Phase II study of SU5416—a small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor—in patients with refractory myeloproliferative diseases

Abstract

BACKGROUND

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with myeloproliferative disorders (MPD), including agnogenic myeloid metaplasia (AMM), chronic myeloid leukemia in blastic phase (CML-BP), and chronic myelomonocytic leukemia (CMML). VEGF is a soluble, circulating, angiogenic molecule that acts through receptor tyrosine kinases (RTK), including VEGF receptor 2 (VEGFR-2). SU5416 is a small-molecule RTK inhibitor (RTKI) that targets VEGFR-2, c-kit, and fms-related tyrosine kinase Flk2.

METHODS

Adult patients with advanced CMML, AMM, CML-BP, or other BCR-ABL negative MPD were entered on a multicenter, Phase II study.

RESULTS

Thirty-two patients (19 patients with BCR-ABL negative MPD, 6 patients with CMML, 4 patients with CML-BP, and 3 patients with AMM) with a median age of 66 years (range, 29–85 years) received SU5416 145 mg/m² twice weekly intravenously for a median of three 4-week cycles (maximum, 12 cycles). Drug-related Grade 3–4 toxicities included acute abdominal pain (13%), bone pain (9%), infusion-related dyspnea (9%) or headache (6%), fatigue (6%), diarrhea (3%), and catheter site reactions (3%). Eleven patients (34%) did not receive a second cycle of therapy (6 patients had progressive disease, 3 because of adverse events; 2 patients withdrew due to lack of response). One patient with AMM achieved a partial response. Eight patients received more than 6 months of therapy.

CONCLUSIONS

SU5416 had minimal clinical activity in patients with MPD. Long-term administration of a twice-weekly, hyperosmolar, intravenous solution containing polyoxyl 35 castor oil was difficult. More tolerable RTKI may be worthy of further investigation in patients with MPD. Cancer 2003;97:1920–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11315

Increased bone marrow vascularity (angiogenesis) is part of the pathophysiology of human myeloproliferative disorders (MPD).1 Patients with agnogenic myeloid metaplasia (AMM) have a marked increase in bone marrow microvessel density (MVD; the average number of microvessels seen in a microscopic field2).3–7 The increase in MVD in patients with AMM is more pronounced compared with the elevated levels documented in patients with essential thrombocythemia or polycythemia vera.4, 6 In patients with AMM, chronic myelomonocytic leukemia (CMML), or chronic myeloid leukemia in blastic phase (CML-BP), increased bone marrow MVD is an independent, adverse prognostic feature.8–13

Vascular endothelial growth factor (VEGF) is the central, proangiogenic molecule involved in tumor-related neovasculature.14 VEGF regulates critical endothelial cell functions, including mitogenesis, permeability, and the production of vasoactive molecules, involved in vessel budding and tube formation. VEGF also is a survival factor required for the maintenance of new blood vessels.15 VEGF acts by binding to three receptor tyrosine kinases (RTK): VEGF receptor 1 f(VEGFR-1; Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4).16 Endothelial cell proliferative and mitogenic responses to VEGF, as well as vascular permeability, are mediated primarily by binding to VEGFR-2.17 Bone marrow and circulating VEGF levels are elevated significantly in patients with AMM.1, 18–20 Elevation in VEGF levels in these patients is not correlated with peripheral blood counts, bone marrow cellularity, degree of bone marrow fibrosis, or organomegaly.1 In addition, patients with CMML or CML-BP have elevated levels of urinary and leukemia blast levels of VEGF.8, 13, 21, 22 In patients with CMML or other myelodysplastic syndromes (MDS), bone marrow VEGFR-2 expression is elevated.16 Bone marrow levels of VEGF and VEGFR-2 correlate with each other and with degrees of increased MVD in patients with CMML or other MDS.16, 23 Increased bone marrow VEGF levels are associated with reduced complete response (CR) rates, disease free survival (post-CR), and overall survival in patients with CMML or other MDS.16 These data suggest that the VEGF/VEGFR-2 pathway affects the biologic behavior of MPD and may be a therapeutic target in patients with these diseases.24

