseline and subsequently every two cycles. Because the International response criteria were not published when this study was initiated (1998), the objective status for each patient was assessed as complete response (CR), partial response (PR), progressive disease, or stable disease according to the Southwest Oncology Group response criteria (15) , with modification of the CR response as follows: CR was defined as the complete disappearance of all measurable and evaluable disease, with no lesions newly detected. Excluded from this definition was the persistence of small residual masses by physical examination (lymph nodes measuring <0.5 x 0.5 cm) or on computer tomographic scans (<1 x 1 cm), provided this lesion was stable at a subsequent examination (16) . In patients with blood involvement, CR also required normalization of peripheral blood. In patients with bone marrow involvement at baseline, a CR also required resolution of disease in bone marrow. PR was defined >=50% decrease from baseline in the sum of products of perpendicular diameters of all measurable lesions. At the same time, there should be no progression of evaluable disease or appearance of new lesions. Progressive disease was defined when a 50% increase or increase of 10 cm2 (whichever was smaller) in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) is seen, or reappearance of any lesion which had disappeared, or appearance of any new lesion/site, or failure to return for evaluation caused by death or deteriorating condition (unless clearly unrelated to the cancer). If progression was not documented and one or more measurable or evaluable sites were not assessed or could not be evaluated, the objective status was unknown.

International Prognostic Index.
The International Prognostic Index was calculated for each patient (17) .

Pharmacokinetic and Pharmacodynamic Sampling and Evaluations.
During treatment cycles 1–3, venous blood samples (5 ml) were taken for determination of SAM486A plasma levels. SAM486A plasma concentrations were determined by high-performance liquid chromatography assay with UV detection. The limit of quantitation of this method was ~25 ng/ml. Data were to be analyzed from all patients for whom at least one data point was available.

Statistical Considerations.
The sample size was based on Simon’s two stage design with the smallest maximum sample size (minimax; Ref. 18 ). The first stage of the study enrolled 18 patients. As at least one response was observed in this group, additional patients were accrued to obtain 32 evaluable patients. At least four responses were required to consider SAM486A sufficiently promising for further testing in this disease indication. The dropout rate was assumed to be 20%, so ~40 patients were required for the study. The primary efficacy end point was best objective response. This was determined from the evaluable population defined as those patients with measurable disease who had completed four cycles of treatment and/or had at least two consecutive tumor evaluations 4 weeks apart after baseline. The intent-to-treat population comprised all patients who received study medication and from whom at least one measurement was obtained. It was determined that an objective response rate of >20% would be of clinical interest. SAM486A was considered to be efficacious if the null hypothesis that the best response rate was <5% could be rejected at the {alpha} level of 10% and that a response rate of 20%, considered to be of clinical interest, was achieved.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Forty-one Caucasian patients were enrolled in this study, including 16 men and 25 women. All patients were evaluable for safety, and 35 were evaluable for best objective response. Their demographic and baseline disease characteristics are detailed in Table 1Citation . The majority of patients had a follicular or a diffuse large B-cell lymphoma (18 and 19 patients, respectively). Three patients had peripheral T-cell lymphomas. One patient had initially a dual histology of mantle cell and follicular lymphoma, and he was included. However, the diagnosis was later changed to mantle cell only. No central pathology review was performed. The majority of the patients had an International Prognostic Index in the low-intermediate risk category (20; 48.8%) or high-intermediate risk category (13; 31.7%).


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  		Table 1 Demographic and disease characteristics for 41 patients with relapsed or refractory non-Hodgkin’s lymphoma

 
Doses Administered
All patients received at least one dose of study medication. The majority of patients (28; 68.3%) completed two treatment cycles (10 treatment doses). Of the patients that stopped treatment after two treatment cycles, 10 did so because of unsatisfactory therapeutic effect (3 patients with follicular lymphoma, the other 7 with diffuse large B-cell lymphoma), 2 because of an unrelated adverse event, and 1 patient withdrew her consent. Only 4 patients (9.8%) completed all eight treatment cycles (40 treatment doses). Two patients had a dose reduction attributable to febrile neutropenia and leukopenia, respectively, and 1 patient received approximately half the required dose on day 5 of the first treatment cycle caused by a dosing error.