The RTK c-kit, which is essential for normal hematopoietic cell development, has a functional role in some patients with MPD.25–30 Binding of the c-kit ligand, stem cell factor (SCF), initiates a signal-transduction cascade that includes receptor autophosphorylation with subsequent phosphorylation of numerous intracellular substrates. Increased tyrosine phosphorylation of c-kit and proliferation upon SCF stimulation occur in most blasts that express c-kit. SCF-induced blast proliferation is synergistic with the blast proliferation induced by granulocyte–macrophage-colony stimulating factor (GM-CSF) or interleukin-3. VEGF directly stimulates the production of several hematopoietic growth factors from human umbilical vein endothelial cells, including GM-CSF and SCF.2, 31 Subsets of patients with CMML show hyperproliferative responses to GM-CSF.32

SU5416 (Z-3-[(2,4-dimethylpyrrol-5-yl) methylidenyl]-2-indolinone) is a small, lipophilic, highly protein-bound, synthetic RTK inhibitor (RTKI) of VEGFR-2.33, 34 It inhibits VEGFR-2 and other RTK targets by binding to the conserved adenosine triphosphate binding site within the kinase domain of the receptor. Thus, it inhibits the autophosphorylation induced by ligand binding to its receptor. SU5416 inhibits VEGF dependent endothelial cell proliferation in vitro and in animal models.35, 36 SU5416 has no direct cytotoxic properties yet produces a dose dependent inhibition of tumor growth in xenograft models, including models of malignant melanoma, glioma, fibrosarcoma, and carcinomas of the lung, breast, prostate, and skin.35 In a human colon carcinoma xenograft model, SU5416 inhibited tumor metastases, microvessel formation, and proliferation.37

In addition to inhibiting VEGFR-2, SU5416 is an RTKI for both c-kit and the fms-related tyrosine kinase Flk2 (FLT3) receptor.38 Both in human myeloid leukemia cell lines and in blasts from patients that express c-kit, SU5416 inhibits SCF-induced tyrosine phosphorylation, reduces cell proliferation, and/or induces apoptosis39, 40 FLT3 also is expressed on hematopoietic progenitors, and dysregulation of FLT3 signaling is associated with acute myeloid leukemia (AML).41–43 Internal tandem duplication (ITD) mutations in FLT3 result in constitutive FLT3 tyrosine kinase activity and are associated with a poor prognosis in patients with AML.44 FLT3-ITD is the most frequently observed molecular defect in patients with AML (25–30% of patients). Recent in vitro studies have shown that SU5416 is a potent inhibitor of both wild type and mutant forms of FLT3.38 SU5416, therefore, may target bone marrow angiogenesis directly through VEGFR-2 and blast cell proliferation by FLT3 and c-kit in patients with MPD. Based on these data, a multicenter, Phase II study was conducted to evaluate the safety and efficacy of SU5416 in patients with MPD.

MATERIALS AND METHODS

This was an open-label, multicenter study to assess the efficacy and toxicity of a twice-weekly infusion of SU5416 in patients with MPD, including AMM, CMML, and CML-BP. All patients provided witnessed, written consent for study participation, and the Institutional Review Boards at all participating institutions approved this protocol.

Patients

Patients who were eligible for enrollment on study were age ≥ 18 years with CML-BP or BCR-ABL negative MPD, including CMML or AMM. Patients must have recovered from the toxic effects of prior therapy with a minimum interval of 7 days from prior therapy. All potentially fertile patients had to agree to use effective contraception. All at-risk female patients had to have a negative serum pregnancy test within 7 days prior to enrollment. Patients were required to have a baseline serum bilirubin < 1.5 times the upper limit of normal (ULN) and serum creatinine < 2.0 mg/dL. Patients were ineligible if they had received prior SU5146, metalloproteinase inhibitors, anti-VEGFR2 monoclonal antibodies, or any other investigational agents targeting the VEGF signaling pathway. Patients also were ineligible if they had evident, active, uncontrolled infection or coagulopathy; overt central nervous system (CNS) disease; prior CNS hemorrhage; a known allergy to polyoxyl 35 castor oil (Cremophor®) or to Cremophor-based drug products; an Eastern Cooperative Oncology Group performance status > 2; uncontrolled cardiac disease; a history of myocardial infarction; or severe/unstable angina or uncontrolled atrial fibrillation in the prior 6 months. Patients with a known cardiac left ventricular ejection fraction < 40% were not eligible. Patients with clinical evidence of severe peripheral vascular disease or patients who had a deep venous or arterial thrombosis (including pulmonary embolism) within the 3 prior months were ineligible.

Treatment Regimen

SU5416 was supplied as a yellow-orange liquid formulation in vials containing 180 mg SU5416 in 40 mL of vehicle for a final concentration of 4.5 mg/mL. Additional components of the formulation included polyethylene glycol 400, polyoxyl 35 castor oil (Cremophor), benzyl alcohol, and dehydrated alcohol. SU5416 was diluted with either water for injection, 0.45% sodium chloride, or 0.9% sodium chloride prior to administration. Doses of SU5416 were administered by infusion pump at a rate of 200 cc per hour except for the initial infusion, which was given at 100 cc per hour for the first 15 minutes in an attempt to decrease the incidence of immediate-onset hypersensitivity to Cremophor.45, 46

SU5416 was administered at a dose of 145 mg/m² twice weekly through a central venous catheter (CVC) or a peripherally inserted central catheter for a total of 8 infusions in each 4-week cycle. Patients received premedication followed by SU5416 infusion (after at least a 30-minute delay for intravenous premedication). Premedication included oral or intravenous administration of 25 mg diphenhydramine or an equivalent H1-blocker and 20 mg famotidine or an alternate H2-blocker. Patients also received dexamethasone at an initial dose of 10 mg intravenously (at least 30 minutes prior to infusion) for the first 3 infusions. This dose subsequently was reduced to 4 mg and again to 2 mg on subsequent occasions, as tolerated.

The primary pathway for metabolism of SU5416 is through sequential oxidative reactions of the 5-methyl group on the pyrrole ring (Fig. 1).47 SU5416 is metabolized by the P-450 liver enzyme, CYP1A2 (an inducible enzyme), and, to a lesser extent, by CYP3A4, CYP2C9, and CYP2C19. Patients who are receiving drugs and agents that inhibit or induce these enzymes, including some antifungal agents48 and macrolide antibiotics,49 may have altered plasma levels of SU5416. Recent data suggest that beverages like coffee and grapefruit juice also inhibit CYP3A.50 These drugs or beverages were avoided while patients were on the study. Patients received full supportive care, including transfusions of blood and blood products, antibiotics, antiemetics, antidiarrheals, and analgesics, as appropriate. Colony stimulating factors were not given to patients on study.

Figure 1. SU5416 structure and metabolism.

Evaluation and Statistics

Complete histories and physical examinations were performed within 3 days of study entry. The following laboratory parameters were obtained ≤ 3 days before entry: complete blood count with differential; electrolyte panel (magnesium, calcium, phosphate, blood urea nitrogen, creatinine, glucose, uric acid, amylase, total protein and albumin, hepatic transaminases, bilirubin, and alkaline phosphatase); coagulation profile (prothrombin time, activated partial thromboplastin time, fibrinogen, and fibrin degradation products); urinalysis; bone marrow aspirate and biopsy with histochemical, cytogenetic, and immunophenotypic analysis; chest X-ray; and, for women of childbearing potential, a pregnancy test. Bone marrow and peripheral blood slides were reviewed centrally. Additional studies (lumbar puncture with cerebrospinal fluid cytospin, computed tomography scans, gallium scans, multiple-gated acquisition, or echocardiogram) were performed when they were indicated clinically.