Tumor Responses
The best objective tumor response is summarized in Table 2Citation . Two patients, both with diffuse large B-cell lymphoma, showed a CR at cycle 3 that was maintained until the end of the study. These patients were still in complete remission 13 and 28 months, respectively, after receiving the last dose of SAM486A. Five patients had a PR at the end of the study. An additional patient who completed the study with stable disease developed a PR 12 months later in the absence of antineoplastic therapy, which was maintained for >=5 months. The overall response rate (CR + PR) was 7 (18.9% for evaluable patients, 17.1% for the intent-to-treat population). The 90% confidence intervals as calculated by Clopper and Pearson were 9.2–32.6% for evaluable patients and 8.3–29.7% for the intent-to-treat population. The probability of concluding that an ineffective treatment (P < 5%) is considered as successful is <0.0021 for the evaluable population and 0.0039 for the intent-to-treat population. For both populations, the targeted response rate lies well within the 90% confidence limits, indicating that SAM486A shows promising antitumor activity.


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  		Table 2 Best objective tumor response for all patients

 
Survival
Progression-free survival, defined as the time from the date of first drug administration to the first observation of disease progression or death attributable to any cause, is presented in Fig. 1Citation . The median progression-free survival time for the 18 (43.9%) follicular lymphoma patients was 113 and 76 days for the 19 (46.3%) diffuse large B-cell lymphoma patients.



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  		Fig. 1. Kaplan-Meier progression-free survival curve, in days, from onset of SAM486A therapy in patients with follicular and large B-cell lymphoma.

 
Safety and Toxicity
Four patients (9.8%) were discontinued from the study because of death: (a) pulmonary embolism; (b) multiorgan failure; (c) renal failure; and (d) chronic renal failure. None of these deaths were considered to be related to SAM486A treatment, and 3 were caused by disease progression. The chronic renal failure of 1 patient was a preexisting condition; therefore, this event was not considered as treatment related. Eighteen patients (43.9%) experienced serious adverse events. Eight patients experienced serious adverse events that were possibly related to treatment. Five patients (12.2%) discontinued the study because of adverse events.

Hematological Toxicity.
Hematological toxicities are summarized in Table 3Citation . Anemia was the primary hematological toxicity and observed in 7 (17.1%) patients. Five patients experienced grade 3/4 anemia, and of these, 3 had a suspected relationship to study medication. These anemia events generally lasted <=5 days. Four patients (9.8%) experienced grade 3/4 febrile neutropenia. All febrile neutropenia events had a suspected relationship to study medication; they lasted between 4 and 11 days. Four patients (9.8%) experienced grade 3/4 thrombocytopenia. For 1 of these patients, there was a suspected relationship to study medication, and the duration of the event was 26 days.


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  		Table 3 Common toxicities

 
Other Toxicities.
Nonhematological toxicities are summarized in Table 3Citation . The most frequent were nausea (39%), vomiting (22%), diarrhea (19.5%), asthenia (17.1%), abdominal pain (14.6%), and flushing (9.8%). The majority of gastrointestinal events was mild to moderate (grade 1 or 2). Twenty-two patients had gastrointestinal events with a suspected relationship to study medication. Only 1 patient experienced grade 3 asthenia, and this did not have a suspected relationship to study medication. Cardiovascular events included grade 4 myocardial infarction (1 patient), grade 4 pulmonary embolism (1 patient), grade 3 hypertension (1 patient), grade 3 hypotension (1 patient), grade 3 sinus arrhythmia (1 patient), and grade 3 supraventricular tachycardia (1 patient). Only two of these events (myocardial infarction and hypotension) were considered possibly related to the study medication.

Pharmacokinetics and Pharmacodynamics
Pharmacokinetic samples from 13 patients were assayed for SAM486A concentrations (Table 4)Citation . The coefficient of variation of mean plasma SAM486A concentrations at the sampling times during cycle 1 was in the range 34–38%. At preinfusion on day 1 of cycle 2, SAM486A concentrations were close to or below the limit of quantitation of 25 ng/ml. This shows that under the dosing regimen used (five daily 1-h infusions of 100 mg/m2 every 3-week cycle), there was no accumulation from the first to second cycle. There were too few patients with concentration data in cycle 3 to make a comparison between cycles 1 and 3. SAM486A concentrations were measured in the autopsy samples of 1 patient ~6 days after the last infusion of SAM486A. The highest SAM486A level was found in the liver (64,400 ng/gram). For this patient, significant drug tumor levels (11,100 and 7,020 ng/gram) and tissue levels (heart 6,940 ng/gram) were achieved, which were several-fold higher than those measured in plasma (in ng/ml), indicating that SAM486A distributes to, and is concentrated in, tissues. Because of the lack of plasma SAM486 concentration data, population analysis was not done. The lack of data also precluded examining the correlation of plasma SAM486 concentrations with pharmacodynamic results (enzyme activities, adenosine metabolites, and polyamine pools) and with clinical efficacy and tolerability data.