Bone marrow specimens were obtained at baseline, on Days 15 and 29 of the first cycle of therapy, every 4 weeks thereafter as indicated clinically, and at the time patients left the study. Physical examination, adverse event evaluation, and hematologic, biochemical and coagulation panels were repeated at weekly intervals and as indicated clinically.

All patients who received any SU5416 were considered evaluable for toxicity analyses. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0). Unacceptable toxicity was defined as toxicity ≥ Grade 3 (excluding headache, nausea/emesis, diarrhea, and hematologic toxicity) that possibly was related to SU5416 administration or Grade 4 headache, nausea /emesis, or diarrhea uncontrolled by maximal medical management.

For patients with CMML or CML-BP, a CR was defined as normalization of the peripheral blood and bone marrow with blasts ≤ 5%; normocellular or hypercellular bone marrow; an absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L, and a platelet count (PLT) ≥ 100 × 10⁹/L. A partial remission (PR) was defined like a CR except for the presence of 6–25% bone marrow blasts. Hematologic improvement (HI) was defined like a CR but with PLT < 100 × 10⁹/L. All other responses were considered failures.

For patients with AMM or other MPD, a CR was defined as 1) the absence of signs or symptoms of the disease; a white blood cell (WBC) count between 1 × 10⁹ L⁻¹ and 10 × 10⁹ L⁻¹ with no peripheral blasts, promyelocytes, or myelocytes and with normalization of bone marrow (< 5% blasts in normocellular or hypercellular marrow) for at least 4 weeks; resolution of pretreatment cytopenia: ANC ≥ 1.0 × 10⁹ L⁻¹; hemoglobin (Hgb) ≥ 12.0 gm/dL (≥ 11.0 gm/dL for females) without erythropoietin or transfusion support; PLT ≥ 100 × 10⁹ L⁻¹ without growth factor or transfusion support; and resolution of pretreatment leukocytosis and/or thrombocytosis (WBC count ≤ 10 × 10⁹ L⁻¹ without peripheral blasts, promyelocytes, or myelocytes and PLT ≥ 100 × 10⁹ L⁻¹ but < 450 × 10⁹ L⁻¹.

A PR was defined as improvement of two or more of the following: 1) an increase in ANC of 100%, up to > 10⁹ L⁻¹ for neutropenia, and a WBC count between 1 × 10⁹ L⁻¹ and 10 × 10⁹ L⁻¹ with persistence of immature cells (blasts, myelocytes, metamyelocytes) for pretreatment leukocytosis; 2) an increase in Hgb of 2 g/dL if the baseline value was < 10 gm/dL and a decrease in transfusion requirements by at least 50% (decrease in frequency and/or volume); 3) for the PLT count, persistent thrombocytosis > 450 × 10⁹ L⁻¹ but < 50% of the pretreatment value; 4) a reduction of bone marrow blasts to ≤ 5% if blasts were > 10% in normocellular or hypercellular bone marrow; and 5) a reduction in splenomegaly and/or hepatomegaly by 50% of pretreatment dimensions. All other responses were considered failures.

Because SU5416 has a novel mechanism of action, a response rate of 10% in a group of patients with a very poor prognosis was considered of sufficient interest to warrant further investigation. A maximum total of 25 evaluable patients with AMM, CMML, CML-BP, or any other defined MPD diagnosis were to be entered on study. This sample size yielded an 82% posterior credibility interval for a probability of response of approximately 0.16 in width. For each group, there was 1 interim analysis after 14 patients had been evaluated. The study would terminate in that patient population if no responses had been observed. In a further measure to guard against exposure of patients to an agent with minimal activity, the aggregate response rate (CR, PR, and HI) was reviewed periodically. If total response rates of ≤ 1 in 26 evaluable patients or ≤ 2 in 42 evaluable patients were observed, then it would be evidence that the probability of < 10% activity in the MPD group of diseases was > 90%.

RESULTS

Patients

Thirty-two patients were enrolled and commenced therapy between October, 2000 and November, 2001. Six patients (19%) had CMML, four patients had CML-BP, and three patients had AMM. All patients other than those with CML-BP were negative for the BCR-ABL rearrangement.51 Baseline patient characteristics are summarized in Table 1. Of the four patients with CML-BP, three patients had failed prior therapy with STI57152 (within 3 months, 6 months, and 10 months of response to this agent, respectively).

Table 1. Clinical and Laboratory Characteristics of the Study Patients

Characteristic	No. of patients (%)
ECOG: Eastern Cooperative Oncology Group; MPD: myeloproliferative disorder; CMML: chronic myelomonocytic leukemia; CML-BP: chronic myeloid leukemia in blastic phase; AMM: agnogenic myeloid metaplasia; WBC: white blood cells.
Gender
Male	19 (58)
Female	13 (42)
Age (yrs)
Median	66
Range	29–85
Performance status (ECOG)
Median	1
Range	0–2
Myeloproliferative diagnosis
MPD	19
CMML	6
CML-BP	4
AMM	3
Prior therapy
No	12
Yes	20
Time from diagnosis (mos)
Median	11
Range	0–126
Baseline peripheral blood counts (range)
WBC (× 10^9 L^−1)	9.3 (1.0–132)
Hemoglobin (g/dL)	9.7 (6.1–14.2)
Platelets (× 10^9 L^−1)	95.0 (12.0–714.0)
Peripheral blood blasts
None	18 (56)
< 5%	7 (22)
5–20%	2 (6)
> 20%	5 (16)
Bone marrow blasts (%)
None	8 (25)
< 5%	16 (50)
5–20%	3 (9)
> 20%	5 (16)

The median time on study was 11 weeks (range, 1–50 weeks), equating to 22 infusions of SU5416. Dose reductions rarely were required, even for patients who were on long-term therapy (11 patients; 34%; > 100 days). The survival of the four patients with CML-BP was 5 days, 16 days, 205 days, and > 266 days; the median survival for all other patients was 39 weeks (range, from 9 days to > 98 days).

The primary reason for patient withdrawal from study was either progressive disease (9 patients; 28%) or dissatisfaction with stable disease as the best response to therapy (10 patients; 31%). Seven patients experienced adverse events (discussed below); two patients died on study secondary to sepsis, which we believed was unrelated to SU5416. Two patients said that inconvenience with twice-weekly infusions was their primary reason for withdrawal; two patients (after seven cycles of therapy) remained stable and were offered continued therapy with SU5416 off study.

Responses

One patient (3%) with AMM had a PR to the first cycle of therapy. The patient, a woman age 49 years with an established history of splenomegaly, anemia, and increasing weakness, had a reduction > 50% in splenomegaly and a significant increase in Hgb. She also had a major improvement in performance status and was able to return to full-time employment. This patient continues on SU5416 therapy on a compassionate basis with ongoing PR of > 1 year in duration. All three patients with AMM received six or more cycles of therapy; the other two patients with AMM had stable disease throughout. Three of four patients with CML-BP were removed from the study within first cycle of therapy (two patients were removed within 2 weeks) because of progressive disease; the fourth patient remained on study with stable disease for five cycles of therapy and then developed rapidly progressive disease. Three of 19 patients (16%) with MPD and 1 of 6 patients (17%) with CMML had stable disease > 6 months in duration.

Adverse Events

All patients were premedicated prior to each SU5416 infusion with antihistamines (oral or intravenous) and intravenous steroids. Two patients (6%) experienced hypersensitivity reactions associated with the SU5416 infusion: One patient had a severe reaction (with associated dyspnea, hypotension, and flushing) on the 11th exposure to the drug. The episode was treated successfully, and the patient continued on study, using a higher dose of steroid premedication. A milder infusion-associated hypersensitivity occurred in a second patient upon first exposure to the drug product: That patient also was treated successfully.