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  		Table 4 Plasma SAM486A concentrations (ng/ml) in 13 patientsa

 
Determination of SAMDC activity in the tumor was either not done for the majority of patients or below the limit of detection.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Since the 1980s, first-generation, doxorubicin-containing regimens, such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) have been considered standard chemotherapies for lymphomas. Acceptable cure rates with cyclophosphamide, doxorubicin, vincristine, and prednisone alone or in combination with radiotherapy have been seen in patients with aggressive NHL (19 , 20) . The results (both response rate and survival) of primary first-line treatment were significantly improved by the addition of the novel monoclonal anti-CD20 antibody, Rituximab, to the CHOP regimen (21) ; CHOP plus Rituximab are now considered the new standard therapy for de novo diffuse large B-cell NHL. As a single agent for refractory or relapsing large B-cell NHL, an objective response rate of 31% could be achieved with Rituximab (22) . In follicular lymphoma, the response rates go <=50% (23) . Nevertheless, in many cases, the disease relapses or responses to standard regimens are incomplete (24) , and for these patients, treatment options are very limited. In follicular lymphoma, there is a wide variety of active drugs, but cure is still impossible for most stage III/IV patients; eventually, drug resistance prevails, and patients die of disease progression. SAM486A is a novel agent with a unique mechanism of action and may offer an additional treatment option for patients with refractory or relapsing NHL.

In the present study, SAM486A was well tolerated at a dose of 100 mg/m2. The incidence of neutropenia or febrile neutropenia (12.2%) and thrombocytopenia (9.8%) was lower than the incidence reported with mitoguazone, another polyamine biosynthesis inhibitor (20 and 26%, respectively; Ref. 9 ). Gemcitabine is another new agent that has been studied in patients with indolent (25) and aggressive (26 , 27) relapsed or refractory NHL. Although the overall response rate was slightly higher than with SAM486A, gemcitabine was associated with a higher level of toxicity, especially hematological toxicity. High hematological toxicity and comparable efficacy (18% PR) was also reported in a study with sequential use of topotecan and etoposide (28) . For SAM486A, dose reduction attributable to hematological toxicity was only necessary for 2 patients.

The overall response rate was 18.9% for the evaluable patients. The targeted response rate for this study of 20% lies well within the 90% confidence interval for the evaluable population, which indicates that SAM486A has some antitumor activity. The response rate was lower than that reported for some other single agent studies in relapsed or refractory NHL, including rituximab (22 , 29) , oxaliplatin (30) , or Bendamustin (31) , but comparable or better than in other single drug studies: (a) infusional Vinorelbine showed an overall response rate of 18% in aggressive NHLs (32) ; and (b) Paclitaxel was reported with 15% ORR in the same disease (33) . However, it is impossible to compare the results of this study to other single agent studies because of differences in patient population and treatment regimens. Nevertheless, it is safe to state that the patients in this study had been very heavily pretreated with >50% having had four or more previous chemotherapies (see Table 1Citation ), including the 2 patients who showed a CR.

Mean SAM486A plasma concentrations at the various sampling times were similar to those observed at three comparable sampling times in a previous study (34) using the same dosing regimen. This indicates that the pharmacokinetics of SAM486A in the NHL patient population were comparable with that in a population of patients with various advanced solid tumors. In the autopsied patient in this study, the finding of much greater concentrations of SAM486A in liver, heart, and tumor tissue than those in plasma indicates that SAM486A is concentrated in tissues. This is consistent with the high mean volume of distribution (Vss = 811 liters/m2) determined for SAM486A in the previous study (34) . The high SAM486A concentrations found in the tumor samples (11,100 and 7,020 ng/gram) clearly exceed the IC50 for in vitro inhibition of SAMDC (4.7 nM or 1.08 ng/ml) and the IC50s for growth inhibition of human tumor cell lines in vitro (0.1–5 µM or 23–1,150 ng/ml). This indicates that potentially effective drug concentrations are reaching the tumors.

To conclude, SAM486A has good clinical activity in patients with poor prognosis NHL, with a manageable safety profile. There might well be a role for SAM486A, either as a single agent or in combination with other drugs in the treatment of NHL, and additional studies should be performed to identify the optimum clinical use of SAM486A.


   FOOTNOTES
 
Grant support: Novartis research grant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Miklos Pless, Medical Oncology, Kantonsspital Basel, Petersgraben 4, CH4031, Switzerland. Phone: 41 61 265 5074; Fax: 41 61 265 5316; E-mail: mpless{at}uhbs.ch

Received 7/ 1/03; revised 11/ 4/03; accepted 11/ 4/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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