Frequently observed toxicities consisted primarily of mild-to-moderate gastrointestinal effects (nausea, diarrhea, emesis, and abdominal pain), headache, fatigue, dyspnea, and catheter site reactions (pain/burning, edema, or tenderness) (Table 2). Grade 3 or 4 bone pain occurred in 9% of patients, and milder degrees of bone pain occurred in another 38% of patients. Thrombosis was observed in two patients (deep venous thrombosis in one patient and CVC in one patient).

Table 2. Nonhematologic Toxicities: Proportions of Overall and Grade 3 or 4 Toxicity in 32 Patients Who Received SU5416 Therapy

Toxicity	Abdominal pain (%)	Infusion-related dyspnea (%)	Bone pain (%)	Diarrhea (%)	Fatigue (%)	Infusion-related headache (%)	Catheter site reactions (%)	Nausea/emesis (%)
Overall	34	69	47	53	44	34	38	47
Grade 3/4	13	9	9	6	6	6	3	0

In total, 11 patients (34%) did not receive a second cycle of therapy: 6 patients because of progressive disease during the first cycle, 3 patients because of adverse events, and 2 patients because they had stable disease, which the investigator and/or patient deemed inadequate. Three patients received only a single infusion of SU5416: two patients because of an adverse event and 1 patient (with CML-BP) due to rapidly progressive disease. Two deaths (in the third and seventh cycles) on study were caused by sepsis: In one patient, the primary focus of infection was believed to be the CVC.

DISCUSSION

This is the first report on an RTKI as a therapeutic approach in patients with MPD. Multiple approaches to inhibition of VEGF activity, including small-molecule RTK inhibitors, antisense or ribozymes that target VEGF or VEGFR mRNA, soluble recombinant VEGFR, and antibodies that directly neutralize VEGF or block its receptors, are being investigated in patients with hematologic malignancies.24 The pivotal role of VEGF in angiogenesis and maintaining the viability of recently formed blood vessels makes it attractive as a therapeutic target in patients with MPD in which increased bone marrow vascularity and/or increased circulating, cellular, and bone marrow levels of VEGF are adverse prognostic features.1, 3–5, 8, 18, 19 Although VEGF binds to three RTKs, most of its biologic functions related to malignancy-associated angiogenesis are mediated by VEGFR-2.16

In this Phase II study, we used standard definitions of response used in protocols of cytotoxic therapy for patients with MPD. The study met its statistical endpoint: Among 26 evaluable patients, there was only 1 PR, which allowed us to conclude that the probability that SU5416 had < 10% activity in the MPD group of diseases was > 90%. Assessment of response rates in this manner may not be an optimal approach in studies of angiogenic modulating agents. SU5416 has no general, direct, cytotoxic properties. Although significant regression in established tumors has been documented in one animal model,53 in most preclinical models, SU5416 caused inhibition of tumor growth, with tumor regrowth upon cessation of therapy.33, 54 A cytostatic agent may be of most clinical benefit to patients with MPD as a maintenance agent in relatively indolent phases of these diseases; however, studies based on disease stability or time to treatment progression carry significant challenges in their design.

The design of a regimen for angiogenic modulators in patients with hematologic disorders is challenging.55 The durability of the in vitro activity of SU5416 initially was attributed to its long-lasting ability to specifically inhibit VEGF-dependent phosphorylation of VEGFR-2 and subsequent downstream signaling, although SU5416 is not an irreversible inhibitor of VEGFR-2.33, 35, 54 In vivo data on a rodent xenograft model predicted that dosing with SU5416 at 3-day to 4-day intervals would be sufficient to inhibit tumor growth without toxicity; in some cell lines, dosing intervals of 7 days also produced significant tumor growth inhibition.33, 54 Thus, the clinical dosing regimen on this study was twice-weekly administration during a 4-week cycle.

The role for VEGF may be greatest early in tumor development.56, 57 Tumor growth, which initially is dependent on VEGF, may become independent of it after reaching a critical size.58 The role of VEGF in MPD changes with disease progression is unknown. The patients on this study had active, symptomatic, advanced MPD that already had been exposed to systemic therapy in 20 of 32 patients (63%). Thus, we may have investigated a VEGF-modulating agent at an inappropriate stage in the disease for some patients by adhering to the standard practice of offering novel agents to patients with very advanced disease. The wisdom of such an approach in patients who have a very poor prognosis at the time of presentation (e.g., many patients with AMM3) may be questionable. Studies that are designed with assessment of time to recurrence or progression (duration of stable disease) as a primary efficacy endpoint and that focused on earlier stage disease may be more appropriate for investigating molecularly targeted therapy in patients with MPD.

Is VEGF the Right Target if we Wish to Modulate Angiogenesis in Patients with MPD?

Preclinical and clinical data indicate that VEGF plays an important role in some patients. However, other factors involved in the angiogenic regulatory cascades are present in abnormal amounts in the circulation and/or bone marrow of these patients. These include transforming growth factor β, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), and thrombopoietin.8, 59–63 The next generation of anti-VEGF RTKIs has differing patterns of inhibition of other angiogenesis-related receptors, including receptors for SCF (c-kit), for PDGF, and for HGF (c-met).24 These latter agents may offer a broader spectrum of RTKI compared with that of SU5416 and, thus, may be of more potential benefit in patients with MPD.

The documentation of responses to thalidomide by a number of investigators in patients with AMM lends some support to the choice of VEGF as a therapeutic target.20, 64–67 Thalidomide is a potent suppressor of VEGF in a number of in vitro models.68 However, thalidomide has numerous other activities, including suppression of bFGF.69 It also is a potent suppressor of tumor necrosis factor (TNF),70 which is present in excess in the circulation and bone marrow of patients with MPD, particularly in patients with AMM, CMML, and CML-BP.8, 9, 71 We recently documented clinical improvements in patients with AMM and MDS with single-agent administration of a soluble TNF receptor, Enbrel.72, 73 Aside from effects on these cytokines, thalidomide has a number of immunomodulatory and antiinflammatory properties that render it difficult to attribute its activity in MPD to a specific mechanism.69 Even if thalidomide's anti-VEGF activity is pivotal to a clinical response, a sustained exposure over a long period may be necessary; despite its adverse effects, this is considerably more feasible with an oral agent than with parenteral agents, such as SU5416. The next generation of RTKIs includes a number of oral agents, such as SU11248, GFKI258, CEP-701, and PKT787.24, 39, 74, 75

In a separate, Phase II study of SU5146 in patients with refractory AML who express c-kit, Fiedler et al. have reported severe bone pain in 3 of 22 patients (14%), with the toxicity considered unexpected and possibly related to SU5416.76 This toxicity has not been reported in patients with solid tumors receiving SU5416. In the current study, Grade 1 or 2 bone pain occurred in 38% of patients and was Grade 3 or 4 in an additional 3 patients (9%). Thus, bone pain is a specific, adverse effect of SU5416 in patients with hematologic malignancies.

A major challenge in developing SU5416 is the drug product itself. Its high concentration of polyoxyl 35 castor oil (Cremophor) and the hyperosmolarity of the diluted drug product contributed materially to the incidence of hypersensitivity and injection site reactions observed on this study. Grade 1 or 2 infection, pain, burning, or erythema at the catheter site were reported in 38% of patients on this study. Although 25% patients achieved stable disease in excess of 6 months, withdrawal from therapy despite a lack of documented progressive disease or an adverse event occurred in 11 patients (34%), primarily due to the inconvenience of chronic intravenous therapy administered twice weekly. Stable disease was not sufficient to encourage patients to continue therapy. Adverse events attributable to Cremophor are a major problem with other agents, e.g., taxanes.45, 46 The use of agents likely to require chronic administration, such as RTKIs, must take into consideration ease of delivery in the development of an acceptable formulation, perhaps one reason that many of the newer RTKIs are being developed as orally administered agents.